198/199: Endocrine Control of Female Reproduction I & II

Question 1

When during the menstrual cycle does progesterone peak?

Answer 1

7 days after ovulation

(When the corpus luteum is chugging along making progesterone)

Question 2

How will levels of the following hormones change in ovarian failure?

• Estradiol:
• LH/FSH:

Answer 2

• Estradiol: low
• LH/FSH: high

Pituitary is trying to get the ovaries to work, sending a strong signal, but the ovaries are not responding.

Vs. hypothalamic amenorrhea, will have low estradiol AND low LH/FSH

Question 3

Which ovarian cells convert androgen to estrogen?

Which gonadotropin stimulates the development of these cells?

Answer 3

Granulosa cells, using aromatase

FSH

Question 4

How will levels of the following hormones change in hypothalamic amenorrhea?

• Estradiol:
• LH/FSH:

Answer 4

• Estradiol: low
• LH/FSH: low

Entire HPG axis is down-regulated. Due to head lesions, genetic defects, or behavioral/environmental (stress, anorexia, etc)

Vs. ovarian failure, will have low estradiol and HIGH LH/FSH

Question 5

How is PCOS diagnosed?

Answer 5

Requires 2/3 of:

• Oligo and/or anovulation
  
  • Oligo-ovulation= irregular or infrequent periods
• Signs of hyperandrogenism (acne, hirsuitism)
• Ultrasound with ≥12 2-9 mm follicles in each ovary OR increased ovarian volume
  
  • The immature follicles look like cysts

Note: criteria has historically been 12 follicles, but I think she mentioned that now with improved imaging techniques we can see follicles better so we may actually see a lot more, and if someone has 12 follicles but no sx of PCOS probably do not need to diangose

Question 6

List the phase of follicular development and predominant hormone that loosly aligns with the following phases of the endometrial cycle:

• Menses:
• Proliferative phase:
• Transition between proliferative and secretory:
• Secretory phase

Answer 6

• Menses
  
  • Follicular phase
  • Low estradiol and progesterone
• Proliferative phase:
  
  • Follicular phase
  • High estrogen
• Transition between proliferative and secretory:
  
  • Ovulation
  • High estrogen, progesterone beginning to rise
• Secretory phase
  
  • Luteal phase
  • High progesterone, estrogen falls

Question 7

List 3 things that increase levels of sex hormone binding globulin

Answer 7

• Hyperthyroidism
• Pregnancy
• Estrogen treatment (OCPs)

All will decrease the effect of sex hormones; bound to SHBG = not biologically active

Question 8

Which gonadotropin supports the corpus luteum?

Which hormone is produced as a result?

Answer 8

LH

Progesterone

• Corpus luteum produces progesterone (supports a pregnancy for first 7 weeks until placenta can produce its own)*
• Note: LH also stimulates theca cells to produce androgens*

Question 9

Which ovarian cells secrete androgens?

Which gonadotropin stimulates these cells?

Answer 9

Theca cells

LH

Question 10

Which hormone supports early pregnancy?

Answer 10

Progesterone from the corpus luteum

Question 11

[hormone] stimulates proliferation of the uterine lining

[hormone] stimulates differentiation of the uterine lining

Answer 11

Estrogen stimulates proliferation of the uterine lining

Progesterone stimulates differentiation of the uterine lining

Question 12

After ovulation, what happens to the granulosa cells and theca cells that are left in the follicle?

Answer 12

They re-organize to become luteal cells

• Angiogenesis! Blood supply needed for delivery of cholesterol precursors for steroid synthesis
• More smooth ER and mito!

This forms the corpus luteum -> progesterone production

Question 13

List 2 causes of gonadal dysgenesis

Answer 13

Turner syndrome (45, XO)

Fragile X carrier

Thank you @Ben Gastevich!

Question 14

Describe the positive feedback loop that triggers ovulation

Answer 14

• Sustained high estrogen + progesterone bump
  
  • Beginning of progesterone rise increases the pituitary response
• -> LH surge
  
  • Normally, LH is inhibited by increased estrogen/progesterone, but switch to positive feedback at high levels
• -> Ovulation!

Question 15

How does hypothyroidism affect menstruation?

(Describe the pathway)

Answer 15

Hypothyroidism = low thyroid horomone

• -> Upregualted TRH secretion from hypothalamus
• -> High TRH increases TSH and prolactin secretion
• Prolactin inhibits GnRH pulses
• -> No FSH/LH
• -> No ovulation
• -> No menstrual cycles

Question 16

What is the most common cause of secondary amenorrhea?

Answer 16

Pregnancy

Secondary amenorrhea = used to have normal menstruation, but it stopped

Question 17

Before treating a patient with PCOS, what diagnostic evaluation must be done?

Answer 17

Rule out other causes of high androgens

• Very high testosterone => Testosterone-secreting tumor
• High DHEAs => adrenal source
• High 17-OH-progesterone => Congenital adrenal hyperplasia
• Elevated free cortisol in urine => Cushing syndrome

Question 18

How is hypothalamic amenorrhea treated?

Answer 18

• To relieve symptoms (ex: low bone mineral density)
  
  • Hormone replacement
• To induce fertility
  
  • Injectable gonadotropins
  • Pulsatile GnRH

Also, behavioral therapy

Note: Leptin is NOT currently a therapeutic option

Question 19

Which gonadotropins are favored by the following GnRH secretion patterns?

• High frequency:
• Low frequency:
• Continuous:

Answer 19

• High frequency: LH secretion
• Low frequency: FSH secretion
• Continuous: No secretion
  
  • ​Desensitization inhibits both LH and FSH

Question 20

Why is it important to treat patients with PCOS, even if they don’t want to become pregnant and are unbothered by hirsutism and/or acne?

