84 - Female Reproduction Flashcards
What surrounds the ovary?
Oviduct/uterine tube
What is female internal genitalia derived from?
Mullerian ducts
What is the border b/w internal and external genitalia of the female?
Upper 1/3 of vagina
GnRH activated at puberty by _____________ (hormone) in the hypothalamus.
Kisspeptin
Increased GnRH pulsatility during REM sleep promotes the devo of:
Secondary sex characteristics
*What is the day/night pattern of GnRH pulsatility frequency during childhood? (low vs. high)
*Puberty?
*Reproductive years?
*Menopause?
- Childhood: low freq during day and night (FSH)
- Puberty: High at night (LH), low during day (FSH)
- Reproductive years: High day and night (LH)
- Menopause: High day and night, same frequency but increased amount due to lack of neg. feedback (somehow both high and FSH is higher)
HPG axis feedback mechanisms generate a cyclical monthly pattern of hormone secretion called the _______________.
“Menstrual Rhythm”
What 2 cycles are contained w/in the menstrual cycle?
Ovarian and uterine cycles
Overall, what does FSH stimulate? (2)
FSH stimulates follicular development and conversion of androgen precursors to estradiol
Overall, what does LH stimulate? (2)
LH stimulates biosynthesis of estrogens, induces ovulation and luteinization (formation of corpus luteum from a mature ovarian follicle)
Recall: FSH acts on __________ cells, LH acts on _________ cells.
- FSH: Granulosa - LH: Theca
Discuss the different roles of hormones released by thecal cells and granulosa cells, and how they feed back on their HPA axis.
What do both cells secrete?
Which secretes androgens? Estrogens? Inhibins/activins?
Both secrete progestins.
Theca cells secrete androgens, which act on granculosa cells.
Granulosa cells secrete estrogens, activins, and inhibins.
(LH acts on theca cells mostly, FSH acts on granulosa cells. Neg/pos feedback at every level of axis)
*Which is higher, FSH or LH, during: Fetus? Infancy? Childhood? Puberty? Reproductive years? Menopause?
- Fetus: FSH
- Infancy: FSH
- Childhood: FSH (but both low)
- Puberty: FSH (rising)
- Reproductive years: LH (monthly surges)
- Menopause: FSH
Recall: what hormones do theca cells produce?
What receptor do they have?
- Produce androgens and progestins
- Have LH receptors
Recall: what hormones do granulosa cells produce?
What receptors do they have?
- Produce estrogens, progestins, inhibins, activins
- Have both LH and FSH receptors
Estrogen has positive and negative feedback at all levels of its HPA axis.
What is its positive feedback important for?
Ovulation
In the menstrual cycle, what is considered “day 1”?
What 2 cycles are contained w/in the menstrual cycle?
First day of menses
- Ovarian cycle and endometrial cycle
What are the 3 phases of the Ovarian Cycle? (describe each phase in 1 phrase)
FoOL
- Follicular phase = growth of dominant follicle
- Ovulatory phase = follicle rupture and release of oocyte
- Luteal phase = formation of corpus luteum
In general, what drives changes during the menstrual cycle?
What, generally, signals the hypothalamus
- HPG axis hormone drive coordinated physiological changes during menstrual cycle.
- Physiological changes signal hypothalamus
Where does the endometrial cycle occur?
What are the 3 phases called?
Uterus
- Menstrual phase
- Proliferative phase
- Secretory phase
How long is each phase of the ovarian cycle?
- Follicular phase: 10-14 days
- Ovulatory phase: 1-3 days
- Luteal phase: 14 days
In the ovarian cycle, what is the follicle?
What does it consist of?
- Follicle: fundamental reproductive unit of the ovary
- Consists of 1 oocyte surrounded by cluster of granulosa cells (AKA germ cell surrounded by endocrine tissue)
What are the 5 things that the follicle will do once it’s fully developed?
