Female Reproductive System Flashcards
what are the gonadotropins? what regulates gonadotropin release?
FSH and LH
- released in response to pulsatile secretion of GnRH from preoptic nucleus of hypothalamus
- secretion regulated by neurotransmitters like endorphins, NP-Y, adrenergics
adrenarche
period of time around 7-9yo when adrenal cortex begins to mature into active steroidogenic tissue
- uptick in adrenal androgen secretion
- not a prereq for puberty! more like a supportive priming of gonadal/neuroendo tissues for growth/maturation
theories re: onset of puberty
- hypothalmic maturation: some signal causes GnRH-secreting neurons within preoptic nucleus of hypothal to turn on GnRH pulse generator
- gonadostat: a developmental switch in the gonadal-hypothal-pit axis decreases sensitivity to negative feedback by gonadal steroids, leading to start of pulsatile release
- nutitional influence: greater fat stores = more adipocytes = more leptin, might trigger early onset of menarche
menstrual cycle
- basic definition
- timeline
ovulation of one mature, viable oocyte during each 28-day reproductive/menstrual cycle
- follicular/proliferative phase: day 1-14
- ovulation: day 14
- luteal/secretory phase: day 15-28
regulated by ovarian-hypothalamic-pituitary axis
ovarian follicles
spheroid structures made up of one oocyte, theca cells, and granulosa cells
HORMONE FACTORIES: pump out stuff to foster growth/maturation of oocyte AND maintain feedback loops
- theca cells: outermost layer of follicle cells, 2 layers (theca interna/externa), vascularized
- basement membrane: separates TC and GC
- granulosa cells: surround oocyte
largest and most mature follicles = selected, preovulatory, Graafian follicles have large antrums filled with follicular fluid (rich in hormones/growth factors
GnRH pulse specifics for secretion of gonadotropins
- slow GnRH pulse frequency = FSH secretion
- rapid high amp GnRH = LH secretion
LH function
targets theca cells and GC to…
- induce steroidogenesis
- cause changes in GC function and structure that enable ovulation
- stimulates luteinization - differentiation between GC and theca cells
before ovulation: luteinization of selected follicle begins just prior to ovulation (LH spike)
after ovulation: stimulates luteinized GC and theca cells in corpus lutuem to produce estrogens/progesterone
FSH function
target GC cells to…
- convert aromatizable androgens (testosterone, androstenedione) into ESTROGENS - steroidogenesis
- regulate GC mitosis during follicular growth
- action is mediated by growth factors, cytokines, steroids secreted in response to FSH or LH
- key: cAMP/PKA cascade important for follicular cell responsiveness to FSH and LH
hypogonadotropic hypogonadism
characterized by low gonadotropins and suppressed gonadal fx
- failure to secrete sufficient levels of FSH and/or LH
- potential causes: lesions in neuroendo system, athletic overtraining
- could be attributed to normal LEVEL but abnormal CYCLING (rise/fall) of hormone
women: low serum estradiol, possibly low FSH and/or LH
ovarian follicular growth/devpt
- recruitment happens during follicular phase of each menstrual cycle
- whole process takes 3-4 cycles
- implication: there are groups of follicles at distinct stages of devpt in all women of repro age
- sequence: primordial, primary, secondary, tertiary (ANTRAL), and pre-ovulatory/dominant/Graafian
primordial follicles
follicles in arrested, immature state
- each contain…
- oocyte: arrested in meiotic prophase I (4n) - WILL NOT PROGRESS PAST THIS PHASE UNLESS OVULATED
-
single layer of squamous granulosa cells surrounding oocyte
- aka pre-GC because theyre non-steroidogenic
recruitment
entry of primordial follicles into growth phase - differentiation into primary and secondary follicles
- GC and oocyte are the first cells to grow/differentiate
- initial phase occurs independent of FSH
- dependent on oocyte-produced growth factors
- counter-modulated by AMH (anti Müllerian hormone, product of GC)
- ABSOLUTELY requires FSH later
development of preovulatory follicles
beyond recruitment/devpt to pre-antral phases, FSH and (later) LH required to sustain follicle
- distinct theca cells prob require LH secretion, happens at same time as vascularization
to get to more mature phases of development, need a jolt of FSH/LH, aka preovulatory gonadotropin surge
