Wagner-Ovarian Control And Function

Front 1

describe the anatomical considerations of the ovaries

Back 1

1. Primary reproductive organs (gonads)-ovaries
2. Reproductive tract
1) 2 oviducts (Fallopian tubes) where fertilization occurs
2) uterus-maintains fetus; consists of 2 layers, myometrium (smooth muscle layer) and endometrium (uterine lining)
3) vagina
4) cervix-distal portion of uterus that projects into vagina
3. Accessory sex glands: breasts
4. External genitalia (vulva)-vaginal opening, lesser vestibular glands (Skene’s glands), greater vestibular glands (Bartholin’s glands), labia minora, labia majora and clitoris
5. Secondary sexual characteristics-features that make up female body configuration: narrow shoulders, wide hips, convergent thighs and divergent arms that give female wide carrying angles, inherent distribution of fat in breasts and buttocks

Front 2

describe the secretions of progesterone and estrogen

Back 2

Secretion of estrogens & progesterone-ovaries secrete 3 estrogens (estradiol, estrone & estriol), and progesterone from distinct functional entities w/in organ; estrogens are C18 steroids synthesized from androgens, w/ estradiol most potent; progesterone is C21 steroid
coordination b/t ovarian thecal & granulosa cells in estrogen biosynthesis-thecal cells produce androstenedione from cholesterol via Δ5 pathway of steroidogenesis, in which androstenedione is formed from pregnenolone by 17-hydroxylation to 17-hydroxypregnenolone, 17-ketosteroid formation via 17,20-lyase to DHEA, and 3-carbon reduction to androstenedione via 3β-hydroxysteroid dehydrogenase
granulosa cells accommodate androgen substrate provided by thecal cells, and convert androstenedione to estrone, then to estradiol

Front 3

describe the role of the corpus luteum in the secretions of progesterone and estrogen

Back 3

progesterone-secreting corpus luteum forms from ruptured antral follicle; steroidogenesis in corpus luteum occurs via Δ4 pathway, in which progesterone rather than 17-hydroxypregnenolone is formed preferentially from pregnenolone, and estradiol is synthesized entirely w/in luteal cell

Front 4

describe the biodistribution of estrogen and progesterone

Back 4

i. estrogen-vast majority of estradiol in plasma is bound to protein (60% to albumin, 38% to GBG); estrogens subject to hepatic glucuronidation or sulfation, then excreted in urine; also secreted into bile and reabsorbed via enterohepatic circulation
ii. progesterone-all progesterone circulates in plasma bound to protein (80% to albumin, 18% to corticosteroid-binding globulin); has short half-life, and readily converted to pregnanediol, conjugated to glucuronic acid and excreted in urine

Front 5

describe the mechanisms of action of estrogen and progesterone

Back 5

i. estrogen-binds to intracellular receptor in nucleus, modifies gene transcription and thus protein synthesis; acts at 2 receptor subtypes (ERalpha and ER-Beta); also alters neuronal excitability and hormone secretion on more rapid time course
ii. progesterone-binds to 2 isoforms of intracellular progesterone receptor (PRA and PRB) to affect gene transcription; also modulates actions of neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor/chloride channel through allosteric modulation of GABA binding

Front 6

describe the mitotic proliferation of oogenesis

Back 6

Oogenesis-has general features in common w/ spermatogenesis, but several prominent qualitative differences exist
mitotic proliferation-occurs during fetal development, giving rise to 6-7 million primary oocytes; no further mitotic proliferation takes place after 5th month of gestation; by end of term reduced to 2 million due to apoptotic cell death; each surviving primary oocyte becomes surrounded by layer of granulosa cells to form primary follicle

Front 7

describe meiosis of oogenesis

Back 7

i. 1st meiotic division-primary oocytes begin 1st meiotic division during later stages of fetal development; remains in “suspended prophase” until follicle is groomed for ovulation
each primary follicle endures 2 possible fates; majority of primary follicles undergo atresia; if maturation begins under conditions which maximize capability to secrete estrogen, primary follicle develops into secondary, then antral follicle (stage characterized by dramatic enlargement of primary oocyte, and growth and differentiation of granulosa cells and other surrounding cell layers)
meiotic division completed just before ovulation; division is asymmetric, resulting in secondary oocyte and 1st polar body
ii. 2nd meiotic division-secondary oocyte immediately begins 2nd meiotic division, but process is arrested in metaphase II and is never completed unless triggered by fertilization; also asymmetric, resulting in mature ovum and 2nd polar body

