3 phases of the ovarian (menstrual) cycle
1) Follicular phase (corresponds to proliferative phase of menstrual cycle)
2) Ovulatory phase
3) Luteal phase (corresponds to secretory phase of menstrual cycle)
Growth of ovarian follicle
Estradiol secretion from ovary
Increased pulse frequency of GnRH secretion
Corresponds to proliferative phase of menstrual cycle
LH surge leads to ovulation
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
3 phases of follicular phase
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
Steroidogenesis during early antral phase of follicular phase (2 cell hypothesis)
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)
How do you explain the difference in LH pulse frequency between follicular and luteal phases?
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
What is it that matters, the LH pulse frequency or pulse amplitude?
Pulse frequency is what matters!
High pulse frequency means high secretion
Note: inverse relationship between pulse frequency and pulse amplitude
What triggers the LH surge (which in turn triggers ovulation)?
Increase in GnRH pulse frequency (GnRH surge)
But estradiol must reach its threshold level to cause this increase in GnRH (positive feedback still remember)
What is menopause?
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
During the luteal phase, what are estrogen and progesterone doing?
"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
What happens if there is no signal for pregnancy?
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
Can you prevent death of CL with continuous treatment with LH?
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
What do E and P do during the follicular phase?
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
What is the "winner" follicle called?
Graffian, dominant, or mature follicle is the one that matures enough to allow ovulation
It's the one that expresses the most FSH receptors
Why is the follicular phase all about estrogen's positive feedback?
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)
What physically allows for ovulation?
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)
When is the peak E and P secretion by the CL during the luteal phase?
8 days after LH surge (day 8 of luteal phase)
Then declines to baseline at day 12 of luteal phase
What do E and P specifically do to the endometrium?
Estradiol: stimulates growth/prolif of epithelial cells; enhances growth of spiral arteries; stimulates blood flow
Progesterone: causes endometrial lining to differentiate and become secretory
What do E and P specifically do in the myometrium?
Estradiol: stimulates spontaneous uterine contractions
Progesterone: counteracts effects of estradiol by inhibiting amplitude and frequency of uterine contractions (facilitates implantation/embryonic development)
What do E and P specifically do in the oviducts (fallopian tubes)?
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
What do E and P specifically do in the cervix?
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)
What is kisspeptin?
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!)
How might kisspeptin explain how estrogen can have both negative and positive feedback on the hypothalamus?
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
How are GnRH and LH pulses related?
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)
What happens if you increase the pulse frequency of GnRH a LOT?
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
How do you treat precocious puberty?
GnRH agonist (suppresses LH and FSH and thus estrogen and progesterone)
Blocks menstruation, arrests development of secondary sexual characteristics
What do E and P do during the follicular phase?
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!)
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
What do E and P do during the luteal phase?
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)
How long can sperm and egg live?
Sperm lives in reproductive tract 1-2 days (some super sperm can live 5 though!)
Oocyte only lives 6hrs to 1 day
How do sperm know where to go?
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
Timing of implantation
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
What does the trophoblast/placenta make?
hCG, hCS/hPL, progesterone, estrogens, relaxin, CRH
What does the uterus make?
Human chorionic gonadotropin (hCG)
Secreted by early syncytiotrophoblast cells
Keeps CL alive and functional (binds to LH receptor)
Detectable in blood by 8 days after fertilization
Human chorionic sommatotropin (hCS) or placental lactogen (hPL)
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)
Structurally similar to insulin
Inhibits uterine myometrial contractions (important for maintaining pregnancy)
Softens cervix and relaxes pubic ligament (important for vaginal delivery)
Causes uterine epithelium to become secretory
Inhibits uterine contractions
Together with estradiol stimulates mammary growth
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)
What factors are involved in activating parturition (labor)?
CRH, CRH binding protein
(multiple and redundant pathways!)
How does oxytocin activate parturition?
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
How do CRH and CRH binding protein activate parturition?
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
How does the estrogen receptor/progesterone receptor ratio activate parturition?
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
Mifepristone/RU-486 and prostaglandin together
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
What tissue has lots of aromatase?
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!