Female Reproductive Physiology (Week 7--Wayne)

Question 1

3 phases of the ovarian (menstrual) cycle

Answer 1

1) Follicular phase (corresponds to proliferative phase of menstrual cycle)
2) Ovulatory phase
3) Luteal phase (corresponds to secretory phase of menstrual cycle)

Question 2

Follicular phase

Answer 2

Growth of ovarian follicle

Estradiol secretion from ovary

Increased pulse frequency of GnRH secretion

Corresponds to proliferative phase of menstrual cycle

Question 3

Ovulatory phase

Answer 3

LH surge leads to ovulation

Question 4

Luteal phase

Answer 4

Formation of corpus luteum (CL) from ovulated follicle

Increased progesterone (and estradiol) secretion from CL

Decreased pulse frequency of GnRH secretion

Corresponds to secretory phase of menstrual cycle

Question 5

3 phases of follicular phase

Answer 5

1) Pre-antral phase (early): primary oocyte grows; granulosa cells proliferate; granulosa cells develop estrogen and FSH receptors; thecal cells with receptors for LH develop; independent of LH and FSH (this phase happens even without LH and FSH)
2) Antral phase (mid): many follicles undergo atresia and death of oocyte; increased synthesis and secretion of estradiol and androgen; conversion of preantral to antral (Graafian) follicle; estradiol and FSH cause LH receptors to develop on granulosa cells (critical for next phase); estradiol switches from negative to positive feedback here
3) Preovulatory phase (late): LH stimulates synthesis and secretion of progesterone and prostaglandins (from granulosa cells (this is why LH on granulosa cells so important for ovulation!) and thecal cells!); LH surge stimulates ovulation and formation of CL

Question 6

Steroidogenesis during early antral phase of follicular phase (2 cell hypothesis)

Answer 6

Thecal cells synthesize androstenedione from cholesterol (stimulated by LH)

Granulosa cells get androstenedione and convert it to estradiol via aromatase (stimulated by FSH)

Granulosa cells also secrete estrogen and induce themselves to proliferate and synthesize more FSH and thus more estrogen (also local positive feedback during follicular phase)

Question 7

How do you explain the difference in LH pulse frequency between follicular and luteal phases?

Answer 7

In follicular phase, there is suppression of normal estradiol negative feedback (positive feedback) so get high frequency of LH pulse secretion

In luteal phase, have negative feedback of estradiol so get low frequency of LH pulse secretion

Note: FSH affected same way as LH

Question 8

What is it that matters, the LH pulse frequency or pulse amplitude?

Answer 8

Pulse frequency is what matters!

High pulse frequency means high secretion

Note: inverse relationship between pulse frequency and pulse amplitude

Question 9

What triggers the LH surge (which in turn triggers ovulation)?

Answer 9

Increase in GnRH pulse frequency (GnRH surge)

But estradiol must reach its threshold level to cause this increase in GnRH (positive feedback still remember)

Question 10

What is menopause?

Answer 10

Progressive failure of reproductive system

Occurs between 45 and 55

Due to failure of ovarian function: number of oocytes down to 10,000, remaining follicles are less responsive to GnRH because of degeneration of granulosa and theca cells

Question 11

During the luteal phase, what are estrogen and progesterone doing?

Answer 11

“Luteinization” of the follicle means LH surge caused ovulation which creates the CL

During luteal phase E and P secreted by CL have negative feedback on HPG axis to decrease pulse frequency of GnRH

This means LH and FSH secretion are low also (good because don’t want follicular growth because don’t want double ovulation!)

Also, E and P from CL prepare the uterus/endometrium for implantation/maintenance of pregnancy

Question 12

What happens if there is no signal for pregnancy?

Answer 12

CL dies because needs LH to sustain it and LH declines after its surge –> E and P were secreted by CL, so now no more E and P –> since E and P were what supported endometrum, now the endometruim sloughs off

Question 13

Can you prevent death of CL with continuous treatment with LH?

Answer 13

No, but we don’t know why not!

hCG is what maintains the CL if a woman becomes pregnant, and hCG actually binds the LH receptor, but we still can’t use LH itself to maintain CL

Question 14

What do E and P do during the follicular phase?

Answer 14

At first there is no E and P because the CL died, so GnRH, LH, FSH are high because no negative feedback fro E and P

A weird thing happens in humans where the brain switches from having E do negative feedback to having it do POSITIVE feedback –> as E increases slowly, it causes an INCREASE in LH and FSH and this stimulates the ovarian follicle

Question 15

What is the “winner” follicle called?

Answer 15

Graffian, dominant, or mature follicle is the one that matures enough to allow ovulation

It’s the one that expresses the most FSH receptors

Question 16

Why is the follicular phase all about estrogen’s positive feedback?