- causes cohorts of young follicles to grow/develop from preovulatory surge through approx mid luteal phase (AMH desensitizes small follicles’ GC from FSH effects)
- stop-and-go pattern of growth/maturation happens from cycle to cycle within a follicular cohort
- continues until dominant follicle is ovulated and other follicles undergo atresia
control of FSH and LH secretion: negative feedback
negative feedback by estradiol17beta
- low serum E2 levels exert negative feedback effect on hypothal/pituitary - suppress FSH and LH
summary: in early follicular phase, FSH and LH decreasing. pattern is maintained by low levels of E2
follicular selection and following events
around tertiary/antral stage, one follicle within recruited cohort is selected to differentiate further (aka dominant follicle)
- not sure how its selected BUT
- its GC express more FSH receptors
- start to make inhibin B: increase during mid-foll phase, fall at mid-cycle: blocks FSH secretion by pituitary further
theory: the increased # FSH receptors in the selected follicle allow it to get by with the low levels of FSH present, whereas the non-selected follicles cant, and therefore undergo atresia
describe the development of the dominant follicle after selection
selection of dominant follicle indirectly causes atresia of other sister follicles in the cohort (via GC cells’ secretion of inhibin B, drop in FSH…)
- dominant follicle grows, antrum becomes filled with follicular fluid, theca cells and GC proliferate
-
theca cells become androgen-producing cells (de novo steroidogenesis)
- turn cholesterol into androstenedione/testosterone
-
GC begin to express high levels of CYP19 (P450 aromatase) and 17betaHSD
- convert androgens into E2
-
theca cells become androgen-producing cells (de novo steroidogenesis)
processes are mediated by FSH and LH, and feedback from intraovarian growth factors/cytokins modulate gonadotropin action
developmental switch in E2 production
in advanced phase of antral follicle growth, seelcted follicle begins to make more E2
- leads to positive feedback effect on production/release of FSH and LH
- rising FSH induces expression of LH-receptors in GC - enables selected follicle to respond to both hormones
-
joint effect of FSH and LH…
- growth and diff of other younger cohorts
- increase in selected follicle steroidogenesis
- initial luteinization of selected follicle (GC cells start making progesterone in addtn to E2)
preovulatory gonadotropin surge [and role of inhibin B]
inhibin b secretion drops just before midcycle, which cuts out its feedback inhibition on activin
activin stimulates GSH secretion, leading to preovulatory surge
how is GnRH pulsatility interrupted?
combo of preovulatory levels of E2, rise in progesterone, rise in inhibin A by GC leads to disruption in GnRH pulsatility
- negative feedback on secretion of FSH (E2 dependent) and LH (progesterone dependent) via ERalpha and progesterone receptors in hypothalamus
- profound drop in gonadotropin secretion on ovulation
two-cell, two-gonadotropin mechanism
theca cells: produce androgens (androstenedione and testosterone)
GC cells: convert androgens from theca cells into E2, required for neuroendo feedback that leads to ovulation
AMH levels, follicular recruitment, and timeline of follicular reserves/devpt
AMH keeps younger cohorts of developing follicles from jumping into devpt too quick - serves as a marker of healthy growing follicles
serum AMH level parallels “level” of ovarian follicular reserve
follicle story:
- increase in recruitement through childhood, peaking at 14-15
- decline
AMH story:
- rises steadily through childhood, fluctuates around puberty, gets secondary increase through about 25, falls off steady after mid20s to undetectable levels around 40-45
ovulation:
hormone changes that precipitate it and their physical effects
dependent on gonadotropin surge; LH is the main player
- once GC begins to express LH receptors, FSH and LH stimulate GC to switch from near-exclusive E2 to production to joint E2 and progesterone production
- progesterone is thermogenic, accompanied by slight rise in temp
- LH stimulates production of prostaglandins and other cascades in GC to increase lysosomal enzyme levels
- collectively, causes intercellular GC connections and basal lamina integrity to drop
- angiogenesis (mediated by prostaglandins, growth factors, cytokines)
*
ovulation:
exit of oocyte
