System Physiology Exam 4: Enodcrinology

Front 1

What organs make up the physiologic anatomy of the female sexual organs?

Back 1

ovaries, fallopian tubes, uterus, vagina

Front 2

Describe the changes of composition of the follicular pool with age.

Back 2

the number of viable follicles DEC with INCing age, during prepuberty ~17% are atretic (dead) follicles while the rest are viable, as a fertile adult, the number of atretic follicles INC, the follicular pool DEC and there are also growing and ovulated follicles present, at postmenopausal period, most are atretic and only a small portion are ovulated

Front 3

What is menopause?

Back 3

it is triggered by the faltering and shutting down of the ovaries, which are a part of the body’s endocrine system, shuts down hormones which make reproduction possible and influence sexual behavior

Front 4

What is GnRH?

Back 4

gonadotropin-releasing hormone 1, AKA LHRH, responsible for the release of FSH and LH from the anterior pituitary which is controlled by the size and freq. of GNRH1 pulses as well as feedback from androgens and estrogens, low freq. GNRH1 pusles lead to FSH release whereas high freq. GNRH1 pusles stimulate LH release, is synthesized and released by the hypothalamus

Front 5

What is FSH?

Back 5

follicle stimulating hormone, synthesized and secreted in the anterior pituitary
1. stimulates the growth and development of secondary follicles, as follicle grows it releases inhibin which shuts off FSH production
2. stimulates granulosa cells to convert androgens to estrogen
3. stimulates the synthesis of LH receptors on granulosa cells

Front 6

What is LH?

Back 6

lutenizing hormone, synthesized and secreted in the anterior pituitary
1. triggers primary oocyte to complete meiosis I and enter meiosis II
2. initiates ovulation with LH surge
3. affects the transformation of remaining granulosa and thece internal cells to luteal cells
4. Lh is necessary to maintain luteal function for the first two weeks

Front 7

What is estrogen?

Back 7

steroid
1. maintains the female reproductive tract
2. responsible for the secondary sexual characteristics of the female
3. responsible for the rebuilding of the uterus (proliferative phase) after menses
4. INCes inhibits FSH (granulosa cells secrete inhibin, follistatin and activin which also regulate FSH secretion)
5. induces a surge in LH levels

Front 8

What is progesterone?

Back 8

1. initiates the conversion from a proliferative uterus to a secretory uterus for implantation
2. maintains the uterus in a secretory phase in pregnancy
3. inhibits LH production
4. hormone of pregnancy
5. if pregnancy does not occur, progesterone levels will DEC, leading to menstruation

Front 9

Describe the approx. plasma concentrations of estradiol.

Back 9

from days 0-14 (with 14 days being ovulation), estradiol INC then reaches a INCing and DECing period, at ovulation DEC rapidly then INC and DEC from day 16-28

Front 10

Describe the approx. plasma concentrations of progesterone.

Back 10

from days 0-14, very low, INC rapidly a day or two after ovulation when estradiol reachces its lowest point after ovulation, then DEC at about day 22

Front 11

Describe the approx. plasma concentrations of FSH and LH.

Back 11

from days 0-12 FSH higher than LH, then at day 12 FSH INC but not as rapidly as LH which overtakes it, corresponds with DEC in estradiol, at ovulation, LH and FSH both DEC and LH becomes lower than FSH again, large surge of LH is what triggers ovulation, progesterone is stimulated by LH, LH receptor located on the theca interna cells

Front 12

Give a summary of the levels of hormones during menstrual cycle.

Back 12

1. follicular development depends on FSH levels, early in the menstrual cycle, FSH levels INC, LH stimulates the production of androstenedione by theca interna cells which is transferred to follicular cells for its aromatization into estrogen (this event is known as theca interna-follicular cell synergism)
2. estrogen and FSh stimulate the synthesis of LH receptor by follicular cells late in the follicular phase, LH stimulates the production of progesterone by follicular cells
3. progesterone and estrogen secretion from the rapidly luteinizing follicle INC in response to LH stimulation
4. high levels of progesterone and estrogen inhibit LH and FSH secretion, the corpus luteus lasts only a few days in the absence of LH, LH is luteotrophic
5. if pregnancy does not occur, luteolysis begins 7 days after ovulation, the production of progesterone, estrogen and inhibin DEC and FSH levels INC gradually, menstruation begins

Front 13

What are some characteristics of the monthly ovarian cycle?

Back 13

duration is on average 28 days, anywhere from 20-45 days, in every cycle one ovum is montly released, uterine endometrium is prepared in advance for implantation

Front 14

What effects do the gonadotropic hormones have on the ovaries?

Back 14

LH and FSH are the main gonadotropic hormones, important in the menstrual cycle, pituitary secretion of LH and FSH progressively INCes starting form 9-12 years of age, normal sexual cycle begins at puberty (ages of 11-15 years), menarche is the first menstrual cycle

Front 15

What are the stages of follicular growth in the ovary?

Back 15

primordial follicle -> primary follicle -> vesicular follicle -> mature follicle -> early, developing and final corpus luteum, ALSO primary follicles -> secondary (preantral) follicles -> antral follicles -> preovulatory (Graafian follicle) -> ovulation

Front 16

Describe the follicular phase of the ovarian cycle.

Back 16

during childhood, primordial follicles (ovum surrounded by a single layer of granulosa cells) are present, at puberty, FSH and LH INC greatly leads to follicle growth, 6-12 primordial follicles are recruited per month

Front 17

Describe the functional synergism between follicular cells and theca interna cells during early folliculogenesis.

Back 17

in the primary and secondary follicle, follicular cells have FSH receptors, in the graafian follicle, LH receptors appear and coexist with FSH receptors, the acquisition of LH receptors is essential for the luteinization of the ruptured follicle following ovulation

Front 18

Describe the production of estradiol by follicular cells.

Back 18

estradiol is the major steroid produced by follicular cells under stimulation by FSH, however, follicular cells depend on the supply of androstenedione by theca interna cells-regulated by LH-to produce estradiol (by aromatization of the androgen) since follicular cells lack the required enzymes for producing the precursor of estradiol

Front 19

Describe the hormonal changes during the cycle.

Back 19

1. FSH causes change from primary to antral follicle
2. estrogen (E2) causes FSH receptors on granulosa cells to INC leading to more stimulation from FSH
3. FSH + H2 leads to an INC in LH receptors on granulosa cells leading to stimulation from LH
4. FSH + LH + E2 leads to rapid growth of the follicles
5. only one follicle matures each month and the remainder undergo atresia

Front 20

Describe ovulation.

Back 20

1. surge of LH is essential for ovulation: 6-10 fold INC with a peak at ~16 hours before ovulation
2. FSH levels also INC (2-3 fold) but not sufficient to induce ovulation
3. LH surge also converts granulosa and thecal cells to progesterone-secreting cells -> E2 levels DEC 1 day before ovulation
4. environment when ovulation occurs (rapid growth of follicles, diminishing E2 levels after a prolonged phase of excessive secretion, onset of progesterone secretion)

Front 21

Describe the physiological steps involved in the release of the egg during ovulation.

Back 21

1. blood vessels of the theca intima proliferate (angiogenesis)
2. at the stigma, proteases from fibroblasts-induced LH surge-degrade collagen fibers of the tunica albuginea and theca externa
3. the follicular cell layer will begin to fold soon after ovulation
4. the basement membrane breaks down, blood vessels from the theca interna invade the follicular cell layer and the antral cavity is filled with blood (corpus hemorrhagicum)

Front 22

Describe the initiation of ovulation.

Back 22

LH INC in significant amounts which leads to an INC in progesterone, this leads to (1) a release of proteolytic enzymes from lysosomes of the theca externa which leads to swelling and degeneration of the stigma and (2) rapid growth of new blood vessels into the follicle wall, this leads to plasma transudation into the follicle which leads to follicle swelling, follicle ruptures and discharges the ovum

Front 23

Describe the formation of the corpus luteum (luteinization).

Back 23

following ovulation the follicular cell layer of the preovulatory follicle becomes folded and is transformed into part of the corpus luteum, a surge in LH is correlated with luteinization

Front 24

Describe the transformations that occur during luteinization.

Back 24

1. the lumen previously occupied by the follicular antrum is filled with fibrin which is then replaced by CT and new blood vessels piercing the basement membrane
2. follicular or granulosa cells enlarge and lipid droplets accumulate, they become follicular or granulosa lutein cells
3. the spaces between the folds of the follicular cell layer are penetrated by theca interna cells, blood vessels and CT, theca interna cells also enlarge and store lipids, they are now theca lutein cells

Front 25

what is the function of the corpus luteum and what role do FSH and LH play in that function?

Back 25

1. FSH stimulates the production of progesterone and estradiol by follicular lutein cells
2. LH stimulates the production of progesterone and androstenedione by theca lutein cells, androstenedione is translocated into follicular lutein cells for aromatization into estradiol
3. during pregnancy, prolactin and placental lactogens upregulate the effects of estradiol produced by follicular lutein cells by enhancing the production of estrogen receptors
4. estradiol stimulates follicular lutein cells to take up cholesterol from blood, which is then stored in lipid droplets and transported to mito for progesterone synthesis

Front 26

What happens to the corpus luteum if fertilization does not occur?

Back 26

luteolysis, involves a programmed cell death sequence, includes:
1. a reduction in the blood flow within the corpus luteum causes a decline in oxygen (hypoxia)
2. T cells reach the corpus luteum and produce interferon-gamma which in turn acts on the endothelium to enable the arrival of macrophages
3. macrophages produce tumor necrosis factor and the apoptotic cascade starts

Front 27

What are the things that happen during the luteal phase of the ovarian cycle when fertilization does not occur?

Back 27

1. involuation of the corpus luteum-E2 + progesterone -> FSH and LH DEC and inhibin from lutein cells leads to FSH DEC
2. onset of the next ovarian cycle-E2 + progesterone DEC -> FSH and LH INC

Front 28

What is the corpus albicans?

Back 28

regressed form of the corpus luteum, formed by macrophages laying down collagen, occurs 12 days after ovulation if not pregnant

Front 29

What happens to the corpus luteum if fertilization does occur?

Back 29

if pregnancy occurs, the corpus luteum survives for 2-4 months under the stimulation of HCG

Front 30

Describe the chemistry of estrogen.

Back 30

in the non-pregnant women it comes mainly from the ovary by ovarian follicular and thecal internal cells, small amount from the adrenal cortices, in the pregnant woman comes from the placenta

Front 31

What are the three types of estrogens?

Back 31

1. beta-estradiol: from ovaries
2. estrone-peripheral tissues (from adrenal and ovarian androgens)
3. estriol-weak estrogen, derivative from estradiol and estrone, in liver

Front 32

Describe the different potencies between the three estrogens.

Back 32

beta-estradiol > estrone > estriol

Front 33

Describe the chemistry of progestins.

Back 33

in the non-pregnant women, from corpus luteum, latter half of each ovarian cycle, in the pregnant women comes from the placenta

Front 34

What are the two types of progestins?

Back 34

1. progesterone: major
2. 17-alpha-hydroxyprogesterone-small amount (same effects)

Front 35

Describe the synthesis of the estrogens and progestins.

Back 35

1. in the ovaries-mainly cholesterol from blood
2. during the follicular phase-progesterone + adnrostenedione (thecal interna cells) -> conversion to E2 in follicular (granulosa) cells
3. during the luteal phase-follilcular lutein and thecal lutein cells produce progesterone

Front 36

How are estrogens and progesterones transported in the blood?

Back 36

estrogens and progesterone bound to plasma albumin and specific binding globulins in the blood

Front 37

Describe the degradation of estrogen in the liver.

Back 37

1. conjugation to form glucuronnides and sulfates -> mostly excreted in the bile, some from the urine
2. conversion from E2/estrone to estriol
3. diminished liver function INC estrogen activity -> hyperestrinism

Front 38

Describe the degradation of progesterone in the liver.

Back 38

1. quick turnover rate-a few minutes
2. major degradation product-pregnanediol

Front 39

What functions do estrogens have on the uterus and external sex organs?

Back 39

1. INC in size-internal (ovaries, fallopian tubes, uterus), external (vagina, fat deposition in the mons pubis and labia majora, enlargement of the labia minora)
2. vaginal epithelium-cuboidal -> stratified, more resistant to trauma and infection
3. uterus-size INC 2-3 fold, proliferation of the endometrial stroma, development of the endometrial glands

Front 40

What functions do estrogens have on the fallopian tube?

Back 40

1. proliferation of the epithelium
2. INC in the number of the ciliated epithelial cells
3. enhancement of cilia activity (beating)

Front 41

What functions do estrogens have on breasts?

Back 41

1. development of the stromal tissues
2. growth of an extensive ductile system
3. deposition of fat in the breasts
4. initiation of the growth of the breasts and of the milk-producing apparatus
5. further growth and function depend on progesterone and prolactin

Front 42

What functions do estrogens have on the skeleton?

Back 42

1. stimulates bone growth-INC in height at puberty
2. uniting of the epiphyses with the shafts of the long bones
3. effect on epiphyses-E2 >> T, girls stop growing earlier
4. females with earlier loss of E2 production tend to be taller

Front 43

Describe osteoporosis in aging women.

Back 43

after menopause, E2 levels DEC which leads to:
1. INC osteoclastic activity
2. DEC bone matrix
3. DEC deposition of Ca2+ and phosphate

Front 44

What are some other functions of estrogen?

Back 44

1. effect on protein deposition-slight INC
2. effect on body metabolism and fat deposition-metabolic rate slightly INC and fat deposition in subQ region, buttocks and thighs
3. effect on hair distribution-results from androgens from the female adrenal glands
4. effect on skin-soft and smooth, more vascular
5. effect on electrolyte balance-retention of Na+ and H2O in the kidney tubules (mainly during pregnancy)

Front 45

What is the function of progesterone on the uterus?

Back 45

1. promotes secretory changes in the uterine endometrium during 2nd half of the cycle-ready for implantation of the fertilized ovum
2. DEC the freq. and intensity of uterine contractions: prevents expulsion of implanted ovum

Front 46

What is the effect of progesterone on the fallopian tubes?

Back 46

promotes secretion of the Peg cells-nutrition for ovum

Front 47

What is the effect of progesterone on the breasts?

Back 47

1. development of the lobules and alveoli-proliferation and enlargement of alveolar cells -> secretory status
2. no milk production without prolactin

Front 48

Describe the proliferative phase.

Back 48

it occurs before ovulation under the influence of estrogens, stromal and epithelial cells proliferate rapidlye (re-epithelialization with 4-7 days after the beginning of menstruation), next 1.5 weeks, stromal cells INC, growth of epithelial glands and new blood vessels into endometrium -> thickness INC to 3-5 mm

Front 49

Describe the secretory phase.

Back 49

occurs after ovulation under the influence of progesterone and estrogens, E2 -> futher cellular proliferation in the endometrium, progesterone -> marked swelling and secretory development of the endometrium

Front 50

What role does progesterone have secretory phase?

Back 50

1. glands more tortuous
2. excess of secretory substance in glandular epithelial cells
3. stromal cell cytoplasm INC with deposition of glycogen and lipid
4. blood supply INC

Front 51

Describe the thickness of endometrium.

Back 51

peak at 1 week after ovulation, 5-6 mm

Front 52

What is the physiologic meaning of the morphologic changes?

Back 52

1. highly secretory endometrium provides large amount of stored nutrients for fertilized ovum from entry to the uterus (3-4 days after ovulation) to implantation (7-9 days after ovulation)
2. once implanted, trophoblast cells digest and absorb nutrients to provide to early implanting embryo

Front 53

what affects the functional layer of the endometrium?

Back 53

1. changes in the blood levels of estrogens and progesterone
2. the blood supply from spinal arteries
3. this layer is partially or totally lost after menstruation

Front 54

What happens to basal layer with changes in the blood levels of estrogens and progesterone?

Back 54

the basal layer is not affected by changes in the blood levels of estrogens and progesterone, the blood supply derives from basal arteries rather than spiral arteries, this layer is not lost after menstruation, the functional layer regenerates after menstruation from the basal-functional layer boundary

Front 55

Describe menstruation.

Back 55

occurs when no fertilization occurs, the corpus luteum degenerates -> E2 and P DEC -> (rapid involution of endometrium, vasospasm of blood vessels: release of prostanglandins), necrosis of the endometrium especially blood vessels, blood -> vascular layer -> hemorrhage areas expand for 24-36 h, necrotic outer layers separate from the uterus, ~48 h after the onset of menstruation all the superficial layers desquamated, uterine contraction-to expel the contents, ~40 mL blood and ~35 mL serous fluid are lost

Front 56

What happens during the premenstrual or ischemic stage?

Back 56

1. periodic contractions of the spiral artery-triggered by a reduction in progesterone-deprive the supply of O2 (hypoxia) to the functional layer
2. a breakdown of the spiral artery floods the lamina propria with blood
3. the functional layer-consisting of glands and decidual-like cells-detaches and sheds into the uterine cavity (menses)
4. the basal layer is not affected because basal straight artereies provide independent blood supply to this layer

Front 57

Describe the regulation of the female monthly rhythm-interplay between the ovarian and hypothalamic-pituitary hormones (GnRH).

Back 57

1. intermittent, pulsatile secretion of GnRH (5-25 min/1-2 hours) -> pulsatile release of FSH and LH (every 90 min)
2. pulsatile secretion of GnRH is essential for its function
3. in mediobasal hypothalamus, especially in the arcuate nuclei
4. regulated by signals from other centers

Front 58

Describe the regulation of the female monthly rhythm-interplay between the ovarian and hypothalamic-pituitary hormones (negative feedback effects of E2 and P).

Back 58

1. estrogen inhibits both FSH and LH
2. progesterone alone-little effects
3. P + E2-strong inhibitory effects on FSH and LH production
4. act on both pituitary and hypothalamus levels
5. inhibit-secreted by granulosa cells, inhibit FSH and LH levels

Front 59

Describe the regulation of the female monthly rhythm-interplay between the ovarian and hypothalamic-pituitary hormones (positive feedback effect of E2 before ovulation).

Back 59

1. LH surge 1-2 days before ovulation
2. FSH shows a smaller surge
3. during 1st half of the cycle, FSH and LH levels are first slightly suppressed and then rapid INC in LH (6-8 folds) and FSH (2 folds) right before ovulation
4. without the LH surge no ovulation
5. mechanism: unknown (positive feedback effect of estrogen, onset of progesterone production by granulosa cells)

Front 60

What happens with an insufficient LH surge?

Back 60

cycle without ovulation = anovulatory cycle, corpus luteum fails to develop: no P production, several days shorter, the first couple of cycles at puberty or cycles several months or a year before menopause, P control the rhythm but not the cycle itself

Front 61

Describe GnRH secretion during puberty and menarche.

Back 61

during childhood there is no GnRH secretion due to suppressive factors in the brain, during puberty there is a gradual INC of gonadotropins, there is an INC in total urinary gonadotropin release from puberty to menopause, when reach menopause INC very rapidly, then starts to DEC, INC before menopause is oscillatory

Front 62

Describe menopause.

Back 62

1. cycle ceases and female hormone production diminishes
2. ovarian burning out
3. before 45, 400 follicles mature and being ovulated
4. after 45, only a few remain to be responsive to FSH and LH -> estrogen levels DEC -> FSH and LH INC
5. loss of estrogen which leads to menopausal syndrome

Front 63

What are the symptoms of menopausal syndrome?

Back 63

1. hot flashes
2. psychic sensation of dyspnea (shortness of breath)
3. irritability
4. fatigue
5. anxiety
6. DEC strength and calcification of bones

Front 64

What is hypogonadonism?

Back 64

1. causes irregularity of menses and amenorrhea-estrogen levels must reach certain points to maintain normal cycle

Front 65

What happens if the ovaries are absent from birth or they become non-functional before puberty?

Back 65

female eunuchism, lack of 2nd sexual characteristics, sex organs remain infantile, prolonged growth of long bones: delayed epiphyses fusion with the shafts -> taller

Front 66

What happened if the ovaries of a fully developed woman are removed?

Back 66

sex organs regress, similar to women after menopause

Front 67

Describe hypersecretion by the ovaries.

Back 67

rare, often associated with granulosa cell tumor (inhibin deficiency)

Front 68

Describe the stimulation of female sexual act.

Back 68

psychic stimulation, local stimulation

Front 69

Describe female erection and lubrication.

Back 69

under parasympathetic signals, erection of clitoris (same mechanism as the penile erection), lubrication (mainly by mucus secreted by the Bartholin’s glands (located beneath the labia minora) and vaginal epithelium)

Front 70

Describe the female orgasm.

Back 70

analogous to male emission and ejaculation, important for fertilization, includes:
1. perineal muscle contract rhythmically caused by spinal cord reflexes -> uterus and fallopian tube motility INC to help transport sperm upward to the ovum
2. dilation of the cervical canal for up to 30 min: easy entry of sperm
3. oxytocin secretion by posterior pituitary -> contraction of the uterus -> facilitate sperm transport

Front 71

Describe the fertile period of each sexual cycle.

Back 71

1. within 24 hour after ovulation
2. sperm in the female tract can survive up to 5 days
3. sperm have to be there from 4-5 days before ovulation and a few hours after ovulation

Front 72

Describe the rhythm method of contraception.

Back 72

1. interval from ovulation to menstruation-13-15 days
2. if a 28 day cycle, ovulation usually occurs within 1 day of the 14th day of the cycle
3. if a 40 day cycle, ovulation should be within 1 day of the 26th day of the cycle
4. avoid intercourse for 4-5 days before the calculated day of ovulation and 3 days afterwards
5. prerequisite-regular periodicity of the menstrual cycle

Front 73

Describe hormonal suppression of fertility-contraceptive pills.

Back 73

1. theory-appropriate quantitiy of estrogen and progesterone in the first half of the cycle inhibits LH surge leading to no ovulation
2. too much of either can cause abnormal menstrual bleeding pattern
3. synthetic estrogens + synthetic progestrins (because avoids liver degradation)
4. taken in the early stage of the cycle and continue beyond the time point of normal ovulation and then stopped to allow menstruation

Front 74

Describe female infertility.

Back 74

incidence of 15% of married couples, 50% are female factor, causes include endocrine, structural and genetic

Front 75

Describe an endocrine abnormality.

Back 75

anovulation due to hyposecretion of gonadotropins which is insufficient to induce ovulation, test urine pregnanediol levels (no surge, no ovulation), body temperature (secretion of progesterone INC body temperature ~0.5F), treatments include HCG, ovulation from multiple follicles, multiple births

Front 76

Describe a structural abnormality.

Back 76

1. ovarian anatomic abnormalities
2. endometriosis-endometrial tissue surrounding uterus, fallopian tubes and ovaries grows in pelvic cavity and even menstruates leads to fibrosis throughout the pelvis which leads to obstruction of ovulation, capture by the fimbriae of the fallopian tubes
3. abnormal secretion of mucus by the uterine cervix

Front 77

What is salpingitis?

Back 77

inflammation of the fallopian tubes

Front 78

Describe a genetic abnormality.

Back 78

mutations in genes essential for follicular genesis

Front 79

Describe the hormonal control of ovarian function.

Back 79

GnRH from the hypothalamus, FSH and LH from the anterior pituitary under the stimulation of GnRH, estrogen from the granulosa and thecal cells

Front 80

what does estrogen do for controlling ovarian function?

Back 80

1. proliferation of endometrium
2. thinning of the cervical mucus
3. stimulate pituitary to secrete LH
4. LH surge at mid-cycle which leads to ovulation
5. stimulate progesterone production

Front 81

Describe ovulation.

Back 81

LH surge causes completion of meiosis I leading to a preovulatory follicle, is then arrested in metaphase of meiosis II 3 hours before ovulation

Front 82

On the ovarian surface, what does an INC in LH do?

Back 82

1. LH INC leads to INC in collagenase, which leads to digestion of fibers around the follicle
2. LH INC leads to INC in prostaglandin which leads to muscular contraction

Front 83

Describe the corpus luteum.

Back 83

composed of lutean cells (granulosa cells and thecal cells), secretes progesterone, progesterone + estrogen leds to uterine mucosa into progestational/secretory stage in preparation for implantation

Front 84

Describe oocyte transport.

Back 84

ovulated oocyte is captured by sweeping movement of the fimbriae of the uterine tube (oviduct) and by the motion of cilia on the epithelial lining, from ampulla to uterine lumen (3-4 days), fertilization occurs at the ampulla of uterine tube

Front 85

What are the different fates of the corpus luteum?

Back 85

1. no fertilization-lutena cells apoptosis leads to corpus albicans which leads to DEC in progesterone which leads menstrual bleeding
2. fertilation-hCG secreted by the syncytiotrophoblast which leads to further growth
3. progesterone production until the end of 4th month leads to trophoblastic secretion of progesterone becomes adequate

Front 86

Describe the transport of spermatozoa in the male.

Back 86

1. passive transfer to epididymis via testicular fluid
2. maturation in epididymis (up to 2 weeks)
3. rapid transit through ductus deferens
4. addition of fluid from seminal vesicle
5. addition of prostatic fluid

Front 87

Describe the transport of spermatozoa in the female.

Back 87

1. sperm depositied in upper vagina (rapid elevation of pH) (10^7)
2. passage through cervix (fast and slow phases) 10^6
3. passage through uterus 10^5
4. entry into uterine tubes 10^4
5. passage up uterine tube by swimming and contractions of tube
6. only a small number of sperm near egg at a given time (10^2-10^3)

Front 88

Describe the transport of the egg.

Back 88

1. delay at amupllary-isthmic junction where fertilization occurs (days 1-2)
2. delay at utero-tubal junction (days 2-3)
3. egg enters uterine cavity as a morula (days 3-4)
4. blastocyst implants (day 7)

Front 89

Describe the steps in fertilization.

Back 89

1. capacitation-maturation of sperm in female reproductive tract leads to removal of the glycoprotein coat and seminal plasma protein form the sperm plasma membrane (important for IVF and IUI)
2. acrosome reaction-release of enzyme by sperm to dissolve zona pellucida (ZP)
3. fertilization occurs at the ampulla of the uterine tube

Front 90

Describe the phases of fertilization.

Back 90

1. phase I-penetration of the corona radiate
2. phase II-penetration of zona pellucida
3. phase III-fusion of the oocyte ad sperm cell membranes

Front 91

Describe the acrosome reaction.

Back 91

sperm reaches the corona radiate, releases its acrosome contents and passes through the corona radiata, then passes through the zona pellucida and plasma membrane of the egg

Front 92

Describe the time course of fertilization.

Back 92

1. zona pellucida (15-25 min)
2. perivitelline space (<1 sec)
3. perivitelline membrane (<1 min) (release of cortical granules and completeion of second meiotic division and formation of polar body)
4. male and female pronuclei visible (2-3 hours)
5. mitotic spindle and first cleavage (24 hours)

Front 93

What does entry of a sperm into the oocyte trigger?

Back 93

1. cortical and zona reactions to prevent polyspermy
2. oocyte completes meiosis II
3. egg is activated

Front 94

Describe the events that occur to the membrane during fertilization.

Back 94

after sperm enters the egg and rapid depolarization of plasma membrane of egg, zona pellucida hardens and sperm receptors inactivate

Front 95

What are the results of fertilization?

Back 95

1. restoration of diploid number of chromosomes
2. sex determination
3. initiation of cleavage

Front 96

Describe what happens during cleavage and formation of the blastocyst.

