Pbl Exam 5 Case 3

Front 1

1. What are the two major phases of female reproductive functions?

Back 1

1. Preparation of the female body for conception and pregnancy

2. The period of pregnancy itself

Front 2

2. What are the steps of the female reproductive system?

Back 2

1. Reproduction begins with the development of ova in the ovaries
2. In the middle of each monthly sexual cycle, a single ovum is expelled from an ovarian follicle into the abdominal cavity near the open fimbriated ends of the two fallopian tubes.
3. This ovum then passes through one of the fallopian tubes into the uterus
4. If the ovum has been fertilized by a sperm, it implants in the uterus, where it develops into a fetus, a placenta, and fetal membranes, and eventually into a baby.

Front 3

3. How does the ovum become an oocyte?

Back 3

1. During fetal life, the outer surface of the ovary is covered by a germinal epithelium, which embryologically is derived from the epithelium of the germinal ridges.
2. As the fetus develops, primordial ova differentiate from this germinal epithelium and migrate into the substance of the ovarian cortex.
3. Each ovum then collects around it a layer of spindle cells from the ovarian stroma, and causes them to take on epitheliod characteristics; they are then called granulosa cells.
4. The ovum surrounded by a single layer of granulosa cells is called a primordial follicle.
5. The ovum at this stage is still immature, requiring two more cell divisions before it can be fertilized by a sperm. At this time, ovum is called a primary oocyte.

Front 4

4. What are the three hierarchies of hormones in the female?

Back 4

1. A hypothalamic releasing hormone, gonadotropin-releasing hormone (GnRH)
2. The anterior pituitary sex hormones, follicle stimulating hormone (FSH), and luteinizing hormone (LH), both of which are secreted in response to the release of GnRH
3. The ovarian hormones, estrogen and progesterone, which are secreted by the ovaries in response to the two female sex hormones from the anterior pituitary gland.

Front 5

5. What is the female monthly sexual cycle?

What are the two significant results of the cycle?

Back 5

The rhythmical pattern of female hormone secretion is called the female monthly sexual cycle, AKA menstrual cycle.

The duration of the cycle averages 28 days; it may be as short as 20 or a long as 45.

The two significant results are:
1. Only a single ovum is normally released from the ovaries each month, so that normally only a single fetus will begin to grow at a time.
2. The uterine endometrium is prepared in advance for implantation of the fertilized ovum at the required time of the month.

Front 6

6. What are the effects of the gonadotropic hormones on the ovaries?

Back 6

The ovarian chances that occur during the menstrual cycle depend completely on FSH and LH.

At age 9-12, the pituitary begins to secrete progressively more FSH and LH, which leads to onset of normal monthly sexual cycles beginning between the ages of 11 and 15 years.

During each month of the cycle, there is a cyclical increase and decrease of both FSH and LH.

Front 7

7. How do FSH and LH stimulate their ovarian target cells?

Back 7

They combine with highly specific FSH and LH receptors int he ovarian target cell membranes.

In turn, the activated receptors increase the cells' rates of secretion and usually the growth and proliferation of the cells as well.

Almost all thees stimulatory effects result form activation of cAMP in the cell cytoplasm, which causes the formation of protein kinase and multiple phosphorylations of key enzymes that stimulate sex hormone synthesis.

Front 8

8. What is the primordial follicle?

Back 8

When a female child is born, each ovum is surrounded by a single layer of granulosa cells; the ovum, with this granulosa cell sheath, is called a primordial follicle.

Front 9

9. What is the purpose of the oocyte maturation inhibiting factor?

From where is this inhibiting factor secreted?

Back 9

The granulosa cells are believed to provide nourishment for the ovum and to secrete an oocyte maturation inhibiting factor that keeps the ovum suspended in its primordial state in the prophase stage of meiotic division.

Front 10

10. What is a primary follicle?

Back 10

After puberty, when FSH and LH from the anterior pituitary gland begin to be secreted, the ovaries within then begin to grow.

The first stage of follicular growth is moderate enlargement of the ovum itself, which increases in diameter 2-3xx.

Then follows growth of additional layers of granulosa cells in some of the follicles; these follicles are known as primary follicles.

Front 11

11. What is the theca?

Back 11

In response to LH and FSH, 6-12 primary follicles grow rapidly each month. The initial effect is rapid proliferation of the granulosa cells, giving rise to many more layers of these cells.

In addition, spindle cells derived from the ovary interstitium collect in several layers outside the granulosa cells, giving rise to a second mass of cells called the theca.

This is divided into two layers, the theca interna, and the theca externa.

Front 12

12. What are the characteristics of the theca interna/externa?

Back 12

The theca interna takes on epithelioid characteristics similar to those of the granulosa cells and develop the ability to secrete additional steroid sex hormones (estrogen and progesterone).

The outer layer, the theca externa, develops into a highly vascular connective tissue capsule that becomes the capsule of the developing follicle.

Front 13

13. What is the antrum?

The early growth of the primary follicle up to the antral stage is stimulated by...?

Back 13

After the early proliferative phase of growth, the mass of granulosa cells secretes a follicular fluid that contains a high concentration of estrogen.

Accumulation of this fluid causes an antrum to appear within the mass of granulosa cells.

*The early growth of the primary follicle up to the antral stage is stimulated mainly by FSH alone. This leads to larger follicles called vesicular follicles.

Front 14

14. The accelerated growth of the vesicular follicles is caused by what three things...?

Back 14

1. Estrogen is secreted into the follicle and causes the granulosa cells to form increasing numbers of FSH receptors.
2. The pituitary FSH and the estrogens combine to promote LH receptors on the original granulosa cells, thus allowing LH stimulation to occur in addition to FSH stimulation and creating an even more rapid increase in follicular secretion.
3. The increasing estrogens from the follicle plus the increasing LH from the anterior pituitary gland act together to cause proliferation of the follicular thecal cells and increase their secretion as well.

Front 15

15. How many follicles fully mature each month?

What causes atresia?

Back 15

Only one; the remaining 5-11 developing follicles involute and they are said to become atretic.

The large amts of estrogen from the most rapidly growing follicle act on the hypothalamus to depress further enhancement of FSH secretion by the anterior pituitary gland, in this way blocking further growth of the less well developed follicles.

Therefore, the largest follicle continues to grow b/c of its intrinsic positive feedback effects, while all the other follicles stop growing and actually involute.

Front 16

16. Why is atresia important?

Back 16

It normally allows only one of the follicles to grow large enough each month to ovulate; this usually prevents more than one child from developing with each pregnancy.

Front 17

17. What is the stigma?

What is the corona radiata?

Back 17

Shortly before ovulation, the protruding outer wall of the follicles swells rapidly, and a small area in the center of the follicular capsule, called the stigma, protrudes like a nipple.

In another 30 min or so, fluid begins to ooze from the follicle through the stigma, and about 2 min later, the stigma ruptures widely, allowing a more viscous fluid, which as occupied the central portion of the follicle, to evaginate outward.

This viscous fluid carries with it the ovum surrounded by a mass of several thousand small granulosa cells, called the corona radiata.

Front 18

18. A surge in what hormone is necessary for ovulation?

What three factors contribute to the initiation of ovulation?

Back 18

Surge of LH is necessary for final follicular growth and ovulation.

1. Rapid growth of the follicle
2. Diminishing estrogen secretion after a prolonged phase of excessive estrogen secretion
3. Initiation of secretion of progesterone that causes ovulation to occur.

W/o the initial pre-ovulatory surge of LH, ovulation will not take place.

Front 19

19. The initiation of ovulation caused by LH leads to...?

What two events are necessary for ovulation to occur? Why?

Back 19

Causes rapid secretion of the follicular steroid hormones that contain progesterone. Within a few hours; two events occur, both of which are necessary for ovulation:

1. The theca externa (capsule of the follicle) begins to release proteolytic enzymes from lysosomes, and these cause dissolution of the follicular capsular wall and consequent weakening of the wall, resulting in further swelling of the entire follicle and degeneration of the stigma.
2. Simultaneously, there is rapid growth of new blood vessels into the follicle wall, and at the same time, prostaglandins are secreted into the follicular tissues.

These two effects cause plasma transudation into the follicle, which contributes to follicle swelling. Finally, the combo of follicle swelling and simultaneous degeneration of the stigma causes follicle rupture, with discharge of the ovum.

Front 20

20. What are lutein cells?

What is luteinization?

Back 20

During the first few hours after expulsion of the ovum from the follicle, the remaining granulosa and theca interna cells change rapidly into lutein cells.

They enlarge in diameter two or more times and become filled with lipid inclusions that give them a yellowish appearance. This process is called luteinization, and the total mass of cells together is called the corpus luteum, which has a well developed vascular supply.

Front 21

21. The granulosa cells in the corpus luteum develop...?

Back 21

They develop extensive intracellular smooth ER that form large amts of progesterone and estrogen.

The theca cells form mainly the androgens androstenedione and testosterone. However, most of these hormones are also converted by the granulosa cells into the female hormones.

Front 22

22. What is the corpus albicans?

Back 22

The corpus luteum grows to 1.5 cm about 7-8 days after ovulation.

Then it begins to involute and eventually loses its secretory function as well as its yellowish, lipid characteristic about 12 days after ovulation, becoming the corpus albicans.

During the next few weeks, this is replaced by connective tissue and then is absorbed.

Front 23

23. What is the function of LH?

Back 23

It "leuteinizes".

The change of granulosa and theca interna cells into lutein cells is dependent mainly on LH secreted by the anterior pituitary gland.

Luteinization also depends on extrusion of the ovum from the follicle. A local hormone in the follicular fluid, called luteinization-inhibiting factor, seems to hold the luteinization process in check until after ovulation.

Front 24

24. What effect does LH have on the corpus luteum?

What are the four stages of luteinization?

Back 24

The corpus luteum is highly secretory, secreting large amts of both progesterone and estrogen.

Once LH has acted on the granulasa and theca cells to cause luteinization, the newly formed lutein cells seemed to be programmed to go through a preordained sequence that occurs in 12 days:

1. Proliferation
2. Enlargement
3. Secretion
4. Degeneration

Front 25

25. Estrogen and progesterone secreted by the corpus luteum have what effects on the ovarian cycle?

Back 25

They have strong feedback effects on the anterior pituitary gland to maintain low secretory rates of both FSH and LH.

Front 26

26. What is inhibin?

What does its secretion result in?

Back 26

The lutein cells secrete small amts of the hormone inhibin, the same as the inhibin secreted by the Sertoli cells of the male testes.

This hormone inhibits secretion by the anterior pituitary gland, especially FSH secretion.

Low blood concentrations of both FSH and LH result, and loss of these hormones finally causes the corpus luteum to degenerate completely via involution.

Front 27

27. The involution process involves what?

Back 27

At this time, the sudden cessation of secretion of estrogen, progesterone, and inhibin by the corpus luteum removes the feedback inhibition of the anterior pituitary gland, allowing it to begin secreting increasing amts of FSH and LH again.

FSH and LH initiate the growth of new follicles, beginning a new ovarian cycle.

Front 28

28. What are the estrogens/progestins, which are most important, and what do they do?

Back 28

Two two types of ovarian hormones are the estrogens and the progestins. By far the most important estrogen is the hormone estradiol, and the most important progestin is progesterone.

The estrogens mainly promote proliferation and growth of specific cells in the body that are responsible for the development of most secondary sexual characteristics of the female.

The progestins function mainly to prepare the uterus for pregnancy and the breasts for lactation.

Front 29

29. What three estrogens are present in significant quantities in the plasma of the human female?

Which is more potent?

Back 29

β-estrodiol, estrone, and estriol.

The principal estrogen secreted by the ovaries is β-estrodiol. Small amts of estrone are also secreted but most of this is formed in peripheral tissues from androgens secreted by the adrenal cortices and by ovarian thecal cells. Estriol is a weak estrogen, ti is an oxidative product derived from both estradiol and estrone.

β-estradiol is 12x more potent than estrone and 80x more than estriol.

Front 30

30. What are the progestins present in the human female?

Back 30

By far the most important is progesterone. However, small amts of 17-α-hydroxyprogesterone are secreted with progesterone and have essentially the same effects.

In the normal nonpregnant female, progesterone is secreted in significant amts only during the latter half of each ovarian cycle, when it is secreted by the corpus luteum.

During pregnancy, large amts of progesterone are also secreted by the placenta especially after the fourth month of gestation.

Front 31

31. How are the progestins and estrogens synthesized?

Back 31

They are all steroids, maining they are formed from cholesterol in the blood but also to a slight extent from acetyl coenzyme A.

During synthesis, mainly progesterone and the male sex hormones are synthesized first; then, during the follicular phase of the ovarian cycle, almost all the testosterone and much of the progesterone are converted into estrogens by the granulosa cells.

During the luteal phase of the cycle, far too much progesterone is formed for all of it to be converted, which accounts for the large secretion of progesterone into the circulating blood at this time.

Front 32

32. How are the progestins and estrogens transported in the blood?

Back 32

They are bound mainly w/plasma albumin and w/specific estrogen and progesterone binding globulins.

The binding is loose enough that they are rapidly released to the tissues over a period of 30 min or so.

Front 33

33. What is the function of the liver in estrogen metabolism?

Back 33

The liver conjugates the estrogens to form glucuronides and sulfates, and about 15 of these conjugated products is excreted in the bile; most of the remainder is excreted in the urine.

Also, the liver converts the potent estrogens estradiol and estrone into the almost totally impotent estrogen estriol.

Therefore, diminished liver function actually increases the activity of estrogens in the body, sometimes causing hyperestrinism.

Front 34

34. What is the fate of progesterone?

Back 34

Within a few min after secretion, almost all the progesterone is degraded to other steroids that have no progestational effect.

The major end product of progesterone degradation is pregnanediol. About 10% of the original progesterone is excreted in the urine in this form.

Front 35

35. What are the effects of estrogens on the uterus and female sex organs?

Back 35

During puberty, the ovaries, fallopian tubes, uterus, and vagina all increase several times in size.

Also, the external genitalia enlarge with deposition of fat in the mons pubis and labia majora and enlargement of the labia minora.

During the first few years after puberty, the size of the uterus increases 2-3x but more important that the increase in uterus size are the changes that take place in the uterine endometrium under the influence of estrogens. As such, there is marked proliferation of the endometrial stroma and greatly increased development of the endometrial glands.

Front 36

36. What transformation occurs in the vaginal epithelium during puberty as a result of estrogens?

Back 36

Estrogens change the vaginal epithelium from a cuboidal into a stratified type, which is considerably more resistant to trauma and infection than is the prepubertal cuboidal cell epithelium.

Vaginal infections in children can often be cured by the administration of estrogens.

Front 37

37. Effects of estrogens on the fallopian tubes?

Back 37

They cause the glandular tissues of this lining to proliferate; especially important, they cause the number of ciliated epithelial cells that line the fallopian tubes to increase.

