Endocrinology of Female

Question 1

LHRH

Answer 1

(also known as GnRH) – 10 amino acids
o Produced: medial pre-optic & arcuate median eminence
o Bind to LHRH receptors on gonadotropic cells of pituitary gland  causes influx of Ca2+ into cells  synthesis and release of LH and FSH by gonadotropic cells
 LH and FSH act on ovary to produce sex steroid class of estrogens
• 17-beta-estradiol = main sex steroid
o long loop negative feedback on LHRH production and secretion at level of hypothalamus and release of LH at pituitary
• Progesterone – negative feedback on hypothalamus and pituitary but much lesser extent; sensitizes the pituitary gland to the presence of 17-beta estradiol which enhances the feedback regulation
o 3 Types of Gonadotropic Cells
 One secretes LH, one secretes FSH, and one secretes both LH and FSH

Question 2

Feedback on LH

Answer 2

o Long Loop Negative Feedback by 17-beta-estradiol
o Negative Feedback by Progesterone
o Kisspeptin – present in some hypothalamic neurons and causes increase in LHRH secretion
o Norepinephrine, epinephrine stimulate LHRH/LH secretion
o Opoid neurons – in hypothalamus – release beta endorphins that decrease LHRH secretion

Question 3

Follicular Cycle

Answer 3

o Ongoing follicular atresia – massive amount of ovarian loss in lifetime
 Born with 2 million ova  400,000 at puberty  ovulate ~400 ova
o Primordial follicle  primary follicle  secondary follicle tertiary (graffian) follicle
 Primary follicle – granulosa cells with basal lamina
 Secondary follicle – zona pellucida, multiple granulosa cells, basal lamina, theca cells
 Tertiary follicle – large fluid filled antrum;cumulus oophorus, zona pellucida, basal lamina, theca interna/externa
o Only 1 follicle will become dominant tertiary follicle each cycle and be released
 Some granulosa cells will be expelled with the tertiary follicle/ova
o Remaining granulosa cells undergo luteinization – driven by high levels of LH
 Transform into luteal cells (main product is progesterone) that form the corpus luteum
o No fertilization – corpus luteum degenerates after 10 days into corpus albicans

Question 4

Gonadotropin Hormones

Answer 4

(LH, FSH, TSH, hCG) all have alpha and beta subunit
o Alpha subunit - same amongst all gonadotropin hormones
o Beta subunit - carries out the gonadotroph hormone’s actual effect

Question 5

Circhoral Rhythm

Answer 5

o Regular pulsatile pattern of LHRH/LH secretion
o Spike in LH levels every 1-2 hours followed by its subsequent decrease
o Experiment: Remove ovaries to get rid of negative feedback loop and look at LHRH/LH levels

Question 6

Sex Steroids

Answer 6

o Begin as Cholesterol and then acted on by cytochrome P450 enzymes  eventually converted into androgens (male sex hormones) or estrogens (female sex hormones)
o Theca cells – LH binds to LH receptors and drives conversion of cholesterol into androstenedione or testosterone  diffuse to nearby granulosa cells
o Granulosa cells – FSH binds to FSH receptor and stimulates aromatase enzyme to aromatize/convert androgens  17-beta estradiol, estrone, and estradiol
 Converting aliphatic ring to an aromatic ring

Question 7

Differentiation between positive and negative feedback of LHRH

Answer 7

o 17-beta estradiol regulates LHRH output by hypothalamus in both positive and negative fashion
o Estrogens bind in arcuate median eminence and medial pre-optic portions of hypothalamus
 Low levels bind to arcuate median eminence providing negative feedback signal
 High levels of estrogen bind to medial preoptic area which is high in kisspeptin neurons (increase LHRH) and provide positive feedback

Experiments
 Single estrogen (low dose) injection  subtle increase in estrogen and decrease in LH
• Low estrogen level = negative feedback
 Series of estrogen (high dose) injections  increase in estrogen above 200pg/ml (if it last for 36 hours then medial preoptic area reds this as positive feedback and increases LH
• Levels must be RISING and NOT plateaued

