Reproductive Physiology Flashcards
Leydig cells
sex hormone producing cells in the testes
- receptors for LH
- produce testosterone
GnRH effect
stimulate gonadotrophs in ant. pituitary to release FSH, LH
- GnRH located in arcuate and medial prepoptic areas of neurons
- limbic system and behavior influence on production
LH in males
target Leydig cells
-stimulate testes to release testosterone
FSH in males
target Sertoli cells
-stimulate testes to produce sperm
aromatase
enzyme in sertoli granulosa cells for the converting testosterone to estrogen
GnRH pulsatility
- short half life –> rapid degradation once released
- pulsatile secretion needed for synthesis and secretion
- long half life –> suppression of LH, FSH
- G protein –> activate IP3 and DAG
How are the GnRH receptors regulated by downstream steroid hormones (estrogen, progesterone, test)?
- regulation of the upstream (afferent) neurons that feed the GnRH neurons (indirect)
- afferent neurons = kisspeptin
regulation of GnRH by upstream neurons
- kisspeptin = activated by AVPV, inhibited by arcuate
- AVPV - GnRH release
- arcuate - GnRH inhibitor - B-endorphin = act on opiate receptors; inhibit GnRH
- neurokinin = stimulate release of GnRH
function of Kisspeptin neuron types
depends on estrogen levels
- low dose estrogen –> arcuate –> inhibit GnRH
- high dose estrogen –> AVPV –> stimulate GnRH
which androgens regulate GnRH pulsatility?
testosterone directly
- also dihydrotestosterone (DHT)
- testosterone prevents progesterones inhibitory effect of GnRH –> overproduction of GnRH and androgens
role of prolactin in males
- suppress GnRH and LH
- need moderate amount - too high/low –> infertility
effect of stress on GnRH secretion
CRH, ADH, ACTH, NE, Epi –> inhibits GnRH release
-inhibiting CRH –> increase GnRH
role of naloxone
block GnRH, LH suppression by CRH –> increase GnRH
-CRH acts like beta endorphins
3 hormones that contain common alpha chain
-LH, FSH, TSH
how do you increase the half life of FSH, LH?
glycosylation (adding sugar)
- increase glycosylation –> slower degradation of FSH, LH
- FSH longer half life than LH
how do you treat prostate cancer or prevent precocious puberty?
give GnRH analog
- continuous (sustained) stimulation of GnRH receptor releasing GnRH at high levels –> shut down FSH, LH
- lost pulsatility effect for gonadotropin synthesis
GnRH frequency effect on FSH, LH production
high frequency of GnRH secretion –> increase LH, not FSH
low frequency of GnRH secretion –> increase FSH, not LH
regulation of GnRH in males
- testosterone = inhibits GnRH and LH, FSH receptors on secreting cells
- activin = activates FSH secretion
- inibin (sertoli) = inhibit FSH secretion
- follistatin (sertoli) = inactivates activin
role of melatonin on GnRH secretion
released at night and suppresses GnRH
-supplements can help prevent precocious puberty
Gonadotropin (FSH, LH) signaling
LHR, FSHR (GPCRs)
- activate cAMP, PKA, gene transcription
- activate Ca++ influx and Ca++ dependent kinases
- activate PLC, IP3, DAG
- activate PKC and COX2 –> increase prostaglandins (suppression through NSAIDs)
- regulate own receptors by endocytosis of receptors
role of cholesterol in steroidogenesis
- either made by Leydig fat cells or bind to cholesterol receptors
- brought into mitochondria by STARD1
- cleaved to pregnenolone by CYP11A1
- adrenal insufficiency w/ STARD1 or CYP11A1 mutations
CYP11A1 (side chain cleavage)
-converts cholesterol to pregnenolone
CYP19A1 (aromatase)
-converts androgens to estrogens
estrogen forms
- estradiol (E2) = most active
- estrone (E1) = most prominent post-menopause
5alpha-reductase enzyme
converts testosterone to dihydrotestosterone
-inhibition for prostate cancer patients to reduce dihydrotestosterone levels
Type I 17betaHSD
convert estrone to estradiol (active)
- weak to strong estrogen
- inactive to active
Type 2 17betaHSD
convert active androgens and estrogens to inactive
-strong to weak
Type 3 17betaHSD
convert weak androgens to strong androgens
-no conversion of estrogens
how can testosterone mediate its effects?