Also, activity of the cilia is considerably enhanced. These cilia always beat toward the uterus, which helps propel the fertilized ovum in that direction.

Front 38

38. Effects of estrogens on the breasts?

Back 38

Estrogens cause (1) development of the stromal tissues of the breasts, (2) growth of an extensive ductile system, and (3) deposition of fat in the breasts.

The lobules and alveoli of the breast develop to a slight extent under the influence of estrogens alone, but it is progesterone and prolactin that cause the ultimate determinative growth and function of these structures.

Front 39

39. Effects of estrogens on the skeleton?

Back 39

Estrogens inhibit osteoclastic activity in the bones and therefore stimulate bone growth.

They also cause uniting of the epiphyses w/the shafts of the long bones, and as a result, growth of the female usually ceases several years earlier than growth of the male.

Front 40

40. After menopause, a deficiency in estrogen leads to...?

Back 40

1. Increased osteoclastic activity in the bones
2. Decreased bone matrix
3. Increased deposition of bone calcium and phosphate

Leads to osteoporosis.

Front 41

41. Effect of estrogens on protein deposition?

Back 41

Estrogens cause a slight increase in total body protein, which causes a slight positive nitrogen balance when estrogens are administered.

Front 42

42. Effect of estrogens on body metabolism and fat deposition?

Back 42

Estrogens increase the whole-body metabolic rate slightly but only about 1/3 that of the increase caused by testosterone.

They also cause deposition of increased quantities of fat in the subcutaneous tissues, especially in the buttocks and thighs.

Front 43

43. Effect of estrogens on hair distribution?

Back 43

They do not greatly affect hair distribution.

However, hair does develop in the pubic region and in the armpits after puberty. Androgens formed in increased quantities by the female adrenals causes this.

Front 44

44. Effect of estrogens on the skin?

Back 44

They cause the skin to develop a texture that is soft and usually smooth, but it is thicker than that of a child or a castrated female.

Also, they cause the skin to become more vascular; this is assoc with increased warmth of the skin and also promotes greater bleeding of cut surfaces than is observed in men.

Front 45

45. Effect of estrogens on electrolyte balance?

Back 45

Estrogenic hormone are similar to adrenocortical hormones. As such they also cause sodium and water retention by the kidney tubules.

Front 46

46. Effect of progesterone on the uterus?

Back 46

The most important function is to promote secretory changes in the uterine endometrium during the latter half of the monthly female sexual cycle, thus preparing the uterus for implantation of the fertilized ovum.

It also decreases the freq and intensity of uterine contraction, thereby helping to prevent expulsion of the implanted ovum.

Front 47

47. Effect of progesterone on the fallopian tubes?

Back 47

Progesterone also increases secretion by the mucosal lining of the fallopian tubes.

These secretions are necessary for nutrition of the fertilized, dividing ovum as it traverses the fallopian tube before implantation.

Front 48

48. Effect of progesterone on the breasts?

Back 48

They promote development of the lobules and alveoli of the breasts, causing the alveolar cells to proliferate, enlarge, and become secretory in nature.

However, they do not cause milk secretion, this is prolactins job.

Progesterone also causes the breast to swell in part due to increased fluid in the tissue.

Front 49

49. What are the three stages of the endometrial cycle?

Back 49

1. Proliferation of the uterine endometrium
2. Development of secretory changes in the endometrium
3. Desquamation of the endometrium, AKA menstruation

Front 50

50. What is the purpose of all these endometrial changes?

Back 50

To produce a highly secretory endometrium that contains large amts of stored nutrients to proved appropriate conditions for implantation of a fertilized ovum during the latter half of the monthly cycle.

Front 51

51. What is menstruation?

What causes menstruation?

Back 51

If the ovum is not fertilized, about 2 days before the end of the monthly cycle, the corpus luteum in the ovary suddenly involutes, and the ovarian hormones decreased to low levels and menstruation follows.

Menstruation is caused by the reduction of estrogens and progesterone, especially progesterone at the end of the monthly cycle. As a result, there is rapid involution and vasospasm of the blood vessels. The vasospasm, decrease in nutrients, and loss of hormonal stimulation initiates necrosis in the endometrium.

Front 52

52. What occurs during menstruation?

Back 52

Blood at first seeps into the vascular layers of the endometrium, and the hemorrhagic areas grow rapidly. Gradually, the necrotic outer layers separate from the uterus until all the superficial layers of the endometrium have been desquamated.

The mass of desquamated tissue and blood in the uterine cavity, plus contactile effects of prostaglandins or other substances act together to initiate uterine contractions that expel the uterine contents.

Front 53

53. Why does menstrual fluid not clot?

Back 53

The menstrual fluid is normally nonclotting b/c a fibrinolysin is released along with the necrotic endometrial material.

Front 54

54. Why does leukorrhea occur during menstruation?

Back 54

During menstruation, tremendous amts of leukocytes are released along w/the necrotic material and blood.

It is probably that some substances liberated by the endometrial necrosis causes this outflow of leukocytes. As a result of these leukocytes, the uterus is highly resistant to infection during menstruation; this is of extreme protective value.

Front 55

55. What stimulates pulsatile release of LH from the anterior pituitary?

Back 55

Intermittent, pulsatile secretion of GnRH by the hypothalamus stimulates pulsatile release of LH from the anterior pituitary.

*Continuous administration of GnRH does not cause the release of LH and FSH; only intermittent release.

Front 56

56. Where does the neuronal activity that causes pulsatile release of GnRH occur?

Back 56

Primarily in the mediobasal hypothalamus, especially in the arcuate nuclei of this area. Therefore, it is believed that these arcuate nuclei control most female sexual activity.

Since multiple neuronal centers in the limbic system transmit signals into the arcuate nuclei, this partially explains why psychic factors often modify female sexual function.

Front 57

57. Estrogens in large amounts does what...

Back 57

They have a strong effect to inhibit the production of both LH and FSH.

Also, when progesterone is available, the inhibitory effect of estrogen is multiplied.

These feedback effects seem to operate mainly on the anterior pituitary gland directly, but they also operate to a lesser extent on the hypothalamus to decrease secretion of GnRH, especially by altering the freq of the GnRH pulses.

Front 58

58. What are the two suggested causes of the preovulatory surge in LH?

Back 58

1. Estrogen at this point in the cycle has a peculiar positive feedback effect of stimulating pituitary secretion of LH, and to a lesser extent, FSH; this is in sharp contrast to its normal negative feedback effect that occurs during the remainder of the monthly cycle.
2. The granulosa cells of the follicles begin to secrete small but increasing quantities of progesterone a day or so before the preovulatory LH surge.

Front 59

59. Postovulatory secretion of the ovarian hormones cause...?

Back 59

All these hormones together have a combined negative feedback effect on the anterior pituitary and hypothalamus, causing the suppression of both FSH and LH secretion, and decreasing them to their lowest levels about 3-4 days before the onset of menstruation.

Front 60

60. What hormone levels are increased/decreased during the follicular growth phase?

Back 60

The hypothalamus and anterior pituitary are released from negative feedback and therefore, pituitary secretion of FSH begins to increase again, as much as 2x, and then several days after menstruation begins, LH secretion increases slightly as well.

These hormones initiate new ovarian follicle growth and a progressive increase in the secretion of estrogen, reaching a peak estrogen secretion at about 12.5-13 days after the onset of the new menstrual cycle.

During the first 11-12 days of this follicle growth, the rates of pituitary secretion of FSH and LH decrease slightly b/c of the negative feedback effect of estrogen. Then, there is a sudden, marked increase in the secretion of LH and FSH.

Front 61

61. Specifically, what hormone surge(s) causes ovulation?

Back 61

Preovulatory surge of LH and FSH causes ovulation. At about 11.5 to 12 days after the onset of the cycle, the decline in secretion of FSH and LH comes to an abrupt halt.

It is believed that the high level of estrogens at this time causes a positive feedback stimulatory effect on the anterior pituitary, which leads to a surge in the secretion of LH and, to a lesser extent, FSH.

Front 62

62. What does anovulatory mean?

Back 62

If the preovulatory surge of LH is not of sufficient magnitude, ovulation will not occur, and the cycle is said to be "anovulatory".

The phases of the sexual cycle continue, but they are altered in the following ways:
1. The corpus luteum does not form due to no ovulation, and thus there is no secretion of progesterone.
2. The cycle is shortened by several days, bu the rhythm continues.

The first few cycles after the onset of puberty are usually anovulatory, as are the cycles occurring several months to years before menopause.

Front 63

63. Puberty and menarche

Why does hypothalamus's not secrete GnRH in childhood?

Back 63

Puberty means the onset of adult sexual life, and menarche means the beginning of the cycle of menstruation.

The period of puberty is caused by a gradual increase in gonadotropic hormone secretion by the pituitary.

It is believed that the hypothalamus is capable of secreting GnRH during childhood, however, it does not. Supposedly, the onset of puberty is initiated by some maturation process that occurs elsewhere in the brain, perhaps in the limbic system.

Front 64

64. What are the five characteristics of estrogen secretion throughout the sexual life of the female human?

Back 64

1. Increasing levels of estrogen secretion at puberty
2. The cyclical variation during the monthly sexual cycle
3. The further increase in estrogen secretion during the first few years of reproductive life
4. The progressive decrease in estrogen secretion toward the end of reproductive life
5. Almost no estrogen or progesterone secretion beyond menopause

Front 65

65. What is menopause?

What causes it?

Back 65

At about 40-50 years, the sexual cycle becomes irregular, and ovulation often fails to occur. After a few month or years, the cycle ceases altogether.

The cause is "burning out" of the ovaries. At about age 45, only a few primordial follicles remain to be stimulated by FSH and LH, and the production of estrogens by the ovaries decreases as the number of primordial follicles approaches zero.

Front 66

66. What are the physiologic changes that occur during menopause?

Back 66

1. Hot flushes
2. Psychic sensations
3. Irritability
4. Fatigue
5. Anxiety
6. Occasionally various psychotic states
7. Decreased bone strength and calcification of bones throughout the body

*Administration of exogenous estrogen in small quantities daily usually reverses the symptoms.

Front 67

67. What is hypogonadism?

What is female eunuchism?

Back 67

Less than normal secretion by the ovaries can result from poorly formed ovaries, lack of ovaries, or genetically abnormal ovaries that secrete the wrong hormones b/c of missing enzymes in the secretory cells.

When ovaries are absent from birth or when they become nonfunctional before puberty, female eunuchism occurs.

Front 68

68. What do eunuch females look like?

Back 68

In this condition, the usual secondary sexual characteristics do not appear, and the sexual organs remain infantile.

Especially characteristic is the prolonged growth of the long bones b/c the epiphyses do not unite w/the shafts as early as they do in a normal women. Thus, the female eunuch is taller.

Front 69

69. How does hypogonadism effect the menses?

Back 69

In hypogonadism or when the gonads are secreting small quantities of estrogens as a result of other factors, such as hypothyroidism, the ovarian cycle often does not occur normally.

Instead, several months may elapse between menstrual periods, or menstruation may cease altogether.

Prolonged ovarian cycles are freq associated w/failure of ovulation, presumably b/c of insufficient secretion of LH at the time of the preovulatory surge of LH.

Front 70

70. When does hypersecretion by the ovaries occur?

Back 70

Extreme hypersecretion of ovarian hormones by the ovaries is rare, b/c excessive secretion of estrogens automatically decreases the production of gonadotropins by the pituitary, and this limits the production of ovarian hormones.

Consequently, hypersecretion of feminizing hormones is usually recognized clinically only when a feminizing tumor develops.

Front 71

71. What is a granulosa cell tumor?

Back 71

A rare granulosa cell tumor can develop in an ovary, occurring more often after menopause then before.

These tumors secrete large quantities of estrogens, which exert the usual estrogenic effects, including hypertrophy of the uterine endometrium and irregular bleeding from the endometrium. In fact, bleeding is often the first and only indication that such a tumor exists.

Front 72

72. Where do the nerves synapse that innervate the female erectile tissue?

Release of what factors causes erection?

Back 72

The erectile tissue is controlled by the parasympathetic nerves that pass thru the nervi erigentes from the sacral plexus to the external genitalia.

In the early phases of sexual stimulation, parasympathetic signals dilate the arteries of the erectile tissue, probably resulting from the release of ACh, NO, and vasoactive intestinal polypeptide at the nerve endings.

Front 73

73. Why is the female orgasm important for fertilization?

Back 73

During the orgasm, the perineal muscles of the female contract rhythmically; it is possible that these reflexes increase uterine and fallopian tube motility during the orgasm, thus helping transport the sperm upward thru the uterus toward the ovum. Also, the orgasm seems to cause dilation of the cervical canal for up to 30 min, thus allowing easy transport of the sperm.

In addition, copulation causes the posterior pituitary gland to secrete oxytocin; this causes increased rhythmical contractions of the uterus, which is thought to cause increased transport of the sperm.

Front 74

74. What is the fertile period of each female sexual cycle?

Back 74

The ovum remains viable and capable of being fertilized after it is expelled form the ovary probably no longer than 24 hours.

Therefore, sperm must be available soon after ovulation if fertilization is to take place. In other words, intercourse must occur sometime between 4 and 5 days before ovulation up to a few hours after ovulation.

Front 75

75. What is the rhythm method of contraception?

Back 75

It is usually stated that avoidance of intercourse for 4 days before the calculated day of ovulation and 3 days afterward prevents conception.

But such a method of contraception can be used only when the periodicity of the menstrual cycle is regular.

Front 76

76. Why does the pill work?

Back 76

The reason for this is that appropriate administration of either of these hormones (estrogen or progesterone) can prevent the preovulatory surge of LH secretion by the pituitary gland, which is essential in causing ovulation.

Immediately before the LH surge occurs, there is probably a sudden depression of estrogen secretion by the ovarian follicles, and this might be the necessary signal that causes the subsequent feedback effect on the anterior pituitary that leads to the LH surge. The administration of sex hormones (estrogens or progesterone) could prevent the initial ovarian hormonal depression that might be the initiating signal for ovulation.

Front 77

77. Why are natural hormones not used in the pill?

Back 77

The natural hormones are almost entirely destroyed by the liver within a short time after they are absorbed from the GI tract into the portal circulation.

However, many of the synthetic hormones can resist this destructive propensity of the liver, thus allowing oral administration.

Front 78

78. What abnormal conditions cause female sterility?

Back 78

The most common cause is failure to ovulate; this can result from hyposecretion fo gonadotropic hormones, in which case the intensity of the hormonal stimuli is simply insufficient to cause ovulation, or it can result from abnormal ovaries that do not allow ovulation.

Front 79

79. What are some ways to test for female sterility?

Back 79

One way to is analyze the urine for a surge in pregnanediol, the end product of progesterone metabolism, during the latter half of the sexual cycle; the lack of this substance indicated failure of ovulation.

