Female Reproduction Flashcards
Amenorrhea
Complete lack of a period. This is also a marker of pregnancy!!!!!!!! Doesn’t matter if patient is 40. Age alone is not enough to diagnose menopause.
Oligomenorrhea
Irregular, random periods
G0P0 would suggest
primary issue. Note that the G means that she is carrying a child
G1P1 would suggest
secondary issue. Note that the P1 means she gave a LIVE birth.
Perimenopausal
Transition period to menopause. Expect hot flushes and unpredictable periods
Presentation of menopausal women.
Night sweats
hot flushes
Diagnos patient with a metabolic panel. Ultrasound wouldn’t help here, can be used.
Describe follicular phase
Follicular (ovarian perspective): PROLIFERATIVE phase (uterine perspective). days 1-14. Menses (period…vaginal bleed) occurs right in the BEGINNING! Within days 1-4/ FSH is increasing, granulose cells proliferate and E2 is secreted. Later, the dominant follicle is selected from the growing cohort. E2 is still increasing. Finally, Remainder of the cohort undergoes atresia (death). Ovulation occurs on day 14.
Describe luteal (secretary) phase
Days 15-28. Focuses more on the uterus.
Describe the Graafian/preovulator/selected follicle
- Teca cells on the outermost shell. Has LH receptors. Makes P4, Androtenedione, and T.
- Granulosa cells are second layer in. Has FSH R. makes E1, E2-17B, and Proesterone.
- Antrum: Follicular fluid filled with a ton of hormones
- Oocyte. the actual egg. The most inward.
What is job of GnRH? Think hypothalmic-pit-ovarian-adrenal axis. What happens to the storoids produced by the follicular cells?
Secretes LH and FSH. Note that granulos cells express both FSH and LH receptors. Theca cells only express LH receptors. Also note that the produced steroids act as negative feedback, killing off GnRH, and thus stopping FSH and LH secretion.
Job of CYP17
makes androens: androstenedione and T.
Job of CYP19, aromatase
estrogens: makes E1, E2-17B (important for bone)
Job of CYP11A
progestins: prenenolone (P5) and progesterone (P4)
What is the involvement of steroid sulfatase?
Think DHEAS, which is secreted from the adrenal cortx. S = sulfate. TO turn into DHEA, you need a desulfatase, which is what this it.
What is the pattern of folliculogenensis. Detail the hormone genesis.
Primordial-primary-preantral-preovulatory-corpus luteum
Story: Nothing is secreted in primordial cells. Period. It is not until primary and preantral development that anything is made. At this point, Thecca cells make more androstenedione and granulosa cells make more E2. Leaving the preantral stage, Thecca stells increases androsteindione and granulosa cells secrete more E2….a bunch more. At preovulatory stage, Thecca cells are makeing a crap ton of androsteindion, and E2 in granulose calls is dumb high. At corpus luteal stage, Adrosteonodione has a sligth drop in production, and up until now progesterone was barely being made. Now, P4 is Sky high. In the case of the granulaose cells, E2 also took a hit inproduciton, but it still a lot. progesterone was also weak up till this point. Now, it is the highest hormone being made, period, ever. Like, beyond dumb high.
Why does P4 get sky high in the corpus luteum stage?
Primes urterus to accept egg. This is day 14.
Describe the general signaling pathway for androgen production on a thecca cell.
LH binds to LH receptor. This causes LDL to drop cholesterol into the cell. The cholesterol passes through StAR protein, and enters the mitochondria innermembrane. Cholesterol is then converted to PREGNENOLONE (P5) via CYP11A (rate limiting step!!!!!!!!). This is a WEAK progesterone. You cannot skip this step. It is only after P5 escapes the mitochondria that it meets 2 enzymes. When passing CYP17, it makes DHEA. When Passing 3b-HSD, it makes PROGESTERONE. Progesterone is then converted further with CYP17 to make androstenedione. Some of this androstenedione runs through 17B-HSD to become T. T and Androstenedione (way more A than T! Like, no competition). BOTH leave the thecca cell. Note that DHEA can be converts to androstenedione with 3B-HSD.