Back 96

1. blastomeres are formed-2, 4, and 8 cell stages, the cells get smaller and smaller
2. compaction occurs-goes from a loose form then compacted form which leads to segregation of inner and outer cells
3. morula forms at day 3 (a 16 cell form), the inner cell mass leads to the embryo proper which eventually forms tissues while the outer cell mass is called the trophoblast which leads to the placenta
4. blastocyst forms-zona pellucida degenerates and the uterine fluid penetrates, this forms the blastocele (cavity), the inner cell mass is now called embryoblast and outer cell mass is called the trophoblast + epithelial wall

Front 97

Describe implantation.

Back 97

occurs during the secretory phase, there are three layer in the endometrium (compact layer, spongy layer, and basal layer), implants along the anterior or posterior wall

Front 98

What effects does progesterone have on the uterine endometrium?

Back 98

make stromal cells highly secretory, secrete glycogen, proteins, lipids and minerals to decidual cells

Front 99

What do trophoblast cells invade?

Back 99

trophoblast cells invade the decidua, this causes to the release of nutrients which leads to embryo growth and development, it is the main source of nutrition for 1-8 weeks, it is gradually replaced by placenta nutrition

Front 100

Describe the different types of villi that occur during the development of the trophoblast.

Back 100

1. primary villus = cytotrophoblastic core + syncytial layer
2. 2nd villus = mesodermal cells penetrate the core of 1st villi
3. 3rd (definitive placental) villus = mesoderm cells -> blood cells + blood vessels

Front 101

Following formation of the villi, describe the further development of the trophoblast.

Back 101

at the end of the 3rd week, maternal vessels penetrate the cytotrophoblastic shell to enter intervillous spaces, which surround the villi, capillaries in the villi are in contact with vessels in the chorionic plate and the connecting stalk, which in turn are connected to intraembryonic vessels

Front 102

What else happens during the further development of the trophoblast?

Back 102

at the end of the 3rd week, 3rd and 2nd villi give the trophoblast a radial shape, intervillous spaces are lined with syncytium, cytotrophoblastic cells surround the entire trophoblast and in contact with endometrium, the embryo is suspended in the chorionic cavity by the connecting stalk

Front 103

What are the functions of the placenta?

Back 103

1. diffusion-from the mother to the fetus (foodstuffs and O2), from the fetus to the mother (excretory products)
2. O2 diffusion-fetal hemoglobin displays high O2-carrying capability
3. 50% higher concentration of fetal hemoglobin
4. Bohr effect-hemoglobin can bind more O2 at a low PCO2 than a high PCO2
5. CO2 diffusion-foodstuffs, wastes (nonprotein nitrogens including urea, uric acid, creatinine

Front 104

Describe human chorionic gonadotropin (HCG).

Back 104

1. origin-syncytial trophoblast cells
2. onset-8-9 days after ovulation
3. peak-10-12 weeks
4. function-prevention of involution of corpus luteum

Front 105

Describe the rescue of the corpus luteum by HCG.

Back 105

note rise of progesterone ~7-10 days after ovulation (arrow in right panel), this marks the first recognition of pregnancy by the mother, the second peak represents placental progesterone secretion, the corpus luteum is no longer necessary for maintaining pregnancy

Front 106

Describe the composition of hCG.

Back 106

common alpha + hCG beta chain + CHO chains
hCG beta-very similar to LH-beta, but has more CHO -> much longer half-life than LH

Front 107

Describe the target of hCG.

Back 107

corpus luteum, fetal Leydig cells -> T -> stimulation of Wolffian ducts

Front 108

Describe the signaling sequence of hCG.

Back 108

LHR -> cAMP -> PKA

Front 109

Describe the secretory pattern of hCG.

Back 109

exponential rise is critical (LH administered in the same manner can also resuce the CL), hCG remains elevated after Cl involutes at the end of the 1st trimester

Front 110

Describe the clinical utility of hCG.

Back 110

diagnosis of pregnancy 7-10 days after fertilization

Front 111

Describe the cell origin, synthesis and significance of estrogens.

Back 111

1. cell origin-syncytial trophoblast cells
2. synthesis-from androgens produced by the fetal and maternal adrenal glands-the placenta cannot convert progesterone to androgens
3. significance of large scale production of estrogens-enlargement of the mother’s uterus, enlargement of the breasts and breast ductile structure, enlargement of external genitalia, relaxation of the pelvic ligament

Front 112

Describe the importance of progesterone.

Back 112

essential for implantation and the maintenance of pregnancy, relaxation of the uterus avoiding spontaneous abortion, decidualization of the endometrial stroma (nutrition), INC secretion from the fallopian tubes (nutrition to the early embryo)

Front 113

What do progesterone and estrogens do to GnRH?

Back 113

inhibits the GnRH pulse generator which reduces LH, FSH, corpus luteum is still alive which leads to blockade of new wave of folliculogenesis

Front 114

Describe the origin of human chorionic somatomammotropin/Human placental lactogen.

Back 114

syncytial trophoblast

Front 115

Describe the composition of human chorionic somatomammotropin/Human placental lactogen.

Back 115

polypeptide, short half-life

Front 116

Describe the actions of human chorionic somatomammotropin/Human placental lactogen.

Back 116

growth of the mammary gland (PRL-like), fetal growth (GH-like, via IGF-II), DEC glucose tolerance (GH-like), not indispensable

Front 117

Describe the secretory pattern of human chorionic somatomammotropin/Human placental lactogen.

Back 117

INC until the 36th week, large amounts

Front 118

Describe the clinical utility of human chorionic somatomammotropin/Human placental lactogen.

Back 118

diagnosis of DEC placental mass (e.g. due to placental infarction)

Front 119

Describe other hormonal factors in pregnancy.

Back 119

1. corticoid secretion
2. relaxin secretion-corpus luteum and placenta
3. pituitary-INC corticotrophin, thyrotropin and prolactin, DEC in FSH and LH

Front 120

What is the response of the mother’s body to pregnancy?

Back 120

1. weight gain: ~24 lbs.
2. metabolism during pregnancy-INC 15%
3. CO INC 30-40% by 27th week followed by a fall in the last 8 weeks for unknown reasons
4. blood volume is 30% above normal due to fluid retentition
5. respiration is 20% above normal
6. amniotic fluid is 500-1000 mL
7. preeclampsia (toxemia of pregnancy)-5% HTN + leakage of protein into urine
8. eclampsia-extreme degree of preeclampsia

Front 121

Describe what happens during parturition (birth of the baby).

Back 121

1. INC uterine excitability which leads to strong rhythmical contractions
2. hormonal factors that INC the uterine contractility
3. mechanical factors that INC the uterine contractility

Front 122

What are the hormonal factors that INC the uterine contractility?

Back 122

1. INC ratio of estrogens to progesterone-after 7th month, estrogens continue to INC while progesterone levels remain
2. oxytocin secreted by the neurohypophysis causes uterine contraction (oxytocin receptors on uterine muscles cells INC, secretion INC and stretching and irritation of uterine cervix which leads to INC in oxytocin
3. fetal hormones-oxytocin from the fetus’s pituitary, cortisol from adrenal glands, prostaglandins

Front 123

What are the mechanical factors that INC the uterine contractility?

Back 123

1. stretch of the uterine musculature
2. stretch of the irritation of the cervix

Front 124

Describe the positive feedback mechanism for the initiation of labor.

Back 124

1. baby’s head stretches cervix
2. cervical stretch excites fundic contraction
3. fundic contraction pushes baby down and stretches cervix some more
4. cycle repeats over and over again

Front 125

Describe the contractions at the onset of labor.

Back 125

Braxoton Hicks contractions occur which are weak and slow labor contractions

Front 126

What is the role of oxytocin in parturition?

Back 126

oxytocin administration can induce labor but oxytocin only starts to INC after the beginning of labor (stretch of the cervix), it hastens delivery, promotes the delivery of the placenta and reduces bleeding

Front 127

Describe the abdominal muscle contractions during labor.

Back 127

1. uterine contraction leads to pain, this pain elicits a neurogenic reflex from the spinal cord to the abdominal muscle that initiates more contraction
2. contraction in uterine fundus >> body >> lower segment near the cervix
3. every 30 mins -> every 1-3 minutes
4. 25 pounds of force each contraction
5. 95% head first

Front 128

Describe the stages of contraction during labor

Back 128

1. 1st stage-cervix dilation to the size of the head of the fetus, ~8-24 hours for the 1st pregnancy, can be a few minutes after
2. 2nd stage-membrane rapture, loss of amniotic fluid, head out, 1-30 mins

Front 129

Describe separation and delivery of the placenta.

Back 129

10-45 min after birth, contraction of the uterus leads to a shearing effect that separates the placenta from the uterine wall, bleeding occurs and is < 350 mL, contraction and prostaglandins

Front 130

Describe labor pains.

Back 130

1st stage-visceral sensory hypogastric nerves, 2nd stage-somatic nerves to spinal cord and brain

Front 131

Describe the involution of the uterus after parturition.

Back 131

4-5 weeks

Front 132

What hormones are involved in the development of the breast and what is their target/action?

Back 132

1. estrogens-target the lactiferous ductrs, stroma and fat
2. progesterone (w/ E2)-target the lobulo-alveolar system
3. cortisol, GH, IGF-I, PRL (nonlactating-levels)-permisive for other hormones
4. hCS/hPL-targets alveoli for milk secretion
5. PRL-targets alveoli for milk secretion

Front 133

What do estrogens and progesterone do to milk secretion?

Back 133

inhibit it

Front 134

What does prolactin do for milk secretion?

Back 134

activates milk secretion

Front 135

Describe the levels of estrogen and progesterone during pregnancy.

Back 135

10-20 time INC during 5th week to brith leading to no milk

Front 136

What supports prolactin?

Back 136

hCS

Front 137

what happens to estrogen and progesterone levels after birth?

Back 137

loss of estrogens and progesterone after birth -> PRL starts to work, leads to milk production (also requires other hormones including GH, cortisol, insulin and parathyroid hormone

Front 138

What happens to the levels of PRL during breast feeding?

Back 138

each time breast feeding, 10-20 fold surge of PRL lasts for ~1 hour

Front 139

What happens to the ovarian cycle after delivery?

Back 139

suppression of the femal ovarian cycles in nursing mothers for many months after delivery, PRL secretion inhibits gonadotropin secretion which leads to suppression of the ovarian cycle

Front 140

What is lactational anovulation?

Back 140

patterns of pulsatile secretion of LH and FSH over a 24 hour period in a fully breastfeeding woman at 4 weeks and 8 weeks postpartum, note suppressed GnRH pulse generator activity

Front 141

Describe the ejection process in milk secretion.

Back 141

is an ejection, not a leak, suckling leds to sensory impulses from nipples to spinal cord and then to hypothalamus, this leads to secretion of oxytocine from posterior pituitary, milk ejection occurs in about 30 sec-1 min, ejection reflex does not diminish with time

Front 142

What does oxytocin do during milk secretion?

Back 142

leads to contraction of myoepithelial cells which releases milk from alveoli to ducts

Front 143

What is required for maintenance of lactation?

Back 143

milk removal

Front 144

When does spermatogenesis start?

Back 144

starts at puberty (~12-14)

Front 145

What are the three phases of spermatogenesis?

Back 145

1. mitiotic-spermatogonial proliferation and differentiation
2. meitotic division of spermatocytes into spermatids
3. haploid-differentiation and morphogenesis of spermatids to spermatozoa

Front 146

Describe the different cell types involved in spermatogenesis.

Back 146

primordial germ cell -> spermatogonia -> proliferation of spermatogonia by mitotic cell division inside testis -> primary spermatocyte -> secondary spermatocyte -> spermatids -> mature sperm

Front 147

What role does testosterone have on stimulating spermatogenesis?

Back 147

1. secreted by the interstitial Leydig cells
2. essential for spermatogenesis, especially for meitotic and haploid phases

Front 148

What role does LH have on stimulating spermatogenesis?

Back 148

1. secreted by the anterior pituitary gland
2. stimulate the Leydig cells to secrete testosterone

Front 149

What role does FSH have on stimulating spermatogenesis?

Back 149

1. secreted by the anterior pituitary gland
2. stimulates the Sertoli cells to secrete factors to maintain quantitative spermatogenesis

Front 150

What role does estrogen have on stimulating spermatogenesis?

Back 150

1. aromatized from testosterone in Sertoli cells
2. re-absorption of luminal fluid in the head of the epididymis, allowing sperm to enter the epididymis concentrated rather than dilute
3. ER-beta on spermatogonia, spermatocytes and Sertoli cells may mediate the actions of xenoestrogens (estrogenic endocrine disruptors)

Front 151

What role do growth factors have on stimulating spermatogenesis?

Back 151

1. secreted from the Sertoli cells or germ cells
2. act on germ cells or somatic cells via their receptors
3. effectors of major hormonal signals
4. paracrine and autocrine regulation under the control of endocrine signals

Front 152

Describe the maturation of sperm in the epididymis.

Back 152

there are 120 million/day, no motility in the head of (caput) epididymis, gain during the transition from the caput to corpus (the middle) epididymis, moderate motility in the cauda (tail of) epididymis

Front 153

What role does the vas deferens have on maturation of sperm?

Back 153

most stored in the vas deferens where motility is remained >1 month, motility is suppressed in the vas deferens

Front 154

Describe the maturation of motility of upon ejaculation.

Back 154

motile upon ejaculation-initial motility, more motile in the female reproductive tracts-hyperactivated motility, survives ~1-2 days in the female tract, can survive in a neutral or slightly alkaline medium but an acidic medium leads to loss of motility

Front 155

What is the function of the seminal vesicles?

Back 155

1. secrete a mucoid material enriched in fructose, citric acid, prostaglandins, fibrinogen and other nutrient substances
2. empty its contents in to the ejaculatory duct
3. provide nutrition to the sperm in the semen
4. prostaglandins-aid fertilization

Front 156

What are the functions of the prostate gland?

Back 156

1. secrete fluid containing Ca2+, citrate ion, a clotting enzyme, and a profibrinolysin
2. during emission, contract together with the vas deferens to add fluid to the semen
3. alkaline to neutralize acidic vas deferens fluid and vaginal secretion (pH 3.5-4.0)

Front 157

Describe the composition of semen.

Back 157

sperm and fluid from the vas deferens (~10%), seminal vesicle (~60%), prostate gland (~30%) and bulbourethral glands (small amount)

Front 158

Describe some physical properties of semen.

Back 158

pH = 7.5, milky appearance, coagulation (clotting enzyme) which dissolves in 15-30 min due to fibrinolysin derived from profibrinolysin, 1 month in vas deferens and epididymis but only 1-2 days in female tract, cryopreservation can keep sperm alive for years (sperm bank)

Front 159

Describe capacitation.

Back 159

1. making sperm capable of fertilizing the egg
2. occurs naturally in the female genital tract
3. takes 1-10 hours

Front 160

What changes occur during capacitation?

Back 160

1. washing off inhibitory factors that suppress sperm activity
2. removing cholesterol vesicles and exposing the acrosome so that acrosomal enzymes can be released
3. sperm membrane becomes more permeable and Ca2+ enter the sperm, triggering hyperactivated motility, which is essential for penetrating zona pellucida

Front 161

What role does human tubular fluid (HTF) have on capacitation of sperm?

Back 161

washing the semen with HTF or capacitating medium can capacitate sperm (first step in IUI)

Front 162

What is the content of acrosome?

Back 162

1. hyaluronidase-dissolves connective tissues among multiple layers of granulose cells
2. proteolytic enzymes-dissolve zona pellucida

Front 163

Where is the acrosome derived from and what is its purpose?

Back 163

derived from golgi apparatus during spermiogenesis, essential for sperm to fertilize eggs

Front 164

What may cause abnormal spermatogenesis and male infertility?

Back 164

temperature problem, requires a temperature ~2C or more below body temperature, scrotum has sweat glands, countercurrent heat exchange, reflex regulation of scrotal surface area, reflex regulation of distance from abdomen

Front 165

What is cryptorchidism?

Back 165

1. 1-3 months before birth
2. descent through inguinal canal into scrotum
3. testosterone from fetal Leydig cells triggers
4. if not usually descent within months after birth
5. testosterone treatment can induce descent
6. after one year need surgical help

Front 166

What happens with patients who have abdominal testes?

Back 166

spermatogenic block -> depletion of germ cells -> sterility, can lead to tumorigenesis

Front 167

Describe low sperm count.

Back 167

in 3.5 mL, average is 120 million/mL (25-200 million/mL), <20 million/mL, infertile, spermatogenic defects (genetic factors)

Front 168

What are the different types of abnormal sperm motility?

Back 168

structural (tail formation, deformation) and metabolic (energy supply, ion signaling)

Front 169

Describe the neuronal stimulus for performance of the male sexual act.

Back 169

1. sexual stimulations form the sex organs: glans penis or areas adjacent to penis
2. impulses -> pudendal nerve -> sacral plexus -> sacral portion of spinal cord
3. psychic stimulation from the brain-thinking, dreaming (nocturnal emissions)
4. impulses from brain and/or sex organs are integrated in the sacral and lumbar spinal cord

Front 170

What are the stages of the male sexual act?

Back 170

1. penile erection-role of parasympathetic nerves
2. lubrication-a parasympathetic function
3. emission and ejaculation-a sympathetic function
4. resolution-1-2 min after ejactulation

Front 171

Describe penile erection.

Back 171

1. parasympathetic impulses -> sacral portion of spinal cord -> pelvic nerves -> penis
2. parasympathetic nerve fibers release NO and/or vasoactive intestinal peptide as well as ACh

Front 172

what does NO do?

Back 172

relaxes penile arteries and trabecular meshwork of smooth muscle fibers in the erectile tissue of the corpora cavernosa and corpus spongiosum in the shaft of the penis (how Viagra works)

Front 173

Describe the lubrication stage of the male sexual act.

Back 173

parasympathetic impulses stimulate secretion of mucus from the urethral glands and the bulbourethral glands

Front 174

describe the emission and ejaculation stages of the male sexual act.

Back 174

1. culmination of the male sexual act
2. reflex center of spinal cord emits sympathetic impulses at T12-L2 -> hypogastric and pelvic sympathetic nerve plexuses -> genital organs -> emission
3. contraction
4. filling of internal urethra -> sensory signals

Front 175

Describe the contraction that occurs during the emission and ejaculation stage of the male sexual act.

Back 175

vas deferens -> expulsion of sperm into the internal urethra -> prostate gland -> seminal vesicle -> prostatic and seminal fluids into the urethra + sperm + mucus from the urethral glands and the bulbourethral glands

Front 176

Describe the filling of the internal urthra during the emission and ejaculation stages.

Back 176

1. rhythmical contraction of internal genital organs and pelvic muscle
2. thrusting movement of the pelvis and penis
3. propel semen

Front 177

What is the nature and origin of testosterone?

Back 177

steroids synthesized from cholesterol, comes from the Leydig cells = interstitial cells, < 5% of testosterone from the adrenals

Front 178

What are the circulating binding proteins for testosterone?

Back 178

SHBG/ABP (produced by Sertoli cells), albumin

Front 179

Describe the conversions of testosterone.

Back 179

conversion to dihydro-testosterone (DHT) by 5-alpha-reductase in liver (type I) and target tissues (type II), low abundance (5% of T in blood), high affinity for androgen receptors, T can also be aromatized -> E2

Front 180

Describe the metabolism and excretion of testosterone.

Back 180

reduction, then conjugation in the liver, excretion by the kidneys or by the gut

Front 181

What is the function of testosterone during fetal development?

Back 181

1. T production starts ~7th week
2. formation of male external and internal sex organs
3. descent of the testes-cyrptorchidism

Front 182

What is the function of testosterone during the development of adult primary and secondary sexual characteristics?

Back 182

1. further development of external and internal genitalia
2. development of secondary sexual characteristics:
a. distribution of body hair
b. baldness-genetic background + large amount of androgen
c. voice
d. INC skin thickness (acne)
e. INC muscle development (abuse by athletes)
f. INC bone matrix and Ca2+ retention
g. INC basal metabolism

Front 183

What is the function of testosterone during the adult stages?

Back 183

gonadal steroid actions are no longer concerned with establishing the individual as a male or female, rather they ensure that the reproductive system functions effectively

Front 184

Describe the basic intracellular mechanism of action of testosterone.

Back 184

ligand binds to androgen receptor which binds to a coregulator, this complex binds to a transcription initiation complex that leads to transcription of specific genes

Front 185

Describe estrogen in men.

Back 185

1. at early follicular phase levels
2. from Leydig cells, Sertoli cells and developing germ cells
3. 2/3 from peripheral conversion (skin, brain, fat and liver)

Front 186

What are the roles of estrogen in men?

Back 186

1. estrogen regulates the reabsorption of luminal fluid in the head of the epididymis, allowing sperm to enter the epididymis concentrated rather than diluted
2. full expression of gonadal negative feedback on pituitary gonadotropin secretion
3. pubertal growth spurt, epiphyseal closure, maintenance of bone mineralization and integrity
4. maintenance of insulin sensitivity
5. ER-beta on spermatogonia, spermatocytes and Sertoli cells may mediate the actions of xenoestrogens (estrogenic endocrine disruptors)

Front 187

Describe GnRH.

Back 187

1. 10 aa peptide
2. secreted by neurons whose cell bodies are located in the arcuate nuclei of the hypothalamus
3. GnRH is transported via blood to anterior pituitary gland
4. intermittently secreted a few minutes per 1-3 hours
5. freq. and amplitude
6. stimulates secretion of LH and FSH by the anterior pituitary
7. cyclic secretion of LH similar to that of GnRH

Front 188

Describe gonadotropin hormones

Back 188

LH and FSH, secreted by the same cells (gonadotropes) in the anterior pituitary, glycoproteins

Front 189

What is the mechanism of action, action and target of LH?

Back 189

1. mech of action-LHR -> cAMP -> PKA
2. actions-T production (direct), spermatogenesis (via T which is absolutely required (at a high concentration) -> Sertoli cells -> growth factors), LHR (down-regulated), Leydig cell growth and differentiation
3. target-Leydig cells

Front 190

What is the mech of action, action and target of FSH?

Back 190

1. mech of action-FSHR -> cAMP -> PKA
2. actions-spermatogenesis (needed for normal quantity and quality), growth, differentiation and maintenance of Sertoli cells, INC LHR on Leydig cells (indirect)
3. target-Sertoli cells

Front 191

What is the role of the GnRH pulse generator and negative feedback control of LH secretion?

Back 191

note the effects of testosterone deprivation on LH levels in blood and on the freq. of LH pulses, the site of T negative feedback is both at the level of the pituitary gland (DECing pulse amplitude) and at the hypothalamic GnRH pulse generator (DECing LH pulse freq.)

Front 192

What is the role of inhibin in control of FSH secretion?

Back 192

male monkeys were castrated and preoperative testosterone levels were maintained by exogenous T administration, note that while LH remained at preoperative levels, FSH levels gradually rose to high concentrations indicating that a testicular factor (inhibin) in addition to T normally controls FSH secretion, C is cryptorchidism

Front 193

Describe inhibin.

Back 193

1. Sertoli cells of the testes produce inhibin, whose role is to control the secretion of FSH
2. FSH secretion from cultured AP cells is inhibited when AP cells are co-cultured with Sertoli cells
3. this is further substantiated by the fact that prior exposure to inhibin suppresses the elevation of FSH release following GnRH administration
4. other evidence suggests that inhibin also suppresses FSH at the hypothalamus level
5. granulosa cells from the ovarian follicle secrete inhibin that acts directly on AP cell cultures derived from the male or female
6. administration of anti-inhibin antisera to rats of either sex causes an elevation in serum FSH, LH remains unchanged

Front 194

What factors affect the hypothalamogonadal axis?

Back 194

1. psychic factors
2. hCG secreted by the placenta during pregnancy stimulates T production by the fetal testes
3. onset of puberty-unknown! childhood no GnRH secretion due to stronger seuppressive effects of sex steroid hormones

Front 195

Describe the male climacteric (andropause).

Back 195

1. starting from 40s, T levels decline
2. sometimes associated with symptoms of hot flashes, suffocation, and psychic disorders, similar to those of menopause syndrome

Front 196

describe the growth of the prostate gland and changes that may lead to abnormalities.

Back 196

1. at puberty, T stimulates growth of prostate until 20 years of age
2. after 50, the prostate starts to involute in some men
3. coincides with the DEC of T levels
4. not caused by T, but by its own tissue
5. T stimulates the growth of cancerous cells
6. benign prostatic fibroadenoma (urinary obstruction)
7. cancer-2-3% of all male deaths

Front 197

Describe the prevalence and distribution of testicular tumors.

Back 197

1. testicular cancer is most common among white males and rare among African Americans, worldwide incidence has doubled since the 1960s with the highest rates of prevalence in Scandinavia, Germany and New Zealand, T cancer is uncommon in Asia and Africa
2. incidence in blacks has doubled from 1988 to 2001 with a bias towards seminoma, the lack of any significant INC in the incidence of early-stage testicular cancer during this timeframe suggests that the overall INC was not due to heightened awareness of the disease
3. although testicular cancer is most common among men aged 15-40 years, it has three peaks (infancy, ages 25-40, and 60)

Front 198

Describe the rates of occurrence of germ cell tumors of the testis.

Back 198

1. seminoma-35%
2. embryonic carcinoma-20%
3. teratoma-5%
4. choriocarcinoma-<1%
5. mixed cell type-40%

Front 199

What are some examples of non-germ cell tumors of the testis?

Back 199

Leydig cell tumors, Sertoli cell tumors

Front 200

What are the three basic types of treatment?

Back 200

surgery, radiation therapy and chemotherapy

Front 201

What are the effects of orchidectomy in the adult on accessory sex organs?

Back 201

prostate, epidydimes, seminal vesicles involute, their epithelia shrink, secretory activity declines -> no seminal plasma

Front 202

What are the effects of orchidectomy in the adult on muscular mass?

Back 202

muscular mass DEC (reversible, role of T, abuse)

Front 203

What are the effects of orchidectomy in the adult on brain/behavior?

Back 203

DEC (not lost) libido (unlike after ovariectomy), chemical castration as treatment of antisocial patterns of sexual behavior, but T is not an aphrodisiac, importance of monitoring of nocturnal penile tumescence (NPT)

Front 204

What are the effects of orchidectomy in the adult on other organs?

Back 204

prevention of male baldness, DEC in kidney and liver weight and erythropoiesis, INC in thymus weight

Front 205

What is the nocturnal penile tumescence (NPT) test.

Back 205

The NPT test may also be called the stamp test or the rigidity test.
Most men have 3 to 5 full erections during deep (rapid eye movement or REM) sleep. Men who are unable to have an erection because of a psychological problem still have erections during deep sleep. Occasionally some sleep disorders or serious depression can prevent these nighttime (nocturnal) erections.
The NPT test determines whether a man is having normal erections during sleep. This test can be done at home or in a special sleep lab. One of two methods may be used:
Use a simple ringlike device called a snap gauge made up of plastic films that fit around the penis. The films break at predetermined pressures.
Use an electronic monitoring device. This method is more expensive than using the snap gauge, but it is more accurate and provides more detailed information about the number, duration, and stiffness of erections that occur.
Testing is usually repeated for at least two nights. If good erections occur during sleep, the major cause of the erection problems probably is not physical.