Another common test is for the woman to chart her body temp throughout the cycle. Secretion of progesterone during the latter half of the cycle raises the body temp about half a degree, with the temp rise combing abruptly at the time of ovulation.

Front 80

80. What is one way to treat lack of ovulation caused by hyposecretion of the pituitary gonadotropic hormones?

Back 80

Can sometimes be treated w/ appropriately timed administration of human chorionic gonadotropin. This hormone, although secreted by the placenta, has almost the same effects as LH and is therefore a powerful stimulator of ovulation.

However, excess use of this hormone can cause ovulation from many follicles simultaneously.

Front 81

81. What is endometriosis?

Back 81

A common cause of female sterility, in which the endometrial tissue almost identical to that of the normal uterine endometrium grows and even menstruates in the pelvic cavity surrounding the uterus, fallopian tubes, and ovaries.

It causes fibrosis throughout the pelvis, and this fibrosis sometimes so covers the ovaries that an ovum cannot be released into the abdominal cavity.

Front 82

82. What is salpingitis?

Back 82

Inflammation of the fallopian tubes; this causes fibrosis in the tubes, thereby occluding them.

In the past this was from gonococcal infection.

Front 83

83. Abnormal mucus secretion by the uterine cervix can cause…?

Back 83

Infertility. Ordinarily, at the time of ovulation, the hormonal environment of estrogen causes the secretion of mucus w/special characteristics that allow rapid motility of sperm into the uterus and actually guide the sperm up along mucous threads.

Abnormalities of the cervix itself, such as low grade infection or inflammation, or abnormal hormonal stimulation of the cervix can lead to a viscous mucous plug that prevents fertilization.

Front 84

84. Maturation of the ovum

Back 84

While still in the ovary, the ovum is in the primary oocyte stage. Shortly before it is released from the ovarian follicle, its nucleus divides by meiosis and a first polar body is expelled from the nucleus of the oocyte.The primary oocyte then becomes the secondary oocyte. In this process, each of the 23 pairs of chromosomes loses one of its partners, which becomes incorporated in a polar body that is expelled.

This leaves 23 unpaired chromosomes in the secondary oocyte. It is at this time that the ovum, still in the secondary oocyte stage, is ovulated into the abdominal cavity. Then, almost immediately, it enters the fimbriated end of one of the fallopian tubes.

Front 85

85. How does the ovum enter the fallopian tube?

Back 85

The fimbriated ends of each fallopian tube fall naturally around the ovaries. The inner surfaces of the fimbriated tentacles are lined w/ciliated epithelium, and the cilia are activated by estrogen from the ovaries, which causes the cilia to beat toward the opening, or ostium, of the involved fallopian tube.

*Ova can even enter the opposite fallopian tube.

Front 86

86. Fertilization of the ovum - where does it occur?

Back 86

Fertilization normally takes place in the ampulla of one of the fallopian tubes soon after both the sperm and the ovum enter the ampulla.

Front 87

87. What is the acrosome reaction?

Back 87

Before the sperm can enter the ovum, it must first penetrate the multiple layers of the granulosa cells attached to the outside of the ovum (the corona radiata) and then bind to an penetrate the zona pellucida surrounding the ovum itself.

Proteolytic enzymes released from sperm dissolve zona pellucida - takes about 30 minutes to penetrate zona pellucida

Front 88

88. Once a sperm has entered the ovum, what happens?

Back 88

Once a sperm has entered the ovum (which is still in the secondary oocyte stage of development), the oocyte divides again to form the mature ovum plus a second polar body that is expelled.

The mature ovum still carries its nucleus (now called the female pronucleus) 23 chromosomes. One of these chromosomes is the female chromosome, known as the X chromosome.

Also, the fertilizing sperm has also changed. On entering the ovum, its head swells to form a male pronucleus. Later, the 23 unpaired chromosomes of the male pronucleus and the 23 unpaired chromosomes of the female pronucleus align themselves to re-form a complete complement of 46 chromosomes (23 pairs) in the fertilized ovum.

Front 89

89. What determines the sex of the fetus?

Back 89

After formation of the mature sperm, half of these carry in their genome an X chromosome (the female chromosome) and half carry a Y chromosome (the male chromosome).

Therefore, if an X chromosome from a sperm combines with an X chromosome from an ovum, giving an XX combination, a female child will be born. But if a Y chromosome from a sperm is paired with an X chromosome from an ovum, giving an XY combination, a male child will be born.

Front 90

90. What happens to the fertilized ovum after fertilization takes place?

Back 90

After fertilization has occurred, an additional 3 to 5 days is normally required for transport of the fertilized ovum through the remainder of the fallopian tube into the cavity of the uterus.

This transport is effected mainly by a feeble fluid current in the tube resulting from epithelial secretion plus action of the ciliated epithelium that lines the tube; the cilia always beat toward the uterus.

Weak contractions of the fallopian tube may also aid the ovum passage.

Front 91

91. What causes the contractions of the fallopian tubes?

Back 91

The fallopian tubes are lined with a rugged, cryptoid surface that impedes passage of the ovum despite the fluid current. Also, the isthmus of the fallopian tube (the last 2 centimeters before the tube enters the uterus) remains spastically contracted for about the first 3 days after ovulation.

After this time, the rapidly increasing progesterone secreted by the ovarian corpus luteum first promotes increasing progesterone receptors on the fallopian tube smooth muscle cells; then the progesterone activates the receptors, exerting a tubular relaxing effect that allows entry of the ovum into the uterus.

Front 92

92. Why is this delayed transport of the fertilized ovum important?

Back 92

It allows several stages of cell division to occur before the dividing ovum, now called a blastocyst, enters the uterus.

During this time, the fallopian tube secretory cells produce large quantities of secretions used for the nutrition of the developing blastocyst.

Front 93

93. When does implantation occur?

Back 93

After reaching the uterus, the developing blastocyst usually remains in the uterine cavity an additional 1 to 3 days before it implants in the endometrium; thus, implantation ordinarily occurs on about the fifth to seventh day after ovulation.

Before implantation, the blastocyst obtains its nutrition from the uterine endometrial secretions, called “uterine milk.”

Front 94

94. What causes implantation to occur?

Back 94

Implantation results from the action of trophoblast cells that develop over the surface of the blastocyst.

These cells secrete proteolytic enzymes that digest and liquefy the adjacent cells of the uterine endometrium.

Some of the fluid and nutrients released are actively transported by the same trophoblast cells into the blastocyst, adding more sustenance for growth.

Once implantation has taken place, the trophoblast cells and other adjacent cells (from the blastocyst and the uterine endometrium) proliferate rapidly, forming the placenta and the various membranes of pregnancy.

Front 95

95. What provides nutrition for the early embryo?

Back 95

Progesterone - when the conceptus implants in the endometrium, the continued secretion of progesterone causes the endometrial cells to swell further and to store even more nutrients.

These cells are now called decidual cells, and the total mass of cells is called the decidua.

Front 96

96. How does the embryo obtain its nutrients in the first 8 weeks?

Back 96

As the trophoblast cells invade the decidua, digesting and imbibing it, the stored nutrients in the decidua are used by the embryo for growth and development.

During the first week after implantation, this is the only means by which the embryo can obtain nutrients; the embryo continues to obtain at least some of its nutrition in this way for up to 8 weeks, although the placenta also begins to provide nutrition after about the 16th day beyond fertilization (a little more than 1 week after implantation).

Front 97

97. Anatomy of the placenta

Back 97

While the trophoblastic cords from the blastocyst are attaching to the uterus, blood capillaries grow into the cords from the vascular system of the newly forming embryo.

By the 16th day after fertilization, blood also begins to be pumped by the heart of the embryo itself. Simultaneously, blood sinuses supplied with blood from the mother develop around the outsides of the trophoblastic cords. The trophoblast cells send out more and more projections, which become placental villi into which fetal capillaries grow.

Thus, the villi, carrying fetal blood, are surrounded by sinuses that contain maternal blood.

Front 98

98. Blood flow through the placenta

Back 98

The fetus’s blood flows through two umbilical arteries, then into the capillaries of the villi, and finally back through a single umbilical vein into the fetus.

At the same time, the mother’s blood flows from her uterine arteries into large maternal sinuses that surround the villi and then back into the uterine veins of the mother.

Front 99

99. How do substances pass through the placental membrane?

Back 99

The total surface area of all the villi of the mature placenta is only a few square meters—many times less than the area of the pulmonary membrane in the lungs.

Nevertheless, nutrients and other substances pass through this placental membrane mainly by diffusion in much the same manner that diffusion occurs through the alveolar membranes of the lungs and the capillary membranes elsewhere in the body.

Front 100

100. What is the major function of the placenta?

Back 100

To provide for diffusion of foodstuffs and oxygen from the mother's blood into the fetus's blood and diffusion of excretory products from the fetus back into the mother.

Front 101

101. How does the permeability of the placental membrane change throughout the pregnancy?

Back 101

In the early months of pregnancy, the placental membrane is still thick because it is not fully developed. Therefore, its permeability is low. Further, the surface area is small because the placenta has not grown significantly. Therefore, the total diffusion conductance is minuscule at first.

Conversely, in later pregnancy, the permeability increases because of thinning of the membrane diffusion layers and because the surface area expands many times over, thus giving a tremendous increase in placental diffusion.

Front 102

102. How does oxygen diffuse through the placental membrane?

Back 102

The dissolved oxygen in the blood of the large maternal sinuses passes into the fetal blood via simple diffusion, driven by an oxygen pressure gradient from the mother's blood to the fetus's blood.

The mean pressure gradient for diffusion of oxygen through the placental membrane is about 20 mm Hg.

Front 103

103. What are the three reasons why the low partial pressure of oxygen is capable of allowing the fetal blood to transport almost as much oxygen to the fetal tissues as is transported by the mother's blood to her tissues?

Back 103

1. The Hb of the fetus is mainly fetal Hb, a type that can carry 20-50% more oxygen than maternal Hb can (shifts O2-Hb curve to the left)

2. The Hb concentration of fetal blood is about 50% greater than that of the mother

3. The Bohr effect provides another mechanism to enhance the transport of oxygen by fetal blood. That is, Hb can carry more O2 at a low pCO2 that it can at a high pCO2. Loss of the CO2 makes the fetal blood more alkaline, whereas the increased CO2 in the maternal blood makes it more acidic.

Front 104

104. What is the double Bohr effect?

Back 104

These changes cause the capacity of fetal blood to combine with oxygen to increase and that of maternal blood to decrease. This forces still more oxygen from the maternal blood, while enhancing oxygen uptake by the fetal blood.

Thus, the Bohr shift operates in one direction in the maternal blood and in the other direction in the fetal blood. These two effects make the Bohr shift twice as important here as it is for oxygen exchange in the lungs; therefore, it is called the double Bohr effect.

Front 105

105. How does the total diffusing capacity of the entire placenta compare to the lung diffusing capacity of the newborn baby?

Back 105

The total diffusing capacity of the entire placenta for oxygen at term is about 1.2 milliliters of oxygen per minute per millimeter of mercury oxygen pressure difference across the membrane.

This compares favorably with that of the lungs of the newborn baby.

Front 106

106. Diffusion of CO2 through the placental membrane

Back 106

Carbon dioxide is continually formed in the tissues of the fetus in the same way that it is formed in maternal tissues, and the only means for excreting the carbon dioxide from the fetus is through the placenta into the mother’s blood.

The pCO2 of the fetal blood is 2 to 3 mm Hg higher than that of the maternal blood. This small pressure gradient for carbon dioxide across the membrane is more than sufficient to allow adequate diffusion of carbon dioxide, because the extreme solubility of carbon dioxide in the placental membrane allows carbon dioxide to diffuse about 20 times as rapidly as oxygen.

Front 107

107. How does glucose/food diffuse through the placental membrane?

Back 107

Other metabolic substrates needed by the fetus diffuse into the fetal blood in the same manner as oxygen does. For instance, in the late stages of pregnancy, the fetus often uses as much glucose as the entire body of the mother uses.

To provide this much glucose, the trophoblast cells lining the placental villi provide for facilitated diffusion of glucose through the placental membrane. That is, the glucose is transported by carrier molecules in the trophoblast cells of the membrane. Even so, the glucose level in fetal blood is 20 to 30 per cent lower than that in maternal blood.

Front 108

108. How do fatty acids, ions, and ketone bodies diffuse through the placental membrane?

Back 108

Because of the high solubility of fatty acids in cell membranes, these also diffuse from the maternal blood into the fetal blood, but more slowly than glucose, so that glucose is used more easily by the fetus for nutrition.

Also, such substances as ketone bodies and potassium, sodium, and chloride ions diffuse with relative ease from the maternal blood into the fetal blood.

Front 109

109. How are waste products excreted through the placental membrane?

Back 109

In the same manner that carbon dioxide diffuses from the fetal blood into the maternal blood, other excretory products formed in the fetus also diffuse through the placental membrane into the maternal blood and are then excreted along with the excretory products of the mother.

These include especially the nonprotein nitrogens such as urea, uric acid, and creatinine.

Front 110

110. How do levels of urea in fetal blood compare to that in maternal blood?

Creatinine levels?

Back 110

The level of urea in fetal blood is only slightly greater than that in maternal blood, because urea diffuses through the placental membrane with great ease.

However, creatinine, which does not diffuse as easily, has a fetal blood concentration considerably higher than that in the mother’s blood.

Therefore, excretion from the fetus occurs mainly, if not entirely, as a result of diffusion gradients across the placental membrane, because there are higher concentrations of the excretory products in the fetal blood than in the maternal blood.

Front 111

111. What hormones are produced by the placenta during pregnancy?

Back 111

1. Human chorionic gonadotropin
2. Estrogens
3. Progesterone
4. Human chorionic somatomammotropin

Front 112

112. What is the importance of human chorionic gonadotropin?

Where is it secreted?

Back 112

Menstruation will begin unless human chorionic gonadotropin is secreted. Thus, the pregnancy would terminate without hCG.

Coincidental with the development of the trophoblast cells from the early fertilized ovum, the hormone human chorionic gonadotropin is secreted by the syncytial trophoblast cells into the fluids of the mother.

Front 113

113. What is the function of hCG?

Back 113

By far, its most important function is to prevent involution of the corpus luteum at the end of the monthly female sexual cycle.

Instead, it causes the corpus luteum to secrete even larger quantities of its sex hormones—progesterone and estrogens—for the next few months.

These sex hormones prevent menstruation and cause the endometrium to continue to grow and store large amounts of nutrients rather than being shed in the menstruum. As a result, the decidua-like cells that develop in the endometrium during the normal female sexual cycle become actual decidual cells—greatly swollen and nutritious—at about the time that the blastocyst implants.

Front 114

114. How does hCG affect the corpus luteum?

Back 114

Under the influence of hCG, the corpus luteum grows to about 2x its initial size, and its continued secretion of estrogens and progesterone maintains the decidual nature of the uterine endometrium, which is necessary for the development of the fetus.