Front 8

describe the control of the ovarian function by the hypothalamus and pituitary

Back 8

1. Hypothalamus
a. gonadotropin-releasing hormone (GnRH)-female reproductive axis driven by episodic bursts of GnRH released from hypothalamus into hypophysial portal vasculature; GnRH pulse frequency is stimulated by noradrenergic input from brainstem, and inhibited by opioid peptides (Beta-endorphin) and GABA; GnRH bursts elicit pulsatile release of FSH and LH
2. Pituitary
a. follicle-stimulating hormone (FSH)-stimulates estrogen synthesis and secretion via cAMP-induced enhancement of aromatase and 17β-hydroxysteroid dehydrogenase activity
b. luteinizing hormone (LH)-acts via cAMP to stimulate enzymatic conversion of cholesterol to androstenedione; granulosa cells express LH receptors in later stages of follicular maturation; thus LH stimulation also contributes toward estradiol production

Front 9

describe inhibin and estrogen control of the ovarian function

Back 9

a. inhibin-released from granulosa cells; inhibits FSH release from anterior pituitary
b. estrogen-vital to proper follicular development; in reproductive tract, estrogen increases uterine contractility and blood flow, and stimulates growth of uterine myometrium and endometrium; also upregulates uterine progesterone receptor expression
in cervix, estrogen causes secretion of clear, fluid mucus; also promotes pubertal breast enlargement, and produces growth of milk ducts w/in breast; facilitates development of the female secondary sex characteristics, and acts w/in hypothalamus to enhance sexual libido
exerts feedback effect on reproductive axis by inhibiting FSH secretion and, depending on stage of reproductive cycle, can either inhibit or stimulate LH secretion

Front 10

describe how progesterone controls ovarian function

Back 10

In “estrogen-primed” uterus, progesterone promotes vascularization of endometrial layer, and causes synthesis and storage of large quantities of glycogen, and accumulation of electrolytes and water
physiologically antagonizes estrogen-induced uterine smooth muscle contraction, and in cervix elicits secretion of thick, viscous mucus; in breast, progesterone stimulates lobular and alveolar development and plays important role in milk secretion during lactation
exerts negative feedback on LH secretion via hypothalamus and anterior pituitary, and potentiates negative feedback effects of estrogen
elicits thermogenesis; responsible for periovulatory increase in body temperature

Front 11

describe disruption of the reproduction axis

Back 11

In females, leads to amenorrhea (absence of menstrual period); ovarian insufficiency before puberty called primary amenorrhea (e.g., anorexia nervosa); that occurring after puberty in individuals w/ previously normal menstrual cyclicity is secondary amenorrhea (e.g., pregnancy, lactation, dramatic decrease in body fat due to excessive exercise)
a. hypergonadotropic hypogonadism-caused by primary gonadal insufficiency and associated w/ elevated GnRH and gonadotropin levels; seen in individuals w/:
1) Turner’s syndrome
2) FSH or LH resistance
3) aromatase deficiency
4) menopausal patients (ovaries have ceased to produce estradiol and progesterone)
b. hypogonadotropic hypogonadism-gonadal insufficiency secondary to compromised hypothalamic or pituitary function; observed in females w/:
1) Kallmann’s syndrome
2) GnRH resistance
3) hypothalamic amenorrhea-caused by excessive levels of endogenous opioid peptides (e.g., Beta-endorphin) that inhibit GnRH burst firing

