Female Hormones + Menstrual Cycle B&B

Question 1

What is the function of the theca and granulosa cells, respectively? Where are these cell populations found in relation to each other?

Answer 1

both found in ovarian follicles - granulosa cells are inner layer while theca cells are outer layer

theca cells: stimulated by LH to convert cholesterol to androstenedione (via cAMP)

granulosa cells: stimulated by FSH to convert androstenedione to estradiol (via cAMP) + produce inhibin (neg feedback for FSH)

considering this, it makes sense that granulosa cells are the inner layer, closer to the oocyte!

Question 2

what enzymes do LH and FSH activate, respectively, to exert their respective effects on theca and granulosa cells?

Answer 2

LH stimulates desmolase in theca cells (cholesterol —> pregnenolone -» androstenedione)

FSH stimulates aromatase in granulosa cells (testosterone —> estradiol, OR androstenedione —> estrone -» estriol)

Question 3

where does progesterone come from? what does it target?

Answer 3

synthesized by corpus luteum (forms after ovulation)

also produced by placenta during pregnancy and small amounts by adrenal glands and testes

mostly bound to albumin, short half-life, targets uterus/cervix/vagina

Question 4

what are the effects of progesterone?

Answer 4

overall, opposes effects of estrogens / produces conditions favorable for pregnancy

—> induces secretory phase of uterine cycle
—> thickens cervical mucous (prevents sperm entry)
—> prevents uterine contractions (via increasing membrane potential)
—> raises body temperature
—> inhibits LH/FSH release

Question 5

what is medroxyprogestrone used for?

Answer 5

aka Depo-Provera

injection, progestin-only contraceptive, administered every 3 months

Question 6

what are the phases of the menstrual cycle?

Answer 6

day 0-13: follicular (growth of follicles)

day 14: ovulation

day 15-28: luteal (ovary produces progesterone to prepare for possible pregnancy)

Question 7

how do levels of the following hormones change throughout the menstrual cycle?
a. FSH
b. LH
c. estrogen
d. progesterone

Answer 7

a. FSH: low except for high spike right before ovulation (day 14)
b. LH: low except for slight surge right before ovulation

c. estrogen: gradually rises to surge before ovulation, then drops and gradually rises/falls during luteal phase, back down to very low (for day 0)
d. progesterone: stays low until luteal phase when it rises greatly, then falls back down to very low (for day 0)

Question 8

which hormones stimulate the start of the follicular phase of the menstrual cycle?

Answer 8

1. increase in GnRH pulse frequency (hypothalamus)
2. this increases FSH secretion from anterior pituitary
3. this increases estradiol production from the ovaries
4. estradiol induces recruitment of follicles + neg. feedback of FSH/LH
5. one dominant follicle is selected for ovulation on day 14

Question 9

how is ovulation triggered?

Answer 9

when estradiol gets high enough, it causes a switch from negative to positive feedback —> increased frequency of GnRH pulses —> LH surge

oocyte released from follicle ~36 hours after LH surge

Question 10

mittelschmerz

Answer 10

pain during mid-menstrual cycle (ovulation) due to enlargement of follicle or follicular rupture with bleeding

causes self-limited mild, unilateral pain (side where the follicle is) - may mimic appendicitis

Question 11

what occurs at the beginning of the luteal phase of the menstrual cycle?

Answer 11

corpus luteum forms - temporary endocrine gland formed from a follicle, produces large amounts of progesterone + some estradiol

negative feedback causes a drop in LH and FSH

Question 12

what triggers menstruation?

Answer 12

corpus luteum (luteal phase) degrades, causing drop in progesterone —> menstruation is triggered 14 days after ovulation (not variable)

Question 13

how is the menstrual cycle suppressed by fertilization?

Answer 13

embryo makes human chorionic gonadotropin (hCG), which maintains the corpus luteum

therefore, progesterone production will continue to suppress LH and FSH so menstrual cycle does not begin again

Question 14

what are the 2 phases of the uterine cycle and how do they correspond to the ovarian cycle?

Answer 14

1. proliferative phase (= follicular phase of ovary): rising estrogen stimulates endometrial proliferation/thickening
2. secretory phase (= luteal phase of ovary): rising progesterone inhibits proliferation of endometrium and induces formation of spiral arteries (preparing for embryo)

Question 15

what hormone stimulates the proliferative phase of the uterine cycle?

Answer 15

estrogen stimulates proliferation/thickening of the endometrium

corresponds to follicular phase of ovary

Question 16

what occurs during the secretory phase of the uterine cycle?

Answer 16

after ovulation, progesterone inhibits further proliferation of endometrium and induces secretions to prepare for embryo

spiral arteries form - critical for implantation

Question 17

how do you interpret the results of a progestin challenge?