Front 206

What is adiposogenital syndrome?

Back 206

AKA Frohlich’s syndrome or hypothalamic eunuchism, the hypothalamus has a deficiency in GnRH production, abnormalities in the feeding center of the hypothalamus leading to overeating and obesity

Front 207

Describe the pineal gland.

Back 207

1. the pineal gland was the last endocrine gland to have its function discovered
2. its location deep in the brain seemed to indicate its importance
3. it is located in the geometric center of the brain, this correlates to the location of the great pyramid in the center of the physical planet
4. this combination led ot its being a mystery gland with myth, superstition and even metaphysical theories surrounding its perceived function

Front 208

What are the functions of the pineal gland?

Back 208

1. produces melatonin
2. it is large in children and begins to shrink at puberty
3. may play a significant role in sexual maturation, circadian rhythm, sleep induction, seasonal affective disorder and depression
4. in animals it is known to play a major role in sexual development, hibernation and seasonal breeding

Front 209

Describe the growth and functional development of the fetus.

Back 209

during the first 2-3 weeks the fetus remains almost microscopic, it then begins to grow in length, pretty steadily throughout the pregnancy, weight of the fetus remains minuscule during the first 12 weeks of gestation then begins to grow, during the last 2 months, weight gain in tremendous averaging 2 lbs. for both the 8th and 9th months of gestation

Front 210

Give an overview of the development of the organ systems.

Back 210

1. within a month of fertilization, all of the organ systems of the fetus have been blocked out
2. during the next 2-3 months, more details of the systems begin to form
3. after the 4th month, the organ systems are grossly the same as in the newborn
4. cellular development of these systems requires the remainder of gestation to complete
5. at birth, structures within the nervous system, kidneys and liver lack full development

Front 211

In general, describe the development of the circulatory system.

Back 211

the human heart starts beating at 26 days following fertilization at ~65 beats/minute, the heart rate INC steadily throughout gestation and reaches 140 beats/minute just before delivery

Front 212

Describe the formation of blood cells.

Back 212

1. nucleated blood cells formed in yolk sac and mesothelial layer of the placenta ~3rd week of fetal development
2. after 4-6 weeks, non-nucleated RBCs begin to form in fetal mesenchyme, fetal blood vessel endothelium and liver
3. from 3rd month to birth, bone marrow forms red and white blood cells, as gestation progresses, bone marrow INC its production of blood components, until birth, when other blood-forming tissues lose their ability to form blood cells

Front 213

What are the time periods for fetal erythropoesis?

Back 213

yolk sac (3-8 week) -> liver (6-30 weeks) -> spleen (9-28 weeks) -> bone marrow (28 week onward) (young liver synthesizes blood)

Front 214

Describe the development of the respiratory system.

Back 214

1. respiratory movements take place during 1st trimester
2. during last 3-4 months of gestation, these respiratory movements are inhibited, possible causes for this inhibition include (1) special chemical conditions in the body fluids of the fetus, (2) presence of fluid in the fetal lungs
3. this inhibition of respiration prevents the filling of the lungs with debris from the meconium secreted from the GI tract, additionally fluids secreted by the alveolar epithelium, keeping the pulmonary sacs with clean secretions

Front 215

What is the meconium?

Back 215

the first intestinal discharges of the newborn infant, greenish in color and consisting of epithelial cells, mucus and bile, composed of unabsorbed residue of the amniotic fluid and excretory products of the GI mucosa and glands

Front 216

Describe the development of the nervous system.

Back 216

skin reflexes develop in the fetus between 3-4 months, most of the higher function of the cerebral cortex are underdeveloped at birth, even myelinization of the major tracts of the nervous system takes ~1 year to complete

Front 217

Describe the development of the GI tract.

Back 217

after ~4.5 months gestation, the fetus ingests and absorbs large quantities of amniotic fluid, during last 2-3 months, GI function approx. that of a newborn infant, meconium is excreted by the fetus

Front 218

Describe the development of the kidneys.

Back 218

fetal kidneys are capable of excreting urine during the last half of gestation and urination occurs in utero, control systems regulating extracellular fluid electrolyte and acid-base balance don’t exist to any degree until ~4.5 months gestation, and don’t develop until months after birth

Front 219

Describe fetal metabolism of Ca2+ and phosphate.

Back 219

fetus accumulates ~23 g of Ca2+ and 14 g of phosphorus during gestation, about half of these total accumulated in the last 4 weeks of gestation, coincident with the period of rapid ossification of fetal bones and rapid weight gain, these Ca2+ totals represent ~1/50th of the maternal bone contents, so that nursing, not growth of the fetus represents the greater drain on the mother’s system

Front 220

Describe the accumulation of iron in the fetus.

Back 220

accumulates somewhat faster than Ca2+ and phosphorus, most of the iron is incorporated into hemoglobin which begins to form ~3 weeks after fertilization, about 1/3 of the iron in a term fetus is stored in the liver for future formation of hemoglobin

Front 221

What is the importance of B vitamins to the fetus?

Back 221

B12 and folic acid are necessary for RBC formation and overall growth

Front 222

What is the importance of vitamin C to the fetus?

Back 222

necessary for bone matrix and connective tissue fiber formation

Front 223

What is the importance of vitamin D to the fetus?

Back 223

necessary fro proper fetal bone growth and stored in liver, must be present in maternal GI tract for Ca2+ absorption

Front 224

What is the importance of vitamin E to the fetus?

Back 224

maintains normal development in early embryo, since deficiencies in experimental animals produce spontaneous abortions

Front 225

What is the importance of vitamin K to the fetus?

Back 225

used by fetal liver for formation of factor VII, prothrombin and other blood coagulation factors, since vitamin K is formed by bacterial action in the colon, only the mother can provide the vitamin, limited storage in the fetal liver is helpful in preventing hemorrhage, especially if the head is traumatized during birth

Front 226

Describe the cause of breathing at birth.

Back 226

if the fetus has not been depressed by anesthetics, a child will exhibit normal respiratory rhythm within seconds of birth, this promptness is probably produced by (1) low O2-a slightly asphyxiated state incident to the birth process. (2) low temperature-cooled skin, if no breathing, further hypoxia and hypercapnia will usually start respiration

Front 227

What is hypoxia at birth and what can cause it?

Back 227

it is delayed and abnormal breathing at birth, can be caused by umbilical cord compression, premature placental separation, excessive contraction of the uterus or excessive anesthesia

Front 228

What is the danger of hypoxia?

Back 228

1. intracranial hemorrhage or brain contusion causes a concussion syndrome
2. serious depression of the respiratory center

Front 229

What degree of hypoxia can an infant tolerate?

Back 229

newborn infants can survive from 10-15 minutes without respiration (adult ~4 min), permanent and very evident brain impairment develops after 8-10 minutes of breathing delay, specific lesions develop in the thalamus, inferior colliculi and other brain stem area thus affecting many of the motor function of the body

Front 230

Describe the expansion of the lungs at birth.

Back 230

1. tremendous force required to open the alveoli the first time, at least 25 mm Hg negative pressure
2. fortunately the first inspirations of the infant can produce as much as 60 mm Hg negative pressure in the intrapleural space
3. the second breath is much easier although breathin is rarely normal until ~40 minutes after birth

Front 231

What is respiratory distress syndrome (RDS)?

Back 231

AKA hyaline membrane disease, premature infants of those born to diabetic mothers develop respiratory distress produced by large quantities of proteinaceous fluid resembling plasma in the alveoli, the fluid also containes desquamated alveolar epithelial cells

Front 232

What causes hyaline membrane disease?

Back 232

1. caused by a lack of surfactant secretion
2. surfactant-a substance normally secreted by type II alveolar epithelial cells into the alveoli that DEC the surface tension of the alveolar fluid therefore allowing the alveoli to open easily
3. infants that lack surfactant have a tendency of collapsed alveoli and development of pulmonary edema

Front 233

When do type II alveolar cells begin secretion?

Back 233

do not begin secretion of surfactant until the last 1-3 months of gestation

Front 234

What are the risk factors for hyaline membrane disease?

Back 234

1. male sex
2. premature birth
3. second born twin
4. perinatal asphyxia
5. maternal diabetes
6. (Lecithin/sphingomyelin), L/S ratio < 2 9used to determine fetal pulmonary maturity

Front 235

What are the clinical features of hyaline membrane disease?

Back 235

1. tachypnea (rapid breathing)
2. nasal flaring
3. grunting
4. cyanosis
5. ground glass appearance on CXR

Front 236

what are the complications of hyaline membrane disease?

Back 236

intrinsic-pneumothorax, pulmonary emphysema
O2 therapy-bronchopulmonary dysplasia, retinopathy

Front 237

Describe the functionality of the lung and liver in fetal circulation.

Back 237

are non- or partially functional, not much blood needed, the placenta does have large quantities of blood

Front 238

Describe the flow of O2 rich blood.

Back 238

umbilical vein -> ductus venosus -> IVC -> right atrium -> foramen ovale -> left atrium -> left ventricle -> vessels of head and forelimbs

Front 239

Describe the flow of O2 deprived blood.

Back 239

SVC -> right atrium -> tricuspid valve -> right ventricle -> pulmonary artery -> ductus arteriosus -> descending aorta -> umbilical arteries -> placenta

Front 240

Describe blood circulation within the placenta.

Back 240

1. fetal circulation in the villous tree
2. maternal circulation in intervillous spae
3. maternal blood pathways
villous tree is anchored on the basal plate, pattern of maternal blood flow through the intervillous space (the cotyledons are separated from each other by placental septa

Front 241

What are the primary changes in pulmonary and systemic vascular resistance at birth?

Back 241

1. loss of tremendous blood flow to the placenta coupled with the approximate doubling of the system vascular resistance, these changes INC aortic pressure and pressures within the left ventricle and left atrium
2. pulmonary vascular resistance greatly DEC as a result of the expansion of the lungs, right ventricular and arterial pressure are reduced

Front 242

Describe the closure of the foramen ovale.

Back 242

the low right atrial and high left arterial pressures that occur cause blood flow to attempt to flow backward through the foramen ovale from the left atrium into the right atrium, a small valve that lies over the foramen ovale on the left side of the atrial septum closes over the opening right after birth

Front 243

Describe the closure of the ductus arteriosus.

Back 243

INC systemic resistance elevates aortic pressure while the DEC pulmonary resistance reduces pulmonary arterial pressure, the consequence is that blood begins to flow backward through the ductus arteriosus, the ductus arteriosus begin to constrict with 1-8 days, producing a functional closure, during the next 1-4 months, fibrous tissue grows to completely occlude the lumen

Front 244

Describe the closure of the ductus venosus.

Back 244

During fetal life, the portal blood from the fetus' abdomen join the blood from the umbilical vein and pass through the ductus venosus directly into the vena cave, bypassing the liver. Obviously, at birth, the umbilical vein blood flow ceases, but the portal blood flow continues into the ductus venosus. Within 1 3 hours, the walls of the ductus venosus begin to constrict, closing off this avenue of blood flow. Portal venous blood flow rises from 0 10 mm Hg, enough to force blood through the liver sinuses.

Front 245

What are some fetal structures that are now fetal remnants?

Back 245

1. epigastric arteries-lateral umbilical ligaments
2. umbilical arteries-medial umbilical ligaments
3. urachus-median umbilical ligament
4. umbilical vein-round ligament
5. ductus venosus-venous ligament
6. ductus arteriosus-ligamentum arteriosus
7. yolk stalk-Meckel’s diverticulum

Front 246

Describe the nutrition of the newborn infant.

Back 246

1. maternal glucose stored in the infant as glycogen only lasts a few hours after birth
2. the newborn liver is marginally functional, insignificant gluconeogenesis occurs, neonatal blood glucose can fall to 30-40 mg/dL, about one half of normal
3. the infant can however utilize the stored fats and proteins for the 2-3 days until mothers milk can be provided
4. since infant body fluid turnover is seven times that of an adult, most infants experience a 5-10% weight loss after birth until mothers milk supply becomes sufficient

Front 247

Describe a special functional problem in the neonatal respiratory system.

Back 247

Normal respiration ~ 40 breaths/minute, with tidal air volume ~16 ml. This yields a total minute respiratory volume of 640 ml/min, about 2x that of an adult. This is compensated for with a functional residual capacity of one half that on an adult in relation to body weight.

Front 248

Describe a special functional problem in the neonatal blood volume.

Back 248

Normal blood volume ~300 ml right after birth. If the infant is left attached to the placenta, this can increase to 375 ml. A combination of this with the fluid loss right after birth increases the hematocrit and reduces the blood volume to normal. This extra blood volume in some instance causes mild pulmonary edema with some degree of respiratory distress.

Front 249

Describe a special functional problem in the neonatal CO.

Back 249

Averages about 2x that of an adult, 550 ml/min.

Front 250

Describe a special functional problem in the arterial pressure.

Back 250

Averages 70/50 at birth and increases over the next several months after birth to 90/60. Blood pressure then slowly increases to adolescent values of 115/70.

Front 251

Describe a special functional problem in the neonatal blood characteristics.

Back 251

RBC count 4 x106/ul, which can increase to 4.75 x106/ul if the umbilical cord blood is stripped into the infant. This falls to 3.24 x106/ul as the hypoxic stimulus for RBC formation disappears. White blood cell counts 45,000/ul at birth, about 5x that of adult values.

Front 252

Describe a special functional problem in the neonatal jaundice.

Back 252

Bilirubin is excreted through the placenta by the fetus, which disappears at birth. Since the neonatal liver is marginally functional, plasma bilirubin rises from < 1 mg/dl at birth to 5 mg/dl after 3 days of life. This condition called physiologic hyperbilirubinemia and associated with mild jaundice.

Front 253

Describe a special functional problem in the neonatal erythroblastosis.

Back 253

Erythroblastosis fetalis produced by Rh incompatibility between the mother and fetus. The maternal system recognizes the infants' RBCs as non self, and destroy them with antibodies, releasing large quantities of bilirubin into the plasma.

Front 254

Is physiologic jaundice unconjugated or conjugated and what are some characteristics about it?

Back 254

unconjugated, 3 to 5 days postnatal, due to INC bilirubin production and relatively immature liver

Front 255

Is breast milk jaundice unconjugated or conjugated and what are some characteristics about it?

Back 255

unconjugated, 2 to 3 weeks after birth, due to INC bilirubin absorption, brief interruption of breast feeding (usually not necessary)

Front 256

Is hemolysis unconjugated or conjugated and what are some characteristics about it?

Back 256

UC, Rh, ABO incompatibility, spherocytosis, G6PDH deficiency

Front 257

Is enzyme defects unconjugated or conjugated and what are some characteristics about it?

Back 257

UC and C, Gilbert (mild, DEC hepatic bilirubin uptake), Crigler-Naijar (severe, deficient glucuronyl transferase) Dubin Johnson (impaired hepatocellular secretion)

Front 258

Is cholestasis unconjugated or conjugated and what are some characteristics about it?

Back 258

C, bile duct stenosis, biliary atresia, hepatitis, CF

Front 259

Is kernicterus unconjugated or conjugated and what are some characteristics about it?

Back 259

UC, unconjugated bilirubin > 20 mg/dl, staining of basal ganglia, lethargy, hypotonia, encephalopathy

Front 260

Describe fluid and acid-base balance, and renal function.

Back 260

1. Some of the most important problems in infancy: dehydration, acidosis, and overhydration.
2. Fluid intake and excretion in the infant is 7x that of an adult. Slight alterations in fluid balance cause large abnormalities in infants.
3. Metabolism 2x that of an adult in infants, which increases 2x the acid formation, making the infant slightly acidotic.
4. Functional development of the kidneys is not complete until ~1 month after birth. Infants can only concentrate urine 1.5x, whereas adults do so ~ 3 4 times.

Front 261

What is some evidence of deficient liver function?

Back 261

1. Conjugate bilirubin with glucuronic acid poorly, which reduces bilirubin excretion.
2. Reduced plasma protein formation, so that plasma proteins drop to 15 20% of older children. Can drop low enough for infant to develop hypoproteinemic edema.
3. Gluconeogenesis almost non existent, producing hypoglycemia in newborns.
4. Forms blood coagulation factors poorly

Front 262

What are some exceptions to newborn’s ability to digest, absorb and metabolize nutrients?

Back 262

through to be similar to older children except for:
1. Reduced pancreatic amylase, reducing starch utilization.
2. Reduced absorption of fats by gastrointestinal tract. High fat milks are not utilized well.
3. Imperfection liver function renders blood glucoses low and unstable
4. Neonates are especially good at utilizing amino acids. As much as 90% of ingested amino acids are utilized in the formation of body proteins

Front 263

Describe the metabolic rate and body temperature of neonate.

Back 263

1. Metabolic rate of the neonate in relation to body weight is 2X that of the adult (2x cardiac output; 2X minute respiratory volume)
2. Body surface area>body mass→ body temperature DEC

Front 264

What are some specific problems concerning nutrition during the early weeks of life?

Back 264

1. Need for calcium and vitamin D: rapid ossification in the neonate→ Vitamin D DEC→ Calcium absorption DEC→ Severe rickets
2. Necessity for iron in the diet: if mother has adequate iron in her diet →enough for 4-6 months for blood cell formation. If not, anemia at ~ 3 month
3. Vitamin C deficiency in infants can result from low content in cow’s milks. Usually rectified with juice supplementation.

Front 265

Describe immunity in the infant.

Back 265

Immunity inherited from the mother protects the infant for ~6 months against major childhood infectious diseases including diphtheria, measles, and polio. Therefore, immunization against these diseases before 6 months is unnecessary.

Front 266

Describe allergies in the infant.

Back 266

While newborns are rarely subject to allergies, once the infant begins to form its own antibodies, allergies begin to appear.

Front 267

What are some endocrine problems in the fetus?

Back 267

1. Pregnant mothers treated with androgenic hormones or who develop androgenic tumors bear female children with masculinization of the sex organs, hermaphrodism.
2. Sex hormones from the placenta and mother often cause neonatal breast development and sometimes milk formation.
3. Infants born to diabetic mothers have considerable hypertrophy and hyperfunction of the islets of Langerhans, caused by the maternal hyperglycemia.

Front 268

What happens in hyperthyroidism in the fetus/newborn?

Back 268

1. Hypofunctional adrenal cortices.
2. Hyperthyroidism or thyroid hormone abuse produce a hyposecreting thyroid gland, temporarily. Also occurs in cases where mother has had thyroid gland removed and pituitary hypersecretes TSH.
3. A fetus lacking thyroid hormone secretion will exhibit poor bone growth and mental retardation. The condition is called CRETIN DWARFISM (congenital hypothyroidism) .

Front 269

What are some special problems of prematurity?

Back 269

1. Immature development of the premature infant
– Respiration: RDS
– GI: Low-fat and high calcium and vitamin D diet
– Other organs:
2. Instability of the control systems in the premature infant
– Body temperature: use of incubator
– Hypoproteinemic edema
3. Danger of blindness caused by oxygen therapy in the premature infant
– O2 INC→new blood vessels in retina DEC
– When stopped, rapid growth of blood vessels →great mass of vessels growing through the vitreous humor→ Blocking light from the pupil to the retina

Front 270

What is APGAR scoring for newborns?

Back 270

A score is given for each sign at one minute and five minutes after the birth. If there are problems with the baby an additional score is given at 10 minutes. A score of 7-10 is considered normal, while 4-7 might require some resuscitative measures, and a baby with apgars of 3 and below requires immediate resuscitation.

Front 271

What are the five APGAR categories?

Back 271

activity (muscle tone), pulse, grimace (reflex irritability), appearance (skin color), respiration

Front 272

Describe the key roles that calcium plays in nerve and muscle exciation, muscle contraction, enzyme function and bone.

Back 272

Calcium is a key actor in many physiologically important processes. It influences nerve excitability and is involved in neurotransmitter release from axon terminals and excitation-contraction coupling in muscle cells. It serves as a second or third messenger in several intracellular signal transduction pathways. Some enzymes use calcium as a cofactor, including some in the blood clotting cascade. Finally, calcium is a major constituent of bone.

Front 273

What function of Ca2+ demands the most careful regulation of plasma calcium?

Back 273

Of all these roles, the one that demands the most careful regulation of plasma calcium is the effect of calcium on nerve excitability. Calcium affects the sodium permeability of nerve membranes, which influences the ease with which action potentials are triggered. Low plasma calcium can lead to generation of spontaneous action potentials in nerve. When the motor neurons are affected, tetany of the muscles of the motor unit may occur (hypocalcemic tetany).

Front 274

What does phosphate do?

Back 274

Phosphate participates in pH buffering and is a major constituent of many macromolecules and of bone. Phosphorus (usually as phosphate) also participates in many important metabolic processes. Phosphate buffer and various metabolic intermediates, DNA, RNA and phosphoproteins all contain phosphate as an integral part of their structure. Phosphate is also a major component of bone.

Front 275

Describe the distribution of calcium.

Back 275

The table below shows the relative distributions of calcium and phosphate in a normal individual. Roughly 99% of the body calcium is in bones. Despite its critical role in E-C coupling, only about 0.3% of total body calcium is located in muscle. About 0.1% of total calcium is in extracellular fluid.

Front 276

Describe the distribution of phosphorus.

Back 276

Of the roughly 600 g of phosphorus in the body the majority (86%) is in bone. Compared to calcium, a much larger percentage of phosphorus is located in cells (14%). The amount of phosphorus in extracellular fluid is rather low (0.08% of body content).

Front 277

Describe the ionic composition of bone.

Back 277

Bone also contains a relatively high percentage of the total body content of several other inorganic substances (see Table). Roughly 80% of the total carbonate in the body is located in bone. This carbonate can be mobilized into the blood to combat acidosis, thus bone participates in pH buffering in the body. Long standing uncorrected acidosis can result in considerable loss of bone mineral. A significant percentage of the body’s magnesium and sodium and nearly 10% of its total water content is in bone.

Front 278

In what forms and concentrations is Ca2+ found in the blood?

Back 278

In humans, the normal plasma concentration is 9-10.5 mg/dl. Plasma calcium exists in three forms: ionized calcium (50% of the total), protein bound calcium (40%) and calcium bound to other anions (10%). The association of calcium with plasma proteins is pH-dependent. At an alkaline pH, more calcium is bound; the opposite is true in acidosis.

Front 279

In what forms and concentrations is phosphorus found in the blood?

Back 279

Plasma phosphorus concentration may fluctuate significantly during the course of a day, from 50% to 150% of what is “normal” for any particular individual. In adults, the normal range of plasma concentration is 3-4.5 mg/dl (expressed in terms of mg of phosphorus). Phosphorus circulates in the plasma primarily as orthophosphate (PO4). At normal blood pH of 7.4, 80% of the phosphate is in the HPO42- form and 20% is in the H2PO4- form. Nearly all of the plasma inorganic phosphate is ultrafilterable. In addition to free orthophosphate, phosphate is present in small amounts in the plasma in organic form, such as in hexose or lipid phosphates.

Front 280

Describe the intake, absorption and excretion amounts of Ca2+.

Back 280

The approximate tissue distribution and average daily flux of calcium between tissues in a normal adult are shown in the next figure. Dietary intakes may vary widely, but an average diet contains approximately 1000 mg/day of calcium. Intakes up to twice that amount are usually well tolerated, but excessive calcium intake can result in soft tissue calcification or kidney stones. Only about one third of ingested calcium is actually absorbed from the GI tract; the remainder is excreted in the feces. The efficiency of calcium uptake from the GI tract varies with the individuals physiological status. The percentage uptake of calcium may be increased in young growing children and pregnant or nursing women, while quite often it is reduced in the elderly.

Front 281

How much Ca2+ actually enters the GI tract from the body?

Back 281

Approximately 150 mg/day of calcium actually enters the GI tract from the body. This component of the calcium flux results in part from sloughing of mucosal cells that line the GI tract and also from calcium that accompanies various secretions into the GI tract. This component of calcium metabolism is relatively constant, so the primary determinant of net calcium uptake from the GI tract is calcium absorption. Intestinal absorption is an important site of regulation of calcium homeostasis.

Front 282

How much Ca2+ is in bone?

Back 282

Bone in an average individual contains approximately 1000 g of calcium. Bone mineral is constantly resorbed and deposited in a process called remodeling. As much as 500 mg/day of calcium may flow in and out of bone (see figure). Since bone serves as an important reservoir in determining plasma calcium concentration, both bone resorption and bone formation are important sites of regulation.

Front 283

Describe the net uptake of Ca2+ in overall Ca2+ balance.

Back 283

In overall calcium balance, the net uptake of calcium from the GI tract presents a daily load of calcium that will eventually require elimination. The primary route of elimination is via the urine, thus the kidneys play an important role in regulation of calcium homeostasis. The 150 mg/day of calcium excreted in the urine represents only about 1.5% of the calcium initially filtered by the kidneys; the remaining 98.5% is reabsorbed and returned to the blood. Therefore, small changes in the amount of calcium reabsorbed by the kidneys can have a dramatic impact on calcium homeostasis.

Front 284

Describe phosphate handling by the GI tract, kidneys and bone.

Back 284

The next figure shows the overall daily flux of phosphate in the body. A typical adult ingests approximately 1400 mg/day of phosphorous. In marked contrast to calcium, most (1300 mg/day) of this phosphorus is absorbed from the GI tract, typically as inorganic phosphate. There is an obligatory secretion of phosphate into the GI tract (approximately 200 mg/day), much like that for calcium, resulting in a net uptake of phosphorus of 1100mg/day and excretion of 300 mg/day via the feces. Note that less phosphorous exchanges with bone per day than calcium because bone mineral contains more calcium than phosphate. Because the majority of ingested phosphate is absorbed by the GI tract, phosphate homeostasis is greatly influenced by excretory mechanisms. Since the majority of circulating phosphate is readily filtered in the kidneys, phosphate reabsorption in the kidney is a primary site of regulation of phosphate homeostasis.

Front 285

Describe Ca2+ absorption.

Back 285

Calcium absorption in the small intestine occurs by both active transport and diffusion. The relative contribution of each process varies with the region and total calcium intake. Uptake of calcium by active transport predominates in the duodenum and jejunum, in the ileum, simple diffusion predominates. Transport across cells involves calcium channels (TRPV6) at the apical membrane, calcium binding proteins within the cell and two transporters (i.e., CaATPase and 3Na/Ca) at the basolateral membrane. The relative importance of active transport in the duodenum and jejunum versus passive diffusion in the ileum depends on a number of factors. At very high levels of calcium intake, active transport processes are saturated and most of the uptake occurs in the ileum, in part because of its greater length as compared to other intestinal segments. With moderate or low calcium intake, however, active transport predominates because the gradient for diffusion is low.

Front 286

What is the regulated variable in control of Ca2+ uptake?

Back 286

Active transport is the regulated variable in control of calcium uptake from the small intestine. Metabolites of vitamin D provide a regulatory signal to increase intestinal calcium absorption.

Front 287

Describe phosphate absorption.

Back 287

The small intestine is also a primary site for phosphate absorption. Uptake occurs by both active transport and passive diffusion, but secondary active transport is the primary mechanism. This involves movement of phosphate into epithelial cells via a Na/Pi symporter along with transport via another carrier at the basolateral membrane. Phosphate is efficiently absorbed from the intestine but is not highly regulated. To a minor extent, active transport of phosphate is coupled to calcium transport. Therefore, when active transport of Ca2+ is low, as with vitamin D deficiency, phosphate absorption is also low.