Front 115

115. What happens when the corpus luteum is removed before the 7th week of pregnancy?

Back 115

Spontaneous abortion almost always occurs, sometimes up to the 12th week.

After that time, the placenta secretes sufficient quantities of progesterone and estrogens to maintain pregnancy for the remainder of the gestation period.

The corpus luteum involutes slowly after the 13-17th week of gestation.

Front 116

116. What effect does hCG have on the fetal testes?

Back 116

hCG also exerts an interstitial-cell stimulating effect on the testes of the male fetus, resulting in the production of testosterone in male fetuses until the time of birth.

Front 117

117. Secretion of estrogens by the placenta - from where does it come from?

Back 117

The placenta secretes both estrogens and progesterone. These two hormones are secreted by the syncytial trophoblast cells of the placenta.

Towards the end of pregnancy, the daily production of placental estrogens increases to about 30x the mother's normal levels of production.

Front 118

118. How is the secretion of estrogens by the placenta different from secretion by the ovaries?

Back 118

Most important, the estrogens secreted by the placenta are not synthesized de novo from basic substrates in the placenta.

Instead, they are formed almost entirely from androgenic steroid compounds, dehydroepiandrosterone and 16-hydroxydehydroepiandrosterone, which are formed both in the mother’s adrenal glands and in the adrenal glands of the fetus.

These weak androgens are transported by the blood to the placenta and converted by the trophoblast cells into estradiol, estrone, and estriol.

(The cortices of the fetal adrenal glands are extremely large, and about 80 per cent consists of a so-called fetal zone, the primary function of which seems to be to secrete dehydroepiandrosterone during pregnancy.)

Front 119

119. What are four functions of estrogen during pregnancy?

Back 119

1. Enlargement of the mother's uterus
2. Enlargement of the mother's breasts and growth of the breast ductal structure
3. Enlargement of the mother's female external genitalia
4. Relaxation of the pelvic ligaments of the mother to allow easier passage of the fetus through the birth canal

Front 120

120. Secretion of progesterone by the placenta

Back 120

In addition to being secreted in moderate quantities by the corpus luteum at the beginning of pregnancy, it is secreted later in tremendous quantities by the placenta, averaging about a 10-fold increase during the course of pregnancy

Front 121

121. What are the four special effects of progesterone that are essential for the normal progression of pregnancy?

Back 121

1. Progesterone causes decidual cells to develop in the uterine endometrium, and these cell play an important role in the nutrition of the early embryo.
2. Progesterone decreases the contractility of the pregnant uterus, thus preventing uterine contractions from causing spontaneous abortion.
3. Progesterone contributes to the development of the conceptus even before implantation, b/c it specifically increases the secretions of the mother's fallopian tubes and uterus to provide appropriate nutritive matter for the developing morula and blastocyst.
4. The progesterone secreted during pregnancy helps the estrogen prepare the mother's breasts for lactation.

Front 122

122. What is human chorionic somatomammotropin?

Back 122

A more recently discovered placental hormone is called human chorionic somatomammotropin. It is a protein and it begins to be secreted by the placenta at about the fifth week of pregnancy.

Secretion of this hormone increases progressively throughout the remainder of pregnancy in direct proportion to the weight of the placenta.

Although the functions of chorionic somatomammotropin are uncertain, it is secreted in quantities several times greater than all the other pregnancy hormones combined.

Front 123

123. What is the first proposed effect of human chorionic somatomammotropin?

Back 123

1. It causes at least partial development of the animal’s breasts and in some instances causes lactation.

Because this was the first function of the hormone discovered, it was first named human placental lactogen and was believed to have functions similar to those of prolactin.

Front 124

124. What is the second proposed effect of human chorionic somatomammotropin?

Back 124

2. This hormone has weak actions similar to those of growth hormone, causing the formation of protein tissues in the same way that growth hormone does.

It also has a chemical structure similar to that of growth hormone, but 100 times as much human chorionic somatomammotropin as growth hormone is required to promote growth.

Front 125

125. What is the third proposed effect of human chorionic somatomammotropin?

Back 125

3. It causes decreased insulin sensitivity and decreased utilization of glucose in the mother, thereby making larger quantities of glucose available to the fetus.

Further, the hormone promotes the release of free fatty acids from the fat stores of the mother, thus providing this alternative source of energy for the mother’s metabolism during pregnancy.

Front 126

126. In sum, what is the role of human chorionic somatomammotropin?

Back 126

It appears that human chorionic somatomammotropin is a general metabolic hormone that has specific nutritional implications for both the mother and the fetus.

Front 127

127. What hormones from the pituitary are secreted/inhibited during pregnancy?

Back 127

The anterior pituitary gland of the mother enlarges at least 50 per cent during pregnancy and increases its production of corticotropin, thyrotropin, and prolactin.

Conversely, pituitary secretion of follicle-stimulating hormone and luteinizing hormone is almost totally suppressed as a result of the inhibitory effects of estrogens and progesterone from the placenta.

Front 128

128. How is corticosteroid secretion different during pregnancy?

Back 128

The rate of adrenocortical secretion of the glucocorticoids is moderately increased throughout pregnancy. It is possible that these glucocorticoids help mobilize amino acids from the mother’s tissues so that these can be used for synthesis of tissues in the fetus.

Front 129

129. If aldosterone secretion increases during pregnancy, what are the possible complications?

Back 129

Pregnant women usually have about a twofold increase in the secretion of aldosterone, reaching a peak at the end of gestation.

This, along with the actions of estrogens, causes a tendency for even a normal pregnant woman to reabsorb excess sodium from her renal tubules and, therefore, to retain fluid, occasionally leading to pregnancy-induced hypertension.

Front 130

130. Secretion by the thyroid gland during pregnancy

What causes the increased secretion?

Back 130

The mother’s thyroid gland ordinarily enlarges up to 50 per cent during pregnancy and increases its production of thyroxine a corresponding amount.

The increased thyroxine production is caused at least partly by a thyrotropic effect of human chorionic gonadotropin secreted by the placenta and by small quantities of a specific thyroid-stimulating hormone, human chorionic thyrotropin, also secreted by the placenta.

Front 131

131. What is 'relaxin' that is secreted by the ovaries and placenta?

Back 131

Its secretion is increased by a stimulating effect of hCG at the same time that the corpus luteum and the placenta secrete large quantities of estrogens and progesterone.

Relaxin is a polypeptide that, when injected, causes relaxation of the ligaments of the symphysis pubis in the rat and guinea pig. This effect is weak or possibly even absent in pregnant women. Instead, this role is probably played mainly by the estrogens, which also cause relaxation of the pelvic ligaments.

Front 132

132. What are the most apparent changes in the pregnant mother?

Back 132

The increased size of the various sexual organs.

For instance, the uterus increases from about 50 grams to 1100 grams, and the breasts approximately double in size. At the same time, the vagina enlarges and the introitus opens more widely.

Also, the various hormones can cause marked changes in a pregnant woman’s appearance, sometimes resulting in the development of edema, acne, and masculine or acromegalic features.

Front 133

133. Weight gain in the pregnant woman

Back 133

The average weight gain during pregnancy is about 24 pounds, with most of this gain occurring during the last two trimesters.

Of this, about 7 pounds is fetus and 4 pounds is amniotic fluid, placenta, and fetal membranes. The uterus increases about 2 pounds and the breasts another 2 pounds, still leaving an average weight increase of 9 pounds. About 6 pounds of this is extra fluid in the blood and extracellular fluid, and the remaining 3 pounds is generally fat accumulation. The extra fluid is excreted in the urine during the first few days after birth, that is, after loss of the fluid-retaining hormones from the placenta.

Front 134

134. Metabolism during pregnancy

Back 134

As a consequence of the increased secretion of many hormones during pregnancy, including thyroxine, adrenocortical hormones, and the sex hormones, the basal metabolic rate of the pregnant woman increases about 15 per cent during the latter half of pregnancy.

As a result, she frequently has sensations of becoming overheated. Also, owing to the extra load that she is carrying, greater amounts of energy than normal must be expended for muscle activity.

Front 135

135. What nutrients are especially important to the mother during pregnancy?

Back 135

Iron, calcium, phosphates, and proteins.

Without sufficient iron, hypochromic anemia develops. Also, vitamin D is necessary b/c calcium can't be absorbed w/o vitamin D.

Finally, shortly before the birth of the baby, vitamin K is often added to the mother's diet so that the baby will have sufficient prothrombin to prevent hemorrhage, particularly brain hemorrhage, caused by the birth process.

Front 136

136. How does blood flow through the placenta and CO change during pregnancy?

Back 136

About 625 milliliters of blood flows through the maternal circulation of the placenta each minute during the last month of pregnancy.

This, plus the general increase in the mother’s metabolism, increases the mother’s cardiac output to 30 to 40 per cent above normal by the 27th week of pregnancy

Then, for reasons unexplained, the cardiac output falls to only a little above normal during the last 8 weeks of pregnancy, despite the high uterine blood flow.

Front 137

137. How does the maternal blood volume change during pregnancy?

Back 137

The maternal blood volume shortly before term is about 30 per cent above normal. This increase occurs mainly during the latter half of pregnancy.

Therefore, at the time of birth of the baby, the mother has about 1 to 2 liters of extra blood in her circulatory system. Only about one fourth of this amount is normally lost through bleeding during delivery of the baby, thereby allowing a considerable safety factor for the mother.

Front 138

138. What causes the increase in blood volume?

Back 138

The cause of the increased volume is likely due, at least in part, to aldosterone and estrogens, which are greatly increased in pregnancy, and to increased fluid retention by the kidneys.

Also, the bone marrow becomes increasingly active and produces extra red blood cells to go with the excess fluid volume.

Front 139

139. How is maternal respiration affected during pregnancy?

Back 139

B/c of the increased metabolic rate, the total amt of oxygen used by the mother shortly before birth is about 20% above normal, and a commensurate amt of CO2 is formed. These effects cause the mother's minute ventilation to increase.

It is believed that progesterone also increases the respiratory center's sensitivity to CO2.

The net result is an increase in minute ventilation of about 50% and a decrease in arterial pCO2 to several mm Hg below that in nonpregnant women.

Also, the growing uterus decreases the diaphagmatic movement, so the respiratory rate is also increased to maintain ventilation.

Front 140

140. How does maternal urine formation change during pregnancy?

Back 140

The rate of urine formation by a pregnant woman is usually slightly increased because of increased fluid intake and increased load or excretory products.

Front 141

141. In addition to increased urine formation, what other special alterations occur in the urinary system?

Back 141

1. The renal tubules' reabsorptive capacity for sodium, chloride, and water is increased as much as 50% as a consequence of increased production of steroid hormones by the placenta and adrenal cortex.

2. The GFR increases as much as 50% during pregnancy, which tends to increase the rate of water and electrolyte excretion in the urine.

When all these effects are considered, the normal pregnant woman ordinarily accumulates only about 6 lbs of extra water and salt.

Front 142

142. Absorption and secretion of amniotic fluid

Back 142

Normally, the volume of amniotic fluid (the fluid inside the uterus in which the fetus floats) is between 500 milliliters and 1 liter, but it can be only a few milliliters or as much as several liters.

Isotope studies of the rate of formation of amniotic fluid show that, on average, the water in amniotic fluid is replaced once every 3 hours, and the electrolytes sodium and potassium are replaced an average of once every 15 hours.

A large portion of the fluid is derived from renal excretion by the fetus. Likewise, a certain amount of absorption occurs by way of the gastrointestinal tract and lungs of the fetus.

Front 143

143. What is preeclampsia?

Back 143

About 5% of all pregnant women experience a rapid rise in arterial pressure to hypertensive levels during the last few months of pregnancy.

This is associated w/leakage of large amts of protein into the urine. This condition is call preeclampsia or toxemia of pregnancy.

It is often characterized by excess salt and water retention by the mother's kidneys and by weight gain and development of edema and hypertension in the mother. In addition, there is impaired function of the vascular endothelium, and arterial spasm occurs in many parts of the mother's body, most significantly the kidneys, brain and liver. Both the renal blood flow and the GFR are decreased. The renal effects also include thickened glomerular tufts that contain a protein deposit in the basement membranes.

Front 144

144. An increased release of what factors can cause preeclampsia?

Back 144

Inflammatorycytokines such as tumor necrosis factor-alpha and interleukin-6.

This can be due to insufficient blood supply to the placenta.

Front 145

145. What is eclampsia?

Back 145

Eclampsia is an extreme degree of preeclampsia, characterized by vascular spasm throughout the body; clonic seizures in the mother, sometimes followed by coma; greatly decreased kidney output; malfunction of the liver; often extreme hypertension; and a generalized toxic condition of the body.

It usually occurs shortly before birth of the baby. Without treatment, a high percentage of eclamptic mothers die. However, with optimal and immediate use of rapidlyacting vasodilating drugs to reduce the arterial pressure to normal, followed by immediate termination of pregnancy—by cesarean section if necessary—the mortality even in eclamptic mothers has been reduced to 1 per cent or less.

Front 146

146. What is parturition, and what two major categories of effects lead up to the intense contractions responsible for parturition?

Back 146

Parturition means birth of the baby.

Two categories of effects that lead to intense contractions:
1. Progressive hormonal changes that cause increase excitability of the uterine musculature
2. Progressive mechanical changes

Front 147

147. What do estrogens have to do with uterine contractility?

Back 147

An increased ratio of estrogens to progesterone helps increase the degree of uterine contractility, partly b/c estrogens increase the number of gap junctions between the adjacent uterine smooth muscle cells.

Front 148

148. What are the four reasons to believe oxytocin increases the contractility of the uterus?

Back 148

1. The uterine muscle increases its oxytocin receptors, and therefore increases its responsiveness to a dose of oxytocin during the latter few months of pregnancy.
2. The rate of oxytocin secretion by the neurohypophysis is considerably increased at the time of labor.
3. Although hypophysectomized animals can still deliver their young at term, labor is prolonged.
4. Experiments in animals indicate that irritation or stretching of the uterine cervix, as occurs during labor, can cause a neurogenic reflex through the paraventricular and supraoptic nuclei of the hypothalamus that causes the posterior pituitary gland to increase its secretion of oxytocin.

Front 149

149. What are the effect of fetal hormones on the uterus?

Back 149

The fetus’s pituitary gland secretes increasing quantities of oxytocin, which might play a role in exciting the uterus.

Also, the fetus’s adrenal glands secrete large quantities of cortisol, another possible uterine stimulant.

In addition, the fetal membranes release prostaglandins in high concentration at the time of labor. These, too, can increase the intensity of uterine contractions.

Front 150

150. How does stretching of the uterine musculature affect uterine contractility?

Back 150

Simply stretching smooth muscle organs usually increases their contractility.