- oocyte is released with surrounding layer of cumulus GC attached
- exits around fimbrae of oviduct and migrates down oviduct towards uterus
- changes in cAMP signaling in GC and oocyte trigger completion of meiosis I (first polar body extruded)
- what’s left (GC + theca cells) is stimulated by LH to become corpus luteum
corpus luteum
- hormones produced & fx
corpus luteum responds to LH to produce progesterone and E2 (both required for implanatation and early stages of preg)
- progesterone
- targets uterus, keeps myometrium from contracting, negative feedback on LH and some on FSH (at chronic elevated levels)
- inhibin A
- negative feedback on gonadotriopin secretion
- E2
- prolif and angiogenic effects in endometrium
effects of no pregnancy
luteolysis
no pregnanacy = LH drops and corpus luteum degenerates (aka luteolysis)
- luteolysis mediated by prostaglandin F2alpha
endometrium basics
barring pregnancy: cycle of proliferation, differentiation, tissue breakdown through healthy adult F life
2 layers: upper functional and deep basal
proliferative phase of endometrial devpt
proliferative phase = regeneration/thickening
endo is stimulated by E2 to express ERalpha, PR, growth factor receptors
goal: prepare endometrium for implantation in case of fertilization
secretory phase of endometrial devpt
secretory phase
-
early: E2 and progesterone target endometrium
- devpt of rich blood supply
-
mid: rising progesterone levels
- PR and ERalpha are downregulated
- P4 cauess changes in gene expression to induce decidualization
-
late: regractory tissue
- waits for implantation to happen.
- if it does, cascade of events to maintain pregnant uterus conds. if not, menstruation.
- waits for implantation to happen.
menstruation
result of steep drop in progesterone and E2 occuring in late luteal phase - leads to upper 2/3 of functional layer to shed
uterus is once again non-pregnant status, endometrium ready to regenerate with the next cycle
infertility
- male/female
- primary vs secondary
- types of factors
inability to conceive after one year of unprotected sex (25% male)
- primary: woman has never conceived
- secondary: woman has conceived before
- 2 types of factors:
- structural: pelvic/cervical anomalies
- functional: devfects in mechanisms leading to ovulation and/or luteal phase
primary amenorrhea
- absence of menses by age 13 without normal growth or secondary sexual devpt
- no menses by age 15 with normal growth and secondary sexual devpt
secondary amenorrhea
having had one or more cycles AND absence of 3 consecutive cycles or none for 6 consecutive months
how do REI clinics attemp to treat infertility?
- shoot for enhanced follicular growth through exogenous manipulation of hormonal regulation of menstrual cycle
- goal: simulatenous devpt of several follicles to retrieve
process
- take control of neuroendo fx via either boosting endogenous GnRH/FSH or blocking endocrine system and admin of exogenous gonadotropin
- boosting endog gonadotropin by blocking negative feedback
- clomiphene (SERM) hits ERalpha in hypothal: releases GnRH from E2 negative feedback
- SPIKE IN GNRH!!! and FSH which leads to enhanced follicular growth
- disrupting GnRH pulsatility via antagonist (clomiphene) or agonist (luprolide)
- drops FSH production/causes pituary downreguation
- can give recombinant FSH
- induce ovulation by giving hCG
describe the events that accompany fertilization
typically, fertilization occurs within the oviduct when a sperm burrows through cumulus GC and binds to zona pellucida of oocyte
sperm is incorporated into ooplasm, causing:
- changes in membrane potential (hyperpol)
- increased intracellular Ca
- cortical granule hardening
collectively prevent additional sperm from binding
fusion of nuclei
- oocyte undergoes meiosis II, extrudes second polar body
- M+F pronuclei fuse to form diploid conceptus and embryonic devpt starts
implantation
embryo burros into endometrium, followed by rapid prolif of trophoblast cells and endometrial cells = formation of placenta
- maternal placenta = endometrial tissue
-
fetal placenta = trophoblast cells aka chorion
- vasculature of chorionic villi, umbilical a/v allow for exchange of gases, nutrients, hormones, wastes by diffusion AND glucose and lactate by facc diff
functions of placenta
- transport
- immune
- endocrine
what steroidogenesis is associated with a pregnancy?