Front 288

What is the composition of Ca2+ in the body that is filterable?

Back 288

Filterable calcium comprises about 60% of the total calcium in the plasma and consists of calcium ion and calcium bound to a filterable anion such as bicarbonate or citrate. The remaining 40% of the total calcium circulates bound to proteins and thus is not filterable. The majority of calcium is reabsorbed in the proximal tubule. Ordinarily, only about 1.5% of filtered calcium is eventually excreted in the urine, with the remaining 98.5% reabsorbed and returned to the plasma.

Front 289

Describe where in the kidneys Ca2+ is absorbed.

Back 289

Approximately 70% of filtered calcium is reabsorbed in the proximal tubule, 20% from the loop of Henle and 9% from the distal tubule, the remaining 1% is excreted in the urine. Calcium excretion is regulated by the kidney primarily at the distal tubule. Calcium reabsorption by the proximal tubule occurs by two pathways: transcellular and paracellular (see figure). Transcellular calcium reabsorption accounts for 20% of proximal reabsorption.

Front 290

Describe the mechanism of Ca2+ reabsorption.

Back 290

Calcium reabsorption through the cell is an active, two step process. Calcium enters the apical membrane into the cell down its electrochemical gradient via a calcium channel (TRPV5). This gradient is exceptionally steep because the ionized calcium concentration in the cell is around 0.1 M while that of tubular fluid is about 6 mg/dl (1.5 mM). The cell interior is electrically negative with respect to the luminal side of the apical membrane and this also favors calcium entry into the cell. Calcium is extruded across the basolateral membrane against its electrochemical gradient via Ca ATPase and a 3Na/1 Ca antiporter. 80% of calcium is reabsorbed between cells across the tight junctions (i.e., paracellular pathway.)

Front 291

Describe Ca2+ reabsorption by Henle’s loop.

Back 291

Calcium reabsorption by Henle’s loop is restricted to the thick ascending limb and is similar to the proximal tubule except that less goes via a transcellular route (recall this region has lower water permeability). Calcium reabsorption by the distal tubule is exclusively transcellular, and the mechanism is similar to that in the proximal tubule.

Front 292

Describe the interaction between Ca2+ and PTH.

Back 292

Calcium and PTH: Parathyroid hormone (PTH) exerts powerful control on renal calcium excretion and is a key factor in maintaining calcium homeostasis. PTH dramatically stimulates calcium reabsorption by the thick ascending limb of Henle and the distal tubule thus promoting calcium retention and lowering urinary calcium.

Front 293

What can disturb Ca2+ excretion?

Back 293

Several factors can disturb calcium excretion. For example, an increase in plasma phosphate elevates PTH levels and thereby decreases calcium excretion. In contrast, a decline in plasma phosphate has the opposite effect.

Front 294

Describe renal handling of phosphate.

Back 294

The majority of ingested phosphate is absorbed from the GI tract and the primary route of excretion of this phophate is via the urine. Kidneys therefore play a key role in regulating body phosphate homeostasis. Ordinarily about 90% of filtered phosphate is reabsorbed and 10% is excreted in the urine. Phosphate reabsorption occurs via secondary active transport process at two sites along the nephron; the proximal tubule and the distal tubule. The majority (80%) of phosphate reabsorption occurs in the proximal tubule and 10% is reabsorbed in the distal tubule. Parathyroid hormone inhibits phosphate reabsorption in the proximal tubule by increasing cAMP levels and thus has a major regulatory effect on phosphate homeostasis. As a result of its actions, parathyroid hormone increases urinary phosphate excretion (phosphaturia) with an accompanying decrease in plasma phosphate concentration.

Front 295

Describe the mechanism of phosphate reabsorption.

Back 295

Phosphate reabsorption by the proximal tubule occurs mainly, if not exclusively, by a transcellular route. Phosphate uptake cross the apical membrane occurs by a 2Na/Pi symport mechanism. Phosphate exits across the basolateral membrane, most likely by a Pi-anion antiporter. The cellular mechanism of phosphate reabsorption by the distal tubule has not been characterized. The major reason why phosphate is excreted is that the levels in the tubular lumen exceed the transport maximum for reabsorption.

Front 296

Describe the inorganic composition of bone.

Back 296

Mature bone can be simply described as inorganic mineral deposited on an organic framework. The mineral portion of bone is composed largely of calcium phosphate in the form of hydroxyapatite crystals (Ca10(PO4)6(OH)2). The mineral portion of bone typically comprises about 25% of its volume and roughly half the weight of bone. Bone also contains considerable amounts of carbonate, magnesium, and sodium in addition to calcium and phosphate.

Front 297

Describe the organic composition of bone.

Back 297

The organic matrix of bone on which the bone mineral is deposited is called osteoid. Type I collagen is the primary constituent of osteoid.. Electron microscopic study of bone reveals needle like hydroxyapatite crystals lying alongside collagen fibers.

Front 298

What is the importance of the interaction of the organic and inorganic composition of bone?

Back 298

This orderly association of hydroxyapatite crystals with the collagen fibers is responsible for the strength and hardness characteristic of bone. Loss of either bone mineral or organic matrix greatly affects the 85 mechanical properties of bone. Complete demineralization of bone leaves a flexible collagen framework, and complete removal of organic matrix leaves a bone with its original shape, but extremely brittle.

Front 299

What are the two basic forms of bone?

Back 299

Cortical (compact) bone is the outer layer of all bones and is generally about 80% of the total bone mass. It is composed of bone mineral and osteoid interrupted by blood vessels and a sparse population of osteocytes nested within the bone. These osteocytes are interconnected with one another and with the osteoblasts on the surface of the bone by canaliculi, through which the osteocytes extend cellular processes. These connections permit the transfer of calcium from the interior of the bone to the surface. Medullary (spongy) bone is composed of thin spicules of bone that extend from the cortex into the medullary cavity. The lacework of bone spicules is lined in many areas by osteoblasts and osteoclasts, the cells involved in bone remodeling. Trabecular bone is constantly being synthesized and resorbed by these cellular elements. Similar bone turnover occurs in cortical bone, but the rate is much lower.

Front 300

What are the three principal cells types involved in bone formation and resorption?

Back 300

The three principal cell types involved in bone formation and resorption are osteoblasts, osteocytes and osteoclasts (see figure).

Front 301

Describe osteoblasts.

Back 301

Osteoblasts are located on the bone surface and are responsible for osteoid synthesis. Numerous cytoplasmic processes connect adjacent osteoblasts on the bone surface and connect osteoblasts with osteocytes deeper in the bone. Osteoid produced by osteoblasts is secreted into the space adjacent to the bone. Eventually, new osteoid becomes mineralized, and in the process osteoblasts are surrounded by mineralized bone.

Front 302

Describe osteocytes.

Back 302

As osteoblasts are progressively engulfed by mineralized bone, they lose much of their bone forming ability and become quiescent. At this point they are called osteocytes. Many of the cytoplasmic connections in the osteoblast stage are maintained into the osteocyte stage. These connections become visible channels, or canaliculi, that provide direct contact for osteocytes deep in bone with other osteocytes and with the bone surface. It is generally believed that these canaliculi provide a mechanism for transfer of nutrients, hormones and waste products between the bone surface and its interior. Osteoblasts arise from primitive cells called osteoprogenitor cells, within the connective tissue of the mesenchyme. A variety of proteins in the bone, known as skeletal growth factors, attract osteoprogenitor cells, direct their differentiation into osteoblasts, and stimulate their growth.

Front 303

Describe osteoclasts.

Back 303

Osteoclasts are cells responsible for bone resorption. They are large, multinucleated cells located on bone surfaces. Osteoclasts promote bone resorption by secreting acid and proteolytic enzymes into the space adjacent to the bone surface. Surfaces of osteoclasts facing bone are ruffled to increase their surface area and promote bone resorption. Bone resorption is a two step event. First, osteoclasts create a local acidic environment that increases solubility of surface bone mineral. Second, proteolytic enzymes secreted by osteoclasts degrade organic matrix of the bone.

Front 304

What role does Ca2+ and phosphate flux have in bone formation and remodeling?

Back 304

The flux of calcium and phosphate into and out of bone each day reflects a turnover of bone mineral and changes in bone structure generally referred to as remodeling. Bone remodeling occurs along most of the outer surface of the bone, making it either thinner or thicker, as required. In long bones, remodeling can also occur along the inner surface of the bone shaft, next to the marrow cavity. Remodeling is a beneficial adaptive process that allows bone to be reshaped to meet changing mechanical demands placed on the skeleton and to store or mobilize calcium rapidly.

Front 305

Describe the differences between formation and resorption during different time periods in life.

Back 305

During the growth years formation exceeds resorption, and skeletal mass increases. A peak in bone mass is reached between ages 20 and 30 years. Thereafter equal rates of formation and resorption stabilize the bone mass until age 35 to 40 years, at which time resorption begins to exceed formation, and the total mass slowly decreases.

Front 306

Describe the mechanism of bone remodeling.

Back 306

Bone remodeling begins with endocrine signals to resting osteoblasts (e.g., PTH and calcitriol). These cells then generate local paracrine signals to nearby osteoclasts and osteoclast precursors. The osteoclasts resorb an area of mineralized bone, and local macrophages complete the cleanup of dissolved elements. The process then reverses to formation as osteoblast precursors are recruited to the site and differentiate into active osteoblasts. These lay down new organic matrix and mineralize it. Thus new bone replaces the previously resorbed mature bone. Various paracrine signals released from osteoblasts include macrophage colony stimulating factor (M-CSF), a TNF cytokine family member (RANK ligand) which stimulates osteoclast formation and bone resoprtion, and osteoprotegerin which is a “decoy receptor” which prevents RANK ligand binding to osteoclasts and their precursors. Recent ongoing studies suggest that the balance between the amounts of RANK ligand and osteoprotegerin produced by osteoblasts are important factors in the pathology of both osteoporosis and osteopetrosis.

Front 307

Describe osteoporosis.

Back 307

is a state of reduced bone mass per unit volume with a normal ratio of mineral to matrix. It is a disease characterized by bone fragility and an increased susceptibility to fractures of the hip, spine, and wrist. Drugs given to treat osteoporosis include bisphosphonates and calcitonin which inhibit osteoclast function. Estrogen also decreases the formation and activity of osteoclasts probably through changes in signals generated by osteoblasts. In postmenopausal women osteoporosis is sometimes treated with estrogen receptor modulators.

Front 308

Describe osteopetrosis.

Back 308

is a rare congenital disorder (present at birth) in which the bones become overly dense.

Front 309

Describe osteomalacia.

Back 309

is a skeletal disorder associated with demineralization. In children this disease is called rickets and it is usually due to lack of vitamin D. The etiology of rickets includes hypocalcemia and skeletal abnormalities.

Front 310

Describe the regulation of plasma Ca2+ and phosphate concentrations.

Back 310

Regulatory mechanisms for calcium include rapid non-hormonal mechanisms with limited capacity and somewhat slower hormonally regulated mechanisms with much greater capacity.

Front 311

Describe protein bound Ca2+.

Back 311

The association of calcium with proteins is a simple reversible, chemical equilibrium process. Protein-bound calcium therefore has the capacity to serve as a buffer of free plasma calcium concentrations. This effect is rapid and does not require complex signaling pathways but its capacity is quite limited and it cannot serve a long term role in calcium homeostasis.

Front 312

Describe the readily exchangeable pool of Ca2+ in bone.

Back 312

Recall that approximately 99% of total body calcium is present in bone, and there is roughly 1-2 kg of calcium in a normal adult. The majority of the calcium in bone exists as mature hardened bone mineral that is not readily exchangeable but can be moved into the plasma via hormonal mechanisms. However, approximately 1% (or 10 g) of the calcium in bone is in a simple chemical equilibrium with plasma calcium. This readily exchangeable source of calcium is primarily located on the surface of newly formed bone. Any change in free calcium in the plasma or extracellular fluid therefore, results in a shift of calcium either into or out of bone mineral until a new equilibrium is reached. Although this mechanism, like that described above, provides for a rapid defense against changes in free calcium concentrations, it too, is limited in its capacity and thus can only provide for very short term fine tuning of calcium homeostasis.

Front 313

Describe the hormonal mechanisms provide high-capacity, long term regulation of plasma Ca2+ and phosphate.

Back 313

Hormonal mechanisms have a large capacity and the ability to make long term adjustments in calcium and phosphate fluxes, but they do not respond instantaneously. It may take several minutes or hours for the response to occur and adjustments to be made. However, these are the principal mechanisms by which plasma calcium and phosphate concentrations are regulated.

Front 314

Describe PTH chemistry and its role in regulating Ca2+.

Back 314

One of the primary regulators of plasma calcium concentrations is parathyroid hormone (PTH). PTH is an 84-amino acid peptide produced by the parathyroid glands. Synthetic peptides containing the first 34 amino terminal residues appear to be as active as the native hormone. There are two pairs of parathyroid glands, located on the dorsal surface of the left and right lobes of the thyroid gland. Because of this close proximity, damage to the parathyroid glands themselves or to their blood supply may occur during surgical removal of the thyroid gland.

Front 315

What is the stimulus for PTH secretion?

Back 315

The primary physiologic stimulus for PTH secretion is a decrease in plasma calcium. The relationship between PTH secretion and total plasma calcium is shown in the graph. It is actually a decrease in the ionized calcium concentration that triggers an increase in PTH secretion. Note in this figure that as calcium concentration decreases from a normal value of 10mg/dl to approximately 8.5-9 mg/dl, there is a significant increase in PTH secretion. The net effect of PTH is to increase the flow of calcium into plasma, and thus return concentrations toward normal.

Front 316

Describe calcitonin chemistry and its role in regulating Ca2+.

Back 316

(CT) is a 32 amino acid peptide produced by parafollicular cells of the thyroid gland. In contrast to PTH, CT secretion is stimulated by an increase in plasma calcium. Hormones of the GI tract, especially gastrin, also promote CT secretion. In bone, CT opposes the action of PTH on osteoclasts by inhibiting their activity. This leads to decreased bone resorption and an overall net transfer of calcium from plasma into bone. CT plays only a minor role in the ongoing regulation of calcium homeostasis. However, nasal application of CT has proved beneficial to individuals with osteoporosis. The CT which is used clinically is actually salmon CT since this peptide has a potency about 100 fold higher than human CT.

Front 317

Describe calcitriol chemistry and its role in regulating Ca2+.

Back 317

The third key hormone involved in regulating plasma calcium is vitamin D3 (cholecalciferol). More precisely, a metabolite of vitamin D3 (i.e., 1,25-dihydroxycholecalciferol or calcitriol) serves as a hormone in calcium homeostasis. Vitamin D3 can be provided by the diet or formed in the skin by the action of ultraviolet light on 7-dehydrocholesterol. In many countries where food is not supplemented with vitamin D, this pathway provides the major source of vitamin D. Typically exposure to moderately bright sunlight for 30-120 min/day provides enough vitamin D to supply the body’s needs without any dietary supplementation.

Front 318

Describe vitamin D3.

Back 318

Vitamins D3 is relatively inactive. However, it undergoes a series of transformation in the liver and kidneys that converts it into a powerful calcium-regulatory hormone. The first step occurs in the liver and involves addition of a hydroxyl group to carbon 25, to form 25-hydroxycholecalciferol. This reaction is largely unregulated, although certain drugs and liver diseases may affect this step. 25-hydroxycholecalciferol is released into the blood, and in the kidney it undergoes a second hydroxylation reaction. The product is 1,25-dihydroxycholecalciferol (calcitriol), the principal hormonally active form of the vitamin. The biologic activity of calcitriol is approximately 1000 times greater than that of 25-hydroxycholecalciferol. The formation of calcitriol in the kidneys is catalyzed by the enzyme 1-hydroxylase, located in proximal tubule cells.

Front 319

Describe the mechanism of action of calcitriol.

Back 319

The net effect of calcitriol (1,25-dihydroxycholecalciferol) is to increase both calcium and phosphate concentrations in plasma. Calcitriol primarily influences the GI tract, although it has actions in bone and kidney as well. In the kidneys, calcitriol increases tubular reabsorption of calcium and phosphate, promoting retention of both ions in the body. However, this is a weak and probably only minor effect of the hormone. In bone, calcitriol enhances the actions of PTH on osteoclasts, thereby increasing bone resorption. In the GI tract, calcitriol stimulates calcium and phosphate absorption by the small intestine, increasing plasma concentrations of both. This effect is mediated by increased production of calcium transport proteins in the intestinal epithelia (see earlier diagram).

Front 320

Describe the control of the activity of 1-alpha-hydroxylase.

Back 320

The activity of 1-hydroxylase is tightly controlled. First, it is enhanced by PTH. Thus, if plasma calcium levels fall, PTH secretion increases and this promotes formation of calcitriol. In contrast, 1-hydroxylase activity is inhibited by an increase in plasma phosphate concentration. This does not appear to involve any intermediate hormonal signals but apparently involves direct effects upon either the enzyme or cells in which the enzyme is located. Finally, the product calcitriol can feed back to inhibit further synthesis.

Front 321

Describe the mechanism of action of PTH.

Back 321

is essential for life. Complete absence of PTH causes death from hypocalcemic tetany within just a few days, but this can be avoided with hormone replacement therapy. The net effects of PTH on plasma calcium and phosphate and its sites of action are shown in the next figure. PTH causes an increase in plasma calcium concentration while decreasing plasma phosphate. This decrease in phosphate concentration is important with regard to calcium homeostasis. At normal plasma concentrations calcium and phosphate are at or near chemical saturation levels. If PTH were to increase both calcium and phosphate levels, they would simply crystalize in bone or soft tissues as calcium phosphate, and the necessary increase in plasma calcium concentration would not occur. Thus, the effect of PTH to lower plasma phosphate is an important aspect of its role in regulating plasma calcium.

Front 322

What actions does PTH have in the kidneys?

Back 322

PTH has several important actions in the kidneys. It stimulates calcium reabsorption in the thick ascending limb and distal tubule, thereby decreasing calcium loss in the urine and increasing plasma concentrations. It also inhibits phosphate reabsorption in the proximal tubule, leading to increased urinary phosphate excretion and a decrease in plasma phosphate. In bone, PTH has 2 actions, i.e., a fast phase called osteolysis which involves stimulation of osteoclasts to transport calcium from the interior of the bone to the blood stream and a slower phase leading to activation of osteoblasts. Both of these actions increase bone resorption and thus the delivery of calcium from bone into plasma. In addition to stimulating existing osteoclasts, PTH stimulates maturation of preosteoclasts into active osteoclasts. The actions of PTH to promote bone resorption are augmented by calcitriol. PTH does not appear to have any major direct effects on the GI tract. However, because it increases calcitriol formation, it ultimately increases absorption of both calcium and phosphate from the GI tract.

Front 323

What role does PTH have in osteoporosis?

Back 323

Interestingly , although PTH enhances bone resorption, in fact administration of PTH has sometimes proved beneficial in patients with osteoporosis since it also stimulates bone remodeling which involves both bone resorption and bone formation. In this way new bone replaces old and the tendency to fracture is reduced.

Front 324

What stimulates bone formation?

Back 324

PTH, calcitrol, insulin, androgens, GH, growth factors

Front 325

What inhibits bone formation?

Back 325

corticosteroids

Front 326

What stimulates bone resorption?

Back 326

PTH, calcitriol, thyroid hormone, corticosteroids, prostaglandins, growth factors

Front 327

What inhibits bone resorption?

Back 327

calcitonin, estrogens

Front 328

Describe primary hyperparathyroidism.

Back 328

Is excessive PTH secreted by a parathyroid adenoma that is no longer under the negative feedback control of calcium. The excess of PTH leads to alterations in functions of bone cells and renal tubules. Thus, it may result in kidney stones and calcium deposition in kidney tubules; osteoporosis and osteomalacia, and hypercalcemia leading to muscular weakness. It is more prevalent in women than men because pregnancy stimulates hypertrophy of the parathyroid glands due to the increased need for calcium mobilization.

Front 329

Describe hypoparathyroidism.

Back 329

These are condition of reduced PTH and defective PTH action, respectively. Hypoparathyroidism can be idiopathic , but most commonly it is of the postsurgical type in which the parathyroids were removed surgically along with a diseased thyroid gland. Effective treatment is calcitriol administration to raise blood calcium levels by promoting intestinal calcium absorption.

Front 330

Describe pseudohypoparathyroidism.

Back 330

These are condition of reduced PTH and defective PTH action, respectively. Pseudohypoparathyroidism is a hereditary disorder and it is characterized by failure to respond to PTH. This results in individuals with short stature, short metacarpals and ectopic calcification.

Front 331

What disorders are classified as hypocalcemia?

Back 331

hypoparathyroidism, pseudohypoparathyroidism, osteomalacia/rickets, chronic renal failure

Front 332

What disorders are classified as hypercalcemia?

Back 332

vitamine D intoxication, primary hyperparathyroidism

Front 333

What is the differential diagnosis of hypoparathyroidism?

Back 333

DEC Ca2+, INC phosphate, DEC PTH, no change in alk. phosphate

Front 334

What is the differential diagnosis of pseudohypoparathyroidism?

Back 334

DEC Ca2+, INC phosphate, INC PTH, no change in alk. phosphate

Front 335

What is the differential diagnosis of osteomalacia/rickets?

Back 335

DEC Ca2+, DEC phosphate, INC PTH, INC alk. phosphate

Front 336

What is the differential diagnosis of chronic renal failure?

Back 336

DEC Ca2+, INC phosphate, INC PTH, INC alk. phosphate

Front 337

What is the differential diagnosis of vitamin D intoxication?

Back 337

INC Ca2+, INC phosphate, DEC PTH, INC INC INC 24 hr. urine Ca2+

Front 338

What is the differential diagnosis of primary hyperparathyroidism?

Back 338

INC Ca2+, DEC phosphate, INC PTH, INC 24 hr. urine Ca2+

Front 339

Give some general info for the hypocalcemia disorders.

Back 339

-In the kidneys, PTH stimulates calcium and inhibits phosphate resorption. PTH also enhances calcitriol formation by stimulating 1-hydroxylase. Hypoparathyroidism therefore leads to hypocalcemia and hyperphosphatemia. Hyperphophatemia per se can also lead to reduced plasma calcium levels. In part this is due to increased “ectopic calcification” as calcium phosphate precipitates out of solution. Recall as well that elevated phosphate levels inhibit 1-hydroxylase activity leading to reduced cacitriol formation in the kidneys. Pseudohypoparathyroidism leads to the same pathology as hypoparathyroidism but in this case it is due to lack of response to PTH.
-Osteomalacia is typically due to lack of calcitriol. This reduces calcium uptake by the intestine. PTH increases due to the resulting hypocalcemia. High PTH inhibits phosphate reabsorption by the kidneys.
-Patients with chronic renal failure have increased serum phosphate levels because of declining renal excretory function. Plasma calcium levels decrease, partly because of the increased phosphate serum concentration, and partly because of decreased synthesis of calcitriol by the kidneys (kidney function is declining). PTH levels increase because of the hypocalcemia leading to bone decalcification (osteomalacia).

Front 340

Give some general info for the hypercalcemia disorders.

Back 340

-Vitamin D intoxication increases calcium (and to some extent phosphate) absorption by the intestine. The hypercalcemia reduces PTH formation. Since PTH inhibits phosphate reabsorption by the kidneys lowering PTH will increase plasma phosphate concentration. The filtered load of calcium in the kidneys is increased due to the hypercalcemia and reabsorption is reduced due to reduced PTH. These effects greatly increase urine calcium levels.
-The cause of hypercalcemia in the vast majority of cases is hyperparathyroidism. Most commonly, hyperparathyroidism is due to a tumor in the parathyroid gland which enhances the synthesis of PTH. High PTH levels increase calcium absorption from the intestine (via calcitriol), from the kidney and from bone leading to hypercalcemia. Urine calcium is high due to the hypercalcemia even though reabsorption is enhanced. Urine calcium goes up more with vitamin D intoxication than with hyperparathyroidism because PTH is reduced in the former. The high PTH levels of hyperparathyroidism reduce phosphate reabsorption by the kidneys leading to hypophosphatemia. With time osteoporosis and osteomalacia develop because of enhanced bone resorption. “Brown tumors” can develop which consist of collections of osteocytes intermixed with poorly mineralized bone.

Front 341

What structures are available for the internal temperature control of the body?

Back 341

1. CNS “thermostat”-hypothalamus
2. cold receptors
3. heat receptors
4. heat loss/conversation mechanisms
5. thermal neutral zone (TNZ)

Front 342

What regulatory events in the anterior hypothalamus help regulate temperature?

Back 342

1. heat dissipation events
2. over-warmed blood and peripheral sensation impulses

Front 343

What regulatory events in the posterior hypothalamus help regulate temperature

Back 343

1. heat conservation events
2. over-cooled blood and peripheral sensation impulses

Front 344

Describe the relationship between environmental temperature zones and heat production (HP).

Back 344

in the thermoneutral zone (from cool -> optimum -> wam) there is a minimal amount of HP and is called the basal metabolic rate (to have muscle tone, CV tone), as the environmental temperature INC pass UCT (heat stress, ~91.45) or DEC pass LCT (cold stress, ~95.5), HP INC linearly, if temperature rises or drops enough can lead to death, death from heat can result more quicker than that for cold stress

Front 345

What heat loss mechanisms (that occurs during hypothermia) are available to maintain homeothermy?

Back 345

1. non-evaporative cooling-radiation, convection and conduction
2. evaporating cooling-respiration, skin

Front 346

What influences heat loss mechanisms that maintain homeothermy?

Back 346

1. body surface area (surface:mass ratio, for a child it is large and will go into hypothermia quickly to protect the brain, low for adults, takes long time for them to go into hypothermia)
2. body coverings (clothes, animals w/ fur)
3. water exchange
4. blood flow
5. environment (temperature (cold INC heat loss), wind (wind chill factor, changes microclimate around the body and changes heat, humidity (more difficulty losing heat))

Front 347

What heat gain mechanisms (that occurs during hyperthermia) are available to maintain homeothermy?

Back 347

the sources of heat gain include
1. food (fatty foods-high metabolic production of heat)
2. body reserves (fat for heat conservation)
3. rumen or cecum fermentation
4. environment (opportunity to stand in shade or sun when hot or cold)

Front 348

What influences heat gain mechanisms that maintain homeothermy?

Back 348

calorigenic hormones, production (milk, meat, wool), muscular activity, maintenance

Front 349

Describe the partitioning of avenues of heat loss from man at 75F.

Back 349

1. radiation-67%
2. evaporation-23%
3. conduction to air (convection)-10%, if a calm environment have less loss via conduction

Front 350

What factors INC heat production (over basal metabolic rate)?

Back 350

1. exercise or shivering
2. imperceptible tensing of muscles
3. chemical INC of metabolic rate
4. specific dynamic action of food
5. disease (fever)

Front 351

What factors DEC heat loss?

Back 351

1. shif in blood distribution
2. DEC in tissue conductance
3. counter-current heat exchange

Front 352

What factors enhance heat loss?

Back 352

1. sweating
2. panting
3. cooler environment
4. INC skin circulation (vasodilation)
5. DEC clothing or shorter fur insulation
6. INC insensible water loss
7. INC radiating surface
8. INC air movement (convection)

Front 353

Describe counter-current heat exchange.