Further, intermittent stretch, as occurs repeatedly in the uterus b/c of fetal movements, can also elicit smooth muscle contraction.

Front 151

151. How does stretching or irritation of the cervix cause uterine contractions?

Back 151

The mechanism is not known. It has been suggested that stretching or irritation of the nerves in the cervix initiates reflexes to the body of the uterus, but the effect could also result simply from myogenic transmission of signals from the cervix to the body of the uterus.

Front 152

152. What are Braxton Hicks contractions?

Back 152

During most of the months of pregnancy, the uterus undergoes periodic episodes of weak and slow rhythmical contractions called Braxton Hicks contractions.

Front 153

153. What is the positive feedback theory in labor?

Back 153

This theory suggests that stretching of the cervix by the fetus's head finally becomes great enough to elicit a strong reflex increase in contractility of the uterine body.

This pushes the baby forward, which stretches the cervix more and initiates more positive feedback to the uterine body.

This process repeats itself until the baby is expelled.

Front 154

154. What are the two known types of positive feedback that increase uterine contractions during labor?

Back 154

1. Stretching of the cervix causes the entire body of the uterus to contract.

2. Cervical stretching also causes the pituitary gland to secrete oxytocin, which is another means for increasing uterine contractility.

Front 155

155. How is the positive feedback used to support false labor, in which the contractions become stronger first and then fade away?

Back 155

Remember that for a vicious circle to continue, each new cycle of the positive feedback must be stronger than the previous one.

If at any time after labor starts some contractions fail to re-excite the uterus sufficiently, the positive feedback could go into a retrograde decline, and the labor contractions would fade away.

Front 156

156. Why is it important for the contractions of labor to occur intermittently?

Back 156

Strong contractions can impede or sometimes even stop blood flow through the placenta and would cause death of the fetus if the contractions were continuous.

Front 157

157. What is the first stage of labor?

Back 157

The first major obstruction to expulsion of the fetus is the uterine cervix. Toward the end of pregnancy, the cervix becomes soft, which allows it to stretch when labor contractions begin in the uterus.

The so-called first stage of labor is a period of progressive cervical dilation, lasting until the cervical opening is as large as the head of the fetus. This stage usually lasts for 8 to 24 hours in the first pregnancy but often only a few minutes after many pregnancies.

Front 158

158. What is the second stage of labor?

Back 158

Once the cervix has dilated fully, the fetal membranes usually rupture and the amniotic fluid is lost suddenly through the vagina. Then the fetus’s head moves rapidly into the birth canal, and with additional force from above, it continues to wedge its way through the canal until delivery is effected.

This is called the second stage of labor, and it may last from as little as 1 minute after many pregnancies to 30 minutes or more in the first pregnancy.

Front 159

159. What causes the labor pains in the first and second stages of labor?

Back 159

With each uterine contraction, the mother experiences considerable pain. The cramping pain in early labor is probably caused mainly by hypoxia of the uterine muscle resulting from compression of the blood vessels in the uterus. This pain is not felt when the visceral sensory hypogastric nerves, which carry the visceral sensory fibers leading from the uterus, have been sectioned.

However, during the second stage of labor, when the fetus is being expelled through the birth canal, much more severe pain is caused by cervical stretching, perineal stretching, and stretching or tearing of structures in the vaginal canal itself. This pain is conducted to the mother’s spinal cord and brain by somatic nerves instead of by the visceral sensory nerves.

Front 160

160. Involution of the uterus

Back 160

During the first 4 to 5 weeks after parturition, the uterus involutes. Its weight becomes less than half its immediate postpartum weight within 1 week, and in 4 weeks, if the mother lactates, the uterus may become as small as it was before pregnancy. This effect of lactation results from the suppression of pituitary gonadotropin and ovarian hormone secretion during the first few months of lactation.

Front 161

161. What is lochia?

Back 161

During early involution of the uterus, the placental site on the endometrial surface autolyzes, causing a vaginal discharge known as “lochia,” which is first bloody and then serous in nature, continuing for a total of about 10 days.

After this time, the endometrial surface becomes re-epithelialized and ready for normal, nongravid sex life again.

Front 162

162. What develops the growth of the ductal system in the breasts?

Back 162

Estrogens

Front 163

163. What develops the growth of the lobule-alveolar system in the breasts?

Back 163

Progesterone - acting synergistically with estrogens.

Front 164

164. Function of estrogen and progesterone on secretion of milk

Back 164

They inhibit the secretion of milk. Conversely, prolactin promotes it.

Front 165

165. What is necessary for maternal milk production?

Back 165

Requires adequate background secretion of hormones but most important are GH, cortisol, PTH, and insulin.

Front 166

166. Prolactin levels following birth

Back 166

After birth of the baby, the basal level of prolactin secretion returns to the nonpregnant level over the next few weeks. However, each time the mother nurses her baby, nervous signals from the nipples to the hypothalamus cause a 10- to 20-fold surge in prolactin secretion that lasts for about 1 hour.

This prolactin acts on the mother’s breasts to keep the mammary glands secreting milk into the alveoli for the subsequent nursing periods. If this prolactin surge is absent or blocked as a result of hypothalamic or pituitary damage or if nursing does not continue, the breasts lose their ability to produce milk within 1 week or so.

However, milk production can continue for several years if the child continues to suckle, although the rate of milk formation normally decreases considerably after 7 to 9 months.

Front 167

167. How does the hypothalamus play a role in prolactin secretion?

Back 167

The hypothalamus mainly stimulates production of all other hormones, but it mainly inhibits prolactin production.

Therefore, it is believed that anterior pituitary secretion of prolactin is controlled by an inhibitory factor formed in the hypothalamus, called prolactin inhibitory hormone; very similar to dopamine.

Front 168

168. When does the menstrual cycle resume in nursing mothers?

Back 168

Not until a few weeks after cessation of nursing b/c the same signals from the breasts to the hypothalamus that cause prolactin secretion inhibit secretion of GnRH by the hypothalamus which suppresses formation of the pituitary gonadotropic hormones.

Front 169

169. What does oxytocin have to do with milk letdown?

Back 169

The milk must be ejected from the alveoli into the ducts before the baby can obtain it.

When the baby suckles, sensory impulses travel to the hypothalamus, where they cause nerve signals to cause oxytocin secretion at the same time as prolactin secretion.

The oxytoxin is carried into the breasts, where it causes myoepithelial cells to contract and the milk can be removed by the baby.

Front 170

170. Antibodies in maternal milk

Back 170

Not only does milk provide the newborn baby with needed nutrients, but it also provides important protection against infection. For instance, multiple types of antibodies and other anti-infectious agents are secreted in milk along with the nutrients.

Also, several different types of white blood cells are secreted, including both neutrophils and macrophages, some of which are especially lethal to bacteria that could cause deadly infections in newborn babies.

Particularly important are antibodies and macrophages that destroy Escherichia coli bacteria, which often cause lethal diarrhea in newborns.

Front 171

171. What is the physiologic function of the immune system?

Back 171

To prevent infections and to eradicate established infections

Front 172

172. What are the host defense mechanisms?

Back 172

They consists of innate immunity, which mediates the initial protection against infections, and adaptive immunity, which develops more slowly and mediates the later, even more effective, defense against infections.

Front 173

173. What is the first line of defense in innate immunity?

Back 173

The epithelial barriers and by specialized cells and natural antibiotics present in the epithelia, all of which function to block the entry of microbes.

Front 174

174. What are the two types of adaptive immunity?

Back 174

1. Humoral immunity
-mediated by proteins called antibodies produced by B lymphocytes
-defends against extracellular microbes

2. Cell-mediated immunity
-mediated by T lymphocytes
-defends against intracellular microbes

Front 175

175. What is one of the most important functions of antibodies?

Back 175

To stop microbes that are present at mucosal surfaces and in the blood from gaining access to and colonizing host cells and connective tissues.

Front 176

176. Important difference between B and T lymphocytes?

Back 176

Most T cells recognize only protein antigens, whereas antibodies are able to recognize many different types of molecules, including proteins, carbs, and lipids.

Front 177

177. What type of immunity is immunization?

Back 177

Passive immunity - useful for rapidly conferring immunity even before the individual is able to mount an active response.

Front 178

178. What are the 7 features of adaptive immune responses?

Back 178

1. Specificity
2. Diversity
3. Memory
4. Clonal expansion
5. Specialization
6. Contraction and homeostasis
7. Nonreactivity to self

Front 179

179. What is clonal expansion?

Back 179

When lymphocytes are activated by antigens, they undergo proliferation, generating many thousands of clonal progeny cells, all w/the same antigen specificity.

This process, called clonal expansion, ensures that adaptive immunity keeps pace w/rapidly proliferating microbes.

Front 180

180. What is the importance of lymphocytes?

Back 180

Lymphocytes are the only cells that produce specific receptors for antigens and are thus the key mediators of adaptive immunity.

These cells are distinguishable by surface proteins that may be identified using panels of monoclonal antibodies.

Front 181

181. What are the three main cells of the immune system?

Back 181

1. Lymphocytes
-B & T lymphocytes, NK cells

2. Antigen presenting cells (APCs)
-dendritic cells; macrophages; follicular dendritic cells

3. Effector cells
-T lymphocytes; macrophages; granulocytes

Front 182

182. B lymphocytes

T lymphocytes

NK cells

Back 182

B lymph: mediators of humoral immunity

T lymph: mediators of cell mediated immunity

NK cells: cells of innate immunity

Front 183

183. Dendritic cells, macrophages, and follicular dendritic cells

Back 183

Dendritic cells: initiation of T cell responses

Macrophages: initiation and effector phase of cell mediated immunity

Follicular dendritic cells: display of antigens to B lymphocytes in humoral immune responses

Front 184

184. What do T cells recognize?

Back 184

The antigen receptors of most T lymphocytes only recognize peptide fragments of protein antigens that are bound to specific MHC molecules on the surface of specialized cells called APCs.

Front 185

185. Why are CD4+ T cells called helper T cells?

Back 185

They help B lymphocytes to produce antibodies and help phagocytes to destroy ingested microbes.

Front 186

186. How are B and T cells different from NK cells?

Back 186

NK cells also kill infected host cells, but they do not express the kinds of clonally distributed antigen receptors that B cells and T cells do and are components of innate immunity, capable of rapidly attacking infected cells.

Front 187

187. Maturation of lymphocytes

Back 187

All lymphocytes are produced in the bone marrow.

B cells mature in the bone marrow and T cells mature in the thymus; these sites where lymphocytes are produced are called the generative lymphoid organs.

Mature lymphocytes leave the generative lymphoid organs and enter the circulation and the peripheral lymphoid organs, where they may encounter antigen for which they express specific receptors.

Front 188

188. Where do effector cells and memory cells come from?

Back 188

When naive lymphocytes recognize microbial antigens and also receive additional signals induced by microbes, the antigen-specific lymphocytes proliferate and differentiate into effector cells and memory cells.

Front 189

189. What are naive lymphocytes?

Back 189

Naive lymphocytes express receptors for antigens but do not perform the functions that are required to eliminate antigens.

These cells reside in an circulate between peripheral lymphoid organs and survive for several weeks or months, waiting to find and respond to antigen.

If they are not activated, naive lymphocytes die via apoptosis and are replaced by new cells that have arisen in the generative lymphoid organs.

Front 190

190. What are lymphocyte effector cells?

What are the effector cells in the B lymphocyte lineage?

Back 190

Effector cells are the differentiated progeny of naive cells that have the ability to produce molecules that function to eliminate antigens.

The effector cells in the B lymphocyte lineage are antibody secreting cells, called plasma cells

Effector CD4+ T cells produce cytokines that activate B cells and macrophages, thereby mediating the helper function of this lineage, and effector CD8+ T cells have the machinery to kill infected host cells.

Front 191

191. How long do effector lymphocytes last?

Back 191

Most effector lymphocytes are short-lived and die as the antigen is eliminated, but some may migrate to special anatomic sites and live for long periods.

Front 192

192. What are memory cells?

Back 192

These are generated from the progeny of antigen-stimulated lymphocytes, and they survive for long periods of time in the absence of antigen.

Therefore, the freq of memory cells increases w/age.

They are functionally inactive; they do not perform effector functions unless stimulated by antigen.

Front 193

193. What are antigen presenting cells?

Back 193

The common portals of entry for microbes (skin, GI tract, and respiratory tract) contain specialized antigen presenting cells located int he epithelium that capture antigens, transport them to the peripheral lymphoid tissues, and display them to lymphocytes.

Front 194

194. What are dendritic cells?

Back 194

Dendritic cells capture protein antigens of microbes that enter thru the epithelia and transport the antigens to regional lymph nodes. Here the antigen-bearing dendritic cells display portions of the antigens for recognition by T lymphocytes.

If a microbe has invaded thru the epithelium, it may be phagocytosed by macrophages that live in tissues and in various organs.

Front 195

195. What are professional APCs?

What are the prototypical professional APCs?

Back 195

These specialized cells respond to microbes by producing surface and secreted proteins that are required, together with antigen, to activate naive T lymphocytes to proliferate and differentiate into effector cells.

The prototypical professional APCs are dendritic cells, but macrophages and a few other cell types may serve the same function.

Front 196

196. What is the follicular dendritic cell and where is it located?

Back 196

The follicular dendritic cells (FDC) resides int eh germinal centers of lymphoid follicles in the peripheral lymphoid organs and displays antigens that stimulate the differentiation of B cells in the follicles.

FDCs do not present antigens to T cells and are quite different from the dendritic cells described earlier that function as APCs for T lymphocytes.

Front 197

197. How do effector cells differ in innate vs. adaptive immunity?

Back 197

In innate immunity, macrophages and some granulocytes directly recognize microbes and eliminate them.

In adaptive immunity, the products of B and T lymphocytes call in other leukocytes and activate them to kill microbes.

Front 198

198. What are the tissues of the immune system?

Back 198

They consists of the generative (AKA primary or central) lymphoid organs, in which T and B lymphocytes mature and become competetent to respond to antigens and the peripheral (or secondary) lymphoid organs, in which adaptive immune responses to microbes are initiated.

Front 199

199. What are the peripheral lymphoid organs?

How is the "organization" set up?

Back 199

They consists of lymph nodes, the spleen, and the mucosal and cutaneous immune systems, and are organized to optimize interactions of antigens, APCs, and lymphocytes in a way that promotes the development of adaptive immune responses.

The anatomic organization of peripheral lymphoid organs enables APCs to concentrate antigens int these organs and lymphocytes to locate and respond to the antigens.

Front 200

200. What are lymph nodes?

Back 200

They are nodular aggregates of lymphoid tissues located along lymphatic channels throughout the body.

As the lymph passes thru lymph nodes, APCs in the nodes are able to sample the antigens of microbes that may enter through epithelia into the tissues.

In addition, dendritic cells pick up antigens of microbes from epithelia and transport them to the lymph nodes.