- Maintain and nuture resident oocyte
- Mature oocyte and release it at appropriate time
- Prepare vagina and fallopian tubes for fertilization
- Prepare the urine lining to accept and implant a zygote
- Maintain hormonal support for the fetus until the placenta acheives this capability
Primordial follicles reach peak at ___ weeks gestation. Only ___% remaining at puberty.
- 20
- 10
- Thru the first 20-24 weeks of gestation (carried in woumb prior to birth), germ cells produce oogonia by mitosis. Some of these oogonia will begin prophase of meiosis and become ________________. All of them have reached this stage by _______ (how long?) after birth.
- Prophase will last until just before ovulation, 12-40 years later. In prophase, no other divisions occur, the _________ process begins and numbers steadily decline.
- Primary oocytes
- 6 months
- Atresia
What is present at the beginning of the follicular phase of the ovarian cycle? (name of structure and what cells are present)
Primordial follicles: outer layer of pregranulosa cells + small oocyte
Describe the state of oocytes in the primordial follicle. Are thecal cells present?
*Oocytes are arrested in diplotene stage of prophase; no thecal cells.
In the follicular phase of the ovarian cycle, what comes after the primordial follicle?
What is required for development into this stage?
Primary follicles: larger oocyte surrounded by cuboidal granulosa cells
- Requires FSH stimulation. Can happen in utero
In the follicular phase of the ovarian cycle, what does the primary follicle develop into?
What occurs to differentiate this stage?
Secondary follicles:
- Differentiation of stromal cells to Theca cells (outside the basal lamina)
- Increased numbers of granulosa cells that become stratified
- Enlargement of oocyte
(note: primary/secondary follicles also called pre-antral)
In the follicular phase of the ovarian cycle, what does the secondary follicle develop into?
Early antral follicle = tertiary follicle
- Granulosa cells secrete fluid and create antrum
- Granulosa cells closest to oocyte secrete mucopolysaccharides to form zona pellucida
In the follicular phase of the ovarian cycle, several antral follicles are “recruited” at the end of each ovarian cycle to become the next ______________.
Dominant follicle
- Recall: How long does maturation of the primary follicle -> Graafian follicle (mature) take?
- About how many of the initial cohort of follicles that started maturing will not undergo atresia?
- 10-14 days
- 1 (usually)
Choosing the dominant (Graafian) follicle is based on senstivity to what hormone?
What paracrine factor (produced by what cells) is also part of the decision?
- Sensitivity to FSH
- Paracrine AMH (produced by granulosa cells)
In the dominant (Graafian) follicle, what cell types do the granulosa cells stratify into? (describe spatial positions)
- Mural = farthest from oocyte.
- Cumulus = near oocyte; shed at ovulation
- Antral = face antrum
Which of the stratified granulosa cell types of the mature follicle have LH receptors?
Which are shed at ovulation?
Which form luteal cells s/p ovulation?
Which are most metabolically active?
- LH receptors: Mural cells
- Shed at ovulation: Cumulus cells
- Form luteal cells s/p ovulation: Antral cells
- Most metabolically active: Mural cells
What happens to the antrum as the follicle becomes fully developed? (general)
Enlarged and fully encircles oocyte
At mature Graafian follicle stage, oocyte is arrested until __________. What day does this occur? (Oocyte is still a primary oocyte until then)
LH surge (day 13-14)
In the ovary, are follicles in the cortex or medulla? What about the neurovascular innervation?
- Follicles: cortex
- Nerves: medulla
Is the ovary a classical or non-classical endocrine gland?
Classical
At end of ovarian cycle, what’s higher, FSH or LH?
Why is this important?
FSH
High FSH important for recruiting a new cohort of follicles to enter follicular phase.
What do the newly recruited follicles produce that exhibits negative feedback on FSH release?
What does this ensure, or what is the reason for this?
Inhibin B
Ensures that only the follicle most sensitive to FSH survives (follicle w/most FSH receptors).
Once FSH levels dip below LH levels, what happens? (or why does this happen?)