Back 353

the key is that major arteries and veins flow next to each other, in order to conserve heat blood is shunted in a maximum amount from the periphery to the central part, in cold, heat can be directed by diffusion from artery to vein so vein can take it back to the center, in heat, heat can be directed by diffusion from vein to artery, takes heat from core to periphery, current is artery to periphery, counter-current is vein to core

Front 354

What is the highest fever that a human can have and still survive?

Back 354

107-108 then start having CNS seizures, can go there under controlled medical conditions

Front 355

What are the signs and symptoms of hyperthermia?

Back 355

dizziness, abdominal distress (sometimes with vomiting), sometimes delirium, sometime seizures, loss of consciousness, INC core body temperature

Front 356

What are some hyperthermia temperatures and what activities are associated with them?

Back 356

102°F-105°F = febrile disease & hard exercise
104°F- 107°F = therapy
106°F-111°F = heat stroke and brain lesions
>111°F-113°F = death likely
>113°F = death almost a certainty

Front 357

Describe fever.

Back 357

Elevated core body temperature caused primarily by leukocyte endogenous pyrogens or bacterial endotoxins. pyrogenic factors released when leukocytes are lysed or killing endotoxins

Front 358

Describe environmental hyperthermia.

Back 358

Elevated core body temperature caused by an inability to loose excess body heat in high ambient environments

Front 359

Describe malignant hyperthermia.

Back 359

A rapidly progressive reaction to certain muscle relaxant and gaseous anesthetic agents in certain people (inherited autosomal dominant trait), seen in about 1:20,000 surgical cases, may be rapidly fatal. Can be reverse with a certain druge that must be quickly administered, caused by certain anesthetics or muscles relaxants like succinyl-choline

Front 360

How is core temperature measured?

Back 360

esophageal temperature can get to level of the heart, gives the core temperature

Front 361

Describe the relationship between age and temperature.

Back 361

there is no statistical difference in skin temperature between young and old, in core temperature there is a difference between old and young (old has a higher core temp), due mostly to counter-current heat exchange (old people have a lower ability to transfer heat via this mechanism are not shifting same amount of blood, may be due to compliance of vascular system), there is a significant difference between elderly and young in forearm vascular conductance

Front 362

What happens with metabolism with INC in age?

Back 362

high metabolism of childhood DEC with age

Front 363

Describe the effect of humidity on temperature.

Back 363

lower humidity makes the temperature feel colder because evaporating more, the degrees given on the chart are not actual temperatures but equivalent temperatures of what the person feels like they are being exposed to

Front 364

What are the signs and symptoms of hypothermia?

Back 364

DEC alertness and consciousness, shivering may or may not be present depending upon the severity of the hypothermia, reduced core body temperature, severe hypothermia may mimic death, therefore no hypothermic patient should be pronounced dead until they are warm and dead

Front 365

What are some hypothermia temperatures and what activities are associated with them?

Back 365

 98.6°F-95°F = maximum shivering occurs
 »94°F = memory impairment
 »92°F = brain recall <30%
 » 92°F = paradoxical undressing (abrupt vasodilation)
 » 90°F = muscle rigidity
 80°F-85°F = loss of consciousness
 <80°F = cardiac arrest and death

Front 366

What happens during frostbite?

Back 366

tissues freeze, the body will do whatever is necessary to conserve the core, will sacrifice limbs, noses to keep the core at a good temperature, when tissues freeze the first thing that happens is that ice crystals are formed in the cells that is bigger in volume than the water in the cell, if have frozen tissue want to thaw it fast (if thaw it slow then ice crystals get bigger and burst leading to even more cell damage)

Front 367

What affect does wind chill have on temperature?

Back 367

as wind chill DEC (DEC in temperature of wind chill) the equivalent temperature felt DEC

Front 368

What effect does depth of submersion and duration of submersion have on decompression?

Back 368

as depth of submersion INC and duration of submersion INC, the INC chance that decompression is required, divers must choose between going deep for 25 mins or remaining near the surface for a much longer period, at 100 ft. have about 30 mins before having to decompress

Front 369

Describe what happens during compression (which occurs under hyperbaric conditions).

Back 369

compression causes N to dissolve in blood, so when pressure is released the dissolved N will come out of solution and causes bubbling, bubbling is bad b/c it can cause embolisms which can cause strokes, heart attacks and serious pulmonary disease

Front 370

What is barotrauma?

Back 370

Decompression illness, characterized by hemoptysis and, frequently, stroke; resulting from pulmonary hyper-inflation leading to alveoli and pulmonary tissue rupture and, frequently, cerebral arterial gas embolism. (physical trauma, come up to lower pressure to quickly)

Front 371

What is bends?

Back 371

Decompression illness, characterized by severe joint pain and other signs of generalized embolitic problems, resulting gas bubble embolism in arterioles and capillaries. (where N bubbles are coming out) (treatment? Put them back in pressure

Front 372

What is Caisson’s disease?

Back 372

For purposes of this course, this is a particular type of decompression illness, characterized by aseptic necrosis of bone, probably resulting from repeated microembolism of bone arterioles.

Front 373

What is nitrogen narcosis?

Back 373

Stupor and mental confusion in divers breathing compressed air caused by the amount of nitrogen dissolved in the blood as a result of the depth and duration of the dive., NO is an anesthetic, if enough N in blood then get similar results, reports that some divers enter a euphoria, experts say only do non-decompression dives, always dive with a partner

Front 374

Describe the relative narcotic potency of gases in deep sea diving relative to N.

Back 374

1. N-1.00
2. He-0.18
3. Ne-0.32
4. H-0.41
5. Ar-1.46
6. Krypton-8.9
7. Xenon-31.8
8. NO-28.3

Front 375

For hyperbaric environments, describe the relationship between atmosphere change and sea water depth.

Back 375

for every 33 feet deeper in sea water get 1 atm atmospheres absolute change

Front 376

Describe the basic concept of the heart-brain circulation.

Back 376

develops by selective ischemia in response to the diving reflex, in normal circulation, venous blood enters heart which sends blood to the lungs for oxygentation, blood then reenters heart and distributes blood to all other tissues, under hyperbaric conditions, the diving reflex takes affect and blood from the heart goes only to the brain and does not reach other tissues

Front 377

What effect does emmersion have on EKG?

Back 377

emmersion results in bradycardia, blood flow into calf is clearly much reduced during dive, some 12 seconds before and after emmersion there is a lot more blood flow to the calf

Front 378

What are the signs and symptoms of acute mountain sickness (AMS)?

Back 378

hypobaric disease, Headache, lightheaded, muscular weakness, anorexia, drowsiness, nausea, vomiting, decreased urine output, difficulty sleeping, memory deficits, skin pallor, and cyanosis of lips and nail beds. Symptoms most severe in 2nd or 3rd day. #1 problem with reduction of O2 (hypobaria)

Front 379

what is the treatment for AMS?

Back 379

With mild symptoms, rest, light diet, increased fluid intake, headache remedy. With severe symptoms, descent to lower altitude and/or oxygen therapy.

Front 380

What are the signs and symptoms of high altitude pulmonary edema (HAPE)?

Back 380

Any of those seen with AMS; dyspnea; persistant, non-productive cough; severe fatigue; hemoptysis in 20% of cases; coma (6-12 hours prior to death); generalized cyanosis; crepitant rales; rhonchi; hypotension; and tachycardia. leakage of capillaries, high altitude has caused the capillaries to fail

Front 381

What is the treatment for HAPE?

Back 381

Bed rest, oxygen administration, descent to lower altitude if possible, diuretics of limited value

Front 382

What are the signs and symptoms of high altitude encephalopathy (HAP)?

Back 382

Any seen with AMS and HAPE; severe occipital headaches; cervical pain; tinnitus; anesthesia/paresthesia of arms and legs; hemiplegia; arthralgia; confusion, stupor; coma; cervical rigidity; abnormal Babinski sign; localized areas of cutaneous anesthesia; and dilation of retinal vessels. real serious, affect on the brain, have all the previous signs and symptoms, but now having those above

Front 383

What is the treatment for HAP?

Back 383

Oxygen administration and descent to lower altitude (portable hypobaric “chamber”)

Front 384

What are the signs and symptoms of chronic mountain sickness?

Back 384

Exceptionally high red cell mass and count, right heart enlargement, and congestive heart failure.

Front 385

What is the treatment for hypobaria?

Back 385

Descent to lower altitude!

Front 386

Describe the relationship between barometric pressure and O2 pressure at high altitude

Back 386

as altitude INC, air and O2 pressure as % of sea level DEC, Reno is about 80%, 5000 ft above there is also an affect on night vision because pigments used in night vision don’t recover quickly

Front 387

What is the metnal effect of hypoxia?

Back 387

a person is put in a pressure chamber and asked to wrist continuously, within 90 seconds start to lose it, make spelling mistakes and duplicate letters, give O2 back at 20% and within 30 seconds he does ok

Front 388

Describe the effects of acute exposure to low atmospheric pressures on alveolar gas concentrations and arterial O2 saturation.

Back 388

at altitude of 0, arterial O2 saturation is 97%, as altitude INC, arterial O2 saturation DEC, at altitude of 30,000 ft arterial O2 saturation goes to 24

Front 389

What is the effect of high altititude on arterial O2 saturation when one is breathing air and when breathing pure O2?

Back 389

when breathing pure O2, takes higher altitude to start seeing a DEC in arterial O2 saturation, but drop in O2 saturation is much more rapid

Front 390

What are various responses to high altitude (14,000 ft) and what does the body to do acclimate to it?

Back 390

1. INC basal rate-basal rate in some subjects returns to normal in 3 days
2. subjects cannot sleep-after 3 days most subjects can sleep
3. all subjects show Cheyne-Stokes respiration during sleep-most subjects cease Cheyne-stokes respiration in sleep, all subjects show INC sensitivity to further INC in altitude
4. resting tidal volume INC conspicuously, the hypoxic drive from chemoreceptors does not change with acclimitizaiton-there is a redistribution of blood, an INC in the chest area, the lung capillary bed is continuously dilated, the functional residual capacity INC
5. uncompensated alkalosis-many subjects achieve normal acid-base equilibrium (time needed varies)
6. O2 delivery to tissues is inadequate-there is an INC in O2 deliverd to tissues, total Hb goes up as much as 90%, the hematocrit rises from a normal of 40-45 to as high as 60-70, Hb goes from 15-22 gm%, blood volumen INC 20-30%, plasma volume stays the same
7. some subjects experience headache and nausea-these symptoms disappear in 3 days

Front 391

What are the responses to 16,000 feet altitude and what is the acclimation to it?

Back 391

fatigue, headache, loss of apetite, sleeplessness (all subjects), systolic and diastolic pressure showed uniform elevation-all returned to normal in 14 days

Front 392

What are the responses to 21,500 feet altitude and what is the acclimation to it?

Back 392

symptoms above returned, plus progressive exertional dyspnea, irritative coughs, impatience, depression and nocturnal muscle cramps, a persistant INC in heart rate, expected even after acclimatization-all improved in 10 days

Front 393

Summarize the changes due to microgravity.

Back 393

1. changes in blood system-DEC immune response, DEC RBC count
2. headward fluid shif-neurovestibular disturbances, INC blood volume in head and trunk (which leads to CV adaptation and INC urine production)
3. DEC weight bearing-muscular decondition and bone demineralization

Front 394

What is the clinical horizon line?

Back 394

line that shows values that humans must stay below to avoid clinical disease from space travel, if stay above this line have clinical disease (such as INC in neurovestibular system, fluids and electrolytes and CV system)

Front 395

Describe the significance of the bone and calcium metabolism line.

Back 395

goes up and won’t come back down, keeps going up and bone anc Ca2+ metabolism will never acclimate to microgravity

Front 396

Describe the significane of radiation effects.

Back 396

still going up too, keeps going up and radiation effects will never acclimate to microgravity

Front 397

What are the components of the vestibular system?

Back 397

visual, inner ear (semicircular canals), proprioceptors in legs

Front 398

What is space adaptation syndrome (SAS, space nausea)?

Back 398

in microgravity, 2 of the systems go nuts, inner ear and proprioception in legs) visual orientation fine, leads to motion sickness

Front 399

What vestibular systems components do fish have?

Back 399

have only vision and semicircular canals, swim in spirals because they are trying to find the gravity vector, swim normally after 3 days because they became visually oriented, ignored the semicircular component, visual input is very powerful

Front 400

What are the results of the SAS experiments?

Back 400

1. no predictors for SAS
2. vestibular disturbance lasts for week or more after landing
3. loss of spatial orientation
4. loss of muscle stamina

Front 401

Describe fluid shift.

Back 401

1. on earth, blood tends to pool in the lower body
2. promptly upon entering weightlessness, fluids shift toward the head, complain about fullness and the head is stuffy, when going into weightlessness, part is overpressurized and blood goes to head
3. after a time, the body adapts to weightlessness, the kidneys reduce the volume of fluid, relieving pressure in the head and chest
4. the body reacts immediately upon reentering Earth’s gravity, fluids are shifted from the head toward the feet

Front 402

Describe the tilt test.

Back 402

heart rate, BP and change in leg volume during a 25-min, 70 degree tilt test protocol, the first and last 5 min being in the horizontal, supine position, pre-flight mean curves are solid lines and the first postflight test values are dashed, heart rate INC, BP stays about the same, leg volume INC as well

Front 403

Describe the lower body pressure test.

Back 403

heart rate and change in leg volume during a 25 min LBNP test protocol, preflight mean curves are dashed and the first postflight test date 3 hour after splashing down are solid lines, heart rate INC, change in leg volume also INC, creates pressure on lower body creating a stress on CV system because it sucks blood into lower body

Front 404

Describe the fluid shift with being bed ridden.

Back 404

lying down shift 11% of the total blood volume away from the legs to the rest of the body, of the volume that shifts, 78% goes to the thorax, 20% to the head and neck, 2% to the abdominal organs

Front 405

Describe CV deconditioning.

Back 405

1. fluid shift
2. DEC heart size
3. reduced exercise capacity
4. orthostatic hypotension (IG)

Front 406

Describe the changes in serum protein, albumin and total Ca2+ levels as a function of flight duration.

Back 406

the mean are the values from nine crewmen for the first 28 days, six crewmen until day 56 and three crewmen until 84 d, changes are shown as percentage change from preflight control levels, serum total Ca2+ INC rapidly and remained INC for the duration of the flight, plasma total protein levels were INC in the first crew during the first month of flight, but remain near control levels for the remaining crews, and plasma albumin levels dropped dramatically during the first few weeks of flight and remained depressed for the remainder of the flight, total serum Ca2+ INC then levels off, total serum protein DEC, then goes back to preflight levels, serum albumin DEC then levels off at a lower level, each takes about 20 days to level off

Front 407

Describe the changes in urine and fecal Ca2+ as a function of flight duration.

Back 407

both urine Ca2+ and fecal Ca2+ INC (fecal Ca2+ DEC initially then INC), during postflight days, takes about 10 days for the fecal and urine Ca2+ levels to go back to normal, we don’t know where the Ca2+ loss in feces will end, by the time reach Mars probably not able to stand up without pathological fractures due to osteoporosis, urine Ca2+ levels off at about 20 days

Front 408

WEhat does weightlessness do for bone and Ca2+ metabolism?

Back 408

have more resorption than formation, if you have too much in the serum it’ll be kicked out in the urine, more Ca2+ is absorbed than secreted from the gut, serum Ca2+ is excreted in urine

Front 409

Describe the relationship between space flight and bed rest.

Back 409

in both there is an effect in cephalad fluid shift and redistribution of bone, there is a DEC in bone formation, Ca2+ balance, and 1,25 (OH)2D, there is an INC in fecal Ca2+, urine Ca2+, in bone resorption (there is an INC/NC), there is an INC in serum Ca+ in space flight, in bed rest there is INC/NC, for PTH there is DEC in space flight and NC in bed rest, for serum osteocalcin there is a DEC for space flight and NC in bed rest, for bone strength there is a DEC in space flight and not done for bed rest

Front 410

Describe the loss of muscle in space.

Back 410

1. static strength reduced by 10 – 40% in calf
2. all other muscle groups had 10-15% atrophy
3. loss of muscle in animals was from 10-30% of wet weight
4. no loss of muscle cells (nuclei) but in mRNA

Front 411

What are the spaceflight induced physiological changes? which are of greatest concern fro long duration missions?

Back 411

CV decondidtioning (*), negative Ca2+ balance (*), space adaptation syndrome, red cell mass reduction (not sure where they go but it really doesn’t cause a problem), immunological changes (*), other mineral changes, hormonal changes, radiation effects (*, high energy cosmic radiation is a large threat due to the magnetic field absence that is normally around the sphere of the earth)

Front 412

What are some characteristics of gap junctions?

Back 412

1. message transmission-directly from cell to cell
2. local
3. specificity depends on anatomic location
4. low resistant, transfer of small molecules from one cell cytosol to the next, diffusion

Front 413

What are some characteristics of synaptic transmission?

Back 413

1. message transmission-across synaptic cleft
2. local
3. specifically depends on anatomic location and receptors
4. how neurons communicate

Front 414

What are some characteristics of paracrine and autocrine transmission?

Back 414

1. message transmission-by diffusion in interstitial fluid
2. locally diffuse
3. specifically depends on receptors
4. works on large EC space

Front 415

What are some characteristics of endocrine signaling?

Back 415

1. message transmission-by circulating body fluids
2. general
3. specifically depends on receptors
4. general type of communication, substance released from cells and released into circulation and transported in bloodstream, can come into contact with all cells but depends on specificity of the receptor on the cell

Front 416

Give some examples of paracrine and autocrine signaling.

Back 416

Paracrine signaling: Glucose -> insulin INC -> glucagon DEC
Autocrine signaling: Insulin is needed for optimal insulin secretion

Front 417

Define hormone.

Back 417

A chemical substance that is:
- released into the blood by specialized secretory cells
- transported to its target by the circulation
- elicits a physiological response in its target cell

Front 418

What is a target cell?

Back 418

A cell that expresses receptors for a hormone

Front 419

What is a hormone receptor?

Back 419

A protein expressed by a target cell that can bind a hormone with high specificity and affinity; and that, upon binding its ligand, elicits physiological effects by activating intracellular signaling mechanisms.

Front 420

What is a binding/carrier protein?

Back 420

A circulating protein to which a hormone can reversibly bind without eliciting physiological effects. Binding proteins protect hormones against loss in the kidney, slow degradation and cellular uptake, and buffer changes in free hormone concentration. are really important because they protect hormones from quick degradation, hormone w/out binding proteins have a very short half life

Front 421

What is an endocrine gland?

Back 421

A “ductless gland” that produces and secretes signaling molecules (hormones) into the circulation. Highly vascularized. May develop from any of the germinal layers

Front 422

What are some examples of classical endocrine glands?

Back 422

Pituitary, thyroid, parathyroids, pancreatic (Langerhans) islets, adrenals, ovaries, testes, placenta.

Front 423

What are some examples of nonclassical endocrine glands?

Back 423

Hypothalamus (neurohormones), heart (atrial natriuretic factor), kidney (renin, erythropoietin, active vitamin D), adipose tissue (leptin, adiponectin, resistin).

Front 424

Describe the synthesis, secretion and metabolism of oligo/polypeptide, protein and glycoprotein hormones.

Back 424

1. Synthesized as any protein; stored in secretory vesicles
2. Preprohormone -> prohormone -> hormone
3. Glycosylation may prolong half-life
4. Metabolized in the circulation, in target cells, liver, kidney

Front 425

Describe the synthesis, secretion and metabolism of steroids.

Back 425

1. Synthesized from cholesterol as needed – no storage
2. Manufactured in the mitochondria and cytosol via a series of enzymatic reactions
3. Reversibly bound to carrier proteins in the circulation
4. May be converted in the periphery into more potent or even different compounds (eg. testosterone -> dihydrotestosterone)
5. Inactivated by reduction and conjugation (sulfate, glucuronide), products can be detected in urine (used for diagnosis)

Front 426

Describe the synthesis, secretion and metabolism of amines.

Back 426

1. Tyrosine derivatives (catecholamines, thyroid hormones)
2. Stored in granules (catecholamines) or as part of a precursor protein (thyroid hormones)
3. Thyroid hormones bind to circulating carrier proteins
4. Metabolized intracellularly into inactive or active products (e.g. thyroxine -> triiodothyronine)
5. Catecholamines are inactivated by conjugation with sulfate or glucuronic acid and can be detected in urine (used for Dx)

Front 427

What patterns of hormone secretion?

Back 427

include pulsatile, circadian, episodic, fluctuations may also occur on longer time scales (montly, seasonal (not typical in humans)), multiple serial measurements may be required for diagnosis, ex: cortisol peaks in deep sleep

Front 428

What are some problems with hormone measurements?

Back 428

- Concentrations in the circulation are VERY low (~nmol/L)
- Most hormones cannot be detected by specific chemical reactions
- Bioassays (quantification by magnitude of effect) are difficult to standardize and interpret and are labor-intensive; some require the use of animals

Front 429

Describe immunoassays.

Back 429

detection is based on antibody-antigeneration, highly specific, very sensitive

Front 430

Describe radioimmunoassay (RIA).

Back 430

typical labels include protein hormones (125 I), other hormones 14 C, 3 H, procedure involves:
1. antibody on solid phase + labeled antien + patient’s serum containing antigen
2. bound activity + free activity, wash the supernatant and measure bound activity (antigen in patient’s serum competes with labeled antigen for binding sides on solid phase antibodies)
3. graph bound activity vs. antigen concentration in patients serum, as more antigen is in patients serum the less bound activity there is

Front 431

Describe Enzyme-linked-Immuno sorbent Assay (ELISA).

Back 431

use fluorescent antibodies as well, steps include:
1. monocional antibodies on solid phase + patient’s serum containing antigen
2. antigen binds to antibodies
3. add enzyme-linked second antibody
4. chemical reaction generates an optical signal (colorimetric assay)

Front 432

Describe the mechanism of action for steroids, thyroid, retinoic acid and vitamin D superfamily.

Back 432

lipophilic hormone diffuses through cell membrane, enters cell and binds to receptor, the receptor may reside in the cytoplasm or bound to DNA, receptors are ligand-activated transcription factors, once hormone is bound to receptor binds to hormone response element and leads to transcription and translation

Front 433

Describe the mechanism that all other hormones act through?

Back 433

act through membrane receptors (G-protein coupled or ion-channel linked receptors), both act to INC Ca2+

Front 434

Describe the courses of hormone action.

Back 434

1. translocation of proteins into cell membranes (within seconds)
2. phosphorylation of metabolic enzymes -> altered activity (10-15 mins)
3. effects on mRNA translation and DNA transcription (hours-days)
4. ex: insulin receptor (enzyme linked receptor, tyrosine kinase), composed of four subunits, alpha are external and react with the substrate

Front 435

What determines how well the target tissue responds to hormonal stimulation?

Back 435

1) Capacity to respond: The magnitude of response to a given concentration of the hormone
2) Sensitivity to stimulation: The concentration of a hormone required for a given effect (e.g. half-maximal response). This is determined by: a) Affinity of receptors: the concentration of a hormone needed to occupy ½ of available receptors, b) Availability of receptors: Up- or down-regulation: the primary mechanisms whereby sensitivity is regulated

Front 436

Describe regulation of hormone secretion.

Back 436

Hormone secretion must be turned on/off at precisely the right times
1) Open-loop control
-Signal ON -> hormone increases -> effect ON
-Signal OFF -> hormone decreases -> effect OFF
Example: suckling -> oxytocin (from hypothalamus) -> milk ejection
2) Negative feedback (closed-loop regulation)
Signal ON -> hormone increases -> effect ON à signal OFF -> hormone decreases -> effect OFF à Signal ON, etc
Example: decrease in blood glucose -> glucagon increases -> blood glucose increases -> glucagon decreases, etc
-Closed-loop regulation occurs around a set point (thermostat)
-Precise regulation requires 2 opposing systems (“A/C & heating”)
-Set point may be changed or overridden (e.g. catecholamines increase blood glucose even when insulin secretion is increased)

Front 437

Describe the negative feedback control of glucose.

Back 437

integrated control of blood glucose occurs by glucagon and insulin, when blood glucose concentration is low, glucagon is high and insulin is low, when blood glucose is high, glucagon is low and insulin is high

Front 438

Describe positive feedback regulation of hormone secretion.

Back 438

Signal ON -> hormone increases -> effect ON -> signal increases -> hormone increases -> effect ON -> signal increases, etc, this eventually leads to a cataclysmic event that terminates the “vicious circle”, Example: fetus’ head -> stretch of uterine isthmus -> oxytocin increases -> contraction of myometrium -> fetus’ head pushed against isthmus -> more oxytoxin produced and released

Front 439

Describe the pituitary gland.

Back 439

The pituitary measures ~1 cm in diameter and is located in the sella turcica. It is connected to the hypothalmus by the pituitary stalk (also known as the infundibulum or the hypophysial stalk)

Front 440

What are the components of the pituitary gland?

Back 440

anterior (adenohypophysis) and posterior (neurohypophysis) lobes, infundibulum and pars intermedia (avascular, separates the anterior and posterior lobe, not much functional significance, more well developed in animals (makes hormones there in some animals, melanocyte stimulating hormone)

Front 441

Describe the embryonic development of the pituitary gland.

Back 441

During embryonic development the two lobes of the pituitary gland originate from different sources:
-ANTERIOR – from an invagination of the pharyngeal epithelium (Rathke’s pouch).
-POSTERIOR – from a neural tissue outgrowth from the hypothalamus
-This explains why the anterior and posterior lobe are so distinct in structure and function

Front 442

Describe the innervation of the neurohypophysis.

Back 442

is the storage area for hypothalamic hormones, has connections with the neurons in the ventral hypothalamus and hypothalamic neurons in the paraventricular and supraoptic nuclei, releases oxytocin and ADH

Front 443

What are the contents of the hypophyseal portal system?

Back 443

1. primary capillary plexus
2. hypophyseal portal veins
3. secondary capillary plexus

Front 444

What does the posterior pituitary secrete?

Back 444

oxytocin and ADH

Front 445

What does the anterior pituitary secreted?

Back 445

TSH, FSH, LH, ACTH, PH, PRL

Front 446

Describe the control of pituitary secretion.

Back 446

 Secretion by the anterior pituitary is controlled by hormones secreted by neurons within the hypothalamus.
 Secretion from the posterior pituitary is from magnocellular neurons which originate in the hypothalamus and terminate in the posterior lobe.

Front 447

What are the acidophiles of the anterior pituitary gland?

Back 447

1. somatotrophes-~40%, include growth hormone (GH, somatotrophin)
2. lactotrophes-AKA mammotrophes, ~20%, include prolactin (PRL, comes from the same protein as GH, just cleaved differently)

Front 448

What are the basophils of the anterior pituitary gland?

Back 448

1. corticotrophes-20%, include adrenocrocticotropic hormone (ACTH)
2. thyrotophres-5%, include thyroid stimulating hormone (TSH)
3. gonadotrophes-5%, include follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

Front 449

What hormones fall in the glycoprotein family and what are their targets and major actions?