either indirectly or through conversion to estrogen or dihydrotestosterone
-ex. need epiphysis closure in bones through estrogen
how does testosterone lead to male development?
acts on Sertoli cells –> secrete AMH –> regress mullerian ducts and stimulate wolffian ducts
what 2 hormones are needed for proper spermatogenesis?
testosterone (stimulated by LH) and FSH
- both act on Sertoli cells
- estrogen also necessary for sperm maturation
what are the effects of elevated testosterone in blood?
suppress GnRH and FSH through negative feedback –> suppress spermatogenesis (infertility)
hypergonadotropic hypogonadism
high LH, FSH but low gonadal functions
-mutation in LHR or FSHR
hypogonadotropic hypogonadism
no gonadotropins (LH, FSH)
- Sheehan’s and Kallmann’s
- reduced steroids, spermatogenesis or both
- caused by lesion in HPG axis
Sheehan’s disease
involution and necrosis of anterior pituitary
-no FSH, LH –> small gonads
Kallmann’s disease
failure of GnRH neurons to migrate to hypothalamus
- no GnRH, LH, or FSH
- no problem with development before birth (hCG dependent)
- problem with puberty (LH, FSH dependent)
testicular feminization
body does not respond to testosterone - no androgen receptor
- become female
- XY female
Sertoli cell functions
- nourish sperm during spermatogenesis
- convert testosterone to estrogen for sperm maturation
- form immune privileged site to protect spermatogenic cells
Del Castillo syndrome
born with Sertoli cells only
-no spermatogenic cells
heat regulation of testes
- optimal temp for spermatogenesis
- kept away from body (pelvis and abdomen too hot)
- pampiniform plexus
- cremasteric muscle in scrotum
pampiniform plexus
counter current heat exchanger
-blood in pampiniform veins cools the blood in the testicular artery
function of acrosome
contains proteolytic enzymes used to penetrate the ovum for fertilization
-provided help from prostasomes in prostate
functions of Sertoli cells
- seminiferous fluid = flush out sperm from epididymis
- secrete ABP = [] testosterone in testes
- release inhibin, follastatin, activin
- convert testosterone to estradiol by aromatase
- contain FSH receptors
- blood testis barrier
- nourishment to sperm cells
- secrete AMH = regress mullerian ducts
- spermeation = plasminogen cut binding of spermatogonia and Sertoli cells to flush out sperm
when can antisperm antibodies attack sperm
when the female has antibodies against the sperm
sexual intercourse
PNS - erection - vasodilation by NO
SNS - ejaculation - spinal reflex (paraplegic can still get erection)
infertility vs. impotence
- infertility = no sperm being made
- impotence = inability to have erection (PRL, damage to PNS, diabetes)
how do you treat erectile dysfunction?
give phosphodiesterase (PDE5) inhibitors to prolong the half life of cGMP
epididymis and ductus deferens
- store and concentrate sperm
- increase mobility and fertility before ejaculation
seminal vesicles
- provide semen
- fructose for energy
- prostaglandins for motility and cervix softening
- secrete fibrinogen
prostate gland
- secrete alkaline fluid to neutralize vagina
- clotting and unclotting factors to hold sperm then allow it to swim freely
- PSA good biomarker for cancer
- prostasomes help in ovum penetration
capacitation of sperm
make sperm motile in female
-estrogen and progesterone play a role
role of estrogen in female
- ova maturation and release
- secondary female sex characteristics
- transport of sperm to oviduct for fertilization
- breast development
role progesterone in female
- preparing environment to nourish embryo/fetus
- helps breast produce milk
What does GnRH –> FSH, LH stimulation release from target organ in female?
estrogen & progesterone
-both have negative feedback on ant. pituitary and hypothalamus
oogonia before ovulation in females?