Question 8

Follicular Rupture

Answer 8

o Middle of female reproductive cycle ~day 14 there is a surge in LH hormone
o LH causes LOCAL production of progesterone inside the follicle/theca cells
 Progesterone does NOT enter systemic circulation
o Progesterone stimulates the production and activation of proteolytic enzymes (like collagenase) that eat away at the stigma – weakened part of follicle wall
 Progesterone also stimulates prostaglandin secretion which causes the transudation of plasma into the follicle; increase fluid in the follicle causes it to swell and RUPTURE

Question 9

Menstrual Cycle Day 1-5

Answer 9

 GnRH and LH at baseline
 Slight rise in FSH
 Estradiol and progesterone are low

Question 10

Menstrual Cycle Day 5-14 (ovulation)

Answer 10

Follicles mature  result in more granulosa and theca cells  more LH receptors
 Increase in LH receptors allows for low levels of LH to have stronger effect and produce more estradiol
 Increase in FSH receptors; FSH levels remain same
 Estradiol levels >200pg/ml for 36 hours results in large increase in LH & small increase of FSH
• Due to medial preoptic area of hypothalamus and positive feedback mechanism
 LH surge results in increase LOCAL progesterone and eventual release of ova + some granulosa cells
 Loss of some granulosa cells results in decrease production of estradiol (below critical/threshold level)  causes negative feedback on LHRH  decreases LH and FSH

Question 11

Menstrual Cycle Day 15-28 (Post-ovulation)

Answer 11

oGranulosa cells in corpus luteum are lutenized by LH and now produce and secrete progesterone and little estradiol in response to LH  reinstates negative feedback on LHRH
 Even if estradiol levels reach 200pg/ml they will not cause another LH surge because they PLATEAU

No Fertilization
o Corpus luteum degenerates and less capable of producing progesterone and estradiol
o Decrease in progesterone, estradiol, inhibin  decreases negative feedback on LH/FSH
 Results in slight increase in FSH that begins next cycle

Question 12

Inhibin

Answer 12

-produced by both follicular and luteal cells inhibits secretion of FSH
o Main regulator of FSH
o Polypeptide hormone composed of an alpha and beta subunit
o Degeneration of corpus luteum results in decrease of inhibin  less feedback on FSH  little increase in FSH (DAY 1 of new cycle)  primordial follicles start developing for new cycle
o Peaks of Inhibin secretion
 During follicular phase as granulosa cells increase
• Surge of LHRH that causes ovulation will override this effect
 During luteal phase to maintain low FSH

Question 13

Uterine Cycle - Proliferative Phase

Answer 13

 Estrogen causes myometrium to thicken; proliferation of endometrial cells and glands
• Spiral arteries lengthen and increase in curl

Question 14

Uterine Cycle - Secretory Phase

Answer 14

 Corpus luteum raises progesterone levels
 Progesterone increases uterine secretions and gland enlargement
• Glands secrete glycogen – potential energy for embryo
 Spiral arteries continue to grow with the tissue to supply nutrients

Question 15

Uterine Cycle - End of Cycle/Menses

Answer 15

 Lack of estrogen (at end of cycle) causes spiral arteries to retract and ischemia results in endometrium
 Shedding of necrotic tissue resulting in menses
• Blood flow washes out the necrotic tissue so that bacteria cannot infect the cells
 Prostaglandins LOCALLY produced irritates myometrial smooth muscle resulting in contractions

Question 16

Additional Effects of Progesterone and Estrogen

Answer 16

o Progesterone is thermogenic agent
 Elevation of basal body temperature occurs after ovulation when progesterone is high
 Causes mucus secretions to thicken to help protect the reproductive tract from bacteria and foreign substance
o Estrogen stimulates growth of epithelial mucosal cells within vagina causing them to become keratinized
 Causes cervical aqueous secretion so that sperm can more easily pass through

Question 17

Polycystic Ovarian Syndrome and Causes

Answer 17

– most common reproductive disorder
o High androgen levels and disrupted menstrual cycle; amenoria (lack of menstrual cycle)
o Male physical appearance with facial hair, increased muscular deposition, male pattern pubic hair, and enlarged clitoris
o Often insulin resistant due to pancreas producing excess insulin in response to excess glucose
 Insulin receptors become less responsive due to consistently high insulin levels
 Thecal cells in ovary have insulin receptors and produce androgens in response to insulin binding
o Associated with high stress  increases cortisol levels
 Cortisol increases blood glucose  stimulates release of insulin  overproduction of androgens by thecal cells
o Adrenal tumor can also cause high androgen levels (very rare)