Front 12

describe the follicular phase of the ovarian cycle

Back 12

Reproductive cycle-parallel cyclical changes occurring in ovary and uterus as reproductive system prepares for ovulation, fertilization and implantation (average cycle lasts 28 days); begins on 1st day of menstrual period
follicular phase-dominated by developing and maturing follicles
i. follicular development and maturation-only follicles that begin development during follicular phase stand chance of becoming mature follicle
During early follicular development, granulosa cells proliferate and secrete zona pellucida, gelatinous barrier b/t primary oocyte and granulosa cells; inner granulosa cells couple to primary oocyte via gap jxns, which allows for transfer of nutrients from granulosa cells to primary oocyte; continued follicular growth triggers differentiation of surrounding CT and formation of thecal cell layer
When follicle gains capacity to synthesize and secrete estrogen, has become tertiary (antral) follicle; antral cavity filled w/ fluid derived from plasma constituents, and enriched in estrogens
Tertiary follicles undergo rapid and expansive growth; one developing tertiary follicle becomes mature (Graffian follicle); at this point, follicle comprised mostly of antral fluid, and primary oocyte, surrounded by zona pellucida and single layer of granulosa cells (collectively called corona radiata), is displaced to one side
1st meiotic division is completed just prior to ovulation; resultant secondary oocyte, still surrounded by corona radiata, bursts through peripheral ovarian surface, into abdominal cavity and is swept into Fallopian tubes

Front 13

describe control of follicular function in the ovarian cycle

Back 13

hormonal support provided by FSH, LH and estrogen required; FSH induces antral formation, and FSH and estrogen act in concert to induce granulosa cell proliferation
LH stimulates androgen production in thecal cells (rate-limiting step), and FSH acts on granulosa cell to aromatize androgens into estrogens; as LH levels rise during follicular phase, so do estrogen levels Throughout follicular phase, estrogen inhibits hypothalamic GnRH release, thereby inhibiting release of FSH and LH; estrogen also decreases sensitivity of anterior pituitary to GnRH stimulation
inhibin decreases FSH release from anterior pituitary; thus, both estrogen and inhibin responsible for steady decline in plasma FSH concentrations over course of follicular phase

Front 14

describe the control of ovulation in the ovarian cycle

Back 14

ovulation triggered by massive mid-cycle LH surge; brings about following changes in Graffian follicle:
1) decreased estrogen output
2) completion of 1st meiotic division
3) prostaglandin-induced ovulation
Thus, in early & mid-follicular phase there is low level of pulsatile LH secretion that is under estrogen negative feedback, whereas during late follicular phase exists preovulatory LH surge that is under positive feedback by peaking levels of estrogen; heightened levels of estrogen increase hypothalamic GnRH burst frequency, increase sensitivity of anterior pituitary to GnRH stimulation, and serve as signal that follicle is ready for ovulation; once ovulation has occurred, this signals end of follicular phase of ovarian cycle

Front 15

describe the formation of the corpus luteum as part of the luteal phase of the ovarian cycle

Back 15

immediately following ovulation, LH surge triggers rapid transformation of remnants of follicle; granulosa and thecal cells collapse into antral cavity caused by follicular rupture; follicular cells undergo proliferation and luteinization, and soon gain capacity to store large quantities of cholesterol in lipid droplets that gives them ability to synthesize and secrete large quantities of gonadal steroids
corpus luteum reaches full maturity in 8-9 days; if fertilization and implantation don't occur, corpus luteum begins to degenerate 4 days prior to next menstrual period, and becomes corpus albicans

Front 16

describe the control of the corpus luteum

Back 16

Once formed, LH maintains viability of corpus luteum, and promotes rise of progesterone (and also estrogen) secretion; marks 1st meaningful rise of progesterone secretion, which dominates luteal phase
Estrogen levels decline after mid-cycle peak (signaling end of follicle), rebound midway through luteal phase; pronounced, progesterone-induced negative feedback prevents another LH surge from occurring, and minimizes possibility for any viable follicular development and ovulation during luteal phase
If fertilization doesn’t occur, corpus luteum begins to degenerate 4 days before start of menstrual period due to steroid-induced decline in LH levels; demise of corpus luteum ends luteal phase, marks beginning of next menstrual period, and thus new reproductive cycle

Front 17

describe the menstrual phase of the menstrual (uterine cycle)