Front 201

201. What is the spleen and what does it do?

Back 201

The spleen is an abdominal organ that serves the same role in immune responses to blodo borne antigens as that of lymph nodes in respones to lymph borne antigens. Blood entering the spleen flows thru a network of channels (sinusoids). Blood born antigens are trapped and concentrated by dendritic cells and macrophages in the spleen.

The spleen contains abundant phagocytes, which ingest and destroy microbes in the blood.

Front 202

202. Where are the cutaneous and mucosal lymphoid systems located?

Back 202

The cutaneous and mucosal lymphoid systems are located under the epithelia of the skin and the GI and respiratory tracts, respectively.

Pharyngeal tonsil and Peyer's patches of the intestine are two anatomically defined mucosal lymphoid tissues.

Front 203

203. In lymph nodes, where are the B cells concentrated?

In the spleen?

Back 203

The B cells are concentrated in discrete structures, called follicles, located around the periphery, or cortex, or each node.

If the B cells in a follicle have recently responded to an antigen, this follicle may contain a central region called a germinal center, which produces antibodies.

The follicles contain the FDCs that are involved in the activation of B cells.

B cells are also located in the follicles of the spleen.

Front 204

204. In lymph nodes, where are the T cells concentrated?

In the spleen?

Back 204

The T cells are concentrated outside, but adjacent to, the follicles, in the paracortex.

The paracortex contains the dendritic cells that present antigens to T lymphocytes.

In the spleen, the T lymphs are concentrated in the PALS surrounding small arterioles.

Front 205

205. Why are B lymphocytes located in the follicles?

Back 205

B lymphs are located in the follicles b/c FDCs secrete a protein that belongs to a class of cytokines called chemokines, for which naive B cells express a receptor.

This chemokine is produced all the time, and it attracts B cells from the blood into the follicles of lymphoid organs.

Front 206

206. Why are T lymphs located in the paracortex of lymph nodes and PALS of the spleen?

Back 206

Naive T lymphs express a receptor, called CCR7 that recognizes chemokines that are produced in these regions of the lymph nodes and spleen.

As a result, T lymphs are recruited from the blood into the parafollicular cortex region of the lymph node and the PALS of the spleen.

Front 207

207. How does the anatomic organization of the peripheral lymph organs help B and T cells interact?

Back 207

As a result of this organization, the B cells and T cells migrate toward each other and meet at the edge of follicles, where helper T cells interact w/and help B cells to differentiate into antibody producing cells.

Front 208

208. Recirculation of T and B lymphocytes

Back 208

Naive lymphs constantly recirculate between the blood and peripheral lymphoid organs. Lymphocytes at distinct stages of their lives migrate to the different sites where they are needed for their functions.

Effector T cells have to locate and eliminate microbes at any site of infection; on the other hand, effector B lymphocytes remain in lymphoid organs and do not need to migrate to sites of infection. Instead, B cells secrete antibodies, and the antibodies enter the blood and find microbes and microbial toxins in the circulation or distant tissues.

Front 209

209. Circulation of T lymphs

Back 209

Naive T lymphs express a surface receptor called L-selectin that binds to carb ligands that are expressed only on the endothelial cells of high endothelial venules (HEVs).

The naive T lymphs migrate from the blood through HEVs into the T cell zones of lymph nodes where the cells are activated by antigens.

Activated T cells exit the nodes, enter the bloodstream, and migrate preferentially to peripheral tissues at sites of infection and inflammation.

Front 210

210. What happens to the T lymph once it is activated?

Back 210

In response to the microbial antigen, the naive T cells are activated to proliferate and differentiate.

During this process, the cells reduce expression of adhesion molecules and chemokine receptors that keep naive cells in the lymph nodes.

At the same time, T cells increase their expression of receptors for sphingosine 1-phosphate, and since the concentration of this phospholipid is higher in the blood than in lymph nodes, activated cells are drawn out of the nodes into the circulation.

Front 211

211. What happens to B lymphs when they respond to an antigen?

Back 211

B lymphs appear to enter lymph nodes through HEVs, but after they respond to antigen, their differentiated progeny either remain in the lymph nodes or migrate mainly to the bone marrow.

Front 212

212. What are the three main strategies the adaptive immune system uses to combat microbes?

Back 212

1. Secreted antibodies bind to extracellular microbes, block their ability to infect host cells, and promote their ingestion and subsequent destruction by phagocytes.
2. Phagocytes ingest microbes and kill them, and helper T cells enhance the microbicidal abilities of the phagocytes.
3. Cytotoxic T lymphs destroy cells infected by microbes that are inaccessible to antibodies.

Front 213

213. What are "signals 1 & 2"?

Back 213

Antigens (often referred to as "signal 1"), and molecules produced during innate immune responses ("signal 2") function cooperatively to activate antigen specific lymphocytes.

Front 214

214. Why is signal 2 important?

Back 214

The requirement for microbe-triggered signal 2 ensures that the adaptive immune response is induced by microbes and not by harmless substances.

Signals generated in lymphocytes by the engagement of antigen receptors and receptors for costimulators lead to the transcription of various genes, which encode cytokines, cytokine receptors, effector molecules, and proteins that control cell cycling.

Front 215

215. What are the different immunoglobulins produced by B cells?

Back 215

Polysaccharides and lipids stimulate secretion mainly of a class of antibody called IgM.

Protein antigens stimulate helper T cells, which induce the production of antibodies of different classes (IgG, IgA, and IgE).

Front 216

216. What is heavy chain class (isotype) switching?

Back 216

This production of different antibodies, all with the same specificity is called heavy chain class (isotype) switching.

It provides plasticity in the antibody response, enabling antibodies to serve many functions.

Front 217

217. What is affinity maturation?

Back 217

Helper T cells also stimulate the production of antibodies w/higher and higher affinity for the antigen.

This process, called affinity maturation, improves the quality of the humoral immune response.

Front 218

218. What is immunological tolerance?

What are the two types?

Back 218

The immune system is capable of reacting to an enormous variety of microbes, but it does not react against each individual's own (self) antigens.

Immunological tolerance is a lack of response to antigens that is induced by exposure of lymphocytes to these antigens.

It may be induced when developing lymphocytes encounter these antigens int he generative lymphoid organs, called central tolerance, or when mature lymphocytes encounter self antigens in peripheral tissues, called peripheral tolerance.

Front 219

219. Why is immunological tolerance important?

Back 219

First, self antigens normally induce tolerance. Second, if we learn how to induce tolerance in lymphocytes specific for a particular antigen, we may be able to use this knowledge to prevent unwanted immune reactions

Front 220

220. What is central T lymphocyte tolerance?

Back 220

The principal mechanisms of central tolerance in T cells are cell death, and, for CD4+ cells, the generation of regulator T cells.

The lymphocytes that develop in the thymus consist of cells w/receptors capable of recognizing many antigens, both self and foreign.

It uses negative selection

Front 221

221. What is negative selection?

Back 221

If an immature lymphocyte strongly interacts w/a self antigen, displaced as a peptide bound to a self MHC molecule, that lymphocyte receives signals that trigger apoptosis, and the cell dies before it can complete its maturation. This process is called negative selection.

Antigens that induce negative selection may include proteins that are abundant throughout the body, such as plasma proteins and common cellular proteins. Surprisingly, many self proteins that are thought to be expressed mainly or exclusively in peripheral tissues are actually also expressed in some of the epithelial cells of the thymus.

Front 222

222. What is the AIRE (autoimmune regulator) protein?

Mutations in this protein cause...?

Back 222

This protein called AIRE is responsible for thymic expression fo many of these otherwise peripheral tissue-resticted protein antigens.

Mutations in the AIRE gene are the cause of a rare autoimmune disorder called autoimmune polyendocrine syndrome.

Front 223

222. The process of negative selection affects what types of cells?

Back 223

It affects CD4+ T cells and CD8+ T cells which recognize self peptides displayed by class II MHC and class I MHC molecules, respectively.

Front 224

223. What is peripheral T lymphocyte tolerance?

Back 224

Peripheral tolerance is induced when mature T cells recognize self antigens in peripheral tissues, leading to functional inactivation (anergy) or death, or when the self reactive lymphocytes are suppressed by regulatory T cells.

Peripheral tolerance is clearly important for preventing T cell responses to self antigens that are present mainly in peripheral tissues and not in the thymus.

Front 225

224. What is anergy?

Back 225

Anergy is the functional inactivation of T lymphocytes that occurs when these cells recognize antigens w/o adequate levels of the costimulators (second signals) that are needed for full T cell activation.

Front 226

225. What is signal 1 and 2 again?

Back 226

Signal 1 is always antigen, and signal 2 is provided by costimulators that are expressed on APCs in response to microbes.

It is beleived that normal APCs in tissues and peripheral lymphoid organs, including dendritic cells, are in a resting state, in which they express little or no costimulators such as B7 proteins.

These APCs are constantly processing and displaying the self antigens that are present in the tissues.

Front 227

226. How does anergy work with signals 1 and 2?

Back 227

T lymphs w/receptors for the self antigens are able to recognize the antigens and thus receive prolonged signals from their antigen receptors, but the T cells do not receive strong costimulation b/c there is no accompanying innate immune response.

Under these conditions, the T cell antigen receptors may lose their ability to transmit activating signals, or the T cells may preferentially engage one of the inhibitory receptors of the CD28 family, CTLA-4 or PD-1.

The net result is long lasting T cell anergy.

Front 228

227. Forced expression of high levels of B7 costimulators in a tissue results in...?

Back 228

Results in autoimmune reactions against antigens in that tissue.

Thus, artificially providing second signals "breaks" anergy and activates autoreactive T cells.

Front 229

228. What happens if CTLA-4 molecules are blocked or deleted in a mouse?

Back 229

That mouse develops widespread autoimmune reactions against its own tissues.

These resutls suggest that the inhibitory receptors are constantly functioning to keep autoreactive T cells in check.

Polymorphisms in the CTLA4 gene have been associated w/some autoimmune diseases in humans.

Front 230

229. What are regulatory T cells?

Back 230

Regulatory T cells develop in the thymus or peripheral tissues on recognition of self antigens and block the activation of potentially harmful lymphocytes specific for these self antigens.

A majority of self-reactive regulatory T cells probably develop in the thymus, but they also ma arise in peripheral lymphoid organs.

Most regulatory T cells are CD4+ and express high levels of CD25, the alpha chain of the IL-2 receptor.

Front 231

230. The development and function of regulatory T cells are dependent on...?

Back 231

A transcription factor called Foxp3.

Mutations of Foxp3 in humans or in knockout mice causes a systemic, multiorgan autoimmune disease, demonstrating the importance of regulatory T cells for the maintenance of self-tolerance.

The survival and function of regulatory T cells are dependent on the cytokine IL-2 and this role of IL-2 accounts for the severe autoimmune disease that develops in mice in which the gene encoding IL-2 or the alpha or beta chain of the IL-2 receptor is deleted.

Front 232

231. What role does TGF-β play in regulatory T cells?

Where does it come from?

Back 232

TGF-β plays a role in the generation of regulatory T cells, perhaps by stimulating the Foxp3 transcription factor.

The source of TGF-β for inducing these cells in the thymus or peripheral tissues is not defined.

Front 233

232. What is deletion - activation-induced cell death?

What are the two mechanisms of death?

Back 233

Recognition of self-antigens may trigger pathways of apoptosis that result in elimination of the self-reactive lymphocytes.

There are two liekly mechanisms of death of mature T lymphs induced by self antigens:
1. Antigen recognition induces the production of pro-apoptotic proteins in T cells that induce cell death via the mitochondrial pathway
2. Recognition of self antigens may lead to the coexpression of death receptors and their ligans

Front 234

233. What is the best defined death receptor:ligand pair involved in self tolerance?

Back 234

A protein called Fas (CD95), which is expressed on many cell types, and Fas ligand (FasL), which is expressed mainly on activated T cells.

Binding of FasL to Fas has been shown to induce death of both T and B cells exposed to self antigens and to mimics of self antigens in experimental animals.

Front 235

234. What happens when one blocks the mitochondrial pathway of apoptosis in mice?

Mutations in fas and fasL genes?

Back 235

It results in a failure of deletion of self-reactive T cells in the thymus and also in peripheral tissues.

Mutations in the fas and fasL genes and children w/mutations in FAS all develop autoimmune diseases w/lymphocyte accumulation.

The human disease called the autoimmune lymphoproliferative syndrome, is rare and the only known example of a defect in apoptosis causing a complex autoimmune phenotype in humans.

Front 236

235. How do self antigens differ from foreign microbial antigens?

Three main differences...

Back 236

1. Self antigens are present in the thymus, where they induce deletion and generate regulatory T cells; by contrast, microbial antigens are actively transported to an concentrated in peripheral lymphoid organs.

2. Self antigens are displayed by resting APCs in the absence of innate immunity and second signals, thus favoring the induction of T cell anergy or death. By contrast, microbes elicit innate immune reactions, leading to the expression of costimulators and cytokines that function as second signals and promote T cell proliferation and differentiation into effector cells.

3. Self antigens are present throughout life and may therefore cause prolonged or repeated TCR engagement, again promoting anergy and apoptosis. On the other hand, microbes have antigens that are usually short lived, as the immune response eliminates that antigen.

Front 237

236. How does B lymphocyte tolerance work?

Back 237

Self polysaccharides, lipids, and nucleic acids are T-independent antigens that are not recognized by T cells.

These antigens must induce tolerance in B lymphocytes to prevent autoantibody production.

Front 238

237. What is central B cell tolerance?

Back 238

When immature B lymphocytes interact strongly w/self antigens in the bone marrow, the B cells either change their receptor specificity (receptor editing) or are killed (negative selection).

Front 239

238. What is receptor editing?

What is its purpose? What happens when it fails?

Back 239

Some immature B cells that recognize self antigens in the bone marrow may reactivate their Ig gene recombination machinery and begin to expres a new Ig light chain.

This new light chain associates w/the previously expressed Ig heavy chain to produce a new antigen receptor that is no longer specific for the self antigen.

This process called receptor editing, reduces the likelihood that potentially harmful self-reactive B cells will leave the marrow. If editing fails, immature B cells that recognize self antigens with high affinity receive death signals and die by apoptosis (negative selection)

Front 240

239. What is peripheral B cell tolerance?

Back 240

Mature B lymphocytes that encounter high concentrations of self antigens in peripheral lymphoid tissues become anergic and cannot again respond to that self antigen.

If B cells recognize an antigen and do not receive T cell help (b/c helper T cells are absent, or tolerant), the B cells become anergic.

Anergic B cells may leave lymphoid follicles and are subsequently excluded from the follicles. These excluded B cells may die b/c they do not receive necessary survival stimuli.

Front 241

240. What is autoimmunity?

What are the principal factors in the development of autoimmunity?

Back 241

Autoimmunity is defined as an immune response against self (autologous) antigens.