Question 18

Polycystic Ovarian Syndrome and Androstenedione

Answer 18

o Androstenedione is often the androgen produced
 Migrates to adipose tissue  their own aromatase enzyme that converts it to estrone
• Estrone increases LH secretion; LH acts on thecal cells causing them to produce even more androgens
• FSH levels have decreased so granulosa cells aromatase enzyme is not stimulated so androgens are not converted to 17-beta-estradiol

Question 19

Polycystic Ovarian Syndrome Treatments

Answer 19

 Estrone antagonists (clomid/clomiphene) can reset the hypothalamus LHRH release
• LH will decrease to stop excessive androgen release
• FSH return to normal levels to act on granulosa cells causing them to produce 17beta estradiol and normal positive feedback occurs
 Diabetic drugs can be used to treat insulin resistance
 Androgen antagonists can be used to reset the system
 Surgical Wedge Resection of ovary
• Ovarian capsule can thicken from excess androgens and becomes a physical barrier to ovulation; due to anabolic action of excess androgens

Question 20

Anorexia Nervosa

Answer 20

– can result in amenorrhea and infertility
o Stress related condition with high levels of corticotropin releasing hormone (CRH) and beta-endorphins
o CRH and beta-endorphins inhibits LHRH secretion
 Decreased LH prevents ovulation and causes patients to become infertile
o Fat cells that normally produce leptin will not be able to make as much
 Leptin triggers release of LHRH

Question 21

Puberty

Answer 21

o Before puberty, LHRH neurons are inhibited (gonadostat)  low gonadotropin throughout body
 GABA (an inhibitory neurotransmitter) is active in prepubertal hypothalamus
• Inhibits LHRH neurons
 Glutamate (excitatory neurotransmitter) can affect LHRH neurons
o Around puberty, nocturnal rises of LH occur
 GABA neurons being turned off; Glutamate neurons being tuned on
o Once large LH pulses continue throughout the day, puberty/sexual maturity has been reached
o Increase in LH will cause ovarian production of estradiol  menstrual cycle occurs
o Gonadostat in reset/raised upward on graph  all levels of hormones are increased

Question 22

Precocious Puberty

Answer 22

o Before puberty, LHRH neurons are inhibited (gonadostat)  low gonadotropin throughout body
o Brain tumor/environmental toxins/trauma may trigger LHRH secretion before normal pubertal age; inhibition of LHRH is removed
o As LHRH levels rise, an LH surge will occur and ovulation can begin
o Treatment: LHRH superagonsits that binds to LH receptors and causes desensitization of LHRH receptors

Question 23

Menopause

Answer 23

o ~50 years old there are no follicles left due to ongoing follicular atresia
o Few remaining follicles are less responsive to stimulation and may not be able to develop to Graffian/Tertiary stage
o Less production of estrogen and progesterone  no negative feedback on hypothalamus and pituitary  LH/FSH levels RISE to try to stimulate follicles but fail to elicit response
 Ovulation cannot occur without rise in estrogen

Question 24

Birth Control

Answer 24

o Maintain high levels of estrogen or progesterone  provides a continuous negative feedback on hypothalamus preventing any midcycle LH surge and ovulation
o Side effects: water retention weight gain, swelling, hypertension
• Remember estrogen increases water retention for cervical mucus secretions
 Increase risk of cancers if history of reproductive tract cancers in family
 Smoking will accelerate platelet aggregation and increase risk of cardiovascular disease
o No “saving” of unreleased follicle  ongoing follicular atresia continues

Question 25

Abortion Pill

Answer 25

o RU-486 – progesterone antagonist that inhibits the action of progesterone  Progesterone is the “pro-gestational” hormone that creates a non-contractile uterus to help preserve pregnancy  Inhibiting progesterones action results in uterus contraction and expulsion of embryo o Morning-After Pill – high estrogen content that blocks ovulation  If ovulation already occurred, the it creates a hostile uterine environment