Increased steroidogenesis in thecal cells (androgens, progestins)
Inhibin B negatively feeds back to the ant pit to inhibit FSH release. What paracrine effect does it have as well?
Positive paracrine effect in thecal cells to augment steroidogenesis
What factors are feeding back to the ant pit, hypo, and/or ovary during the follicular phase?
- Inhibin inhibits ant pit
- Estrogen inhibits ant pit, stimulates ovary
Growing follicle produces increasing amount of E2. E2 feedback favors LH over FSH (high frequency, low amplitude GnRH pulses).
Note: this negative feedback (by estrogen) is not a complete shutdown, it just keeps the “volume” down as capacity builds.
What factors are feeding back to the ant pit, hypo, and/or ovary during the ovulatory phase?
- Estrogen stimulates ant pit, stimulate ovary
What factors are feeding back to the ant pit, hypo, and/or ovary during the luteal phase?
- Estrogen inhibits ant pit
- Progesterone inhibits hypo; maybe ant pit as well
What is higher during the follicular phase, ovulatory phase, and luteal phase: FSH or LH?
- Follicular: First FSH, then LH
- Ovulatory: Spike in both, but LH spike is bigger
- Luteal: First LH higher, at and end FSH is higher
Explain the amounts of estradiol during the follicular phase, ovulatory phase, and luteal phase.
- Follicular: pretty low
- Ovulatory phase: spikes
- Luteal phase: plateaus at med/high level
Explain the amounts of progesterone during the follicular phase, ovulatory phase, and luteal phase.
- Follicular: almost absent
- Ovulatory: very small spike
- Luteal: huge increase and plateau
Explain the amounts of inhibin a vs. b during the follicular phase, ovulatory phase, and luteal phase.
- Follicular: B > A
- Ovulatory: B spikes, A rises some
- Luteal: B drops, A goes up
Explain the amounts of T and Androstenedione x10 during the follicular phase, ovulatory phase, and luteal phase.
T is 2x higher than androstenedione the entire time. Both gradually peak during the ovulatory phase.
In the 2 part theory of E2 synthesis, what do receptors do thecal cells have? What do thecal cells synthesize?
Have LH receptors, synthesize androgens (from chol)
What (2) androgens are made in the thecal cells?
Which go to the blood?
Which can enter granulosa cells?
- Androstenedione, testosterone
- Both can go to the blood
- Androstenedione (can then be converted to T there)
What receptors do granulosa cells have that thecal cells don’t have?
What hormones can granulosa cells synthesize that thecal cells cannot? (and via what enzyme?)
- FSH receptors
- E2 (via CYP19 AKA aromatase)
- Androstenedione -> T -> E2
- Androstenedione -> estrone -> E2
Estradiol (E2) also enters the blood, like T and androstenedione
What important hormone stimulates the synthesis for increased LH receptors on granulosa cells?
What is important for?
FSH!
Important for sponse to LH surge
In what phase of what cycle does the LH surge occur?
How long does it last?
Ovulatory phase of the ovarian cycle.
32-36 hrs
What occurs during the LH surge (periovulatory period), in terms of neg/pos feedback?
Switch from negative to positive feedback
What happens to the follicle and oocyte during the LH surge?
- Follicle continues to mature
- Oocyte completes meiosis I and enters meiosis II – secondary oocyte arrested at metaphase II. (polar body present as well)
After the LH surge, the secondary oocyte becomes arrested in metaphase II. When does it complete meiosis II?
Upon fertilization
What are the 3 general things that happen during ovulation? (read first time)
- Expulsion of oocyte-cumulus complex out of ovary
- Increased inflammatory cytokines
- Breakdown of ovarian wall
Why is the LH surge switching from pos to neg feedback? (and what hormone is involved?)
Increased LH leads to more E2; more E2 leads to more LH….. POSITIVE feedback. Leads to LH surge – positive feedback is unsustainable >>> OVULATION.
What effect does the increase in progesterone (leading up to the LH surge) have on progesterone receptors?