It is an important cause of disease and is increasing in prevalence.

The principal factors in the development of autoimmunity are the inheritance of susceptibility genes and environmental triggers, such as infections.

Front 242

241. What does autoimmunity result in?

Back 242

May result in the production of antibodies against self antigens or the activation of T cells reactive w/self antigens.

Front 243

242. What are the genetic factors in autoimmunity?

Back 243

Most autoimmune disease are polygenic and are associated w/multiple gene loci, the most important of which are the MHC genes.

Many autoimmune diseases in humans and inbred animals are linked to particular MHC alleles.

Front 244

243. How do particular MHC alleles contribute to the development of autoimmunity?

Back 244

They are inefficient at displaying self antigens, leading to defective negative selection of T cells, or b/c peptide antigens presented by these MHC alleles may fail to stimulate regulatory T cells.

It is important to point out that an HLA allele may increase the risk of developing a particular autoimmune disease, but the HLA allele is not, by itself, the cause of the disease.

Front 245

244. HLA-B27 allele and relative risk...?

Back 245

People who have the HLA-B27 allele have a 80-100x higher risk of developing ankylosing spondylitis than in B27 negative people.

Front 246

245. What two non-HLA genes are also associated with autoimmune diseases?

Back 246

Two genes that have been associated w/autoimmune diseases in humans:

1. The gene that encodes the tyrosine phosphatase PTPN22 (protein tyrosine phosphatase N22), is associated with numerous autoimmune diseases

2. The cytoplasmic microbial sensor NOD-2 (nucleotide binding oligomerization domain - containing protein 2), is associated with Crohn's disease.

Front 247

246. AIRE

Back 247

Autoimmune poly endocrine syndrome

- mechanism is defective expression of tissue antigens and elimination of self-reactive T cells in the thymus

Front 248

247. Complement proteins (C2, C4)

Back 248

Lupus like disease

-mechanism is defective clearance of immune complexes or defects in B cell tolerance

Front 249

248. Fas, FasL

Back 249

Lymphoproliferative and generalized lymphoproliferative disease, also causes ALPS (Autoimmune lympoproliferative syndrome)

-mechanism is defective elimination of self-reactive lymphocytes

Front 250

249. FcγRIIb

Back 250

Lupus like disease

-mechanism is defective feedback inhibition of B cell activation

Front 251

250. Foxp3

Back 251

Causes X-linked polyendocrinopathy and enteropathy (IPEX)

-mechanism is deficiency of regulatory T cells.

Front 252

251. IL-2; IL-2Rα/β

Back 252

Causes several autoimmune diseases (increased risk with polymorphisms)

-mechanism is deficiency of regulatory T cells as well

Front 253

252. NOD-2

Back 253

Causes Crohn's disease

Mechanism is defective resistance or abnormal responses to intestinal microbes

Front 254

253. PTPN22

Back 254

Causes several autoimmune diseases

-mechanism is abnormal tyrosine phosphatase regulation of lymphocyte activation

Front 255

254. Infections, autoimmunity, and molecular mimicry

Back 255

Infections may activate self-reactive lymphocytes, thereby triggering the development of autoimmune diseases.

Microbes may activate the APCs to express costimulators, and when these APCs present self antigens, the specific T cells are activated, rather than being rendered tolerant.

Also, some microbial antigens may cross-react w/self antigens (mimicry). Therefore, immune responses initiated by the microbes may become directed at self cells and tissues. (Ex: rheumatic fever caused by streptcocci).

Front 256

255. What are the major components of innate immunity?

Back 256

The major components of innate immunity are epithelial barriers that block entry of environmental microbes, phagocytic cells (mainly neutrophils and macrophages), natural killer (NK) cells, and several plasma proteins, including the proteins of the complement system.

Front 257

256. What do phagocytes recognize?

Back 257

Phagocytes recognize microbes by several membrane receptors. These include receptors for mannose residues and N-formyl methionine containing peptides, which are produced by microbes but not by host cells, and a family of receptors that are homologous to a Drosophila protein called Toll.

Front 258

257. What are toll-like receptors (TLRs)?

Back 258

Different Toll-like receptors (TLRs) are involved in responses to different microbial products.

Upon recognition of the relevant microbial structure, the TLRs signal by a common pathway that leads to the activation of transcription factors, notably NF-κB (nuclear factor κB).

Phagocytes internalize microbes into vesicles, where the microbes are destroyed by reactive oxygen and nitrogen intermediates and hydrolytic enzymes.

Front 259

258. What is NF-κB?

Back 259

NF-κB stimulates production of cytokines and several proteins that are responsible for the microbicidal activities of the phagocytes.

Front 260

259. How is the complement system activated in adaptive vs. innate immune systems?

Back 260

In innate immunity, the complement system is activated by binding to microbes using the alternative and lectin pathways.

In adaptive immunity, it is activated by binding to antibodies using the classical pathway.

Front 261

260. What are the two main types of adaptive immunity, and what mediates each?

Back 261

There are two main types of adaptive immunity-cell-mediated (or cellular) immunity, which is responsible for defense against intracellular microbes, and humoral immunity, which protects against extracellular microbes and their toxins.

Cellular immunity is mediated by T (thymus derived) lymphocytes, and humoral immunity is mediated by B (bone marrow-derived) lymphocytes and their secreted products, antibodies.

All these mechanisms of adaptive immunity are capable of causing injury to the host and subsequent disease.

Front 262

261. What is the structure of the T-cell receptor?

Back 262

In approximately 95% of T cells, the TCR consists of a disulfide-linked heterodimer made up of an α and a β polypeptide chain, each having a variable (antigen-binding) and a constant region.

The αβ TCR recognizes peptide antigens that are displayed by major histocompatibility complex (MHC) molecules on the surfaces of antigen presenting cells.

T-cell receptors are capable of recognizing a very large number of peptides; each T cell expresses TCR molecules of one structure and specificity.

Front 263

262. The presence of TCR gene rearrangements demonstrated by molecular analysis is a marker of...?

Back 263

T-lineage cells; every somatic cells has TCR genes from the germ line. Rearrangements of these genes occur only in T cells during their development in the thymus.

Front 264

263. What are most TCRs linked to?

What do these chains do?

Back 264

Each TCR is noncovalently linked to a cluster of five polypeptide chains, three of which form the CD3 molecular complex and two are a dimer of the ζ chain. The CD3 and ζ proteins are invariant.

They do not bind antigen but are involved in the transduction of signals into the T cell after the TCR has bound the antigen.

Front 265

264. What is the importance of TCRs composed of γ and δ polypeptide chains?

Where are they located?

Back 265

A minority of mature T cells express another type of TCR composed of γ and δ polypeptide chains. The γδ TCR recognizes peptides, lipids, and small molecules, WITHOUT a requirement for display by MHC proteins.

γδ T cells tend to aggregate at epithelial surfaces, such as the mucosa of the respiratory and GI tracts, suggesting that these cells are sentinels that protect against microbes that try to enter through these epithelia.

Front 266

265. What are NK-T cells?

What do they recognize?

Back 266

Another small subset of T cells expresses markers that are found on natural killer (NK) cells; these cells are called NK-T cells.

NK-T cells express a very limited diversity of TCRs, and they recognize glycolipids that are displayed by the MHC-like molecule CD1.

Front 267

266. In addition to CD3 and ζ proteins, what else do T cells express?

Back 267

T cells express a number of nonpolymorphic, function-associated molecules, also called accessory molecules, including CD4, CD8, CD2, integrins, and CD28.

CD4 and CD8 are expressed on two mutually exclusive subsets of αβ T cells

Front 268

267. What is CD4 and where is it found?

What does it recognize?

Back 268

CD4 is expressed on approximately 60% of mature CD3+ T cells.

During antigen presentation, CD4 molecules bind to the nonpolymorphic portions of class II MHC molecules expressed on antigen-presenting cells.

CD4+ helper T cells can recognize and respond to antigen only in the context of class II MHC molecules.

Front 269

268. What is CD8 and where is it found?

What does it recognize?

Back 269

CD8 is expressed on about 30% of T cells.

CD8 molecules bind to class I MHC molecules.

CD8+ cytotoxic T cells recognize cell-bound antigens only in association with class I MHC molecules

Front 270

269. What provides signal 1 of 2?

Back 270

Signal 1 is provided when the TCR is engaged by the appropriate MHC-bound antigen, and the coreceptors CD4 and CD8 bind to MHC molecules.

Front 271

270. What provides signal 2 of 2?

Back 271

Signal 2 is delivered by the interaction of the CD28 molecule on T cells with the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) expressed on antigen-presenting cells.

Front 272

271. What happens when T cells are activated by antigen and costimulators?

Back 272

They secrete locally acting cytokines.

Under the influence of IL-2, the T cells proliferate, thus generating large numbers of antigen-specific lymphocytes. Some of these cells differentiate into effector cells, which perform the function of eliminating the antigen that started the response.

Other activated cells differentiate into memory cells.

Front 273

272. Role of CD4+ T cells

Back 273

The CD4+ T cell can be viewed as a master regulator-the mafia boss.

By secreting cytokines, CD4+ T cells influence the function of virtually all other cells of the immune system, including other T cells, B cells, macrophages, and NK cells.

Front 274

273. What are the two functionally distinct populations of CD4+ helper cells, and what doe they produce?

Back 274

1. The T-helper-1 (TH1) subset synthesizes and secretes IL-2 and interferon-γ (IFN-γ).
- the TH1 subset is involved in facilitating delayed hypersensitivity, macrophage activation, and synthesis of opsonizing and complement-fixing antibodies, such as IgG2a in mice, all of which are actions of IFN-γ.

2. TH2 cells produce IL-4, IL-5 and IL-13.
- the TH2 subset aids in the synthesis of other classes of antibodies, notably IgE (mediated by IL-4 and IL-13) and in the activation of eosinophils (mediated by IL-5).

Front 275

274. What are CD8+ T cells?

Back 275

They function mainly as cytotoxic cells to kill other cells but, similar to CD4+ T cells, they can secrete cytokines, primarily of the TH1 type.

Front 276

275. Where are B cells found in the spleen and in lymph nodes?

Back 276

In lymph nodes, they are found in the superficial cortex. In the spleen, they are found in the white pulp.

At both sites, they are aggregated in the form of lymphoid follicles, which on activation develop pale-staining germinal centers

B cells are located in follicles, the B-cell zones of lymphoid organs, because the cells express receptors for a chemokine that is produced in follicles.

Front 277

276. How do B cells recognize antigen?

Back 277

Via the B-cell antigen receptor complex.

IgM and IgD, present on the surface of all naive B cells, constitute the antigen-binding component of the B-cell receptor complex.

Front 278

277. The presence of what in a lymphoid cell is used as a molecular marker of B-lineage cells?

Back 278

Rearranged immunoglobulin genes.

As with T cells, each B-cell receptor has unique antigen specificity, derived in part from somatic rearrangements of immunoglobulin genes.

Front 279

278. What happens after B cells are activated via antigenic stimulation?

Back 279

After antigenic stimulation, B cells form plasma cells that secrete immunoglobulins, which are the mediators of humoral immunity.

Antibody-secreting cells reside in lymphoid organs and mucosal tissues, and some plasma cells may migrate to the bone marrow and live for many years in this tissue.

Secreted antibodies enter mucosal secretions and the blood and are able to find, neutralize, and eliminate antigens.

Front 280

279. What are B-cell antigen receptors composed of?

Back 280

In addition to membrane immunoglobulin, the B-cell antigen receptor complex contains a heterodimer of nonpolymorphic transmembrane proteins Igα and Igβ.

Similar to the CD3 proteins of the TCR, Igα and Igβ do not bind antigen but are essential for signal transduction through the antigen receptor.

Front 281

280. What else do B cells express?

Where does the Epstein-Barr virus infect?

Back 281

B cells also express several other nonpolymorphic molecules that are essential for B-cell function. These include complement receptors, Fc receptors, and CD40.

*It is worthy of note that complement receptor-2 (CD21) is also the receptor for the Epstein-Barr virus (EBV), and hence EBV readily infects B cells.

Front 282

281. B-cell responses to antigens require help from...?

How?

What is this necessary for?

Back 282

B-cell responses to protein antigens require help from CD4+ T cells.

Helper T cells activate B cells by engaging CD40, a member of the tumor necrosis factor (TNF)-receptor family, and by secreting cytokines. Activated helper T cells express CD40 ligand, which specifically binds to CD40 expressed on B cells.

This interaction is essential for B-cell maturation and secretion of IgG, IgA, and IgE antibodies.

Front 283

282. Patients with mutations in the CD40 ligand have...?

Back 283

Patients with mutations in the CD40 ligand have an immunodeficiency disease called X-linked hyper-IgM syndrome,

Front 284

283. What are three features of macrophages?

Back 284

1. Macrophages that have phagocytosed microbes and protein antigens process the antigens and present peptide fragments to T cells. Thus, macrophages are involved in the induction of cell-mediated
immune responses.

2. Macrophages are important effector cells in certain forms of cell-mediated immunity, such as the delayed hypersensitivity reaction. As mentioned earlier, macrophages are activated by cytokines, notably IFN-γ produced by the TH1 subset of CD4+ cells. Such activation enhances the microbicidal properties of macrophages and augments their ability to kill tumor cells.

3. Macrophages are also important in the effector phase of humoral immunity. They phagocytose microbes that are opsonized (coated) by IgG or C3b.

Front 285

284. What are interdigitating dendritic cells?

Back 285

AKA dendritic cells

These cells are the most important antigen-presenting cells for initiating primary immune responses against protein antigens

Front 286

285. What are four reasons for why dendritic cells have a key role in antigen presentation?

What are Langerhans cells?

Back 286

1. These cells are located at the right place to capture antigens - under epithelia, and in the interstitia of all tissues (immature dendritic cells within the epidermis are called Langerhans cells).
2. Dendritic cells express many receptors for capturing and responding to microbes, including TLRs and mannose receptors.
3. In response to microbes, dendritic cells express the same chemokine receptor as do naive T cells and are thus recruited to the T-cell zones of lymphoid organs.
4. Dendritic cells express high levels of MHC class II molecules as well as the costimulatory molecules B7-1 and B7-2. Thus, they possess all the machinery needed for presenting antigens to an activating CD4+ T cells.

Front 287

286. What are follicular dendritic cells?

Back 287

These cells are present in the germinal centers of lymphoid follicles in the spleen and lymph nodes.

These cells bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or complement proteins. Such cells play a role in ongoing immune responses by presenting antigens to B cells and selecting the B cells that have the highest affinity for the antigen, thus improving the quality of the humoral immune response.

These cells also have a role in the pathogenesis of AIDS.

Front 288

287. What are NK cells?

What two cell surface molecules are used to identify NK cells?

Back 288

NK cells make up approximately 10% to 15% of the peripheral blood lymphocytes and do not bear T-cell receptors or cell surface immunoglobulins.