Describe the general signaling pathway for androgen production on a granulosa cell.
FSH binds to FSH receptor. This causes LDL to drop cholesterol into the cell. The cholesterol passes through StAR protein, and enters the mitochondria innermembrane. Cholesterol is then converted to PREGNENOLONE (P5) via CYP11A (rate limiting step!!!!!!!!). This is a WEAK progesterone. You cannot skip this step. Although pregennelone is made, this is not the important part. What is important is that the binding of the FSH tot eh receptor caused the chain tha tled to steroid horomone expression. This allows for the androstenedione and T that were made from the thecca cells to actually enter the granulosa cells. The granulosa cells then tale the androstenedione, convert it with cyp19 to make E1. The T s converted with the same CYP19 to make E2. E1 and E2 are rleeased as E2. Both E1 and E2 are released, but WAAAAY more E2 is released than E1.
What is a corpus luteum?
It is the remains of the ovulation of the egg. Upon follicle bursting and egg release, the thecca and granulosa cells are left. This is a terminal differentiated state. The granulosa and thecca cells are now titled grulosa lutein and thecca lutein cells.
What is the new job to the granulosa LUTEIN cells (that are now the corpus luteum?)
LH binds to LH receptor. Yes, THE GRANULOSA CELLS NOW HAVE LH RECEPTORS, in addition to the FSH receptors they always had. This causes LDL to drop cholesterol into the cell. The cholesterol passes through StAR protein, and enters the mitochondria innermembrane. Cholesterol is then converted to PREGNENOLONE (P5) via CYP11A (rate limiting step!!!!!!!!). This is a WEAK progesterone. You cannot skip this step. When P5 leaves the mitochondria, it is converted with 3B-HSD to make a BUNCH of progesterone. There is still E2 remaining from thecal androgens tho. Both Progesteone and E2 are released, but Progesterone is released in LARGER quantities…E2 is still being produced in a solid amount tho. Note that the combo of Progesterone and E2 are released to prepare the uterus fro implantation.
What kind of cell signaling is involved in the hormone productions of the ovaries?
cAMP-PKA and pPKA.
What are the 5 families of steroid hormones?
glucocorticoid, mineralcorticoids, androgens (T), estrogens, progestines
What hormone presence could screw up GnRH? What is common between cushings syndrome fertility?
- Prolactin
2. These guys are all infertile.
T or F: The recruitment of cohort of follicles depends on LH or FSH
HARD FALSE. That releases is controlled by the ovaries intrinsically. All of the growth and development that occurs AFTER recruitment depends on FSH and LH.
How many months does it take for a cohort to finish and select the chosen one follicle?
3-4 months. Note the cascade effect. Each month, a new cohort is selected.
Why do you need all of these growing follicles present at different stages?
In order to support the entire process, since each one of the follicles in their respective cohorts are secreting growth hormones and such, which effect all of the present cohorts in a paracrine manner.
When is FSH and LH needed for follicular growth?
Transition from primary to secondary follicle size and beyond. Note that during this process, random follicles go through atresia (die off). More than 98% of all growing follicles die.
Describe the hormonal control of folliculogenesis
- Primordial to primary…intraovarian growth factors. NO FSH or LH present.
- Secondary and beyond…growth factors are numerous, cytokines are numerous, FSHS AND LH ARE SQUAD DEEEP. Steroid hormones come thru too.
- Oocyte matures
- Growth/steroidogenic differentiation of granulosa and thecca cells
- Angiogenesis, allows fro ovulation of fertilizable oocyte.
What controls the hormonal events during the luteal phase of the cycle?
Corpus luteum
Prior to the preovulatory surge, what are the TWO reasons FSH stays so low? Where is the estrogen coming from?
- E2 is still causing that negative feedback at the level of the GnRH pulse gen, so FSH is not being released enough
- Granulosa cells are secreting Inhibin B, which stops FSH secretion
Note that the estrogen is coming from the Graafian follicle.