Back 17

menstrual (uterine) cycle-cyclical fluctuations in gonadal steroid hormone levels give rise to parallel changes in uterus; variations are termed menstrual (uterine) cycle, follow same time course as ovarian cycle
menstrual phase-characterized by discharge of blood endometrial debris from vagina; plasma estrogen and progesterone levels are low due to degeneration of corpus luteum from previous cycle
As result, hormonal support for endometrial lining is absent, and integrity declines; local release of prostaglandins causes vasoconstriction and disruption of blood supply; local hemorrhage flushes endometrial layer into uterine lumen, and prostaglandin-induced contractions of uterine myometrium expel debris from uterus as menstrual flow
For some women, contractions cause painful cramping (primary dysmenorrhea); severe, NSAID-resistant menstrual cramping termed secondary dysmenorrhea (caused by IUD contraceptives, pelvic infection, uterine tumors or endometriosis)
total blood loss resulting from single menstrual period ranges from slight spotting to 150 ml; menstrual phase lasts anywhere from 5-7 days, corresponding to early follicular phase of ovarian cycle; plasma levels of FSH and LH rise to help orchestrate maturation of new set of ovarian follicles, which secrete estrogen that promotes repair and growth of endometrium

Front 18

describe the proliferative and secretory phases of the menstrual cycle

Back 18

a. proliferative phase-begins w/ cessation of menstrual flow concurrent w/ latter part of follicular phase; estrogen increases thickness of endometrial lining due to ability to stimulate proliferation of epithelial cells, secretory glands and blood vessels; peak estrogen concentration observed at end of proliferative/follicular phase triggers preovulatory LH surge
c. secretory (progestational) phase-begins after ovulation, and temporally coincides w/ luteal phase of ovarian cycle; progesterone acts on estrogen-primed endometrium to help create richly vascularized, glycogen-filled uterine lining capable of sustaining early embryo until placenta is formed; corpus luteum degenerates if fertilization and implantation don't occur, which signals beginning of new follicular and menstrual phase of reproductive cycle

Front 19

describe puberty in females

Back 19

3 major events take place:
1) thelarche (breast development)
2) pubarche (appearance of axillary and pubic hair)
3) menarche (1st menstrual period)
initial reproductive cycles are anovulatory, but regular ovulation begins 1 year after menarche
a. onset of puberty-triggered by episodic bursts of hypothalamic GnRH release due to reduced sensitivity of GnRH neurons to steroid-induced negative feedback; bursts of GnRH elicit pulsatile release of gonadotropins, which stimulate ovarian function; resultant rise in estrogen secretion promotes growth of reproductive tract and development of secondary sexual characteristics; pubertal rise in adrenal androgens (adrenarche) causes axillary and pubic hair growth
b. precocious puberty-characterized by early development of secondary sexual characteristics and oogenesis
c. delayed or absent puberty-associated w/ primary amenorrhea caused by hypopituitarism, anorexia nervosa, as well as Turner’s or Kallmann’s syndrome

Front 20

describe menopause

Back 20

disappearance of reproductive cycles due to depletion of primary ovarian follicle reserve that occurs b/t 45-55 years of age; reproductive cycles 1st become irregular as ovaries begin to lose capacity to respond to gonadotropin stimulation; estrogen and progesterone levels steadily decrease, until reproductive cyclicity completely ceases
gradual transition from sexual maturity to loss of reproductive function known as climacteric; menopausal women exhibit hypergonadal hypogonadism and secondary amenorrhea, characterized by elevated levels of GnRH and gonadotropins, due to loss of gonadal steroid-induced negative feedback

Front 21

describe the effects of menopause

Back 21

a. effects on reproductive tract-reproductive tract and external genitalia suffer considerable atrophy; postmenopausal women still retain some libido due to low levels of sex steroids produced by other tissues (adrenal cortex, adipose tissue, liver, brain) in small amounts; levels insufficient to maintain integrity of vaginal lining, and resultant vaginal dryness can cause discomfort during sexual intercourse; estrogen replacement therapy can effectively resolve these issues
b. other effects-75% of menopausal women experience “hot flashes," incidence of which decreases following menopause; loss of estrogen also associated w/ osteoporosis caused primarily by increase in cytokine stimulation of osteoclast maturation and activity, and is exacerbated by risk factors such as low physical activity, smoking, and alcohol and caffeine use; effects reversed by estrogen replacement therapy