-begin 1st part of meiotic division at the end of fetal life forming primary oocyte –> remain in meiotic arrest until ovulation
folliculogenesis
development of follicles
- strongest one survives, all others die
- combination of oocyte, granulosa cells, theca cells
when is the 1st meiotic division completed?
during ovulation - need LH surge
when does the 2nd meiotic division occur?
during fertilization by sperm
primordial follicle
primary oocyte surrounded by flat (pregranulosa) cells
-conversion to primary follicles do not require hormones
primary follicle
primary oocyte surrounded by cuboidal (granulosa) cells
-granulosa cells become cuboidal & form zona pellucida
role of PRL on ovarian cycle
suppresses GnRH inhibiting menstrual cycle
follicular phase in ovarian cycle
follicle grows/matures
luteal phase in ovarian cycle
corpus luteum (formed from rupture of follicle)
what is the clear zone b/w granulosa cells and oocyte?
zona pellucida which envelopes the egg
- hardens as egg is fertilized to prevent polyspermy
- prevents immune attack against sperm
secondary follicular stage
- proliferation of granulosa cells
- gonadotropin dependent - FSH for follicle maturation
- stromal (interstitial) cells form theca –> interna/externa
role of theca interna cells
secrete androgen
-converted to estrogen by granulosa cells
role of granulosa cells
respond to FSH to make more estrogen
-aromatase enzyme to convert androgen to estrogen
role of testosterone and androstenedione in theca cells
move to granulosa cells and converted to estrogen by aromatase
- testosterone –> Estradiol (E2)
- androstenedione –> Estrone (E1)
what hormone do theca cells respond to?
LH
what hormone do granulosa cells respond to?
FSH initially
- both FSH and LH later on
- no FSH –> no folliculogenesis
- FSH also increases aromatase
what can too many theca cells lead to?
excess androgens –> granulosa cells cannot convert to estrogens –> androgens enter blood shutting down the negative feedback from estrogen and progesterone –> more LH release –> more androgen production
-HIRSUITISM
what does excess testosterone for a prolonged time in females lead to?
converted to DHT by 5alpha-reductase
- DHT shuts down aromatase leading to excess androgens in blood
- seen in polycystic ovaries
tertiary follicular stage
- theca cells expand
- fluid filled sacs (antrum) to house hormones
- form Graafian follicle
- higher amount of fluid –> selected to be ovulated bc it has more nutrition and hormones
what happens with decreased blood supply to ovarian follicle?
atresia (degeneration of follicle)
-not enough gonadotropins
estrogen level effects
high level –> GnRH release through AVPV
low level –> inhibit GnRH release through arcuate
effects of LH surge
caused by high estrogen levels
- stimulates kisspeptin
- increase collagenase (breaks cells apart)
- causes oocyte to finish meiosis I
- increase muscle contraction, progesterone, luteinization
- increase prostaglandin and histamine to increase vascularization and blood supply
which follicles are selected for ovulation?
-one with the best blood supply and gonadotropin receptors (accumulate more FSH, LH)
-higher aromatase
-
what does high dihydrotestosterone (DHT) indicate?
- high testosterone and deficiency in aromatase
- death signal for follicles causing atresia
what allows the follicle to undergo ovulation?
-collagenase breaks down collagen and plasminogen breaks down fibrin –> disperse theca and granulosa cells through rupture making it easier for ovulation
function of LH surge
maturation of dominant follicle to resume meiosis and activate proteolytic enzymes and prostaglandins
-causes ovulation
luteal phase
- last 14 days of cycle
- old follicular cells form corpus luteum which (maintains pregnancy)
- no fertilization or implantation of ovum –> luteum degenerates forming corpora albicans
corpus luteum
- needed to maintain pregnancy
- secrete progesterone for decidualization of endometrium and maintenance; also secrete estrogen
- no fertilization –> shut down LH, FSH through negative feedback on GnRH –> shut down corpus luteum
function of hCG
keeps corpus luteum alive during pregnancy by binding to same receptors as LH –> keep producing testosterone and progesterone
what leads to the LH, FSH surge?
excessive levels of estradiol –> stimulate kisspeptin to increase GnRH levels through AVPV –> increase LH, FSH levels
why are FSH levels slightly elevated at the beginning of the menstrual cycle?