describe the shift in hormone dependency that takes place
placental GnRH drives production of trophoblast/chorionic hCG approx 7-14 days after ovulation
function of hCG
-
hCG binds to LH-receptor and stimulates corpus luteum to secrete high levels of progesterone
- if corpus luteum is lost in first 35 days, spontaneous aportion
- after 46 days though, loss of CL doesn’t make a different
- implication: shift in dependence from luteal to placental progesterone in early first trimester
*shift in E2 and progesterone production (from corpus luteum to placenta) = “maternal recognition of pregnancy”
what is the effect of elevated progesterone in pregnancy?
how are these levels of elevated progesterone maintained?
disruption of GnRH pulge generator leads to STOP in secretion of all pituitary gonadotropins
- no FSH or LH? no folliculogenesis or ovulation
- placental progesterone production has access to abundant LDL supply in general and from mom’s circ
- CYP11 is almost always near saturation-level of cholesterol
- negative feedback effect on FSH and LH is maintained
- meanwhile, estrogen production (estriol) continues using fetal DHEA as substrate
general patter of hormone expression during pregnancy
- starting in early 1st trimester, progesterone, e1/e2/e3 (estrogens), and corticotropin-releasing hormone (CRH) all increase
- hCG is high during first trimester, then falls off
- progesterone, estrogens, CRH all peak in 3rd trimester before parturition
- roles: progesterone maintains quiet uterus, E2/E3 can stimulate myometrial contraction
-
myometrium does not contract in normal circumstances due to balanced E2:E3 ratio!!!
- imbalance in the ratio, either by increased E3 (end of gestation) or decreased E3 (fetal death) causes contraction
describe the hormonal regulation that leads to contractions
when present in approx equal amount, E2 and E3 antagonize activation of ER so that uterine contraction doesnt happen
changes in the E2:E3 ratio leads to changes in gene transcription and expression of contractile proteins, leading to contraction
-
at end of gestation, peak in CRH leads to increase in fetal adrenal DHEAS
- placental 16alpha-hydroxylase adds OH at 16alpha position on DHEAS and processing puts it into a pathway for placental E3 production
- increased E3:E2 = myometrial contraction
-
opposite situation: fetal death leads to drop in E3
- decreased E3:E2 = myometrial contraction
cortisone
relatively inactive (low receptor affinity) metabolite of cortisol
cortisol –11betaHSD2–> cortisone
describe the role of placental CRH in the feed-forward mechanism for upregulating glucocorticoids
why are glucocorticoids important for the fetus?
why might they be detrimental? how is this pro/con managed?
glucocorticoids are critical for fetal organogenesis and maturation
- generally, CRH (hypothal) - ACTH (ant pit) - glucocorticoids/androgens (adrenal cortex)
- in pregnancy, cortisol upregs placental CRH and DHEAS serves as estrogen precursor
cortisol -CRH - ACTH - more cortisol leads to potentially harmful levels of cortisol in mom’s serum
workaround: placenta expresses 11betaHSD2, which converts cortisol into cortisone
fetal health is dependent on O2/nutrient supply from maternal circ
what changes occur in maternal cardio to make this happen?
-
intravascular volume increases up to 50%
- progesterone stimulates erythropoeisis (poorly understood) - 30% jump in RBC volume
-
E2 stimulates RAS which leads to aldosterone secretion
- Na reabs in distal nephron, pulls water with it
- vasoconst of AII not seen due to local vasodilatory factors!!
- AVP is very active - water reabs and lowered osmolality
-
cardiac output increases (40% - stroke volume accounts for 25-30% of it)
- increased
-
physiological anemia: HB content is elevated, but higher increase in plasma leading to dilutional anemia
- O2 delivery maintained bc of increase in CO and vasodil
kidney function with new volume
- GFR increases, both creatinine and BUN drop
- high GFR can saturate SGLT2 in prox tubule, so preg women often show non-pathologic glucosuria (50%)
fetal health is dependent on O2/nutrient supply from maternal circ
what changes occur in maternal pulm to make this happen?