Answer 16

There is distant positive feedback on the HPG axis (increase GnRH secretion, increase LH (and FSH) secretion)

There is local positive feedback on the granulosa cells themselves (estradiol secreted by granulosa cells themselves causes proliferation of themselves and more expression of FSH receptors on them to create aromatase to make even more estradiol)

Question 17

What physically allows for ovulation?

Answer 17

The follicular wall becomes thinner and ruptures at the stigma about 16 hours after peak of LH surge and causes follicular fluid to pour out, carrying oocyte with it (not an explosion, no change in antral pressure!)

Proteolytic enzymes released from follicular cells cause thinning of follicular wall (possibly prostaglandins and progesterone involved in this)

Question 18

When is the peak E and P secretion by the CL during the luteal phase?

Answer 18

8 days after LH surge (day 8 of luteal phase)

Then declines to baseline at day 12 of luteal phase

Question 19

What do E and P specifically do to the endometrium?

Answer 19

Estradiol: stimulates growth/prolif of epithelial cells; enhances growth of spiral arteries; stimulates blood flow

Progesterone: causes endometrial lining to differentiate and become secretory

Question 20

What do E and P specifically do in the myometrium?

Answer 20

Estradiol: stimulates spontaneous uterine contractions

Progesterone: counteracts effects of estradiol by inhibiting amplitude and frequency of uterine contractions (facilitates implantation/embryonic development)

Question 21

What do E and P specifically do in the oviducts (fallopian tubes)?

Answer 21

Estradiol: stimulates cilia formation; increases contractility of oviduct muscular wall

Progesterone: increases secretions into oviduct lumen

Note: this could affect transport of gametes, fertilization, growth of blastocyst

Question 22

What do E and P specifically do in the cervix?

Answer 22

Estradiol: causes cervix to be more vascular and edematous; stimulates cervical muscle relaxation; stimulates watery endometrial secretions (during follicular/proliferative phase)

Progesterone: hardens cervix; reduces secretions (during luteal/secretory phase)

Question 23

What is kisspeptin?

Answer 23

DON’T MEMORIZE

Kisspeptin is a peptide (kiss1 is the gene) that is important in regulating the onset of puberty, stimulation of GnRH pulse frequency and steroid positive feedback

Kisspeptin binds to the G-protein coupled receptor GPR54

Side note: also is a cancer metastasis suppressor gene (kisspeptin-54 = metastin) but also might help breast cancer cells grow (so don’t give to enhance fertility!)

Question 24

How might kisspeptin explain how estrogen can have both negative and positive feedback on the hypothalamus?

Answer 24

NEW MODEL, DO NOT MEMORIZE

Kiss1 neurons express estrogen receptors and GnRH neurons do NOT! Kiss1 neurons synapse ONTO GnRH neurons!

Estrogen –> Kiss1 neuron –> GnRH neuron

Kiss1 neurons in the ARC are inhibited by estradiol

Kiss1 neurons in the AVPV are stimulated by estradiol

Note: we still don’t know how brain decides whether ARC or AVPV gets activated at any given time

Question 25

How are GnRH and LH pulses related?

Answer 25

Every pulse of GnRH **causes** pulse of LH However, during preovulatory surge of GnRH/LH that causes ovulation, **GnRH surge is longer than LH surge** This is because: 1) **Releasable pool** of LH runs out! 2) GnRH receptor **downregulation** (**endocytosis**, **inhibition** of second messenger receptor pathway, **tx** of GnRH receptor **inhibited**)

Question 26

What happens if you increase the pulse frequency of GnRH a LOT?

Answer 26

GnRH receptors on the anterior pituitary get downregulated so you get no LH and FSH secretion 1) **Internalization** of GnRH **receptors** 2) **Inhibition** of second messenger activation 3) Inhibition of **transcription** of GnRH-receptor gene

Question 27

How do you treat precocious puberty?

Answer 27

**GnRH agonist** (suppresses LH and FSH and thus estrogen and progesterone) Blocks menstruation, arrests development of secondary sexual characteristics

Question 28

What do E and P do during the follicular phase?

Answer 28

End goal: sperm penetration into uterus, oocyte transport along oviduct, sets up environment for implantation of blastocyst Progesterone doesn't do much (not much P there!) **Estrogen**: Stimulates growth and **proliferation** of uterine epithelial cells Enhances growth of **endometrial spiral arteries** and stimulates blood flow Stimulates spontaneous **contractions** of uterine **myometrium** Stimulates **cilia** formation and activity of oviduct lining Stimulates **contractility** of **oviduct** muscular wall Causes **cervix** to become more **vascular** and edematous, to secrete **watery** stuff from epithelium Stimulates cervical muscles' **relaxation**

Question 29

What do E and P do during the luteal phase?

