Lectures 11 & 12 - Female Reproductive Endocrinology I & II

Question 1

What hormone does the hypothalamus secrete to stimulate the release of FSH and LH by the anterior pituitary? 2 names

Answer 1

Luteinizing hormone releasing hormone (LHRH) = gonadotropin-releasing hormone (GnRH)

Question 2

What portions of the hypothalamus releases LHRH? How do they differ?

Answer 2

1. Medial preoptic area/nucleus: detects high concentrations of estrogen, and translates that into positive feedback of LHRH secretion
2. Arcuate nucleus: detects low concentrations of estrogen as a signal for negative feedback on LHRH secretion

Question 3

Where does the hypothalamus release LHRH?

Answer 3

Portal venous system, here it courses to the gonadotropic cells of the anterior pituitary gland

Question 4

What kind of molecules are FSH and LH?

Answer 4

Glycoprotein hormones = large polypeptides that have specific sugar moieties attached to a peptide backbone, allowing them to fold specifically to interact specifically with their respective receptors

Question 5

What are 4 glycoprotein hormones? What do they all have in common? How do they differ? What to note?

Answer 5

1. FSH
2. LH
3. TSH
4. hCG

All have the same alpha subunit and differ in their beta subunit

Note: due to similar structures, if one of these hormones is made in huge quantities due to some kind of pathology, the high concentration may begin to interact with some of the other glycoprotein hormone receptors that they are not intended to be stimulating

Question 6

Main estrogen produced by ovary?

Answer 6

17-beta-estradiol

Question 7

Feedback from ovaries to ant pit?

Answer 7

1. 17-beta-estradiol inhibits gonadotropic cells from secreting FSH/LH (LH specifically) by decreasing sensitivity of those cells to LHRH by reducing # of receptors
2. 17-beta-estradiol binds to hypothalamic LHRH secreting cells of the arcuate nucleus to inhibit them
3. 17-beta-estradiol binds to hypothalamic LHRH secreting cells of the medial preoptic nucleus to stimulate them

Mainly negative feedback, except right before ovulation

Question 8

In what manner are LHRH and LH secreted? What is this called? Purpose?

Answer 8

Pulsatile/episodic manner every 1-2 hrs = circhoral rhythm

Purpose: prevents desensitization of the receptors => prevents downregulation

Question 9

What are 3 types of neurons that mediate LHRH secreting neurons in the hypo?

Answer 9

1. NE containing neurons to stimulate LHRH secretion
2. Opoid neurons containing beta-endorphins to inhibit LHRH secretion
3. Gonadotropin inhibiting factor neurons (GiHN) to inhibit LHRH secretion

Question 10

What 3 hormones regulate the secretion of LHRH by the hypo?

Answer 10

1. CRH: inhibits via the GiHN
2. Estrogen: inhibits or stimulates
3. Beta-endorphins: inhibit via the GiHN

Question 11

How many oocytes ovulated over a lifetime?

Answer 11

About 400

Question 12

How are estrogen and progesterone synthesized?

Answer 12

1. Cytochrome P450 enzymes in theca cells act on cholesterol to produce progesterone, androstenedione, and testosterone
2. Granulosa cells convert androstenedione/testosterone to estrogen with aromatase

Question 13

What cells of the ovary are stimulated by LH?

Answer 13

Thecal cells producing androstenedione/testosterone

Question 14

What cells of the ovary are stimulated by FSH? How?

Answer 14

Granulosa cells to produce estrogen (by stimulating aromatase)

Question 15

Describe the action of aromatase?

Answer 15

Aliphatic ring into aromatic ring in androgens

Question 16

What happens when high concentrations of estrogen bind the medial preoptic nucleus of the hypo?

Answer 16

All LHRH secreting neurons of the hypo synchronize and release LHRH

Question 17

Why are the estrogen levels increasing during the follicular phase?

Answer 17

Follicles are developing and growing, so are able to produce more estrogen because more theca/granulosa cells and more LH/FSH receptors

Question 18

How are estrogen plasma levels affected by ovulation?

Answer 18

Big dip in levels right at ovulation because many granulosa/theca cells lost with ovulation but levels rise up again to a constant level due to formation of corpus luteum which does not reach the threshold level and induces negative feedback on the hypo

Question 19

Describe progesterone levels through the ovarian cycle.

Answer 19

Very low until after ovulation where levels rise very high once the corpus luteum forms (higher levels than estrogen)

Question 20

What is the role of the hormone inhibin in the ovarian cycle? Effect?

Answer 20

Large polypeptide hormone produced by granulosa cells of follicles and by the corpus luteum (more so by CP) to inhibit FSH secretion by ant pit, which means that after the CP degenerates there is a modest rise in FSH => drives beginning of next round of follicular development in the ovary

FSH has lower baseline and peak values during the pulsatile secretion due to the inhibitory effects of inhibin

Question 21

How do FSH levels fluctuate during the ovarian cycle?