- diaphragm rises, chest diameter increases: drop in FRC and ERV
- minute ventilation rises about 30-50%
- largely due to increase in tidal volume
- partly due to progesterone’s stimulation of medullary resp drive center
- partly due to increased CO2 production (from fetus)
higher minute ventilation leads to…
- lower PaCO2 = better offloading of fetal CO2
- lower PaCO2 = reduced PACO2 = increased PA02 = better gradient for transfer of oxygen from alveolus to blood
- resp alkalosis, accompanied by renal excretion of HCO3 as compensation
- either compensated chronic resp alk or chronic resp alk with comp metabolic acidosis
describe the changes in and role of Hb in maintaining maternal/fetal health in pregnancy
- O2 carrying capacity increased due to more RBC and more Hb
- existing dilutional anemia is compensated for by increased cardiac output
- fetal Hb-O2 curbe is shifted left due to lower levels of 2,3-DPG
- increased affinity for O2 = max extraction of O2 from maternal blood
describe the hormonal changes that precede labor during the third trimester
corpus luteum secretes relaxin, which rises during 3rd trimester (softens pelvic ligaments)
signals accompanying initiation of labor
- change in CRH
- change in progesterone receptor affinity/activity
-
fetal membrane activation: inflammation that knocks out inhibitors of prostaglandin production
- prostaglands are critical in two labor events: cervical ripening/softening and contraction
how?
synergy between estrogens, prostaglandins, oxytocin, CRH peak-cortisol, surfactant in amniotic fluid
myometrial activation
- contraction-associated proteins enhance actin/myosin interaction, increase myocyte excitability, stimulate synchonous contractions
- changing role of estrogens: shift from induction of uterine growth to not
- later one, growing fetus induces tension/stress related contraction
prolactin (PRL) and oxytocin
- PRL: secreted from ant pit lactotrophs
- regulation
- inhibited by dopamine binding to D2 receptors
- stimulated by E2, oxytocin, prolactin-releasting peptide
- fx
- upreg milk production
- regulation
milk production vs milk let-down
- in pregnancy, let down prevented by elevation in maternal estrogens and progesterone
- after preg, maternal estrogen and progesteron fall, allowing suckling-indued mechanism to cause milk let down
- suckling inhibits dopamine release (blocks the blockers), induces secretion of oxytocin (induces milk let down)
- suckling blocks activity in preoptic nucleus: no GnRH (and therefore FSH, LH) and blocks gonadotropins - disrupts normal repro cycling
hyperprolactinemia
- symptoms
- galactorrhea
- repro dysfunction (since affects GnRH pulse generator and gonadal fx)
- women: amenorrhea, oligomenorrhea, menorrhagia, regular menses with infertility
- men: loss of libido, erectile dysfunction, premature ejaculation, imparied spermatogenesis
reproductive aging in women
occurs via follicles leaving reserves through apoptosis (throughout life) or recruitment into follicular cohort (post-pub)
shorter reproductive lifespan than men
- decline in ovarian foll reserve around 25 through menopause
- decline in FERTILITY occurs around 30-35 due to lower numbers of follicles recruited/making it to maturity
- drasticallyreduced oocyte viability as aging continues past 40
perimenopause and menopause
perimenopause: usually starts around mid-late 4th decade. lasts 3-4 years.
- fewer follicles = fewer GC = less inhibin/more FSH and also less E2/test production
- changes in steroidogenesis lead to menstrual irregs due to prolonged follicular phase of cycle
menopause: 12 months of amenorrhea
- prior to 40 = IRREGULAR = primary ovarian insufficiency
- onset of ovarian failure occurs in presence of increased plasma FSH
describe the changes in hormone levels that characterize menopause
from 2 years prior to last menstrual period to 2 years after…
increasing FSH
decreasing E2
why? depleted numbers of follicles!