to increase aromatase for conversion of testosterone to estrogen
Why is there a drop in estrogen levels after the LH, FSH surge?
internalization of LH, FSH receptors –> less binding
when is the 1st day of the uterine cycle?
during 1st day of menstruation (menstrual phase)
- bleeding caused by collapse of endometrium in absence of progesterone and estrogen –> due to degradation of corpus luteum
- FSH elevated due to no negative feedback
proliferative phase of uterine cycle (1st half)
endometrium back to normal due to estrogen –> proliferation of endometrial cells
secretory phase of uterine cycle (2nd half)
uterus development under effect of high levels of progesterone
function of fibrinolysin during menstrual cycle
prevent blood clotting during bleeding
-heavy cycle (bleeding) –> not enough fibrinolysin to prevent clotting –> have blood clots
role of prostaglandins during menstrual phase?
needed for contraction of uterus to prevent heavy bleeding
- do not give NSAIDs to someone in menstrual phase
- also helps expel blood and endometrial debris from uterus
proliferative phase
- estrogen increases proliferation of endometrial lining and increases receptors for progesterone
- LH surge by kisspeptin stimulation –> ovulation
secretory phase
- occurs after ovulation
- corpus luteum secretes estrone and progesterone
- decrease uterine contractions
- endometrium secretes glycogen
- no fertilization –> ischemic phase –> degenerate corpus luteum
effects of progesterone during secretory phase
- help endometrium secrete glycogen for nutrition
- make endometrium softer
- antagonizes estrogen –> prevent uterine contractions that expel things by relaxing smooth muscle
what happens to progesterone and estrogen levels when reaching full term?
progesterone declines and estrogen increases –> allows for smooth muscle contraction to expel baby
estrogen and progesterone effect on oviduct
- estrogen increases motility of oviduct
- progesterone relaxes smooth muscle allowing implantation of zygote
why is there an increased risk of osteoporosis for post-menopausal women?
estrogen helps prevent osteoclast activity
-more bone breakdown without estrogen
estrogen and progesterone effect on aldosterone
- estrogen –> aldosterone mimic –> Na++ and water retention
- progesterone –> aldosterone antagonist
estrogen and progesterone role on cervical mucous plug
- estrogen = thins mucous plug allowing sperm to enter easier
- progesterone = thickens mucous plug preventing sperm and microbes from entering (protective effect)
- progesterone contraception to prevent fertilization
how does oral contraception prevent ovulation?
contains modified estrogen (long lasting) –> inhibits GnRH, LH, FSH –> no folliculogenesis or pregnancy
-suppresses LH surge
how does the morning after pill prevent pregnancy?
progesterone antagonist –> cannot maintain pregnancy leading to miscarriages
menopause effects
triggered by hypothalamic changes or ovarian failure
- higher risk of cardiovascular disease & osteoporosis
- hot flashes due to absence of estrogen –> cannot regulate hypothalamus
- high gonadotropins (FSH mainly)
why are females less susceptible to cardiovascular disease?
estrogen and progesterone have a protective effect
-increased risk in menopause
E1, E2, E3 dependent on age
- E2 most active during reproductive age
- E1 most active in post-menopausal women
- E3 most active during pregnancy
what is estrogen mostly bound to?
higher affinity for SHBG, lower affinity for albumin
-more albumin so more estrogen bound by albumin
what does progesterone bind to?
corticosteroid-binding protein
-metabolized to pregnanediol which can be used as a marker for ovulation
causes of female infertility
- PCOS
- caused by high androgens and insulin resistance
- testosterone blocks negative feedback –> stimulate GnRH –> high TSH, LH
- treat with androgen antagonists or contraceptives - hypogonadotropism
- hyperprolactinemia
where is the site of fertilization?
ampulla of the oviduct
-ovulated egg only lasts 24 hr before it degrades
how does female reproductive tract help in sperm migration?
