Endocrinology, lecture on Reproductive Endocrinology
XIX. Reproductive Endocrinology - Gonadal Axis
A. GnRH (also LHRH or luliberin) and GnIH
1. GnRH is a decapeptide cleaved from a 92 aa preprohormone
made in the arcuate mediobasal nuclei and preoptic nuclei
a. release is stimulated by Glu inputs
b. release is stimulated by NE from the locus ceruleus
c. release is stimulated by kisspeptins
i. inhibited by b-endorphin, also CRH, ACTH, B/F
d. release also stimulated by leptin from adipose cells
i. controls reproduction based on energy storage
e. GnRH cells colocalize galanin
2. receptors on gonadotropic cells of the pituitary
a. 2nd messengers: Gs /AC /cAMP + IP3 /DG /Ca++
b. stimulates the release of both LH and FSH
i. manner of feedback determines
manner of gonadotropin release
1) + vs - : modified by activin, inhibin,
leptin, galanin
ii. pulsatile release necessary for gonadotropin secretion
3. mechanism & function of pulsatile release
a. GnRH cells in ARC have intrinsic oscillatory capacity
i. may be enhanced or paced by extra-ARC transmitters
1) NE, NPY, GABA pulse synchronously
a) NPY and GABA are transmitters
used for timing by the SCN
ii. autocrine +feedback control
1) pacemaker ® V gated Ca++® + GnRH ® + IP3/Ca++
(a) Ca++ ® + NOS ® + NO ® + GnRH
2) ultrashort -feedback inhibits spontaneous
pulsatility during 2nd phase (habituation?)
iii. preovulatory surge stimulated by Glu (NO?) + NE
1) timed/inhibited by b-endorphin
b. pulsatility maintains [GnRH-R]
c. autopriming ® LH/FSH release
4-6X higher on 2nd dosage of GnRH
4. GnIH = GnRIH
a. discovered in fish and birds
B. Gonadotropins - LH and FSH
1. gonadotropes are large round/oval cells uniformly distributed
and comprising 10-15% of the pars distalis
a. LH and FSH may be secreted by different cells
i. secreted differentially by means of feedback
1) even though both respond to GnRH
(a) both also respond to leptin
and galanin
2) inhibin turns off FSH/ activin stimulates FSH
2. LH & FSH secretion are pulsatile
a. no LH (or FSH) surge in males
3. Cyclic secretory patterns are intrinsic
to female reproductive physiology
a. positive feedback necessary for LH surge and ovulation
i. negative feedback for control of secretion
at all other phases of the cycle
4. Function of FSH
a. stimulation of ovarian follicle cells
i. follicular growth precedes ovulation
1) 15 - 20 follicles grow, only 1 ovulates
2) [FSH] in the antral fluid may determine
which ovulates
ii. growth of the follicle precedes steroidogenesis
iii. FSH necessary for converting T to E2
b. FSH also stimulates spermatogenesis
c. FSH stimulates production of SBP
d. up-regulates FSH and LH receptors
i. FSH receptors 2nd messenger = Gs /AC /cAMP
1) ATP activation of cAMP requires Mg++
5. LH Functions
a. steroidogenesis: androgens, estrogens and progestogens
i. LH stimulates steroid release
ii. FSH necessary for conversion from T to E2
b. ovulation
i. LH surge in menstrual or estrous cycle causes
the follicle to burst and the ovum to be expelled
ii. new test predicts ovulation (like hCG pregnancy tests)
c. spermiation - final step in maturation
then release of spermatozoa
d. luteinization
i. changing the primary steroid pathway
from estrogen to progesterone production
1) D5 to D4 pathway
a) converting pregnenolone to P
rather than 17OHpreg and DHEA
ii. corpus luteum is the remainder of the follicle
after ovulation
1) CL secretes more P than E2
e. LH receptors 2nd messenger = Gs /AC /cAMP
i. ATP activation of cAMP requires Mg++