Answer 17

if there is bleeding - indicates estrogen is present but not progesterone (exogenous sources required to trigger bleeding), suggesting anovulation (corpus luteum is not forming to make progesterone) … classic cause is PCOS

if no bleeding occurs - either no estrogen present or there is anatomical menstrual outflow problem … classic cause is menopause

Question 18

Your patient undergoes a progestin challenge for secondary amenorrhea, and bleeding occurs. You should start further workup for which disorder?

Answer 18

if there is bleeding - indicates estrogen is present but not progesterone (exogenous sources required to trigger bleeding)

this suggests anovulation (corpus luteum is not forming to make progesterone) … classic cause is PCOS

Question 19

Pt is a 16yo F presenting with primary amenorrhea. Her weight is healthy and she has no significant PMH. Blood tests reveal normal levels of estrogen, progesterone, LH, and FSH. What could be causing her amenorrhea?

Answer 19

Mullerian dysgenesis: failure of müllerian duct to develop —> absent upper vagina and/or uterus, but normal ovaries

Question 20

how can a prolactinoma cause secondary amenorrhea?

Answer 20

prolactin inhibits GnRH release —> decreased LH and FSH levels

no LH surge to trigger ovulation

Question 21

what becomes the main source of estradiol after the onset of menopause?

Answer 21

menopause triggered by loss of estradiol production from the theca/granulosa cells

however adipose also contains aromatase and can convert androstenedione to estrone (weak androgen)

Question 22

what is a good biochemical marker to detect the beginning of menopause?

Answer 22

in menopause, there is loss of inhibin production from follicles, causing a rise in FSH release, which can be measured as an early marker

eventually LH levels will rise as well

Question 23

how does hormone replacement therapy for menopause differ for women with an intact uterus?

Answer 23

progestin must be added to estradiol regiment to prevent endometrial hyperplasia

Question 24

what is the indication and associated risks of hormone replacement therapy for menopause?

Answer 24

indication is to relieve hot flashes + improve bone density

but increased risk of DVT/stroke/MI and breast cancer

Question 25

how does PCOS cause secondary amenorrhea?

Answer 25

genetics + diet/obesity causes an increase in ratio of LH:FSH

LH drives androstenedione (androgen) production from theca cells, some of which will be converted to estrone by adipose (contains aromatase)

estrogen induces negative feedback of FSH —> anovulation

Question 26

what are the key clinical features of PCOS (3) and why do these occur?

Answer 26

disease process begins with genetics + diet/obesity

1. hyperinsulinemia: PCOS associated with insulin resistance
2. hirsutism/acne: high LH:FSH ratio causes some androstenedione (theca cells) to be converted to testosterone
3. anovulation/follicular cysts: high LH:FSH ratio causes some androstenedione to be converted to estrone (in adipose), leading to suppression of FSH

Question 27

what are key biochemical markers for diagnosis PCOS? (2)

Answer 27

usually diagnosed clinically (obese women with hirsutism + amenorrhea)

1. total testosterone - high
2. LH:FSH ratio - high (LH and FSH themselves may be normal - must measure ratio!)

Question 28

what is the mainstay of therapy for PCOS?

Answer 28

oral contraceptives - suppress LH (recall LH:FSH ratio is high) + estrogen component will increase SHBG (sex hormone binding globulin), which will tie up free androgens

only works if women is not looking to become pregnant

Question 29

what type of cancer are patients with PCOS at risk for and why?

Answer 29

endometrial cancer - due to unopposed estrogen (produced by adipose)

increases risk of endometrial hyperplasia and carcinoma (lack of progesterone to inhibit proliferation)

Question 30

how will FSH levels preset in each of the following causes of amenorrhea?
a. Mullerian Dysgenesis
b. PCOS
c. menopause

Answer 30

a. Mullerian Dysgenesis (primary amenorrhea): normal FSH
b. PCOS: low FSH
c. menopause: high FSH

Question 31

what hormonal changes occur in the selected (dominant) follicle for ovulation?

Answer 31

during advanced stage of antral follicle growth, estrogen production greatly increases, causing a switch from negative to positive feedback on FSH secretion

rising FSH then induces expression of LH receptors on glomerulosa cells (“luteinization”), such that the selected follicle can respond to both FSH and LH —> further differentiation, robust increase in steroidogenesis

Question 32

which female gonadal cells produce testosterone vs estradiol (E2)?

Answer 32

theca cells (stimulated by LH) —> testosterone

granulosa cells (express P450 aromatase/ CYP19, stimulated by FSH) —> estradiol (E2)

Question 33

____ is a marker of healthy growing follicles and correlates with fertility

Answer 33

AMH (anti-müllerian hormone) - product of glomerulosa cells within preantral and small antral follicles (represents the number of follicles that have begun development)

Question 34

how does extrusion of the first polar body into the ooplasm indicate?

Answer 34

first polar body: haploid product of meiosis I that contains 1 set of 23 chromosomes, which fragments and disappears

can be seen following first meiotic division in the oocyte (before it leaves via the oviduct)