What cause the negative feedback of E2 to switch to positive feedback (referring to before ovulation). What happens to Inhibin B?
A sudden increase in E2 production. This causes pulse generator of GnRH to change firing pattern, leading to the increased release of FSH. Note that the gonadotropes secrete FSH and LH. In this particular case, the gonadotropes start to secrete Activin (inhibin B is cut out). It acts in an autocrine manner, turning around and telling the gonandotropes to secrete FSH.
What happens post-ovulation? What happens to the granulosa cells?
P4 and E2 are produced like no other from the corpus luteum. P4 and E2 in it of itself is likely enough to kill off FSH production (remember, the negative feedback…contraceptive concept). In terms of the granulosa cells in the corpus luteum, they are now granulosa lutein cells. These guys no longer secrete Inhibin B. They secrete Inhibin A. Inhibin A, just like Inhibin B, knocks down FSH secretion at the level of the ant pit.
Why does FSH have to keep changing the way it does during the menstrual cycle?
When FSH is low, follicle growth and differentiation is at a bare minimum. So a lot of the follicles die at the the early and later days. They are too small, and have less FSH receptor, so they can’t grab onto the small amounts of FSH.
What causes granulosa cellls prior to ovulation to develop LH receptors, in addition to the FSH receptos it already had? What does LH cause graulosa cells to do?
The increase in FSH (caused by the increases in E2, remember?). Note that this happens because the follicle is getting ready to become the corpus LUTEUM. It also causes the granulosa cells to produce Inhibin A, which was already established to reduce FSH in the granulosa luteal cells of the corpus luteum. Note that ovulation has not yet occurred. It is about to tho.
What horomon is absolutely necessary for follicle growth?
FSH
What is the difference in pattern of secretion of LH from FSH?
There is none.Same exact pattern. Same negtaive and positive feedbacks caused by steady and then an increase in E2. Same ovulatory surge. The same increase in P2 and E2 from corpus luteum still causes FSH to decline again due to negative feedback. You still have Inhibin B and then Inhibin A from the respective granulosa cells.
Describe the pattern of estrogen production throughout the cycle.
E2 levels are relatively low until they gradually increase closer to the date of ovulation (peak is preovulatory). It peaks out right about the time of ovulation. Note that E2 stays relatively high through the mid luteal phase, and then starts to decrease. Note that the main source of E2 is still from the preovulatory follicle.
Describe the pattern of progesterone production throughout the cycle.
Stay dumb low through most of the follicular phase of the cycle. THere’s then a preovulatory “blip” of P4 caused by the fact that the preovulatory follicle is starting to become a corpus luteum. Skyrockets in the luteal phase as soon as ovulation occurs. Peak levels are also mid-luteal, just like E2.
Where is most of the E2 coming from in the follicular stage? Progesterone in the follicular phase? Where are most of the steroid hormones come from in the luteal phase of the cycle?
- Preovulatory follicle. Note that the other follicles present are contributing.
- Preovulatory follicle
- Corpus luteum
What is associated with the increase in progesterone production?
Rise in body temp. Note that progesterone is a thermogenic hormone.
Describe how progesterone can be used to determine pregnancy.
Increase in body temp (BBT) only happens is increase in P4, if corpus luteum is formed, if ovulation occured, if there was an LH surge at ovulation day 14, if there was E2 feedback (positive and negative), if there was a health dominant follicle with supporting follicles, if FSH/LH secretion was A1, if neruoendocrine function was normal. If you knock out one of these, there is no increase in body temp?
What is the first test you do on a woman that comes in suspecting infertility issues?
hCG test. Note that if patient is in amenorreia, they could very well be pregnant. You can’t have a cycle if you have a baby growing in you.. Do this after you checked the body temp and ruled out paternal issues.
How does progesterone during luteal phase affect the hypothalamus? Where is the progesterone coming from? Why is this all important?