Back 449

comprised of alpha and beta subunits + carb chains
1. TSH-targets the thyroid gland, INC synthesis and secretion of thyroid hormones
2. FSH-targets the ovary and INC folliculogenesis and estrogen synthesis there, also targets the testis (Sertoli cells) and INC sperm maturation
3. LH-targets the ovary (Graafian follicles to INC ovulation and formation of the corpus luteums) and the (corpus luteum to INC estrogen and progesterone synthesis), also targets testis (Leydig cells to INC testosterone synthesis)

Front 450

What hormones fall in the GH/PRL family polypeptides?

Back 450

1. GH-target most tissues to INC growth in stature and mass, INC IGF-1 production, INC protein synthesis, DEC glucose utilization, INC fat utilization
2. PRL-targets mammary glands to INC milk secretion and INC growth of mammary glands
oversecretion of GH leads to oversecretion of PRL as well

Front 451

What hormones fall in the pro-opiomelanocortin (POMC) family (polypeptides that are products of the same POMC gene)?

Back 451

1. ACTH-target adrenal cortex (zona fasciculate and reticularis) to INC synthesis and secretion of adrenal cortical steroids
2. beta-lipotropin-target fat to Inc fat mobilization, little activity in humans
beta-endorphins and melanocyte-stimulating hormone (MSH) are members of the POMC family released from the intermediate lobe of the pituitary in human embryos and pregnant women

Front 452

Describe the cleavage of the POMC gene.

Back 452

cleavage of POMC occurs by endopeptidases (prohormone convertases), cleavage of POMC gene forms beta-lipotropin, ACTH, gama-lipotropin and beta-endorphin, corticotrophe forms JP, ACTH, gama-lipotropin and beta-endorphin, melanotrophe forms JP, alpha-MSH, CLIP, gamma-lipotropin and beta-endorphin, cleavage shown below dashed line occurs in intermediate lobe (non-functional in adult humans)

Front 453

What enzymes make ACTH?

Back 453

cleavage of POMC gene by PC1 and PC2

Front 454

Describe the hypothalamic-hypophysial portal system.

Back 454

Hypothalamic releasing / inhibitory hormones are secreted in the hypothalamus; enter the portal system and are conducted to the anterior pituitary where they influence secretion from glandular cells. The hypophysial portal blood flow only represents a tiny fraction of the cardiac output. Only minute amounts of neural secretions are needed for effect. this is an example of neuroendocrine regulation (fast and highly specific), transports hormones from hypothalamus to the anterior pituitary

Front 455

Describe the regulation of the anterior pituitary.

Back 455

contains long loop negative feedback, ultra-short loop negative feedback and short loop negative feedback, hypothalamus is a collecting center for environmental and sensory information, release of hypothalamic releasing/inhibitory factors can be influenced by pain, emotions, light and dark, sleep rhythms, exercise, concentrations of electrolytes and hormones in the blood

Front 456

What is the structure and primary action on the anterior pituitary of thyrotropin-releasing hormone (TRH)?

Back 456

a peptide that INC synthesis and secretion of TSH and PRL

Front 457

What is the structure and primary action on the anterior pituitary of gonadotropin-releasing hormone (GnRH)?

Back 457

a peptide that INC synthesis and secretion of LH and FSH

Front 458

What is the structure and primary action of corticotrophin release hormone (CRH) and argining vasopressing (AVP)?

Back 458

peptides that INC synthesis and secretion of ACTH

Front 459

What is the structure and primary action of growth hormone releasing hormone (GHRH)?

Back 459

a peptide that INC synthesis and secretion of GH

Front 460

What is the structure and primary action of growth hormone inhibitory hormone (somatostatin)?

Back 460

a peptide that DEC GH secretion

Front 461

What is the structure and action of prolactin inhibiting hormone?

Back 461

a dopamine that DEC synthesis and secretion of PRL

Front 462

Describe hypothalamic releasing/inhibitory hormones (hypophysiotropic hormones)

Back 462

• Hypothalamic hormones stimulate pituitary hormone secretion by increasing intracellular [Ca2+] via G-protein-coupled receptors. 2nd messengers include cAMP, IP3 and DAG.
• Several hypothalamic hormones are released in a pulsatile fashion but only pulsatile GnRH release is critical for pituitary (gonadotropin) secretion.

Front 463

Describe the regulation of LH release by GnRH.

Back 463

GnRH was sampled in pituitary portal blood.
LH was sampled in peripheral blood.
Note the rapid regulation of pituitary hormone (LH) secretion by the hypothalamic neurohormone (GnRH).

Front 464

Describe the cells and hormones of the posterior pituitary gland.

Back 464

secrete ADH (anti-diuretic hormone, vasopressin) and oxytocin
 The posterior pituitary is comprised primarily of glial-like cells called pituicytes – these cells do not secrete hormones.
 Hormones of the posterior pituitary are secreted by neurons.
 The bodies of these neurons are located in the hypothalamus
 The hormones are synthesized in the cell bodies and transported down the nerve axons into the posterior pituitary.

Front 465

Describe the magnocellular neurosecretory system.

Back 465

regulates the posterior pituitary via the paraventricular and supraoptic nucleus, oxytocin and vasopressin is produced by the magnocellular system in the paraventricular nucleus into the posterior pituitary

Front 466

Describe the structure, origin, binding/carrier protein, half-life, functions and mechanism of action of oxytocin.

Back 466

-Structure: nonapeptide
-Origin: magnocellular neurons in the paraventricular (oxytocin) & supraoptic nuclei (ADH)
-Binding/carrier protein: neurophysin I, bind at the axoplasm
-Half-life (T½): ~2 min
-Functions:
1. Milk ejection – contracts myoepithelial cells that surround the mammary alveoli
2. Hastens delivery, promotes delivery of the placenta, reduces bleeding – contracts uterine smooth muscle
(NOT THE PHYSIOLOGICAL TRIGGER FOR PARTURITION)
-Mechanism of action: via G-Protein coupled receptor; 2nd messengers: IP3, DAG

Front 467

Describe the regulation of oxytocin secretion.

Back 467

suckling and cervical stretch receptors stimulate the CNS to communicate with the paraventricular and supraoptic nuclei to tell the posterior pituitary to release oxytocin, oxytocin tells the mammary glands to let-down milk and tells the uterus to contract which has a positive feedback role of stimulating cervical stretch receptors and INC oxytocin release

Front 468

What is the structure, origin, binding/carrier protein, half-life, functions and mechanism of action for ADH/(AVP)?

Back 468

-Structure: nonapeptide
-Origin: magnocellular neurons in the supraoptic & paraventricular nuclei
-Binding/carrier protein: neurophysin II
-Half-life (T½): ~2 min
-Functions & mechanisms of action:
1. Reabsorption of water in connecting/collecting tubules via V2 rec. -> cAMP -> insertion of aquaporin-2 into the luminal membrane
2. Vascular smooth muscle contraction via V1 rec. -> IP3, DAG -> INC [Ca2+]i

Front 469

Describe the regulation of ADH secretion.

Back 469

volume receptors in the thorax and osmoreceptors in the hypothalamus stimulate the CNS, paraventricular and supraoptic nucleis to tell the posterior pituitary to release ADH, ADH stimulates water reabsorption in the kidney which INC plasma volume which stimulates volume receptors (+ feedback) as well as DEC plasma osmolality which stimulates osmoreceptors (+ feedback)

Front 470

Describe the problem, causes and principle symptoms of diabetes insipidus.

Back 470

-Problem: Unable to conserve water due to ↓ADH synthesis (central DI) or insensitivity to ADH at the collecting ducts (nephrogenic DI)
-Causes: trauma, tumors, infection (e.g. meningitis)
-Principle symptoms: -INC water loss from kidneys (polyuria) triggers, INC thirst (polydipsia)

Front 471

Describe the problem, causes and principle symptoms of syndomre of inappropriate ADH secretion (SIADH)?

Back 471

-Problem: inappropriate ADH secretion -> INC Water retention -> atria of heart stretched -> -INC ANF, DEC plasma renin activity -> sodium loss -> hyponatremia and DEC plasma osmolality; concentrated urine
-Causes: Ectopic: ADH secreted from lung cancer, etc., Eutopic: Stroke, infection
-Principle symptoms: asymptomatic during early stages especially if serum sodium falls slowly. Rapid fall associated with confusion, drowsiness, convulsions, coma and death.

Front 472

Describe the morphology of the adrenal glands.

Back 472

from outermost to innermost, zona glomerulosa (aldosterone) -> zona fasciculate (cortisol and androgens) -> zona reticularis (cortisol and androgens) -> medulla (catecholamines), direction of blood flow is from capsule -> outermost to innermost

Front 473

Describe the adrenal glands.

Back 473

 The adrenals are required for maintenance of life: Complete adrenal insufficiency (e.g. Addison’s disease), if untreated, leads to death within 2 weeks. Cause of death: circulatory collapse (shock) or hypoglycemic coma.
 composed of 4 functional zones:
 The adrenals often act as one functional unit to cope with a change in the external or internal environment that threatens HOMEOSTASIS.

Front 474

What are the four functional zones of the adrenal glands, what hormones are there and what controls it?

Back 474

1. zona glomerulosa-mineralcorticoids, controlled by kidney (renin-angiotensin)
2. zona fasciculate-glucocorticoids, controlled by hypothalamic-pituitary axis via ACTH
3. zona reticularis-androgens, controlled by hypothalamic-pituitary axis via ACTH
4. medulla-catecholamines, controlled by sympathetic nervous system

Front 475

Describe the adrenal medulla.

Back 475

~10% of the adrenal mass
-Origin: neuroectoderm
-Microanatomy: modified postganglionic neurons (chromaffin cells) innervated by cholinergic preganglionic neurons from the thoracolumbar spinal cord.
-Secretory products: epinephrine : norepinephrine = 5:1, The adrenals are the sole source of epinephrine. Norepinephrine is also released from sympathetic terminals and extraadrenal chromaffin cells.
-The adrenal medulla is not essential for survival as long as the sympathetic nervous system is intact.

Front 476

Describe the biosynthesis of catecholamines.

Back 476

1. tyrosine -> DOPA (via tyrosine hydroxylase (TH), rate-limiting step (inhibited by catecholamines)
2. DOPA -> dopamine (via aromatic L-amino acid decarboxylase (AAD))
3. dopamine -> norepinephrine (via dopamine beta-hydroxylase (DBH), occurs within secretory granule)
4. norepinephrine -> epinephrine (via phenylethanolamine-N-methyltransferase (PNMT), inducible by glucocorticoids)

Front 477

Describe the storage, release, metabolism and excretion of adrenal medullary hormones.

Back 477

-Storage: in granules with ATP, enkephalins & b-endorphin
-Release: ACh -> nicotinic receptors -> Na+ influx -> depolarization -> VSCC -> [Ca2+]i INC -> fusion with membrane (exocytosis)
-Metabolism: Uptake into sympathetic nerve terminals; reused as NE or degraded by MAO (monoamine oxidase), Capillary endothelium, heart, liver, etc.: metabolization by COMT (catecholamine-ortho-methyl-transferase)
-Excretion: inactivated products are conjugated with glucuronic acid & sulfates -> urine (can be exploited for diagnostic purposes)

Front 478

What is the main function of adrenal medullary hormones?

Back 478

To make rapid, short-term adjustments to actual or threatened changes in the external or internal environment (“fright, flight, or fight”). In the longer term, actions are supported by glucocorticoids.

Front 479

What is the target tissues of the adrenal medullary hormones?

Back 479

Coordinated actions to ensure survival: INC cardiac output, INC perfusion of brain & working muscles, INC supply of energy-rich fuels, INC pulmonary ventilation, INC visual acuity, INC muscular performance, quiescence of the gut to permit diversion of blood flow

Front 480

What is the mechanism of action for the adrenal medullary hormones?

Back 480

a1 receptors coupled to Gaq -> IP3/DAGINC
a2 receptors coupled to Gai -> cAMP DEC
b1 & b2 receptors coupled to Gas -> cAMP INC
for beta-E > NE, for alpha-NE > E

Front 481

What is the regulation of adrenal medullary hormones?

Back 481

hypothalamus -> sympathetic preganglionic fibers

Front 482

What do the beta-receptor mediated adrenal medullary hormones do?

Back 482

1. INC force and rate of heart contractions (beta1), arteriolar dilation (skeletal muscle)
2. INC glycogenolysis (beta2) and INC lipolysis (beta1)
3. relaxation of bronchial muscle (beta2)
4. DEC motility of GI tract (relaxation, beta2)
5. relaxation of urinary bladder (beta2)
6. relaxation of uterus (beta2)
7. INC renin secretion
8. INC tension generation and INC neuromuscular transmission

Front 483

What do alpha receptor mediated adrenal medullary hormones do?

Back 483

1. arteriolar constriction (skin, renal, splanchnic, genital, alpha1)
2. INC gluconegogenesis
3. INC sphincter contraction of Gi tract
4. INC sphincter contraction of urinary gladder
5. sweating
6. pupil dilation (contraction of radial muscle)

Front 484

What is pheochromocytoma?

Back 484

-What is it?-Chromaffin cell tumor
-Why is it a problem? Causes over secretion of catecholamines
-What are the dominant features? Elevated heart rate, Systemic hypertension, Anxiety, Pallor and sweating, Hyperglycemia
-How is it diagnosed? Detection of increased levels of catecholamines and their metabolites in the blood and urine

Front 485

What is the origin, microanatomy, and chief secretory products of the adrenal cortex?

Back 485

-Origin: mesoderm
-Microanatomy: lipid-containing, cuboidal cells arranged in clusters, bundles or tangled networks
-Chief secretory products: steroids (products of the fetal adrenal cortex will be covered elsewhere)
-Z. glomerulosa: aldosterone (mineralocorticoid)
-Z. fasciculata: cortisol (glucocorticoid) corticosterone (glucocorticoid)
-Z. reticularis: after puberty: dehydroepiandrosterone (DHEA) and -sulfate (DHEAS), androstendione (androgens)

Front 486

Describe the biosyntehsis of adrenal cortical hormones.

Back 486

starts from cholesterol, the rate limiting step is side chain cleavage by desmolase that forms pregnenolone which is the precursor for all the cortical hormones, progesterone is rapidly converted not secreted, aldosterone synthase is found only in the z. glomerulosa

Front 487

What is the transport, half-life, normal blood concentration, metabolism and excretion of adrenal cortical hormones?

Back 487

-Transport in blood: Corticosteroid Binding Globulin (CBG; transcortin), albumin. Approx. 90-95% of cortisol is bound; 60% of aldosterone is bound.
-Half-life: cortisol: 60-90 min; aldosterone: ~20 min
-Normal blood concentration: Aldosterone: 6ng/dL (secretory rate 0.15 mg/day; Cortisol 12µg/dL (secretory rate 15-20 mg/day)
-Metabolism: Liver: reduction + conjugation with glucuronic acid & sulfates.
-Excretion: 25% excreted in bile ® feces. Remaining conjugates are filtered by kidneys ® urine.

Front 488

What is the cellular mechanism of action of adrenal cortical hormones?

Back 488

Adrenal cortical hormones are steroids – elicit effects by producing changes in gene transcription. Effects are not immediate - require 45-60 min for proteins to be synthesized; full effect may take hrs or days to develop.

Front 489

Describe the glucocorticoids.

Back 489

-Cortisol (also known as hydrocortisone; very potent; accounts for 95% of all glucocorticoid activity)
-Corticosterone (less potent than cortisol; accounts for ~4% of all glucocorticoid activity)
-Main function: Effects on metabolism of proteins, carbohydrates and fats. Glucocorticoids have widespread actions which help restore homeostasis after stress. In the absence of glucocorticoids, even mild physical or mental stress can be deadly.
-Targets: many – see table. Virtually every tissue is affected.

Front 490

What are the actions of the glucocorticoid hormones?

Back 490

1. DEC corticotrophin-Releasing hormone (negative feedback)
2. DEC ADH secretion
3. INC gluconeogenesis
4. INC maturation and surfactant production during fetal development
5. DEC ACTH secretion and synthesis (negative feedback)
6. INC GFR (needed to excrete dilute urine)
7. INC protein catabolism, DEC glucose oxidation, DEC insuling sensitivity, DEC protein synthesis
8. DEC blood concentration of eosinophils, basophils and lymphocytes
9. DEC cellular immunity

Front 491

What happens when glucocorticoids act on proteins?

Back 491

they INC protein breakdown which leads to INC in blood urea nitrogen, preservation of carb reserves and mobilization of alternative, high energy fuels (protein and fat)

Front 492

What are the actions of glucocorticoids in injury and stress?

Back 492

Glucocorticoid secretion increases in stressful situations (i.e. trauma, infection, surgery, intense cold or heat.) Why is this beneficial?...Not fully understood. Mobilization of amino acids and fats may be beneficial as this makes them available for energy and synthesis of other compounds required for maintenance and reproduction of new cells (e.g. glucose, new proteins, purines, etc.), In addition, cortisol has anti-inflammatory effects. Sometimes the inflammation associated with a disease or trauma can be more damaging than the condition itself. e.g. rheumatoid arthritis.

Front 493

What is the therapeutic utility in allergies, autoimmune diseases and transplantation of glucocorticoids?

Back 493

• Stabilizes lysosomal membranes – proteolytic enzymes are confined to lysosomes.
• Decreases production of T cells and antibodies (DEC B cell proliferation).
• Decreases formation of prostaglandins and leukotrienes, thus DEC vasodilation DEC capillary permeability DEC mobility of white blood cells (WBCs).
• Reduces fever by decreasing release of interleukin-1 (IL-1) and other inflammatory cytokines from WBCs.

Front 494

Describe the regulation of glucocorticoid secretion.

Back 494

-Cortisol secretion controlled by adrenocorticotropic hormone (ACTH) secreted by anterior pituitary. Cortisol exerts negative feedback effects on the hypothalamus and anterior pituitary gland – DEC ACTH.
-ACTH secretion is controlled by corticotrophin-releasing hormone (CRH) secreted into the hypophysial portal system of hypothalamus.

Front 495

How does ACTH stimulate adrenal steroid synthesis?

Back 495

¬ 1. INC cholesterol liberation from LDL
¬ 2. INC transcription of LDL receptors and enzymes involved in hormone synthesis
¬ 3. INC transfer of cholesterol over the mitochondrial membrane
¬ [Long term ACTH stimulation also causes hypertrophy and proliferation of adrenocortical cells]

Front 496

Describe the circadian rhythm of glucocorticoid secretion.

Back 496

CRH, ACTH and cortisol secretion are high in the early morning but low in the late evening (diurnal rhythm). Release is pulsatile and the diurnal rhythm reflects changes in the pulse amplitude. therefore Measurements of blood cortisol levels must be expressed in terms of the time in the cycle.

Front 497

describe the mineralcorticoids.

Back 497

-Aldosterone (very potent; accounts for 90% of all mineraldocorticoid activity)
-Desoxycorticosterone, corticosterone & cortisol (also provide mineralocorticoid activity; cortisol 1/3000 as potent as aldosterone but plasma concentration of cortisol 2000 times higher)

Front 498

what are the main actions of the mineralcorticoids?

Back 498

1. Sodium retention Required for the reabsorption of ~2% of filtered Na+. Accompanied by absorption of water (corresponds to ~ 3.5L EC fluid per day). Sodium and water retention can escape from long-lasting stimulation by aldosterone (15-25mm Hg increase in arterial pressure produces pressure natriuresis & diuresis)
2. Potassium excretion
3. Proton excretion & bicarbonate retention

Front 499

What are the targets of the mineralcorticoids?

Back 499

principal cells of the distal tubule & collecting duct; intercalated cells in the collecting duct; colon; sweat & salivary glands

Front 500

What are the genomic and non-genomic effects of aldosterone?

Back 500

-Genomic effects: Transcription of genes involved in ion transport: Increases reabsorption of Na+ and excretion of K+
-Non-genomic effects: activation of second messenger system: Increases H+ secretion and bicarbonate retention

Front 501

describe the regulation of aldosterone secretion.

Back 501

ACTH and angiotensin II stimulate alodsterone secretion, aldosterone secretion stimulates renal K+ excretion which DEC K+ concentration which stimulates aldosterone secretion, aldosterone secretion also stimulates renal Na+ retention which INC blood volume and inhibits the JG apparatus, that secretes renin, renin turns angiotensinogen into angiotensin I which (via angiotensin converting enzyme) turns into angiotensin II

Front 502

Describe the regulation of aldosterone synthesis by angiotensin II.

Back 502

angiotensin II binds to receptor which activates PLC which INC Ca2+ levels via DAG and IP3, Ca2+ activates CAM kinase which stimulates cholesterol synthesis into aldosterone

Front 503

Describe the adrenal androgens.

Back 503

-Dehydroepiandrosterone (DHEA)
-Androstenedione, dehydroepiandrosterone sulfate (DHEAS)

Front 504

What are the main actions of the adrenal androgens?

Back 504

Normally only weak effects in humans. May contribute to early development of male sex organs; growth of the pubic and axillary hair in females. In the testes adrenal androgens converted to testosterone.

Front 505

What is hypoadrenalism (Addison’s disease)? what causes it?

Back 505

destruction of the adrenal cortex by autoimmunity (80%), tuberculosis, cancer

Front 506

What happens with mineralcorticoid deficiency?

Back 506

Loss of Na+ and water -> DEC EC fluid, DEC plasma volume, hemoconcentration, hyponatremia. Retention of K+ and H+ ions -> hyperkalemia, mild acidosis. DEC cardiac output -> circulatory shock -> death

Front 507

What happens with glucocorticoid deficiency?

Back 507

impaired fuel mobilization, DEC gluconeogenesis -> hypoglycemia, weight loss, weakness, Extreme sensitivity to stress -> death

Front 508

Describe the pigmentation associated with Addison’s disease.

Back 508

Lack of normal negative feedback to hypothalamus and anterior pituitary by cortisol -> ACTH + MSH release increased -> melanin formation increased.

Front 509

What causes hyperadrenalism (Cushing’s syndrome)?

Back 509

(1) Hypersecretion of CRH or ACTH (from the pituitary: Cushing’s disease [70%]); (2) adrenal cortex adenomas [20-25%]; (3) ectopic secretion of ACTH (e.g. in lung cancer); (4) large doses of glucocorticoids for long periods.

Front 510

What happens with glucocorticoid excess with hyperadrenalism?

Back 510

 increased gluconeogenesis -> hyperglycemia, reduced sensitivity to insulin -> ‘adrenal diabetes’
 increased fat mobilization from lower body and redistribution to the thoracic and abdomen (buffalo torso); facial edema (moon face)
 protein loss (in muscle, skin, bone, collagen & lymphoid tissue, not in the liver) -> weakness, osteoporosis, striae on skin
 increased susceptibility to infections -> death

Front 511

What happens with androgen excess with hyperadrenalism?

Back 511

acne, hirsutism (excess growth of facial hair)

Front 512

What is the cause of primary aldosteronism (Conn’s syndrome)?

Back 512

Small, aldosterone-secreting tumor of the zona glomerulosa

Front 513

What happens with mineralcorticoid excess with Conn’s syndrome?

Back 513

 hypokalemia -> occasional periods of muscle paralysis
 modest hypervolemia -> hypertension
 Excess aldosterone + INC arterial pressure leads to feedback suppression of renin secretion therefore low plasma renin concentration

Front 514

What is the cause of adrenogenital syndrome due to adrenocortical tumor?

Back 514

Adrenocortical tumor secreting excessive quantities of androgens

Front 515

What happens with androgen excess due to adrenogenital syndrome?

Back 515

 Female – masculinisation (including beard growth, deepening of voice, body hair, growth of clitoris)
 Male –rapid development of male sexual organs in prepubertal males

Front 516

How is adrenogential syndrome diagnosed?

Back 516

levels of 17-ketosteroids (androgen metabolite) in the urine may be 10-15 times normal

Front 517

What causes congenital adrenaly hyperplasia?

Back 517

Autosomal recessive disorder – enzyme inefficiencies most commonly leading to deficient production of cortisol and aldosterone together with excessive production of sex steroids. 95% of cases due to P450c21 hydroxylase deficiency

Front 518

What are the different types of P450c21 hydroxylase deficiencies?

Back 518

-Severe P450c21 deficiency: Life-threatening vomiting & dehydration in first weeks of life. Ambigious genitalia of genetically female infants due to prenatal virilization.
-moderate P450c21 deficiency: prepubertal virilization
-Mild P450c21 deficiency: infertility in women due to anovulation

Front 519

Describe the morphology of the thyroid gland.

Back 519

thyroid gland is composed of follicles (100-300 microM diameter), filled with colloid (major constituent is thyroglobulin) and lined with cuboidal epithelial cells

Front 520

What are the thyroid hormones?

Back 520

-Tetraiodothyronine (Thyroxine; T4)-Comprises 93% of total secretion (~80 µg/day)
Most is converted to T3 in the tissues
-Triiodothyronine (T3)-Comprises 7% of total secretion (~4 µg/day) Similar function as thyroxine but 4 times more potent, Concentration in the plasma is much less than T4, Shorter half-life than thyroxine (1 day vs. 6 days)

Front 521

What are the stages of the biosynthesis of thyroid hormones?

Back 521

1. iodide trapping-transport of iodide into the thyroid follicles
2. formation and secretion of thyroglobulin
3. oxidation of iodide and coupling of iodine with thyroglobulin
4. endocytosis of thyroglobulin and release of thyroid hormones
5. recycling of iodine for reuse

Front 522

Describe stage 1 of the biosynthesis of thyroid hormones.

Back 522

Ingested iodine is absorbed through the small intestine and transported in the plasma to the thyroid.
-Iodide pumps (sodium iodide symporters) located on the basal membrane of the thyroid epithelial cell actively pump iodide ions into the cytosol.
-Concentration of iodide inside the thyroid cells can be 30-250 times higher than in the blood.

Front 523

Describe stage 2 of the biosynthesis of thyroid hormones.

Back 523

• Thyroglobulin, a large glycoprotein, is synthesized by the endoplasmic reticulum and Golgi apparatus of the thyroid cells.
• Thyroglobulin is then secreted into the follicular colloid.
• Each molecule of thyroglobulin contains ~70 tyrosine amino acids.

Front 524

Describe stage 3 of the biosyntehsis of thyroid hormones.

Back 524

• Iodide exits apical membrane and is oxidized by thyroperoxidase in the presence of hydrogen peroxide.
• Oxidized iodine binds with tyrosine amino acids within the thyroglobulin molecule (organification). Promoted by iodinase – within seconds to minutes 1/6th of the tyrosines become bound.
• Successive iodination and coupling of iodotyrosine residues results in the formation of T3 and T4 (see next slide).

Front 525

Describe the steps in the formation of T3 and T4.

Back 525

1. tyrosine -> monoiodotyrosine (MIT) via iodinase
2. MIT -> diiodotyrosine (DIT)
3. MIT + DIT -> 3,5,3 triiodotyrosine (T3)
4. DIT + DIT -> thyroxine (T4)

Front 526

Describe stage 4 of the biosynthesis of thyroid hormones.

Back 526

• After coupling, each thyroglobulin contains up to 30 T4 molecules and a few T3 molecules.
• Thyroglobulin is isolated from the EC fluid therefore must renter the follicular cell prior to secretion. Uptake is via endocytosis by pseudopodia.
• Lysosomes in the cell cytoplasm fuse with pinocytotic vesicles. Proteases in lysosomes mix with colloid. T3 and T4 released and diffuse through basal membrane into bloodstream.