Answer 21

1. Follicular phase: decrease due to estrogen (-) feedback
2. Ovulation: small spike due to estrogen (+) feedback
3. Luteal phase: very low until corpus luteum degenerates => decrease inhibin => small rise to begin next round of follicular development

Question 22

How do progesterone levels affect body temperature? Explain. What does this mean?

Answer 22

Increase in basal body temperature by 0.5 degrees Celsius during the luteal phase of the ovarian cycle

Progesterone is a thermogenic hormone that acts on the temperature controlling centers of the hypothalamus, so women can track their ovarian cycle by measuring their basal body temp

Question 23

What is the most common reproductive disorder in female patients?

Answer 23

Polycystic Ovarian Syndrome (PCOS)

Question 24

What is PCOS?

Answer 24

Genotypic XX female who previously had normal menstrual cycles exhibits signs of excess androgens (especially androstenedione):

1. Amenorrhea: absence of menstruation
2. Hirsutism: excessive hair growth
3. Clitoromegaly
4. Virilization: development of male physical characteristics

Question 25

Describe the ovaries of patients with PCOS. What to note?

Answer 25

Thickened white tissue capsule around the ovary (a physical barrier to ovulation) due to the anabolic effects of the high levels of androgens + cystic follicles

Note: cystic follicles are NOT the same as ovarian cysts

Note: PCOS refers to the cystic appearance of the secondary follicles that are arrested in their pre-ovulatory state

Question 26

Where do the excess androgens come from in PCOS patients?

Answer 26

Either ovaries, adrenal glands, or both

Question 27

How does adipose tissue play a role in PCOS?

Answer 27

1. Adipose tissue contains aromatase that converts the excess androstenedione into estrone
2. Excess estrone disrupts the usual pulsating secretion of LHRH secreted by the hypothalamus => excess LH secretion + decreased FSH secretion
   3a. Increased LH levels stimulate the theca cells of the ovary to secrete even more androgens => vicious cycle
   3b. Decreased FSH levels fail to stimulate the granulosa cells of the ovary, resulting in decreased follicle maturation and decreased levels of estradiol => chronic anovulation

Question 28

Why do PCOS patients often develop insulin resistance? Impact?

Answer 28

Tend to be obese => higher glucose levels => pancreas produces more insulin => insulin resistance => increased insulin levels act on theca cells to increase androgen production

Question 29

3 treatments for PCOS?

Answer 29

1. Metformin = drug used to treat diabetes, used if patients have insulin resistance with PCOS
2. Clomiphene = estrone antagonist that blocks the action of excess estrone
3. Wedge resection = if neither of the above work, we can surgically remove a wedge of the ovary to decrease the amount of androgens secreted and eliminate the physical barrier of ovulation

Question 30

What is the relationship between stress and PCOS?

Answer 30

In many PCOS patients, the symptoms were preceded by a period of chronic stress, which affects the menstrual cycle in the following ways:

1. Increases CRH => increased GiHN => inhibits LHRH release by hypo => decrease LH & FSH secretion by ant pit => infertility
2. High glucose levels => high insulin => theca cells produce more androgens
3. Increases CRH => increases ACTH secretion by hypo => stimulates adrenal gland production of not only cortisol, but also adrenal androgens

Question 31

Through wha 2 NTs regulate does estrogen regulate hypo LHRH secretion?

Answer 31

1. GABA: inhibitory

2. Glutamate: excitatory

Question 32

Does the pulsatile secretion of LH by the ant pit happen throughout life?

Answer 32

Yes, but baseline and peak levels change

1. Pre-puberty: low estrogen => high GABA/low glutamate => low baseline/peak LH levels
2. Mid-puberty: estrogen levels increase as the ovaries grow and mature => reduces GABA/increases glutamate => nocturnal LH spikes and and daytime levels drop to pre-pubertal levels => further increase in estrogen ovarian secretion => eventually estrogen levels are high enough to cause the first LH surge = menarche
3. Adulthood: high estrogen => low GABA/high glutamate => high baseline/peak LH levels

Question 33

What causes precautious puberty? Treatment? What to note?

Answer 33

Premature hypothalamic neuron activation (trauma to the brain, hypothalamic tumor, or other organic brain disease) => early LHRH release => early LH & FSH release => early puberty

Treatment: LHRH agonist analog to desensitizes the LHRH receptors on the anterior pituitary so it can’t respond to the excess LHRH

Note: can stop administering the analog at an appropriate age to resume puberty

Question 34

What causes menopause?

Answer 34

By about 50, the number and robustness of the follicles in the ovaries have decreased significantly => less primary follicles developing each month => less estrogen is produced => reduced negative feedback on the hypothalamus and causes an increase in LH and FSH secretion => initial increase in gonadotropins which continues menstruation => eventually there are so few follicles that menstruation stops entirely => individual becomes infertile

Question 35

Type of receptor of glycoprotein hormones?

Answer 35

GPCRs