Progesteone from corpus luteum at sustained, elevated levels, increases progesterone receptors in the hypothalamus. This leads to a decrease in GnRH pulse frequency, which decreases FSH and HEAVILY decreases LH production. Note that the placenta also makes progesterone, and this too will cause the same effect. Also note that progesterone contraceptives work the same way too, elevating P4 and increasing progesterone receptors, decreasing the GnRH pulse freq. Please remember that without the gonadotropins of LH and FSH, you CANNOT ovulate. Goes back to the whole follicular development. You need both for the follicles to continue to grow and differentiate.
How does estrogen affect the GnRH pulse generator? What makes this so brutal? How does T affect GnRH pulse freq? Where is T coming from? If T is not coming from the leydig cells, where could it be coming from?
E2 from the granulosa cells of the dominant follicle binde to ER-alpha in the GnRH pulse generator. This causes a decrease in the GnRH puls freq, which heavily cuts down FSH, but also cuts down LH. Remember that P4 cuts down the opposite, cutting down LH more than it cuts down FSH. Just remember that FSH and E2 are from the same granulosa cells. Blocking FSH more brutally kills follicle development. Follicles would be even more likely to reach the preovulatory stage without FSH. Leydig cells can also screw up FSH anf LH production through a similar mech. They crease T, which is converted to E2 with CYP19. E2 then bindes to ER-alpha and does the dame damage described above. Note that this process could just as easily happen in patients with an condition of HYPERandrogenemia such as PCOS (these guys can’t cycle. too much T, so too much E2, so this described pathway keeps occuring) and anabolic androgen abuse (same deal).
What happens at the end the cycle? (days leading up to d28)
Endometrium sheds and menstrual bleed occurs, feeding into the next follicular phase.
Describe thw difference between luteal phase defects and follicular phase deffects.
Luteal phase defects: screws with mechs needed to implant egg and cause pregnancy, as well as feedback needed to start next cycle.
Follicular phase defect: disrupts folliculogenesis, oocyte maturation, and most certainly adversely affects ovulation.
Describe the dominant follicle before and after the gonadotropin surge at d14.
Before: High E2. In early luteogenesis, tehre’s an onset of P4 to prime the uterus.
After surge: High P4 and E2 which supports the endometrium. The P4 is specifically there to relax and quiet the corpus luteum.
Describe the changes in the endometrium at the beginning and end of the follicular/proliferative stage
Beginning (days 1-4): There is a lot of angiogenesis repair because of the shedding of the endometrium prior.
End: There is a rise in E2 (from follicle), which triggers progeserone receptor, estrogen receptor, growth factors, and ultimately the proliferation and angiogenesis.
Describe the changes in the endometrium throughout the secretary/luteal stage.
Early in luteal phase, the P4 and E2 high levels promote angiogenesis. Mid way in the luteral phase, P4 lowers presence of P4 and E2 receptors. Reason: preparing endometrium to shed. THe suddon drop in E2 and P4 support (late luteal phase) leads to the period bleed. This withdrawl causes shedding of endometrium. Note that without P4 and E2, the endometrium does not have the support it needs to function.
What is REI? ART
REI: reproductive endocrinology and infertility (fellowship, subspecialty)
ART: Assisted reproductive technologies
Job of FSH
Stimulates ollicle growth and differntiation. More FSH - more follicle growth and differentiation.
Job of LH
Triggers final phase of maturation of selected follicle and ovulation
Job of E2 and P4
prepare receptive uterus for implantation
Describe the Clomiphene protocol goal and mech
Goal: promote endogenous FSH by blocking negative feedback
Mech: Remember: E2 is the specific hormone responsible for FSH negative feedback. So, you give an ER-alpha ANTAGONIST. This prevents E2 from binding to the hypothalamus and messin up the GnRH pulsatile setup. So, FSH runs free, and you get way more follicle stimulation. When this is done, you’ll see series of GnRH spikes, and FSH will be super stimulated, leading tot the maturation of SEVERAL (not one) preovulatory follicles. Track their growth via ultrasound to prevent maternal death. At intened ovulation date, you aspirate the eggs, conduct invertro fertilization during mid luteal phase, the n add P4 support into first trimester. The P4 is used to quiet and stabilize her uterus.