Front 527

Describe stage 5 of the biosynthesis of thyroid hormones.

Back 527

• ~75% of the iodinated tyrosine in thyroglobulin never becomes T3 or T4, but remains as monoiodotyrosine (MIT) and diiodotyrosine (DIT).
• When thyroglobulin is digested MIT and DIT are freed into the cytosol of the thyroid cell.
• Iodine is cleaved from MIT and DIT by tyrosine deiodinase and recycled.

Front 528

Describe the use of radioiodide to assess thyroid function.

Back 528

pics compare uptake of radioactive iodide by normal thyroid gland and a cold nodule that does not take up tracer (is indicative of compromised thyroid function), radioactive iodide can also accumulated in follicular lumen, the urinary excretion of radioiodide can also be used as a test of thyroid function

Front 529

Describe the storage of thyroid hormones.

Back 529

-The thyroid gland can store enough thyroid hormone to supply the body with its normal
requirements for 2-3 months.
-Thyroid hormones remain part of the thyroglobulin molecule during storage in the follicular colloid.
-Thyroid hormones are also ‘stored’ in blood and target tissues bound with plasma and intracellular proteins and are used slowly over days/weeks.

Front 530

Describe the transport of thyroid hormones in the blood.

Back 530

In the blood over 99% of T3 and T4 combine immediately with thyroxine-binding globulin (>70%), thyroxine-binding prealbumin and albumin - plasma proteins synthesized by the liver. Binding proteins are not saturated and store 3x the amount secreted per day, therefore:
-acute changes in hormone secretion have very little effect on free hormone concentrations thyroid hormones are not minute-to-minute regulators.
-changes in binding protein levels that occur in liver or kidney disease have significant effects on thyroid hormone concentrations.
The binding proteins’ affinity for T4 is 10 times higher than for T3 Therefore the half-life for T4 is longer (6 days) than for T3 (1 day)

Front 531

Describe thyroid hormone metabolism

Back 531

93% of thyroid hormone released by the thyroid gland is T4. However ~50% of the secreted T4 is deiodinated in extrathyroidal tissues to T3.

Front 532

Describe the different types of deiodinase.

Back 532

• Deiodinase type I: liver, kidney, CNS, ant. pituitary, thyroid, removal of 1 iodine from the outer ring à T3, removal of 1 iodine from the inner ring à reverse T3 (rT3): INACTIVE
• Deiodinase type II: brain, pituitary, T3 for local use.
• Deiodinase type III: in many tissues, Only removes iodine from the inner ring à degradation.

Front 533

Describe the further degradation of rT3 and T3.

Back 533

rT3 and T3 can be further deiodinated by type I and type III deiodinases à degradation Thyroid hormones can also be conjugated (to glucuronic acid) and excreted in the bile

Front 534

Describe the cellular mechanism of thyroid hormone action.

Back 534

Thyroid hormone receptors have a much higher affinity for T3 than T4. (More than 90% of the thyroid hormone molecules that bind with the receptors is T3), Thyroid hormone receptors (TRs) are nuclear receptors. TRs are located at thyroid response elements of genes. Upon activation, TRs initiate transcription and thus formation of new proteins.

Front 535

Describe the cellular metabolic activity action of thyroid hormones.

Back 535

-Thyroid hormones increase metabolic activity of almost all tissues. Basal metabolic rate can be increased 60-100% above normal if large quantities are secreted.
-INC number and SA of mito, INC ATP formation, INC Na+-K+ ATPase activity and INC protein synthesis leads to INC O2 consumption and INC in basal metabolic rate (BMR)

Front 536

Describe the role of thyroid hormone in carb metabolism.

Back 536

Increases glucose absorption, glucose uptake by cells and oxidation, glycolysis, gluconeogenesis, insulin secretion and glycogenolysis.

Front 537

Describe the role of thyroid horomone in lipid metabolism

Back 537

Enhances lipogenesis in liver and fat cells, mobilization of lipids from fat stores and oxidation of free fatty acids. Decreases plasma cholesterol by increasing hepatic cholesterol excretion into the bile (via ­LDL receptors in liver).

Front 538

Describe the role of thyroid hormone in nitrogen metabolism.

Back 538

Increased protein synthesis & degradation. In excess, protein degradation predominates.

Front 539

What does the role of thyroid hormone in metabolism do to BMR?

Back 539

Enhanced mobilization of carbohydrate, fat and protein increases INC O2 consumption therefore INC BMR

Front 540

What role does thyroid hormone have on the skeletal system?

Back 540

T3 is required for attainment of normal adult stature and bone maturation. T3 is permissive for growth hormone synthesis, secretion & action.

Front 541

What role does thyroid hormone have on CNS?

Back 541

Maturation of the central nervous system during the perinatal period is absolutely dependent on T3. Cerebral & cerebellar growth, myelinization, vascularization, axonal & dendritic density, cell migration & differentiation are all affected.

Front 542

What amount of thyroid hormone is necessary for proper functioning of the body?

Back 542

Appropriate amounts are required for the normal operation of virtually all organs. T3 acts as a modulator rather than an all-or-none signal.

Front 543

What role does thyroid hormone have on the CV system?

Back 543

INC heart rate (via INC b-adrenergic receptors); Increased metabolism causes rapid O2 consumption and production of metabolic end products and need for heat elimination. Result: vasodilation, INC blood flow, INC cardiac output.

Front 544

What role does thyroid hormone have on temperature regulation?

Back 544

T3 maintains sensitivity to, and acts in synergism with, sympathetic stimulation to regulate body temperature.

Front 545

What role does thyroid hormone have on CNS?

Back 545

Hyperthyroidism increases excitability and nervousness. Hypothyroidism causes lack of energy, slowness of speech, dulled mental capacity. Mechanisms are unclear.

Front 546

What role does thyroid hormone have on ANS?

Back 546

Thyroid hormones amplify the effects of sympathetic stimulation by increasing the number of b-adrenergic receptors, upregulating Galphas and downregulating Galphai.

Front 547

What is the principal regulator of thyroid synthesis and release?

Back 547

Thyroid Stimulating Hormone (TSH; thyrotropin) [Secreted by thyrotropes of anterior pituitary gland], TSH receptor couple to Galphas -> INC cAMP -> INC PKA

Front 548

What are the genomic effects of TSH?

Back 548

promotes gene transcription for :
1. Iodide pump, thyroglobulin, enzymes involved in T3 & T4 synthesis
2. Nitric oxide synthase ® vasodilation therefore INC blood flow
3. local growth factors ® hyperplasia and hypertrophy of gland

Front 549

What are the non-genomic effects of TSH?

Back 549

1. INC iodide pump activity ® INC iodide trapping
2. INC iodination of tyrosine ® INC synthesis of T3 & T4
3. INC proteolysis of thyroglobulin ® INC release of T3 & T4

Front 550

What is the principal regulator of TSH secretion?

Back 550

Thyrotropin Releasing Hormone (TRH),TRH release can be increased by certain emotional states (i.e. excitement & anxiety)

Front 551

What are the actions of TRH?

Back 551

INC gene transcription and glycosylation of TSH, INC release of TSH (via Gaq à INC IP3 & DAG). Stimulation by TRH is required for optimal TSH secretion.

Front 552

Describe the negative feedback abilities of thyroid hormone.

Back 552

it inhibits:
(1) TRH synthesis & secretion in the hypothalamus
(2) Gene expression for TSH and for the TRH receptor in the pituitary
(3) TSH release from the pituitary

Front 553

Describe the causes of autoimmune hyperthyroidism.

Back 553

AKA (Graves’ disease, Basedow’s disease, Parry’s disease, toxic goiter, thyrotoxicosis)
Cause: Autoantibodies stimulate TSH receptors producing prolonged stimulation of thyroid hormone synthesis. T4 and T3 high, TSH low.

Front 554

Describe the signs and symptoms of autoimmune hyperthyroidism.

Back 554

-Excitability, heat intolerance, sweating, weight loss, diarrhea, palpitations, nervousness, muscle weakness, fatigue, inability to sleep, tremor of the hands (largely due to increased sympathetic activity).
-Enlargement of thyroid gland (diffuse goiter) due to hypertrophy and hyperplasia. Colloid volume is greatly reduced (see left panel; right panel shows normal histology)
-Autoimmune reaction causes edematous swelling of retro-orbital tissues and degeneration of extraocular muscles ® exophthalmos (protrusion of the eyeballs), thyroid stare (inability to achieve or maintain convergence, limited superolateral or upward gaze), blurred or double vision, feeling of pressure behind the eyes. Can lead to irritation/ulceration of the cornea as eyelids do not close completely when blinking or asleep.

Front 555

What is the treatment for autoimmune hyperthyroidism?

Back 555

thyroid resection, competitive inhibitors of iodide trapping (thiocyanate, percholate and nitrate ions), inhibitors of iodide oxidation and organification (propylthiouracyl), glucocorticoids, b-blockers.

Front 556

Describe thyroid adenoma.

Back 556

autonomous hypersecretion of thyroid hormones -> low TSH -> secretory activity of the remainder of the thyroid is almost totally inhibited.

Front 557

What are the causes of hypothyroidism?

Back 557

• Autoimmune disease (Hashimoto’s disease): autoantibodies against thyroglobulin, thyroperoxidase, TSH receptor (blocking type) [low T4 and T3, elevated TSH levels]
• Dietary iodine deficiency
• Inherited defects of hormone synthesis
• Defects in TSH and TSH receptor
• Antithyroid substances (e.g. p-aminosalicylic acid, lithium)
• Iatrogenic (treatments for hyperthyroidism)

Front 558

What are the signs and symptoms of hypothyroidism?

Back 558

fatigue, muscular sluggishness, slow heart rate, reduced cardiac output, weight gain, constipation, mental sluggishness, myxedema (more generalized than in hyperthyroidism), intolerance to cold, thick tongue, hoarseness. Goiter (often nodular due to TSH stimulation of healthy areas) Hypercholesterolemia due to reduced excretion by liver.

Front 559

What is the treatment for hypothyroidism?

Back 559

daily oral thyroxine or iodide replacement.

Front 560

What causes cretinism?

Back 560

Extreme hypothyroidism during fetal life and infancy due to congenital lack of thyroid gland or dietary iodine insufficiency

Front 561

What are the signs and symptoms of cretinism?

Back 561

The neonate may have normal appearance and function (maternal thyroid hormones). Symptoms appear a few weeks after birth: sluggish movements, retarded physical and mental development. Unless treatment begins immediately, mental growth remains permanently and severely retarded (CRITICAL TIME WINDOW). Skeletal growth is more inhibited than soft tissue growth leading to a stocky, short appearance; the enlarged tongue may even choke the child. Physical growth can be rescued by treatment initiated at any time during childhood.

Front 562

What is the treatment for cretinism?

Back 562

daily oral thyroxine or iodide replacement.

Front 563

Define growth.

Back 563

organized addition of new tissue that occurs normally in development. With the exception of longitudinal growth, many of the processes involved continue to operate throughout life (e.g. tissue remodeling). Growth involves genetic, nutritional and environmental factors as well as actions of the endocrine system.

Front 564

Describe growth hormone.

Back 564

-Other names: Somatotropic hormone or somatotropin
-Nature: Polypeptide
-Secreted from: somatotropes of anterior pituitary
-Mode of secretion: irregular pulses. Largest burst during deep sleep. Pulse amplitude max. at puberty and declines thereafter.
-Binding protein: Only binds weakly to plasma proteins therefore relatively short half-life of 20 min.
-Receptor: GH binding to enzyme-linked receptor produces activation of kinase cascade which ultimately alters gene transcription.
-Metabolism: reabsorbed & destroyed by the kidney; also degraded by target cells.
-Excretion: minimal amounts in urine.

Front 565

What affect does GH have on body organs?

Back 565

Unlike other anterior pituitary hormones, Growth hormone does not function through a target gland – it exerts its effects directly on almost all tissues of the body. Increases size and number of cells and causes specific differentiation of certain cell types.

Front 566

What effect does GH have on skeletal growth?

Back 566

(1) INC proliferation of epiphyseal cartilage.
(2) INC conversion of cartilage to new bone (INC length of long bones & skeleton - until epiphyses of long bones fuse with shafts)
(3) INC proliferation of periosteal osteoblasts causing bone thickening
(4) INC bone remodeling

Front 567

What effect does GH have on metabolism?

Back 567

INC protein synthesis, DEC protein breakdown [DEC BUN], INC fat utilization, DEC glucose uptake & utilization, INC glucose production by liver

Front 568

Describe somatomedin hypothesis.

Back 568

‘Somatomedin hypothesis’: Growth effects of GH are mediated by Insulin-like Growth Factors (IGFs). Somatomedin C (IGF-I) is the most important IGF (Pygmies and Laron dwarfs lack IGF-1).

Front 569

Describe the production of somatomedin.

Back 569

Produced in the liver and also at local site of action (i.e. bone and tissues). Stimulate chondrocytes & osteoclasts – INC bone elongation, In the blood IGFs bind strongly to binding proteins (IGFBPs) which are produced in response to GH, IGF-1 & insulin. IGF-I released slowly to the tissues therefore half-life ~20 h. Prolongs actions of GH.

Front 570

What stimulates the secretion of GH?

Back 570

(1) Growth hormone releasing hormone (GHRH)
(2) starvation, protein deficiency
(3) DEC blood glucose
(4) DEC blood fatty acids
(5) Exercise
(6) Excitement
(7) Trauma
(8) Estrogen & androgens
(9) Sleep

Front 571

What inhibits secretion of GH?

Back 571

(1) Somatostatin
(2) obesity
(3) INC blood glucose
(4) INC blood fatty acids
(5) Aging
(6) Somatomedins (IGFs)
(7) Growth hormone (-ve feedback)

Front 572

What role does growth hormone releasing hormone (GHRH) have on regulation of GH secretion?

Back 572

released by the arcuate nucleus, INC GH synthesis and secretion

Front 573

What role does somatostatin (SST) have on GH secretion?

Back 573

AKA GH inhibitory hormone, released by the peri- and para- ventricular nucleus, has no affect on GH synthesis, but DEC GH secretion

Front 574

What role does GH-releasing peptide (ghrelin) have on GH secretion?

Back 574

secreted by the arcuate nucleus, INC GH and GHRH synthesis and secretion, INC GHRH actions

Front 575

What is the cause, effect and treatment for dwarfism?

Back 575

-Cause: Congenital defect, pituitary tumor or trauma causing panhypopituitarism (DEC secretion of all anterior pituitary hormones) or isolated GH (or IGF-I) deficiency.
-Effect: Slow and reduced growth (to ~4 ft). Juvenile appearance (small maxilla & mandible). If due to panhypopituitarism will also have hypothyroidism, hypogonadism and low glucocorticoids.
-Treatment: human GH +/- thyroxine, cortisol

Front 576

What is the cause, effect and treatment for panhypopituitarism in the adult?

Back 576

-Cause: pituitary tumors, thrombosis of pituitary blood vessels, trauma.
-Effect: lethargy (hypothyroidism), weight gain (DEC fat mobilization due to lack of adrenocortical and thyroid hormones) and loss of sexual function (DEC gonadotropic hormones).
-Treatment: thyroxine, cortisol

Front 577

What is the cause, effect and treatment for gigantism (GH hypersecretion during childhood)?

Back 577

-Cause: hyperactivity of otherwise normal cells, pituitary tumor.
-Effect: Rapid growth of all tissues (up to 8 ft tall). Hyperglycemia (leading to diabetes mellitus in 10%).
-Treatment: somatostatin analogs, surgery

Front 578

What is the cause, effect and treatment for acromegaly (GH hypersecretion in the adult)?

Back 578

-Cause: pituitary tumor after adolescence.
-Effect: Bones grow in thickness (not length): cranium, nose, supraorbital ridges, mandible, vertebrae (kyphosis). Enlargement of hands and feet, elongation of ribs (barrel-chested appearance). Enlarged tongue, liver, kidneys, heart. Diabetes.
-Treatment: somatostatin analogs, surgery
-In general, excessive growth hormone can cause ketosis & insulin resistance due to metabolic disturbances

Front 579

What effect does thyroid hormone have on GH?

Back 579

Permissive for GH synthesis, release (via INC GHRH receptor) & actions (INC GH receptor, INC IGF-I, INC IGF-I receptor).

Front 580

What effect does insulin have on GH?

Back 580

Required for optimal effects of growth hormone (IGF-I is low in diabetes). Growth hormone fails to cause growth in an animal that lacks a pancreas or if carbohydrate is excluded from the diet – lack of energy source and attenuated transport of amino acids into cells.

Front 581

What effect does gonadal hormones have on GH?

Back 581

Estrogens produce pubertal growth spurt by increasing GH pulse amplitude & frequency; termination of growth (epiphyseal closure) IN BOTH SEXES. Androgens increase muscle mass.

Front 582

What effect does glucocorticoids have on GH?

Back 582

Permissive for optimal growth: INC GHRH receptor & GH synthesis. High concentrations inhibit growth (e.g. pharmacological doses to treat asthma & inflammations).

Front 583

What is the nature and action of epidermal growth factor?

Back 583

1. nature-polypeptide (produced by many normal cell types and by some tumors)
2. action-growth, proliferation and differentiation of mesenchymal and epithelial cells

Front 584

What is the nature and action of nerve growth factor?

Back 584

1. nature-polypeptide (secreted by neuron’s target)
2. action-growth and differentiation of sympathetic and sensory neurons

Front 585

What is the nature and action of fibroblast growth factor?

Back 585

1. nature-polypeptide (heparin-binding proteins)
2. action-wound healing angiogenesis, limb formation

Front 586

what is the nature and action of platelet-derived growth factor?

Back 586

1. nature-polypeptide (carried in the alpha-granulesj of platelets)
2. action-initiates replication of CT cells in response to trauma

Front 587

Describe the morphology of the pancreas.

Back 587

Richly vascularized and innervated by sympathetic and parasympathetic fibers.
Composed of: (1) acini: secrete digestive juices into duodenum and (2) Islets of Langerhans: secrete insulin and glucagon into blood

Front 588

What doe the Islets of Langerhans contain?

Back 588

Alpha (a) cells (25%): secrete glucagon, periphery
Beta (b) cells (60%): secrete insulin and amylin, center
Delta (d) cells (10%): secrete somatostatin, between alpha and beta
PP cells (<5%): secrete pancreatic polypeptide

Front 589

What role do secreted hormones have on feedback?

Back 589

Secreted hormones can ‘feedback’ on adjacent cells, directly regulating secretion. (e.g. insulin: DEC glucagon, amylin: DEC insulin, somatostatin: DEC insulin & glucagon)

Front 590

Describe glucagon.

Back 590

-Origin: alpha (a) cells of the islets of Langerhans
-Nature: simple, large polypeptide (29 amino acids)
-Synthesis: preproglucagonà proglucagonà glucagon
-Carrier protein: none
-Half-life: 5 min
-Targets: liver, β cells (?)
-Sites of degradation: liver, kidney, plasma

Front 591

How does glucagon INC blood glucose concentration?

Back 591

glucagon stimulates glycogenolysis, gluconeogenesis

Front 592

Describe glycogenolysis.

Back 592

(breakdown of liver glycogen to glucose), Mechanism of action: activates adenylyl cyclase ® cAMP formation ® protein kinase activation ® activates phosphorylase b kinase ® converts phosphorylase b into phosphorylase a ® INC degradation of glycogen to glucose-1-phosphate ® dephosphorylated & glucose released

Front 593

Describe gluconeogenesis.

Back 593

(formation of glucose from non-carbs) Mechanism of action: cAMP/PKA second messenger system activates enzymes required for gluconeogenesis (secs to mins). Also enhances gene transcription of enzymes involved in gluconeogenesis (mins to hrs)

Front 594

What are some other actions of glucagon?

Back 594

[When the concentration of glucagon increases above normal], Mobilization of fatty acids from adipose tissue by activating adipose cell lipase (INC lipolysis), Decreases uptake and storage of triglycerides by the liver

Front 595

What is the most potent factor which controls glucagon secretion?

Back 595

glucose concentration

Front 596

What stimulates alpha cells to release glucagon?

Back 596

amino acids, acetylcholine, epinephrine, NE, VIP, CCK

Front 597

What inhibits alpha cells to release glucagon?

Back 597

glucose (via feedback signals), insulin, somatostatin, ketones (via feedback signals), FFA (via feedback signals)

Front 598

Describe insulin.

Back 598

-Origin: b cells of the pancreatic islets
-Nature: small, 2-chain protein
-Synthesis & processing: preproinsulin ® proinsulin ® insulin + C-peptide. C-peptide and proinsulin are also secreted but are inactive.
-Carrier protein: none
-Half-life: ~6 min
-Degradation: by insulinase (in liver, kidney, muscle)
-Targets: ~80% of the body’s cells (most brain cells are NOT targets)

Front 599

What is the cellular mechanism of action for insulin?

Back 599

1. Insulin receptor is an enzyme-linked receptor.
2. Insulin binds with a-subunits of insulin receptor.
3. b-subunits of receptor become auto-phosphorylated.
4. Activation of tyrosine kinase causes phosphorylation of many intracellular enzymes (including Insulin Receptor Substrates (IRS), PI 3-kinase, Ser/Thr kinases) which are either activated or inactivated producing the cellular response.

Front 600

What are the effects of insulin stimulation and time course of responses?

Back 600

1. within seconds-Increases translocation of glucose transporter proteins (e.g.GLUT4) to cell membranes, facilitating glucose uptake. (This occurs in ~80 % of the body’s cells, especially muscle and adipose, but NOT neurons in the brain), Increases uptake of amino acids, PO43- and K+ into cells (by INC Na+/K+ ATPase activity).
2. 10-15 mins-Phosphorylation of intracellular metabolic enzymes, altering their activity (incl. INC PDE leading to DEC cAMP).
3. hours-days-Alters rates of DNA transcription and mRNA translation therefore changing gene expression & protein synthesis

Front 601

Describe the effects of insulin on muscle.

Back 601

Resting muscle membrane is only slightly permeable to glucose (fatty acids used as energy source). Glucose usage by muscles increases with exercise (muscle contraction increases permeability to glucose) and stimulation by insulin.

Front 602

What does insulin stimulation cause?

Back 602

• Rapid increase in glucose uptake.
• Storage of excess glucose as glycogen.
• Increased glucose metabolism due to decreased release of fatty acids from adipose and decreased utilization of fatty acids by muscle.
• Increased protein storage by increasing amino acid uptake and protein synthesis while decreasing protein degradation (conserves protein stores + acts in synergism with growth hormone)

Front 603

What are the effects of insulin on the liver?

Back 603

-Increases glucose uptake (by INC glucokinase activity; phosphorylated glucose cannot diffuse back through the cell membrane) Note: Glucose transporter (GLUT-2) is NOT regulated by insulin in the liver!
-Increases glycogenesis and reduces glycogenolysis. Insulin promotes conversion of excess glucose into glycogen by INC glycogen synthase activity. Breakdown of glycogen inhibited by inactivating liver phosphorylase.
-Inhibits gluconeogenesis by decreasing activity of enzymes (plus less amino acids available as release from muscle decreased)
-Stimulates conversion of excess glucose* into fatty acids. (*glucose not used for metabolism or storage as glycogen).

Front 604

What are the effects of insulin on adipose?

Back 604

-Increases uptake of fatty acids from dietary fat & triglycerides released by the liver. It does this by INC lipoprotein lipase in capillaries of adipose tissue. (DEC circulating lipoproteins).
-Increases glucose uptake (via GLUT4) into fat cells – Glucose used to make glycerol which combines with fatty acids to form triglycerides (storage form of fat in adipose).
-Inhibits breakdown of triglycerides already stored in adipose. It does this by DEC hormone-sensitive lipase. (DEC circulating lipoproteins).
-net effect-preservation of fat stores

Front 605

What other effects does insulin have on adipose (not direct on adipose but has a net effect is to preserve fat stores)?

Back 605

-Increases glucose uptake and metabolism in most of the body’s tissues (saving fat stores).
-Increases uptake of glucose into liver cells leading to INC fatty acid synthesis. [When liver glucagon concentration reaches ~6% all further glucose used to make fat]. Glucose ® pyruvate ® acetyl-CoA ® fatty acids.
-Increased glucose metabolism leads to excess citrate ions which INC acetyl-CoA carboxylase – INC fatty acid synthesis

Front 606

What stimulates the release of insulin from beta cells?

Back 606

1. those that do not stimulate secretion much if glucose is low-glucose, amino acids, fatty acids, ketones, acetyl choline, GI hormones, glucagon
2. excessive amounts can cause insulin resistance + secondary diabetes-GH and cortisol
3. insulin can act back and inhibit glucose, amino acids, fatty acids and ketones

Front 607

What inhibits the release of insulin form beta cells?

Back 607

somatostatin, epinephrine, NE

Front 608

Describe the mechanism for the stimulation of insulin secretion by glucose.

Back 608

Glucose entry à oxidative metabolism à INC ATP/ADP à inhibition of KATP channels à depolarization à opening of voltage-sensitive Ca2+ channels à INC [Ca2+]i à insulin secretion

Front 609

Describe the regulation of insulin secretion by glucose.

Back 609

Insulin levels are low at fasting blood glucose levels and increase substantially in response to hyperglycemia to restore normal blood glucose concentration.

Front 610

What are the phases of insulin secretion?

Back 610

1. rapid dumping of preformed insulin
2. release of preformed + freshly synthesized insulin: glucose à INC insulin gene transcription, INC processing of proinsulin

Front 611

Describe somatostatin as a regulator of glucagon and insulin secretion.

Back 611

-Origin: delta (d) cells of the islets of Langerhans (& hypothalamus [role of growth hormone inhibitory hormone])
-Nature: polypeptide (14 amino acids)
-Half-life: 3 min
-Targets: pancreatic a and b cells, gallbladder, GI tract (& anterior pituitary [inhibits growth hormone secretion])

Front 612

What are the actions of somatostatin?

Back 612

-Action: Prevents rapid exhaustion of food substrates by:
• Decreasing insulin and glucagon secretion from the pancreas
• Decreasing motility of the stomach, duodenum and gallbladder
• Decreasing secretion and absorption in the gastrointestinal tract

Front 613

Describe amylin.

Back 613

-Origin: beta (b) cells of the islets of Langerhans
-Nature: polypeptide
-Half-life: ~6 min
-Targets: Autonomic brain centers incl. dorsal vagal nuclei

Front 614

What does amylin do?

Back 614

Action: Reduces glucose influx by inhibiting food intake, gastric emptying, and glucagon secretion

Front 615

What is diabetes mellitus (DM)?

Back 615

-a syndrome of impaired metabolism caused by either: lack of insulin secretion (Type I) or insulin resistance AND impaired insulin secretion (Type II).
-Note: Classification based on insulin dependence (Insulin-Dependent DM vs. Non-Insulin-Dependent DM) is now less common.
-(Type I is always IDDM; Type II is usually NIDDM but can be IDDM.)

Front 616

Describe the epidemiology of DM.

Back 616

~5.1% of US population (~15 million). 800,000 new cases/year (~90% type II). Type II-like or type II-like DM may also develop as a consequence of other conditions (e.g. fibrosis, alcohol consumption, genetic & endocrine disease, pregnancy, etc.).

Front 617

What are the principal metabolic changes that occur during DM?

Back 617

(1) increased blood glucose concentration, (2) decreased utilization of glucose, (3) increased utilization of fat and proteins.