Increased (progesterone at highest and plateaus during luteal phase)
How does the LH surge end?
How does this effect E2 and LH?
- Rupture of follicle causes decrease in E2.
- Loss of E2 positive feedback decreases LH
Durng the ovulatory phase (ovarian cycle), the follicle matures.
- Which of the 3 stratified granulosa cell types expands? What 2 new zones form?
- What happens to the oocyte, in terms of where it is positioned and w/what?
- Where does the follicle settle? What is it then called?
- Cumulus cell expansion. Forms corona radiata and cumulus oophorus
- Detachment of cumulus-oocyte complex: free floats in antrum
- Follicle forms bulge against ovarian wall (stigma)
During the ovulatory phase (ovarian cycle), the oocyte matures. Where is it in terms of meiosis?
- Oocyte completes meiosis I
- Arrests at metaphase in meiosis II
- Now a secondary oocyte + a polar body
Recall: what is ovulation ovulation? (what ruptures/how is this accmplished?)
Rupture of the follicle and release of the oocyte into the peritoneal cavity.
- Occurs via proteolysis of the BM
Once the oocyte is released into the peritoneal cavity during ovulation, where does it go?
Extrusion of cumulus-oocyte complex: drawn into the fallopian tubes by the actions of the fimbriae.
(remaining follicles undergo atresia)
After the follicle ruptures and releases the cumulus-oocyte complex, what happens to the ruptured Graafian follicle, as well as the granulosa and thecal cells?
All remain in the follicular cavity, as this structure reorganizes to form the corpus luteum.
Also, an increase in vascularization occurs to support it.
During corpus luteum formation, mural granulosa cells differentiate into _____________ cells; thecal cells into____________ cells.
- Large luteal cells
- Small luteal cells
During the LH surge, how is the increase in GnRH achieved?
Increasing the frequency of GnRH pulses
What organ determines timing of the LH surge?
Ovary
As the increase in E2 causes the switch from neg to pos feedback during the LH surge, what also occurs in the ant pit?
Increase in density of GnRH receptors on gonadotrophs
What are 2 others names for the corpus luteum?
- Remnant follicle
- “Yellow body”
What is the major hormone product of the corpus luteum? Why is it needed?
Why does the corpus luteum produce the hormones that it does?
- Progesterone (lowers levels of E2)
- Progesterone has a huge plateau s/p ovulation
- *Optimize implantation and maintain the zygote
What does the follicle stop producing that there’s less neg feedback on FSH?
What does the corpus luteum produce instead?
- Inhibin B
- Inhibin A
(FSH still less than LH)
What happens to the corpus luteum if there is no fertilization?
What structure will it then eventually become?
- Regresses, undergoes luteolysis, becomes necrotic.
- Corpus albicans
During the luteal phase of the ovarian cycle, what is the effect of progesterone and E2 on higher level hormone release?
Results in decreased FSH/LH/GnRH secretion
Loss of LH during the luteal phase will cause the corpus luteum to degrade unless it is rescued by the equivalent hormone secreted by implantation of the fertilized embryo, known as:
hCG
If there is no LH or hCG during the luteal phase, what will happen?
What is the symptom that indicates the beginning of the next phase?
E2 and progesterone decrease, endometrium degrades, “withdrawal” bleeding (menses) indicates beginning of the next phase.
Summarize the hormones of the ovarian cycle. (image)
- Corpus luteum dies, E and P levels fall.
- Pit responds to falling E and P by increasing FSH secretion
- FSH recruits a cohort of large antral follicles to enter rapid growth phase. Follicles secrete low amounts of E and inhibin
- E and inhibin negatively feed back on FSH
- Declining FSH levels progressively cause atresia of all but 1 follicle–leading to selection of the dominant follicle, which produces high levels of E
- High E has positive feedback on gonadotropes–LH (and some FSH) surges
- LH surge induces meiotic maturation, ovulation, and luteinization. The corpus luteum produces high P, along with E and inhibin
- High P, E, and inhibin negatively feed back on LH and FSH, returning them to basal levels
- The corpus luteum progressively becomes less sensitive to basal LH–dies if levels of LH-like activity (i.e. hCG) do not increase
Recall: what are the 3 phases of the ovarian cycle?