- contract uterus to propel sperm toward oviduct
- progesterone relaxes ovarian ducts for zygote to pass
capacitation
activates sperm making it more motile
-occurs by Ca++ influx
role of protasomes
help sperm penetrate zona pellucida for fertilization
-added to acrosome during ejaculation
process of fertilization
- acrosomal reaction = sperm binds zona pellucida releasing acrosomal contents
- sperm pulled into ovum
- completes 2nd meiotic division - sperm and egg fuse –> zygote
zona reaction
Ca++ causes cortical granules be exocytosed changing the structure of the membrane –> prevents polyspermy
how does blastocyst implant into endometrial lining?
enzymes released from trophoblasts digesting endometrium –> carves holes for implantation and embryo used endometrium for nutrition
significance of embryo being enclosed by zona pellucida
physical and immunological protection from mother
Decidualization
uses progesterone to make endometrium softer for implantation
role of chorionic villi
secrete hCG during development
-placenta provides hCG for the corpus luteum the 1st few weeks of development
why does fetal blood have higher affinity for O2?
high Hb concentration and contains fetal Hb
How do you get the conversion to estriol, the most abundant estrogen during pregnancy?
- placenta produces estrogen and progesterone
- progesterone reaches fetus through umbilical cord
- fetus makes DHEA and cortisol
- DHEA goes back to placenta to convert to estriol (E3) by aromatase to maintain pregnancy
role of fetal cortisol
- lung maturation
- decreases progesterone and increases estrogen for smooth muscle contraction to expel baby
what type of estrogen is most common during pregnancy?
estriol (E3) coming from fetal DHEA
-maintains pregnancy
how does high levels of progesterone lead to respiratory alkalosis?
increase respiratory centers –> blow off CO2 –> release more bicarb in urine to compensate
hCG
- maintains corpus luteum during the 1st few weeks bc aren’t producing estrogen and progesterone by placenta yet
- inhibits uterine contractions (like progesterone)
- increases thyroid hormones (like TSH)
- declines at 10-12 weeks bc placenta is making own estrogen and progesterone
human chorionic somatomammotropin (human placental lactogen)
- hybrid b/w GH and PRL
- acts like GH on metabolism –> increase mother sugar level
estriol (E3)
- weakest estrogen
- formed from DHEA from fetus
- breast & duct growth, proliferate uterine muscles, increase oxytocin receptors and gap junctions
- contract uterus if no progesterone present
- aldosterone mimic –> HTN
placental progesterone
- maintains pregnancy
- prevents contraction of uterus
- inhibits milk secretion
- converted into fetal DHEA and cortisol due to lack of 3betaHSD
the role of fetal cortisol
- at the end of pregnancy, suppresses progesterone and increases estrogen synthesis for uterine contractions
- formed by placental progesterone
- development of fetal lungs
- assist milk secretion after birth
role of fetal oxytocin
myometrium contraptions during labor and contraction to eject milk during lactation
what happens to thyroid hormone levels during pregnancy
hCG acts like TSH and increases total thyroid hormones (T3,T4, Tg)
fetal DHEA
formed from placental progesterone
-used by placenta to make estriol
why can’t maternal cortisol enter placenta the 1st 6 months?
11betaHSD2 converts it to cortisone (inactive form)
ACTH
acts on fetal adrenal gland for development
-stimulate fetal cortisol and DHEA release
CRH
increased before birth due to fetal stress signals
-fetus head pushing against cervix –> increase CRH and ACTH
fetal insulin
increased in response to high maternal glucose
-oversized fetus in uncontrolled diabetic mothers
Parturition (labor, birth)
- dilation of cervix –> increase oxytocin for uterine contractions
- increase estrogen levels –> increase oxytocin receptors and gap junctions
- fetal stress signals
fetal stress signals during parturition
fetal stress signals –> increase CRH, ACTH –> increase cortisol release –> labor, increase milk secretion
oxytocin during parturition & lactation
- uterine contractions in labor (+ feedback)
- expel placenta
- stop bleeding
- milk ejection (contract myoepithelial cells)
stages of labor
- cervical dilation
- delivery of baby
- delivery of placenta
uterus shrinks to pregestational size
lactation
- high estrogen, progesterone –> develop breast ducts, alveoli
- milk synthesis by PRL - inhibited by progesterone until birth
- milk ejection by oxytocin
- expel placenta –> steroid withdraw –> lactation
- sucking –> increase oxytocin and PRL