NK cells are endowed with an innate ability to kill a variety of tumor cells, virally infected cells, and some normal cells, without previous sensitization.

NK cells do not rearrange T-cell receptor genes and are CD3 negative. Two cell surface molecules, CD16 and CD56, are widely used to identify NK cells.

Front 289

288. Importance of CD16 in NK cells?

Back 289

CD16 is the Fc receptor for IgG and it endows NK cells with another function, the ability to lyse IgG-coated target cells.

This phenomenon is known as antibody-dependent cell-mediated cytotoxicity.

Front 290

289. How is the functional activity fo NK cells regulated?

Back 290

The functional activity of NK cells is regulated by a balance between signals from activating and inhibitory receptors.

The activating receptors stimulate NK cell killing by recognizing ill-defined molecules on target cells, some of which may be viral products; the inhibitory receptors inhibit the activation of NK cells by recognition of self-class I MHC molecules.

Front 291

290. What are killer inhibitor receptors?

Back 291

The class I MHC-recognizing inhibitory receptors on NK cells are called killer inhibitory receptors.

They are biochemically distinct from T-cell receptors. It is believed that NK cells are inhibited from killing normal cells because all nucleated normal cells express self-class I MHC molecules.

If virus infection or neoplastic transformation perturbs or reduces the expression of class I MHC molecules, inhibitory signals delivered to NK cells are interrupted, and lysis occurs.

Front 292

291. What activates NK cells?

Back 292

Several types of activating receptors have been discovered, including members of the NKG2D family and some Iglike receptors.

The NKG2D receptors recognize stress-induced proteins that are normally expressed by only a few cells in the gut epithelium but whose expression increases on many cells following viral infection or neoplastic transformation.

Other activating receptors recognize viral proteins that are structurally similar to class I MHC molecules.

Thus, NK cells are activated by contact with virus-infected and tumor cells, both of which often express reduced levels of class I MHC molecules and therefore do not engage inhibitory receptors.

Front 293

292. What do NK cells secrete?

What regulates their activity?

Back 293

NK cells also secrete cytokines, such as IFN-γ, TNF, and granulocyte macrophage colony-stimulating factor (GM-CSF).

The activity of NK cells is regulated by many cytokines, including IL-2, IL-15, and IL-12.

IL-2 and IL-15 stimulate proliferation of NK cells, whereas IL-12 activates killing and secretion of IFN-γ.

Front 294

293. Which cytokines mediate innate immunity?

Back 294

Included in this group are IL-1, TNF (tumor necrosis factor, also called TNF-α), type 1 interferons, and IL-6.

Some cytokines, such as IL-12 and IFN-γ, are involved in both innate and adaptive immunity against intracellular microbes. Certain of these cytokines (e.g., the interferons) protect against viral infections, whereas others (e.g., IL-1 and TNF) promote leukocyte recruitment and acute inflammatory responses.

Front 295

294. Which cytokines regulate lymphocyte growth, activation, and differentiation?

Back 295

Within this category are IL- 2, IL-4, IL-12, IL-15, and transforming growth factor-β (TGF-β).

IL-2 is an important growth factor for T-cells, IL-4 stimulates differentiation to the TH2 pathway and acts on B cells as well, IL-12 stimulates differentiation to the TH1 pathway, and IL-15 stimulates the growth and activity of NK cells.

Other cytokines in this group, such as IL-10 and TGF-β, down-regulate immune responses.

Front 296

295. Which cytokines activate inflammatory cells?

Back 296

In this category are IFN-γ, which activates macrophages; IL-5, which activates eosinophils; and TNF and lymphotoxin (also called TNF-β), which induce acute inflammation by acting on neutrophils and endothelial cells.

Front 297

296. Which cytokines affect leukocyte movement?

Back 297

AKA chemokines.

Most fall into two structurally distinct subfamilies, referred to as C-C and C-X-C chemokines, on the basis of the position of cysteine (c) residues.

The C-X-C chemokines are produced mainly by activated macrophages and tissue cells (e.g., endothelium), whereas the C-C chemokines are produced largely by T cells.

Front 298

297. Which cytokines stimulate hematopoiesis?

Back 298

Many cytokines derived from lymphocytes or stromal cells stimulate the growth and production of new blood cells by acting on hematopoietic progenitor cells.

Some members of this group (e.g., GM-CSF and G-CSF) act on committed progenitor cells, whereas others, exemplified by stem cell factor (c-kit ligand), act on pluripotent stem cells.

Front 299

298. How are the actions of cytokines pleotropic?

Back 299

Means that any one cytokine may act on many cell types and mediate many effects.

For example, IL-2, initially discovered as a T-cell growth factor, is known to affect the growth and differentiation of B cells and NK cells as well. Cytokines are also often redundant, meaning that different cytokines may stimulate the same or overlapping biologic responses.

Front 300

299. In what three ways do cytokines induce their effects?

Back 300

1. Autocrine, such as when IL-2 produced by antigen-stimulated T cells stimulates the growth of the same cells.

2. Paracrine, as when IL-7 produced by bone marrow or thymic stromal cells promotes the maturation of B-cell progenitors in the marrow or T-cell precursors in the thymus, respectively.

3. Endocrine, such as IL-1 and TNF, which produce the systemic acute-phase response during inflammation.

Front 301

300. How do cytokines mediate their effects?

Back 301

They bind to specific high-affinity receptors on their target cells.

For example, IL-2 activates T cells by binding to high-affinity IL-2 receptors (IL-2R). Blockade of the IL- 2R by specific antireceptor monoclonal antibodies prevents T-cell activation.

Front 302

301. What is the main function of the cell surface MHC molecules?

What genes encode these molecules?

Back 302

The principal physiologic function of the cell surface histocompatibility molecules is to bind peptide fragments of foreign proteins for presentation to antigen-specific T cells.

In humans, the genes encoding the most important histocompatibility molecules are clustered on a small segment of chromosome 6, the major histocompatibility complex, or the human leukocyte antigen (HLA) complex in humans

Front 303

302. Roles of MHC class I, II, and III?

Back 303

Class I and class II genes encode cell surface glycoproteins involved in antigen presentation.

Class III genes encode components of the complement system.

Front 304

303. Antigen binding cleft differences between Class I and II MHC molecules?

Back 304

Class I: The extracellular region of the heavy chain is divided into three domains: α1, α2, and α3 . Crystal structure of class I molecules has revealed that the α1 and α2 domains form a cleft, or groove, where peptides bind to the MHC molecule.

Class II: The extracellular portions of the α and β chains have two domains each: α1, α2 and β1, β2. Crystal structure of class II molecules has revealed that, similar to class I molecules, they have an antigen-binding cleft facing outward.

In contrast to class I molecules, however, the antigen-binding cleft is formed by an interaction of the α1 and β1 domains of both chains, and it is in this portion that most class II alleles differ.

Front 305

304. What do class II molecules present?

Back 305

In general, class II molecules present exogenous antigens (e.g., extracellular microbes, soluble proteins) that are first internalized and processed in the endosomes or lysosomes.

Front 306

305. In what two ways do MHC molecules play a key role in regulating T-cell mediated immune response?

Back 306

1. B/ different antigenic peptides bind to different class II gene products, a person will mount an immune response against an antigen only if he or she inherits the gene(s) for those class II molecule(s) that can bind the antigen and present it to helper T cells.

2. Second, during their maturation in the thymus, only T cells that can recognize self-MHC molecules are selected for export to the periphery. Thus, the type of MHC molecules that T cells encounter during their development influences the reactivity of mature peripheral T cells.

Front 307

306. Inflammatory diseases

Back 307

Include ankylosing spondylitis and several postinfectious arthropathies, all associated with HLA-B27

Front 308

307. Inherited errors of metabolism

Back 308

21-hydroxylase deficiency (HLA-BW47) and hereditary hemochromatosis (HLA-A)

Front 309

308. Autoimmune diseases

Back 309

Autoimmune diseases, including autoimmune endocrinopathies, associated mainly with alleles at the DR locus.

Front 310

309. What drugs are given to treat hypothyroidism?

Back 310

Levothyroxine (T₄) and Liothyronine (T₃)

Front 311

310. What is the DOC for hypothyroidism?

Back 311

Levothyroxine, b/c the extended half-life of T₄ allows a patient to take just one thyroid hormone replacement pill per day.

Front 312

311. Levothyroxine (T₄) and Liothyronine (T₃)

Back 312

MOA: Replace missing endogenous thyroid hormone w/exogenous thyroid hormone

PURPOSE: Hypothyroidism and myxedema coma

ADVERSE: Hyperthyroidism, osteopenia, pseudotumor cerebri, seizure, myocardial infarction

CONTRA: Acute MI, uncorrected adrenal cortical insufficiency, untreated thyrotoxicosis

NOTE: DOC for hypothyroidism

Front 313

312. Therapeutic considerations for Levothyroxine (T₄) and Liothyronine (T₃)

Back 313

1. Cholestyramine and sodium polystyrene sulfonate decrease absorption of synthetic hormone

2. Rifampin and phenytoin increase metabolism (hepatic excretion) of synthetic thyroid hormone

3. T₃ may be preferred in myxedema coma due to its faster onset of action.

Front 314

313. What are inhibitors of iodide uptake used for?

What are their names?

Back 314

These drugs compete w/iodide for uptake into the thyroid gland follicular cell. This results in a decreased amt of iodide available for thyroid hormone synthesis.

Names:
1. Perchlorate
2. Thiocyanate
3. Pertechnetate

Front 315

314. Perchlorate, Thiocyanate, and Pertechnetate

Back 315

MOA: Compete with iodide for uptake into the thyroid gland follicular cells via sodium-iodide symporter, thereby decreasing intrathyroidal supply of iodide available for thyroid hormone synthesis.

PURPOSE: Hyperthyroidism and radiocontrast agents

ADVERSE: Aplastic anemia, GI irritation

CONTRA: None

NOTES: Clinical use in hyperthyroidism is limited due to the risk of developing aplastic anemia

Front 316

315. What is the Wolff-Chaikoff effect?

Back 316

High levels of iodide inhibit thyroid hormone synthesis and release.

This is called the Wolff-Chaikoff effect.

This negative feedback effect of high intrathyroidal iodide concentrations is reversible and transient; thyroid hormone synthesis and release returns to normal a few days after the plasma iodide concentration is increased.

Front 317

315. What are the inhibitors of organification and thyroid hormone release?

Back 317

1. ₁₃₁ I⁻ (Radioactive iodide)
2. Iodide (high concentrations)
3. Propylthiouracil (PTU)
4. Methimazole

Front 318

316. ₁₃₁ I⁻ (Radioactive iodide)

Back 318

MOA: Emits beta particles that are toxic to the thyroid follicular cells

PURPOSE: Hyperthyroidism

ADVERSE: May worsen opthalmopathy in Graves' disease, hypothyroidism

CONTRA: Pregnancy

NOTES: Alternative to surgery in the treatment of hyperthyroidism; excess radiation can destroy thyroid, thereby causing hypothyroidism

Front 319

317. Iodide (high concentrations)

Back 319

MOA: High-concentration iodide inhibits iodide uptake and organification via Wolff-Chaikoff effect

PURPOSE: Hyperthyroidism

ADVERSE: May worsen toxic goiter symptoms

NOTES: Used for temporary suppression of thyroid gland function; also used before thyroid gland surgery to allow technically easier excision

Front 320

318. Propylthiouracil

Back 320

MOA: Propylthiouracil nhibits thyroid peroxidase and conversion of T₄ to T₃.

PURPOSE: Hyperthyroidism

ADVERSE: Agranulocytosis, hepatotoxicity, vasculitis and hypoprothrombinemia; rash and arthralgias

NOTES: PTU is the preferred agent in thyroid storm due to additional peripheral inhibition of T₄ to T₃ conversion

*This is the DOC in pregnancy b/c it has a more extensive safety record

Front 321

319. Methimazole

Back 321

MOA: Methimazole inhibits thyroid peroxidase; by competing for oxidized iodide, thioamine treatment causes a selective decrease in thyroid hormone production

PURPOSE: Hyperthyroidism

ADVERSE: Agranulocytosis, hepatotoxicity, vasculitis; rash and arthralgias

CONTRA: Pregnancy and breast feeding

NOTES: Methimazole is generally preferred in the treatment of hyperthyroidism due to lower incidence of serious adverse effects.

Front 322

320. What are the inhibitors of thyroid hormone metabolism?

Back 322

Beta blockers (esmolol) and Ipodate

Front 323

321. Beta blockers (esmolol)

Back 323

The smpatholytic effect of beta-blockers is more important in treating the symptoms of hyperthyroidism than the minor effect of these drugs on 5'-deiodinase

Esmolol is the DOC for treatment of thyroid storm b/c of its rapid onset of action and rapid elimination half life (9 minutes).

Front 324

322. Ipodate

Back 324

MOA: Blocks T₄ to T₃ conversion by inhibiting the enzyme 5'-diodinase

PURPOSE: Hyeprthyroidism

ADVERSE: Uticaria, serum sickness, may occasionally exacerbate hyperthyroid symptoms

CONTRA: Hypersensitivity to radiocontrast agents

NOTES: Formerly used as radiocontrast agent; no longer commercially available.

Front 325

323. Lithium

Back 325

MOA: Lithium is actively concentrated in the thyroid gland, and high levels have been shown to inhibit thyroid hormone release from thyroid follicular cells

PURPOSE: Bipolar disorder and hyperthyroidism

ADVERSE: Can cause hypothyroidism

Front 326

324. Amiodarone

Back 326

MOA: Amiodarone resembles thyroid hormone, and as a result, contains a large amt of iodine. Metabolism of amiodarone releases this iodine as iodide, resutlign in increase plasma concentrations of iodide. This can result in hypothyroidism via the Wolff-Chaikoff effect. It also competitively inhibits type I 5'-deiodinase, which results in decreased T₄ to T₃ conversion.

Front 327

325. How can amiodarone cause hyperthyroidism?

Back 327

1. In type I thyrotoxicosis, the excess iodide load provided by amiodarone leads to increased thyroid hormone synthesis and release.

2. In type II thyroiditis, and autoimmune thyroiditis is induced that leads to release of excess thyroid hromone from the colloid.

B/c of its close structural similarity to thyroid hormone, amiodarone may also act as a homologue of thyroid hormone at the level of the receptor.

Front 328

326. Corticosteroids

Back 328

MOA: Corticosteroids such as cortisol and glucocorticoid analogues inhibit the 5'-deiodinase enzyme that converts T₄ to T₃.

Because T₄ has less physiologic activity than T₃, treatment w/corticosteroids reduces net thyroid hormone activity.

In addition, the decreased serum T₃ results in increased release of TSH. The increased TSH stimulates greater T₄ synthesis, until the amt of T₄ produced generates a sufficient level of T₃ to inhibit the hypothalamus.