- Follicular phase = growth of dominant follicle
- Ovulatory phase = follicle rupture and release of oocyte
- Luteal phase = formation of corpus luteum
Recall: what are the 3 phases of the endometrial cycle (uterus)?
- Menstrual phase (early follicular phase)
- Proliferative phase (coincident with follicular phase for ovary)
- Secretory phase (coincident with luteal phase for ovary)
Name and describe the 3 layers of the uterus.
- Endometrium- innermost; mucosal layer
- Myometrium- thick muscular layer
- Perimetrium- outer CT and serosa
What is the cervix?
Narrow necklike passage forming the lower end of the uterus (distinct from the endometrium)
Which cervical layer is the functional zone, and which is the basal zone?
Which is shed during menstruation?
- Functional zone = endometrium (shed during menstruation)
- Basal zone = myometrium
Uterine glands are found in the basal zone and sprout into the functional zone. What do they do, generally?
Secrete substances for embryo survival
Spiral aa. are found in the basal zone and then change into normal aa. in the functional zone. What are the important for?
Reduced blood flow to spiral arteries results in ischemia, then necrosis of endometrial layer
What hormone is dominant during the proliferative phase of the endometrial cycle?
What does this hormone do? (2)
What else occurs during this phase, in terms of bv’s?
- E2
- Stimulates uterine cell growth
- Increases expression of progesterone receptors
- Increased vascularity
What hormone is dominant during the secratory phase of the endometrial cycle?
What does this hormone do? (1)
What occurs w/the uterine glands? Bv’s?
- Progesterone
- Has anti-estrogenic effects – stops further uterine growth
- Uterine glands begin secreting large amounts of carbohydrate-rich mucus, becomes engorged
- Stroma becomes edematous; undergo predecidualization (change cell type)
- Vascularization continues to increase
What is the source of the progesterone that is acting on the uterus during the secretory phase of the endometrial cycle?
Corpus luteum
How do hormone levels change during the menstrual phase of the endometrial cycle? Why do they change this way?
What else occurs (2)?
- Low P4 and E2 due to demise of corpus luteum
- Reduced blood flow to spiral arteries results in ischemia and necrosis
- Proteolytic enzymes increase, digest tissue
Why doesn’t blood clot during the menstrual phase of the endometrial cycle?
Due to fibrolysins released from necrotic tissue
What hormone dominates the vagina change during the mid-late follicular phase of the endometrial cycle?
What’s the subsequent effect on the vag?
- Estrogens
- Vaginal epithelial cells become large, squamous, cornified with small or absent nuclei
What hormone dominates the vagina change during the luteal phase of the ovarian cycle?
Progesterone
How does the cervical mucus change from the follicular phase to the ovulatory phase of the ovarian cycle?
Why does it change like this?
- Follicular phase: cervical mucus increases, becomes more alkaline and less viscous
- Ovulatory phase: Characterized by Spinnbarkeit (stretchable mucus); Ferning – pattern when dried on glass slide (primitive test for ovulation)
- *Changes promote survival and transport of sperm
If large mucus crystals are seen on the Spinnbarkeit, it’s a sign of ovulation. What if small, normal mucus crystals are seen?
Could be either pre- or post-ovulatory
Summarize 5 key actions of E2.
- Inhibit growth of cohort follicles
- Prime GnRH action on LH secretion to evoke ovulatory surge of LH
- Prepare uterine endometrium for progesterone to evoke secretory response
- Affect fallopian tube to favor transport of ovum and zygote
- Alter cervical mucus to enhance sperm xport
Increase in what hormone directly leads to the LH/FSH spikes?
Estrogen (E2)