Answer 29

End goal: reduce sperm penetration, facilitate implantation, promote maintenance of pregnancy **Estrogen** secreted from the CL continues to enhance uterine endometrial **vasculature** **Progesterone** from the CL causes endometrial lining to differentiate and become **secretory** Progesterone counteracts estrogen by **inhibiting** amplitude and frequency of spontaneous contractions of the myometrium Progesterone **hardens cervix** and reduces secretions (**thickened mucus**)

Question 30

How long can sperm and egg live?

Answer 30

**Sperm** lives in reproductive tract **1-2 days** (some super sperm can live 5 though!) **Oocyte** only lives **6hrs** to **1 day**

Question 31

How do sperm know where to go?

Answer 31

Sperm move to the fallopian tube with the Graafian follicle/ovulated egg because of **myometrial contractions** (uterine peristalsis) due to **estrogen** that the follicle is producing probably Used radioactive beads to show that within 20 seconds the woman's uterus/fallopian tube transports stuff to the ovary with the dominant follicle--NOT necessary for sperm to swim

Question 32

Timing of implantation

Answer 32

LH surge then 16 hours later ovulation occurs **1 day for oocyte to be fertilized** before it dies **3 days in oviduct** **1 day in uterus** **Total of 5 days to implantation** This is good because it **coincides** with elevated progesterone and estradiol so cushy, quiescent, secretory, vascularized uterine environment

Question 33

What does the trophoblast/placenta make?

Answer 33

hCG, hCS/hPL, progesterone, estrogens, relaxin, CRH

Question 34

What does the uterus make?

Answer 34

Oxytocin

Question 35

Human chorionic gonadotropin (hCG)

Answer 35

Secreted by early **syncytiotrophoblast** cells Keeps **CL alive** and functional (binds to LH receptor) Detectable in blood by 8 days after fertilization

Question 36

Human chorionic sommatotropin (hCS) or placental lactogen (hPL)

Answer 36

Synthesized and secreted by **trophoblast** cells Rises throughout pregnancy then falls after parturition, but some women have no rise in hCS/hPL and babies and lactation are fine Member of GH/prolactin family of peptides (but no growth effect in humans) Possible physiological role in **suppressing insulin sensitivity** (gestational diabetes)

Question 37

Relaxin

Answer 37

Structurally similar to insulin **Inhibits** uterine myometrial **contractions** (important for maintaining pregnancy) **Softens** **cervix** and **relaxes pubic ligament** (important for vaginal delivery)

Question 38

Progesterone

Answer 38

Causes uterine epithelium to become **secretory** **Inhibits** uterine **contractions** Together with estradiol stimulates **mammary growth**

Question 39

Estrogens

Answer 39

Estradiol helps maintain uterine endometrium and stimulates **uterine blood flow** Estradiol stimulates expression of **oxytocin receptors** on myometrium (important for parturition) Side note: estriol decreases brain lesions in patients with MS (neuroprotective during pregnancy, can be used as drug)

Question 40

What factors are involved in activating parturition (labor)?

Answer 40

CRH, CRH binding protein Oxytocin Prostaglandins ER/PR ratio (multiple and redundant pathways!)

Question 41

How does oxytocin activate parturition?

Answer 41

Powerful **stimulator of myometrial contractions**, especially at the end of pregnancy after **estradiol** stimulated **expression** of oxytocin receptors on myometrium Note: studies noted that oxytocin in the blood only went up AFTER labor started so they thought it couldn't be involved in activating labor, but in fact oxytocin is just **secreted locally** and doesn't get into systemic circulation much Note: **Pitocin** is synthetic oxytocin used to induce labor

Question 42

How do CRH and CRH binding protein activate parturition?

Answer 42

**CRH levels increase** at the end of pregnancy and **CRH-BP levels fall** creating increased free CRH Low-affinity CRH receptors predominate early to mid-gestation to inhibit myometrial contraction, but there's a switch to **high-affinity receptor** near end of pregnancy which causes strong myometrial **contractions** (synergizes with **oxytocin**) CRH also activates **fetal ACTH** which stimulates production of **prostaglandins** to stimulate uterine contractions

Question 43

How does the estrogen receptor/progesterone receptor ratio activate parturition?

Answer 43

High levels of both hormones, so it's the level of their receptors that determines how much action they will have **Progesterone withdrawal** (essentially what happens if you have more ER than PR) stimulates **myometrial contractions**

Question 44

Mifepristone/RU-486 and prostaglandin together

Answer 44

Mifepristone/RU-486 is progesterone inhibitor, so get **contractions of myometrium** and will abort fetus **Prostaglandin** can be used with it to **increase the strength** of contractions

Question 45

What tissue has lots of aromatase?

Answer 45

**Adipose tissue** has lots of aromatase so converts T and androstenedione into estrogen in the periphery Makes sense because females are fatter and have more estrogen!