Front 618

In diabetes, what happens in metabolic disturbances due to DM?

Back 618

-DEC glucose uptake and DEC glucose utilization
-INC hepatic glucose production (even during hyperglycemia)
-INC fat utilization (oxidation of free fatty acids can lead to ketonemia in type I DM)
-INC release of free fatty acids from adipose and DEC lipogenesis in adipose

Front 619

What is the etiology of type I DM?

Back 619

injury to β cells causing impaired insulin secretion; due to autoimmune disorder or viral infection. Genetic tendency for susceptibility to b cell destruction from these insults or for b cell degeneration. Usual age of onset ~14 years.

Front 620

What is the pathophysioloogy of Type I DM?

Back 620

1. DEC glucose utilization and production
2. INC fat utilization
3. protein depletion

Front 621

Describe #1 on the pathophysiology of type I DM.

Back 621

• Hyperglycemia 300–1200 mg/dL
• Glycosuria when blood glucose >180 mg/dL
• Polyuria due to osmotic diuresis à thirst (polydipsia)
• Dehydration due to INCosmotic pressure in extracellular fluid (H2O leaves cells) + osmotic diuresis; in extreme cases: circulatory failure à hypotension à decreased renal blood flow à coma, death.
• Tissue damage (long-term): high glucose concentrations + metabolic abnormalities lead to cellular disruption à vasculopathies, neuropathies, retinopathy, nephropathy.

Front 622

Describe #2 on the pathophysiology of type I DM.

Back 622

-Ketonemia due to formation of keto acids at a speed that exceeds their utilization à ketonuria, acetone breath
-Metabolic acidosis due to ketonemia and dehydration à hyperventillation (rapid & deep breathing): compensation through CO2 loss but depletion of bicarbonate reserves à coma, death
-Hypercholesterolemia (due to excess fat utilization; long term) à arteriosclerosis

Front 623

Describe #3 on the pathophysiology of type I DM.

Back 623

-Aminoacidemia due to increased protein catabolism in muscle à glucose production by gluconeogenesis
-Asthenia (Lack of energy), weight loss (loss of protein & fat) despite increased appetite and polyphagia à severe wasting
-Note similarities to starvation.

Front 624

What is the etiology of Type II DM?

Back 624

impaired β cell function AND insulin resistance. The ultimate causes are unknown but genetic factors probably play a role. Obesity, decreased activity and aging contribute to the insulin resistance. Usual age of onset 50-60 years.

Front 625

What is the traditional view for the pathogenesis of type II DM?

Back 625

insulin resistance in muscle and adipose tissue à compensatory INC hepatic glucose production to provide fuel + compensatory INC insulin production to overcome insulin resistance. DM manifests when increased insulin secretion can no longer compensate for the increased glucose output.

Front 626

What does recent studies suggest for the pathogenesis of type II DM?

Back 626

indicate that impaired glucose-induced insulin secretion (mitochondrial defect) may be the primary metabolic abnormality. Once acquired, insulin resistance further worsens condition.

Front 627

What is a third idea for the pathogenesis of type II DM?

Back 627

insulin resistance in liver à INC hepatic glucose production plus insulin resistance in β cells à insufficient INC insulin secretion in response to high BG

Front 628

What is the pathophysiology of type II DM?

Back 628

1. DEC insulin sensitivity to insulin
2. DEC meal-induced insulin secretion

Front 629

Describe #1 pathophysiology of type II DM?

Back 629

• Insulin resistance in liver & muscle (DEC translocation of GLUT4) – however, contraction and IGF-I signaling in muscle can stimulate GLUT4 translocation
• Insulin resistance in adipose tissue may INC insulin resistance in other tissues via the release of free fatty acids and the hormones resistin and adiponectin
• Insulin resistance in b cells (prevents compensatory increase in β cell mass)
• result-DEC glucose utilization and storage, hyperglycemia and compensatory hyperinsulinemia

Front 630

Describe #2 pathophysiology of type II DM.

Back 630

• Hepatic glucose production doesn’t stop promptly in response to elevated blood glucose
• RESULT: postprandial hyperglycemia and compensatory hyperinsulinemia

Front 631

Describe glucotoxicity.

Back 631

(1) Chronic hyperglycemia may further desensitize β cells to glucose stimulation.
(2) Chronic hyperglycemia may block GLUT4 mobilization and worsen insulin resistance.

Front 632

Describe lipotoxicity.

Back 632

(1) High levels of circulating free fatty acids can inhibit insulin secretion and insulin signaling.
(2) Excess fatty acids inhibit glucose utilization and may stimulate gluconeogenesis in liver.

Front 633

Describe the roles of genetic factors in DM.

Back 633

Studies suggest that genetic factors may determine whether an individuals pancreas can sustain the high output of insulin that is necessary to avoid clinically significant diabetes mellitus

Front 634

Describe the clinical characteristics of type I DM.

Back 634

1. usual age at onset-<20 years
2. onset-rapid
3. body mass-low (wasted)
4. plasma insulin-low or absent
5. plasma glucagon-high, can be suppressed
6. plasma glucose-INC
7. insulin sensitivity-normal
8. therapy-insulin

Front 635

Describe the clinical characteristics of type II DM.

Back 635

1. usual age at onset->40 years
2. onset-slow
3. body mass-obese
4. plasma insulin-variable
5. plasma glucagon-high, resistant to suppression
6. plasma glucose-INC
7. insuline sensitivity-reduced
8. therapy-weight loss, drugs, insulin

Front 636

Describe micro- and macrovascular complications.

Back 636

INC risk for heart attack, stroke, nephropathy and end-stage kidney disease, retinopathy and blindness, ischemia and gangrene of limbs, Hypertension (secondary to renal injury) Atherosclerosis (due to abnormal lipid metabolism)

Front 637

Describe peripheral neuropathies and ANS dysfunction.

Back 637

- impaired cardiovascular reflexes
- impaired bladder control
- distal sensory neuropathy (reduced sensation in extremities)
- gastroenteropathy (gastroparesis, constipation with episodes of diarrhea)
-onset-1-25 years after diagnosis, prevalence-up to 50-60% in type I, less common in type II

Front 638

Describe the complications of DM.

Back 638

tubby triglyceride, hungry muscle, impaired kidney, upset stomach, depressed HDL, hyperactive liver, burned-out pancreas

Front 639

How is diabetes diagnosed?

Back 639

1. Urinary glucose: normal person glucose undetectable; diabetic loses glucose in small to large amounts
2. Fasting blood glucose: normal fasting blood glucose 80-100 mg/dL; values above this indicative of DM.
3. Fasting insulin levels: Type I – insulin levels very low or undetectable; Type II – severalfold higher than normal
4. Glucose tolerance test: assesses time course of blood glucose after ingestion of 1g glucose per kg body weight. Diabetics show greater rise in BG and it takes much longer to return to control levels
5. Acetone breath: due to conversion of keto acids to acetone – can be diagnostic of type I and severe type II DM

Front 640

What is the therapy for DM?

Back 640

1. Exercise and dieting: in an attempt to induce weight loss and improve insulin sensitivity.
2. Antidiabetic drugs: Metformin inhibits gluconeogenesis, Thiazolidinediones improve insulin sensitivity, Sulfonylureas (KATP channel blockers) stimulate insulin secretion
3. Insulin: Human insulin produced by recombinanant DNA process. Precipitated with zinc or protein derivatives to extend duration of action to 10-48 hrs.
However, current forms of treatment do not mimic physiological secretion and can’t fully prevent chronic complications.
4. Emerging therapies: aim at strict glycemic control, orally active analogs, pancreas/islet transplantation or the transplantation of β cells derived from adult or embryonic stem cells.

Front 641

What causes hyperinsulinism?

Back 641

Excessive levels of insulin due to adenoma of an islet of Langerhans (Insulinoma;10-15% malignant; metastases can also secrete insulin) OR insulin overdose in diabetic patient

Front 642

What are the symptoms and signs of hyperinsulinism?

Back 642

‘Insulin shock’ & hypoglycemia
Brain cells almost exclusively use glucose for energy therefore symptoms reflect CNS dysfunction:
50-70 mg/dL: hunger, extreme nervousness, trembling, hallucinations, cold sweat
20-50 mg/dL: seizures, loss of consciousness
<20 mg/dL: coma (unlike hyperglycemic coma: no acetone breath, no hyperventillation), permanent brain damage, death.

Front 643

What is the treatment for hyperinsulinism?

Back 643

Immediate IV of large quantities of glucose. Administration of glucagon or epinephrine (INC glycogenolysis in the liver). Permanent damage to the CNS can result if blood glucose levels are not restored rapidly.

Front 644

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Lecture 12 Endocrine hormones and metabolism

Back 644

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Lecture 12 Endocrine hormones and metabolism

Front 645

Describe homeostasis, metabolic substrates and their stores.

Back 645

-Availability of metabolic fuels must be constant in spite of intermittent food intake
-Homeostasis requires storage of fuels whenever intake is possible and their mobilization in need
-Homeostatic regulation is provided by the endocrine system and the autonomic nervous system

Front 646

Describe glucose and glycogen and their storage.

Back 646

Glucose-all cells can oxidize it, small molecule à only small amounts can be stored total EC glucose = 20 g= energy for 1 hour
Glycogen-polymer form of glucose,large molecule à 300g can be stored= energy for <1 day

Front 647

Describe protein storage.

Back 647

-More concentrated than glycogen
-By-products are “expensive” to remove (urea, sulfur-containing amino acids)
-Practically no inert depot à utilization leads to functional deficits -> death (respiratory muscle failure); max. 50% (5-6 kg) can be used

Front 648

Describe fat storage.

Back 648

-Triglycerides can be stored in an almost limitless capacity in adipose tissue
- The most concentrated energy store: 250g = energy for 1 day. Normal stores are sufficient for 30-40 days of starvation
-Energetically expensive to build; only the glycerol portion can be converted to glucose
-Limited solubility in water -> transport requires proteins or conversion into small molecules (ketone bodies)

Front 649

Describe transport of fat to brain.

Back 649

-Protein-bound lipids cannot enter the BRAIN. Only after 4-5 days of total starvation does the concentration of ketone bodies become high enough that the brain starts to use them – but can only cover 2/3 of its needs. The rest of the brain’s energy must come from blood glucose (no glycogen, no gluconeogenesis).
- Cannot be utilized anaerobically

Front 650

Describe the metabolic action of catecholamines (in seconds).

Back 650

Mobilization of fuels in response to, or in preparation for, “fright, flight or fight”
• INC glycogenolysis & gluconeogenesis à hyperglycemia
• INC lipolysis à INC free fatty acids
• INC lactate and pyruvate production in muscle
• INC glucagon and DEC insulin secretion

Front 651

Describe the metabolic actions of glucocorticoids. (long term actions: hours).

Back 651

Preservation of carbohydrate reserves and mobilization of alternative fuels
• DEC glucose utilization, INC gluconeogenesis, DEC sensitivity to insulin à hyperglycemia (long term stimulation can lead to diabetes)
• INC lipolysis and fatty acid utilization
• INC protein degradation and amino acid release

Front 652

Describe the metabolic actions of GH (hours).

Back 652

-Shift from utilization of glucose to free fatty acids without increased protein breakdown
-DEC glycogenolysis (muscle)
-INC release of free fatty acids from adipose tissue
-INC protein synthesis & DEC degradation.
-DEC insulin sensitivity à hyperinsulinemia à diabetes

Front 653

Describe the metabolic actions of thyroid hormone (in days)

Back 653

-Overall increase in metabolism
-INC glucose absorption, oxidation, gluconeogenesis, glycogenolysis
¬ -INC lipogenesis & lipolysis
¬ -INC protein synthesis & degradation.
-(In excess, lipolysis and protein degradation predominate)

Front 654

Describe the integration of energy balance.

Back 654

substrate fluxes are regulated by hormones
-fuel storage-insulin
-fuel mobilization-glucagon, catecholamines, glucocorticoids, GH, thyroid hormone

Front 655

What are normal levels of blood glucose?

Back 655

Normal fasting BG = 80-90 mg/100ml
Normal postpriandial = 120-140/100ml

Front 656

Why is tight control of blood glucose so important? What happens if too low?

Back 656

-Brain cells almost exclusively use glucose for energy therefore symptoms of hypoglycemia reflect CNS dysfunction (see notes on hyperinsulinism)
-Glucose is also the only nutrient used by the retina, germinal epithelium and red blood cells.
-Hypoglycemia can be due to insulin overdose, benign or malignant adenoma of the Langerhans islets (insulinoma), Addison’s disease, hypopituitarism, severe liver disease.

Front 657

Why is tight control of blood glucose so important? What happens if too high?

Back 657

Complications of hyperglycemia (see notes on diabetes; effects of cellular dehydration and damage)

Front 658

Describe hyperglycemia.

Back 658

INC Insulin
• Acts rapidly to inhibit glucose output and to replenish glycogen stores in the liver.
• Stimulates glucose uptake and glycogen synthesis in other tissues.
• Stimulates glucose utilization in liver and other tissues (slower action).

Front 659

Describe hypoglycemia.

Back 659

INC Glucagon, INC Catecholamines
• Help to restore blood glucose levels via glycogenolysis and gluconeogenesis
• Catecholamines decrease demand for glucose by stimulating utilization of alternative fuels in muscle and adipose
• Catecholamines also inhibit insulin and stimulate glucagon secretion

Front 660

What happens during sustained hypoglycemia (hours)?

Back 660

In addition to glucagon and catecholamines, glucocorticoids and growth hormone become important, ensuring that:
• The peripheral drain on glucose reserves is minimized by decreasing glucose consumption by muscle and replacing with alternative fuels (free fatty acids, ketones)
• The liver contains enough glycogen to satisfy minute-to-minute needs of glucose-dependent cells by stimulating gluconeogenesis

Front 661

Describe the integrative hormonal response to hypoglycemia.

Back 661

This integrative response is launched to ensure blood glucose levels are high enough to satisfy the needs of glucose-dependent cells.
-INC in plasma epinephrine, NE, glucagon, cortisonl and plasma growth hormone

Front 662

Describe the integrative control of blood glucose concentration.

Back 662

1. glucose production-stimulated by epinephrine, NE, glucagon and glucocorticoids, inhibited by insulin, occurs in liver
2. glucose consumption-stimulated by insulin, inhibited by glucocorticoids, GH, occurs in muscle and adipose tissue

Front 663

Describe hormone secretion during postpandial period.

Back 663

-Increased secretion of insulin, sympathoadrenal activity is low
-Insulin dominates:
• glucose, amino acids, fatty acids are transferred to stores
• dietary glucose is used as fuel
• glucose & fatty acid mobilization from stores is inhibited

Front 664

Describe hormone secretion during postabsorptive period (3 to < 24 h after meal; BG ~90)

Back 664

-Insulin, growth hormone and cortisol at low basal levels; glucagon is relatively low
Glucagon dominates:
• Glycogen and gluconeogenesis provide source of blood glucose for glucose-dependent cells (brain, RBCs)
• Increased utilization of free fatty acids by muscle

Front 665

Describe hormone secretion during fastring for 1-3 days (BG ~70-80)

Back 665

DEC insulin, INC glucagon, INC GH, cortisol levels unchanged but diurnal pattern of release plays a permissive role in reducing glucose utilization
Conversion of T4 to T3 is attenuated to reduce BMR
• glucose is only used by the brain & blood cells
• glucose is from gluconeogenesis (muscle protein, glycerol from TG)
• free fatty acids provide primary fuel in muscle, kidney, etc.

Front 666

Describe hormone secretion during fasting for >3 days.

Back 666

As above, however now exaggerated oscillations in GH but no longer stimulates IGF-I à anabolic effect inhibited
• diminished glucose utilization
• mobilization and utilization of fat continues to increase producing ketones (ketosis): fuel for brain
• gluconeogenesis -> INC NH4+ excretion

Front 667

Describe hormone secretion during terminal starvation.

Back 667

When fat stores become depleted, protein stores are consumed rapidly for energy (several hundred grams per day, instead of the normal 30-50g per day)
• Increased gluconeogenesis from protein until respiratory muscle failure à death

Front 668

Describe hormone secretion during fasting.

Back 668

glucose DEC, insulin DEC, glucagon INC, cortisol, stays pretty constant, GH INC, T3 DEC

Front 669

Describe hormone secretion during short-term maximal effort (100-yd dash) exercise.

Back 669

Energy source for muscle activity: creatine phosphate; glycogen (producing lactate). Reinforced by INC sympathoadrenal activity
Role of the endocrine system: regeneration of stores after exercise: dietary intake -> INC insulin -> replenishment of glycogen stores

Front 670

Describe hormone secretion during sustained (moderate) aerobic exercise.

Back 670

-Fuel: 1-2 h: glucose from blood glucose + liver and muscle glycogen, >3 h: increased use of fats to a maximum of 70% total energy consumed
-Hormones: INC catecholamines -> DEC insulin; INC glucagon; INC cortisol; INC GH
à glycogenolysis, gluconeogenesis, mobilization of fat
-Increased glucose uptake by working muscles - independent of insulin

Front 671

Describe hormone secretion during sustained exercise.

Back 671

insulin DEC, INC in epinephrine, NE, glucagon, cortisol, GH

Front 672

Describe appetite control via hypothalamic feeding and satiety centers.

Back 672

-Lateral Hypothalamic Area (LHA) ‘hunger center’-Stimulation à hyperphagia; Lesion -> hypophagia, Melanin-Concentrating Hormone: INC food intake, Orexins: arousal, INC food-seeking behavior à INC food intake
-Ventromedial nucleus (VMN) ‘satiety center’-Stimulation à satiety, aphagia; Lesion -> hyperphagia, obesity, Brain-derived neurotrophic factor: DEC food intake
-Paraventricular Nucleus (PVN)-Integrates signals from arcuate nucleus, brain stem and periphery Initiates changes in endocrine systems (via CRH & TRH)
-Dorsomedial nucleus (DMN)-Lesions of this area normally depress eating behavior

Front 673

What role does the arcuate nucleus have on appetite control?

Back 673

-The principal integration site where signals from the gastrointestinal tract and adipose tissue converge to regulate appetite and energy expenditure. It is accessible to peripheral signals (no blood-brain barrier)
-Neurotransmitters and hormones acting on the hypothalamic feeding and satiety centers can be classified as being either:(1) Anorexigenic (inhibit feeding) or (2) Orexigenic (stimulate feeding)

Front 674

What is the anorexigenic circuit?

Back 674

nueonrs of the arcuate nuclei releasing a-MSH and CART

Front 675

What does alpha-melanocyte-stimulating hormone (a-MSH) do?

Back 675

• Derived from proopiomelanocortin (POMC)
• act on melanocortin receptors on neurons of PVN
• Release increased by feeding, reduced by fasting
• Activation of MCR-3/4 receptors à DEC food intake and INC energy expenditure by INC sympathetic activity
• Mutations or lack of MCR-4 cause over-eating (hyperphagia) and obesity; excessive activation has been linked to anorexia

Front 676

What does cocaine- and amphetamine-regulated transcript (CART) do?

Back 676

• Co-localized with a-MSH
• Release reduced by fasting
• Inhibits food intake

Front 677

what is the orexigenic circuit?

Back 677

neurons of the arcuate nuclei releasing neuropeptide Y and agouti-related peptide, Both NPY & AGRP stimulate feeding by activating neurons of the PVN, by inhibiting a-MSH neurons, and by antagonizing effects of a-MSH

Front 678

Describe neuropeptide Y (NPY).

Back 678

• Release increased by fasting, reduced after feeding
• Stimulation increases appetite à hyperphagia, obesity, DEC energy expenditure and DEC heat production (DEC sympathetic activity)

Front 679

Describe agouti-related peptide (AGRP).

Back 679

• 90% co-localized with NPY
• competitive inhibitor of a-MSH
• Increased in fasting, reduced after feeding
• INC food intake, DEC energy expenditure, DEC heat production
• Gene mutations causing excess AGRP à hyperphagia & obesity

Front 680

Describe the role of the brain stem on appetite control.

Back 680

• The actual mechanics of feeding are controlled by the brain stem
• The nucleus tractus solitarius (NTS) makes reciprocal connections with the hypothalamus
• Accessible to peripheral signals (GI & fat hormones): area postrema: no blood-brain barrier

Front 681

Describe the role of higher centers (including amygdala and prefrontal cortex) on appetite control.

Back 681

• Play important roles in the control of appetite and feeding
• Lesions of amygdala alters feeding behavior
• Destruction of amygdala à loss of appetite control that determines the type and quality of food eaten

Front 682

What role does GI distension have on regulating food intake?

Back 682

Stretch of the stomach and duodenum activates inhibitory signals which are sent via the vagus nerve to suppress the hypothalamic feeding center

Front 683

What role does GI hormones have on regulating food intake?

Back 683

-Cholecystokinin (CCK): anorexigenic; released in response to fat entering duodenum.
-Peptide YY: anorexigenic; delays gastric emptying. Secretion is proportional to calories ingested
-Glucagon-like peptide: anorexigenic; INC insulin (which further; Reduced levels may contribute to obesity
-Ghrelin: orexigenic; secretion from stomach and intestine increased during fasting and in anticipation of food.

Front 684

What factor help maintain energy stores?

Back 684

• Circulating concentrations of blood glucose, amino acids and lipids: Glucostatic, aminostatic, lipostatic theories: when substrate levels decrease the desire for feeding increases to restore homeostasis – Detected via glucosensitive neurons of the hypothalmus
• Feedback signals from adipose tissue: Leptin: Peptide hormone released from adipocytes that acts to reduce fat storage via various pathways (see next slide)

Front 685

Describe leptin.

Back 685

-Protein product of the ob gene expressed in adipose tissue
-Leptin receptors expressed in hypothalamic nuclei; activation causes: DEC orexigenic substances NPY & AgRP, INC a-MSH (anorexigenic) à DEC food intake, INC Sympathetic activity à INC metabolic rate, DEC Insulin à DEC energy storage
-Leptin levels positively correlate with food intake and adiposity
-Mutations in leptin or its receptor cause hyperphagia, obesity, diabetes
-However, no leptin deficiency in most obese humans and peripherally administered leptin has only very modest effects on body weight – may be linked to leptin resistance

Front 686

What is the definition of obesity?

Back 686

-Body mass index (BMI) = weight (lbs) × 703 / height2 (in.)
-Overweight: Body weight > 110% of ideal OR BMI > 25
-Obesity: Body weight > 130% of ideal OR BMI > 30

Front 687

What is the epidemiology of obesity?

Back 687

~127×106 (~65%) adults in the U.S. are overweight, 60×106 (~31%) are obese and 9×106 are extremely obese (BMI > 40). ~15% of children and adolescents are overweight.

Front 688

What is the significance of obesity?

Back 688

Increased risk for a host of diseases, particularly when combined with other risk factors (“metabolic syndrome X”: insulin resistance, excessive abdominal fat, high blood glucose, high blood pressure and high cholesterol)

Front 689

What is the cause of obesity?

Back 689

-Food intake > expenditure
-Contributing factors: Genetics (25-75%), endocrine/regulatory imbalance, environment, culture.

Front 690

Describe anorexia nervosa.

Back 690

• Psychiatric disorder mainly in adolescent/young women due to distorted body image
• Compulsive dieting, self-imposed starvation à profoundly low body weight
• Delayed gastric emptying, endocrine problems including infertility

Front 691

Describe bulimia nervosa.

Back 691

• Recurrent episodes of binge eating with feeling of lack of control over eating. Often followed by self-induced vomiting; use of laxatives or diuretics
• Weight usually does not fall below normal
• Not accompanied by endocrine or GI pathology (aside from dyspepsia)

Front 692

What is the definition of sleep?

Back 692

unconsciousness from which the person can be aroused by sensory or other stimuli

Front 693

What are the two types of sleep?

Back 693

slow-wave sleep, REM sleep (paradoxical sleep, desynchronized sleep)

Front 694

Describe slow-wave sleep.

Back 694

brain waves are very large but very slow, characterizes most sleep each night, deep, restful sleep, associated with a DEC in both peripheral vascular tone and many other vegetative functions of the body, also 10 to 30 percent DEC in BP, respiratory rate, and basal metabolic rate, consolidation of the dreams in memory does not occur here

Front 695

Describe REM sleep.

Back 695

rapid eye movement, in this sleep eyes undergo rapid movements despite the fact that the person is still asleep, occurs in episodes during sleep, ~25% of sleep, recurs about every 90 minutes, associated with vivid dreaming, lasts 5-30 minutes, INC with more sleep

Front 696

What are the characteristics of REM sleep?

Back 696

1. it is usually associated with active dreaming and active bodily muscle movements
2. even more difficult to arouse, but people usually awaken spontaneously in the morning during an episode of REM sleep
3. depressed muscle tone, indicates strong inhibition of the spinal muscle control areas
4. irregular heart and respiratory rate
5. irregular muscle movements
6. highly active brain in REM sleep, brain patterns similar to wakefulness

Front 697

What is thought to cause sleep?

Back 697

believed to be caused by an active inhibitory process, transecting the brain stem at the level of the midpons creates a brain whose cortex never goes to sleep, there seems to be some center located below the midpontile level of the brain stem that is required to cause sleep by inhibiting other parts of the brain

Front 698

What are some of the areas through to cause sleep?

Back 698

1. raphe nuclei in the lower half of the pons and in the medulla-these neurons secrete serotonin (if serotonin formation is blocked, animals can’t sleep for several days)
2. nucleus of the tractus solitaries-the sensory region of the medulla and pons also promotes sleep, these signals perhaps act by exciting the raphe nuclei and the serotonin system
3. stimulation of regions in the diencephalon promote sleep (include rostral part of hypothalamus and diffuse nuclei of the thalamus)

Front 699

What is the major problem with the serotonin theory of sleep?

Back 699

the blood concentration of serotonin are lower during sleep than during wakefulness

Front 700

What happens with lesion in sleep-promoting centers?

Back 700

can cause intense wakefulness with lesions in raphe nuclei

Front 701

What role does muramyl peptide have on sleep?

Back 701

accumulates in the CSF and urine in animals kept awake for several days, when add micrograms of this into 3rd ventricle, almost natural sleep occurs in minutes, also nonapeptide from blood and neuronal subsntaces in brain can cause sleep, thought that prolongede wakefulness causes progressive accumulation of sleep factors

Front 702

What are some possible causes of REM sleep?

Back 702

drugs that mimic the action of ACh INC the occurrence of REM sleep, thought that large ACh-secreting neurons in the upper brainstem reticular formation might activate many portions of the brain

Front 703

Describe the effects that sleep has on the nervous system.

Back 703

more important, any person who has a transected spinal cord in the neck shows no harmful effects in the body beneath the level of transaction that can be attributed to a sleep-wakefulness cycle, prolonged wakefulness is associated with progressive malfunction of the throught processes and sometimes even causes abnormal behavioral activites (sleep is through to restore normal levels of brain activity and normal balance among the different parts of the CNS), sleep restores the principal value of sleep is to restore the natural balance among the neuronal centers

Front 704

Describe the effects that sleep has on other functional systems of the body.

Back 704

during slow-wave sleep, sympathetic activity DEC while parasympathetic INC, leads to arterial BP falling, pulse rate DEC, skin vessels dilate, activity of GI tract INC, skeletal muscles fall into a mainly relaxed state and the overall BMR falls by 10 to 30%