Answer 20

PCOS = unopposed estrogen

→ endometrium always proliferating

→increased risk of endometrial cancer

• Must protect the endometrium (either with ovulation or OCPs that include progestin)

Question 21

Will people with PCOS have a positve or negative progestin challenge?

Answer 21

Positive (will have bleeding, proves that estrogen is present)

• Estrogen is present, but abnormalities in hormone signaling prevent progesterone production, LH surge

Question 22

Which hormone suppresses prolactin?

Answer 22

Dopamine

• Dopamine tonically inhibits prolactin release
• Decreased dopamine -> increased prolactin*

Question 23

What does a positive progestin challenge imply about the cause of a patient’s secondary amenorreha?

Answer 23

Implies normal outflow tract, adequate estrogen

=> Cause of amenorreha is not enough progesterone to induce ovulation

Progestin challenge mimics little rise in progesterone before ovulation

Question 24

How is menopause diagnosed?

(lab test, assuming consistent clinical picture)

Answer 24

High FSH with low estrogen

• Due to lack of inhibin, lack of estrogen negative feedback

Question 25

List 2 causes of hypothalamic amenorreha

Answer 25

* Genetic defect: **Kallman syndrome** * GnRH neurons fail to migrate * -\> Primary amenorrhea * **Functional hypothalamic amenorrhea** * **​**May cause primary or secondary amenorrhea * Usually associated with increased stress (Nutritional, environmental, behavioral)

Question 26

Why are estrogen-progestin challenges rarely done?

Answer 26

We can pretty easily measure estrogen levels in the blood If normal and no bleed after progestin challenge, implies abnormal outflow tract

Question 27

How does prolactin affect ovulation? How is this adaptive (evolutionarily)?

Answer 27

Prolactin **inhibits ovulation** * Prolactin suppresses GnRH pulses * -\> No LH/FSH * -\> No positive feedback loop from estrogen * -\> No ovulation **Prolactin is high during lactation** - adaptive to not be able to have another bably while breastfeeding a new one

Question 28

What causes polyglandular autoimmune disease?

Answer 28

Auto-antibodies to endocrine organs Can target ovaries -\> **premature ovarian failure**

Question 29

What is the most common cause of anovulation in the setting of normal estrogen?

Answer 29

PCOS * Ovary is "stuck" in the follicular phase * Theca cells are making andorgens, but granulosa cannot keep up with aromatization * High estrogen AND androgens, but androgens interfere with signaling * Cannot select dominant follicle

Question 30

What defines menopause?

Answer 30

1 year has gone by since last menstrual period *Technically it's the last menstrual period, but hard to know if it \*really\* is the last one until a year has gone by*

Question 31

Which gonadotropin is required to maintain the corpus luteum?

Answer 31

**Continous LH secretion** Since LH drops after ovulation, the corpus luteum will die unles hCG takes over (if a pregnancy occurs) *No pregnancy -\> corpus luteum dies -\> no progestrerone to support endometrial lining -\> ovulation*

Question 32

What is the difference between menstrual bleeding and the bleeding that people on birth control pills experience during the placebo pills?

Answer 32

* Menstrual bleeding = bleeding 14 days after ovulation * When the corpus luteum dies and there is no progesterone to support the endometrial lining * Bleeding on placebo pills = hormone withdrawal bleeding * OCPs suppress ovulation * Stopping the estrogen/progesterone in the pills has a similar effect as the corpus luteum dying, **but this bleeding is not in response to ovulation** ## Footnote **​**

Question 33

How is the dominant follicle selected during oocyte maturation?

Answer 33

At the pre-antral stage, follicles **develop FSH receptors** * Basically, **the first follicle that develops FSH receptors becomes dominant** * **​**FSH helps the follicle grow * Induces more FSH receptors -\> this follicle responds best to FSH * Causes **granulosa cell proliferation and more estrogen - \> follicle grows rapidly, becomes an _antral follicle_** * The granulosa cells will also develop LH recetpors -\> **can make progesterone too (required for ovulation)** * When FSH levels fall (2/2 estrogen secretion from the dominant follicle), **the other follicles will become atretic**

Question 34

What is the most common endocrine disorder of reproduction?

Answer 34

Polycystic Ovarian Syndrome (PCOS)

Question 35

How does kisspeptin affect GnRH release?

Answer 35

Kisspeptin stimulates GnRH

Question 36

List 4 symptoms of hyperprolactinemia

Answer 36

* Galactorrhea * Infertility * *Can be present even w/o menstrual distrubances* * Menstrual disturbances * *Oligomenorrhea, amenorrhea* * Hypogonadism * *Low estrogen sx: hot flashes, vaginal dryness, decreased bone density*

Question 37

List 3 ovarian _peptide_ hormones synthesized in the granulosa cell and their functions

Answer 37

* **Inhibin** - inhibits FSH * *Secretion stimulated by LH* * **Activin** - stimulates FSH, increases FSH receptors in ovary * **Follistatin** - inhibits activin -\> less FSH

Question 38

At what stage of follicular development is a dominant follicle selected

Answer 38

Pre-antral -\> antral * There can be many pre-antral follicles, but then a dominant one is selected and there is only 1 antral follicle* * The rest become atretic follicles*

Question 39

Which gonadotropin promotes follicle development (egg maturation) in the ovary? Which hormone is elevated as a result?

Answer 39

FSH Estrogen *Granulosa cells proliferate in resonse to FSH; then they aromatize androgens (from theca cells) to estrogen*

Question 40

Which dopamine agonist is most effective for treating hyperprolactinemia AND producing ovulation?

Answer 40

**Cabergoline**