-
low inhibin B overall secreted by GC in perimenopause (due to lower number of follicles)
- inhibin B suppresses FSH secretion…low inhibin B means higher FSH secretion
- more follicles recruited, leading to quicker exhaustion of the reserve
-
lower AMH overall secreted by GC as woman ages (lower number of follicles)
- AMH prevents FSH from affecting/causing maturation in young follicles…low AMH means FSH can stimulate those follicles too
- more follicles (even those too young/not ready) can be stimulated, leading to quicker exhaustion of reserve
*AMH can be measured, declines to the point of being unmeasurable in menopausal women.
post-menopausal changes
- FSH:LH ratio is higher
- E2 production is significantly reduced
- might see increase in LDL:HDL, atherosclerosis, risks for CVD
- urinary incont
- vasomotor changes: hot flashes, night sweats
hormone therapy
- some benefits, but not sweeping ones
- can alleviate some vasomotor and sleep disorder symptoms
- not shown to reduce CVD or cancers
- can increase bone mineral density/anti-osteoporotic
- NOT TX FOR OSTEOPOROSIS, and no drop in fracture risk
- can alleviate some vasomotor and sleep disorder symptoms
- general rules
- can be useful, but should only be prescribed on individual basis, and not forever
- with uterus: estrogen + progesterone
- without uterus: estrogen
- can be useful, but should only be prescribed on individual basis, and not forever
androgen therapy
- most ovarian testosterone is converted to E2, but not all
- drive sexual desire, arousal, uscle devpt/lean body mass, aggression
- loss of androgen in ovarian failure/menopause might result in loss of libido
- could treat with androgen therapy/administration
reproductive disorders:
disruption of hypothalmic-pituitary axis
GnRH secretion is supposed to occur in a pulsatile manner
sustained elevation of GnRH will downregulate FSH and LH (progesterone and high levels of E2 can exert negative feedback)
-
GnRH secreting tumor could upset the normal pattern and mess with reproductive viability
- REI clinics might aim to shut down a woman’s GnRH production during initial stages of protocols!
- sustained use of exogenous androgens (anabolic-androgenic steroids) can cause infertility the same way
endometriosis
cause and symptoms
how can ectopic endometrial tissue attach/implant/survive?
abnormal extra-uterine deposits of E2-responsive endometrial tissue
- pelvic pain (dysmenorrhea, dyspareunia-painful intercourse) and possibly infertility
may occur via retrograde menstruation which deposits endometrial fragments in extrauterine places (ex. pelvic peritoneum, ovaries, rectovaginal septum)
how do ectopic endometrial cells survive?
changes in gene expression which let them attach/implant/survive in diff environment
- able to avoid destruction by normal immune-mediated response but still attract macrophages = inflammation
- produce growth factors/cytokines which promote neoangioenesis
- increase CYP19 expression and decrease 17betaHSD2 expression (higher E2)
- promote progesteron resistance
net effect: keep cells in follicular stage, keep from transitioning to secretory stage
PCOS: criteria
polycyctic ovary syndrome - most common endocrine disorder in women of repro age
clinically: infertility resulting from oligomenorrhea (<9 cycles/yr) and/or amenorrhea
criteria
- history of irregular menses and anovulation
- measurable hyperandrogenemia (free and total test, hirsutism)
- exclusion of other hormone pathology (CAH, Cushing’s, hyperprolactinemia, adenomas, hyperthecosis)
four combos
- hyperandrogenism + chronic anovulation
- hyperandrogenism + PCO + ovulation
- chronic anovulation + PCO - hyperandrogenism
- chronic anovulation + PCO + hyperandrogenism
***any two (hyperand, chr anov, PCO) or all three
PCOS: causes/symptoms
- follicles are arrested in follicular phase: do not ovulate, but are v steroidogenically active
- usually overweight with abd fat distribution
- can exacerbate glucose intolerance, insulin resistance, hyperandrogenemia
- hyperandrogenemic (high levels of hormones) or show hyperandrogenism (show effects of high levels of hormones)
- high levels of test, DHT, DHEA-S > often high levels of E2!!
- disruptions in…
- insulin sensitivity
- androgen production
- gonadotropiin secretion (high LH)
OVERLAP IN MANY PCOS SYMPTOMS AND METABOLIC SYNDROME
PCOS:
LH-insulin relationship
LH stimulates theca cell androgen production
insulin has a synergistic effect
LH + insulin drive theca androgen production way up
PCOS: treatment
- weight loss/lifestyle changes
- pharma
- oral contraceptives to normalize menstrual cyclicity and reduce endometrial hyperplasia due to unopposed E2
- clomiphene: GnRH agonist
- metformin: insulin sensitizing drug
- anti-androgens: reverse hirsutism
