Ovulatory Dysfunction

Question 1

What is the general progression of compounds from cholesterol to estrogen?

Answer 1

cholesterol to progesterone to androgens that are aromatized to estrogen

Question 2

Which cells produce estrogen and progesterone and what pituitary hormone controls each?

Answer 2

LH stimulates theca cells to produce progesterone (and androgens)
FSH stimulates granulosa cells to produce estrogens (by aromatizing androgens)

Question 3

How does one signal GnRH regulate two different hormones, LH and FSH?

Answer 3

faster frequency of GnRH pulses favors LH and slower frequencies of GnRH favor FSH

Question 4

How is GnRH secretion regulated by ovarian hormones?

Answer 4

1) negative feedback, low estradiol stimulates LH and FSH (menopause) and very high levels suppress LH and FSH (OC)
2) moderate estradiol increases pulses (favors LH) and progesterone feedback decreases pulse frequency (favors FSH)

Question 5

How does the ovulation cycle get started?

Answer 5

early follicular growth occurs independent of FSH over the prior few months and eventually a group grows large enough to become gondaotropin dependent (undergo atresia if not rescued by FSH) and enter int eh antral follicle stage

Question 6

Describe the process by which the astral follicle becomes a dominant follicle.

Answer 6

demise of CL leads to rise in (decrease in estradiol and progesterone) FSH, rescuing follicles

under FSH stimulation follicles synthesize estrogen

estrogen feeds back to decrease FSH and FSH levels gradually decline

estrogen stimulates expression of FSH receptors on granolas cells, larger follicles produce more estrogen and have more FSH receptors (allowing for more sensitivity to lower FSH levels)

larger follicules also produce androgens to inhibits neighbors and the largest follicles are protected by their thick granulosa cell buffer

Question 7

Describe the process by which the dominant follicle is ovulated.

Answer 7

rising E2 levels lead to increase in GnRH pulse frequency, favoring LH production

at a certain level of E2, E2 feedback becomes positive, causing LH surge and ovulation

Question 8

What is the role of the corpus luteum in the ovulation cycle?

Answer 8

CL produce estrogen and large amounts of progesterone which slow the GnRH pulse frequency, favoring FSH

unless the GL is rescued by hCG, CL demise causes a decline in E2, triggering rise in gonadotropins and the rise in FSH leads into next cycle

withdrawal from progesterone triggers menses

Question 9

Name the 3 different disorders associated with ovulatory dysfunction related to hypothalamic/pituitary disease.

Answer 9

1) pituitary hypofunciton
2) hyperprolactinemia
3) hypothalamic amenorrhea: low weigh, or heavy exercise cause a low or absent GnRH pulsatility (LH and FSH inappropriately low for low estrogen levels)

Question 10

Name the 3 main categories of clinical symptoms associated with PCOS?

Answer 10

hyperandrogenism
insulin resistance
ovulatory dysfunction

Question 11

Name 3 pathophysiologic features that contribute to hyperandrogenemia in PCOS.

Answer 11

1) theca cells are inherently more efficient than normal at converting steroid precursors to androgens
2) insulin resistance leads to hyperinsulinemia but steroidogenesis remain insulin sensitive and insulin stimulates ovarian androgen production
3) cycle remains with elevated LH due to anovulation (androgens prevent follicle development), LH stimulates androgen production in the theca cell

Question 12

While treatment is targeted to the specific issues of each patient what is considered the “magic bullet” of PCOS?

Answer 12

weight loss improves insulin sensitivity, menstrual cycles, pregnancy rates and decreases androgens as well as the risk of progression to DM2

Question 13

How are combination estrogen and progestin OCPs used in PCOS tx?

Answer 13

progesterone stabilizes endometrium and periodic withdrawal induces shedding (protects from endometrial hyperplasiae

estrogen suppresses ovarian steroid synthesis and reduces SHBG levels leading to a decrease in androgen effects

Question 14

What meds are used to specifically address the effects of androgens?

Answer 14

spironolactone can block the mineralocorticoid receptor, reducing androgen precursor and is a **moderate blocker of androgen receptor in the hair follicle

DO NOT USE in pregnancy but can have a synergistic effect on OCP

Question 15

What med is used in addressing the insulin insensitivity?

Answer 15

metformin can improve menstrual cycles, ovulation and fertility but is only modestly effective in hirsutism

Question 16

What is the preferred treatment of PCOS in women who which to become pregnant?

Answer 16

both weight loss and metformin can decrease insulin sensitivity and decrease androgen production, normalizing follicular development

clomphene (anitestrogen) or letrozol (aromatase inhibitors) are first line and usually effective– reduce negative feedback of estrogen and boost FSH

exogenous gonadotropins (injectables) are also used

Question 17

What is the diagnostic criteria for PCOS?

Answer 17

hyperandrogenism, irregular menses +/- polycystic ovaries on U/S

Question 18

How does non-classical CAH result in ovulatory dysfunction?

Answer 18

with minor impairment of 21-hydroxylase, cortisol synthesis is still normal but the resulting back-log of precursors is shunted to the androgen pathway

elevated circulating androgens disrupt ovulation
(looks clinically like PCOS- irregular menses, hirsutism and infertility)

Question 19

What is the treatment for non-classical CAH?

Answer 19

use steroids (glucococorticoids, cortisol) to suppress adrenal androgen production and induce ovulation

Question 20

Define premature ovarian failure, what is the most likely cause? How is it treated

Answer 20

menopause prior to age 40, symptoms include infertility and risk of bone loss

40% result from autoimmune disorder (others: genetic, cancer tx)

tx with estrogen and progestin until typical menopause to decrease risk of bone loss

Question 21

What is the hormonal basis and symptoms of menopause?

Answer 21

(dx after 1 year of amenorrhea, ave. 51y)
FSH is high (have run out of follicles) and estrogen is low

symptoms include hot flashes, genital mucosal atrophy, bone loss (occurs earlier than most suspect)

Question 22

What is the primary sign of involution?

Answer 22

irregular periods occur with ovulatory dysfunction