C. Feedback
1. Negative Feedback
a. normal long- short- and ultrashort loops
i. males and females
b. selective control of LH and FSH secretion
i. inhibin - made by the gonads
1) turns off only FSH
a) inhibin receptors mark
FSH gonadotropes
ii. activin - made by the gonads
1) selectively stimulates FSH
2. Positive Feedback
a. females only (similar response in homosexual males)
i. 2nd area of the hypothalamus =
Anterior Hypothalamic-Supraoptic-Suprachiasmatic-Center
= APS or avPV (anteroventral Periventricular nucleus)
ii. regulated by estrogen levels
1) positive count of plasma [E2]
iii. [E2]threshold triggers GnRH release
GnRH release ®+ LH surge ®+ ovulation
b. E2 stimulates avPV Kp54 neurons
i. few Kp54/GPR54 synapses on GnRH neurons
1) GPR54 = Kiss-R ® Ý PLC & ERK
ii. very little needed - 100 fmol
iii. E2 determines Kp54 circadian rhythm
1) Circadian rhythm timed by SCN
a) regulated by AVP and VIP
2) AVP ® Ý Kp54
c. Thresholds Reached (2 coordinated thresholds)
i. at E2 threshold
1) Kp54 and ® ÝGPR54 ® Ý GnRH maximum stimulation
d. at circadian/daytime threshold ® Ý Kp54 stimulation
e. E2 threshold adds Glu to NE stimulation
i. Glu/NMDA ® Ý Kp54
f. timed/inhibited by b-endorphin
i. b-End gene expression
+ release directly inhibited by E2
g. GnRH autocrine feedback in both males and females
i. GnRH first stimulates then inhibits its own release
D. Estrous/Menstrual cyclicity - many different periods
1. Human Menstrual Cycles ~ 28d, rats ~ 4d
a. initiated at menarche (humans) by adequate fat deposition
i. fat contains aromatase, converts T ® E ® +feedback
ii. Ý fatcritical ® Ý leptin ® Ý GnRH, LH, FSH
1) via ob/obb receptors
(ob/oba are tanycyte transport-R)
2) anorexia ® ¯ fat ® loss of cyclicity:
leptin restores it
2. Follicle
a. LH stimulates outer thecal layer to produce androstenedione
b. diffuses into inner granulosa, converted to T
i. FSH stimulates T ® E2
c. LH stimulates ovulation and luteinization
3. Corpus Luteum
a. Ý P \ E/P < 1
i. Ý negative feedback ® ¯ GnRH ® ¯ FSH ®
no follicular growth
b. Luteolysis
i. ¯ P and ¯ E ® loss of support for endometrium
ii. Prostaglandin F2a (from corpus luteum)
1) causes endometrial sloughing by constricting blood
vessels, restricts blood flow
iii. Oxytocin (OT; from corpus luteum)
1) causes production of PGF2a
iv. ¯ LH ® regression
1) but LH does not extend luteal life
E. Pregnancy
1. Chorionic Gonadotropin (hCG)
a. produced by cells of the chorion or trophoblast
b. hCG prolongs the life of the corpus luteum
and the production of P
c. hCG stimulates placental production of E and P
2. Progesterone
a. Placenta takes over following luteolysis
b. necessary for endometrial support and secretion
c. exerts negative feedback on LH and FSH
3. Feto-Placental Unit - Estrogens
a. P (placenta) ® DHEA (fetal adrenal) ® DHEAS (liver) ® E3 (placenta)
4. Chorionic Somatomammotropin = Placental Lactogen
a. hCS = hPL like prolactin (PRL) help prime the mammary glands
for later milk secretion
i. with estrogens and progesterone
b. and has effects similar to GH
5. Relaxin secreted (corpus luteum and then placenta)
a. Loosens connective tissue
b. inhibits spontaneous uterine contractions
6. Change in hormone levels during pregnancy
F. Labor and Parturition
1. Maturation of fetal adrenal/adrenal axis
® cortisol helps convert P to E in the placenta
a. adrenal maturation in fetus
i. Ý adrenal cortisol (sheep) or androgens (humans)
1) F ® Ý P450C17b and 17-20 lyase: P ® E2
2) adrenal androstenedione ® T ® E2
b. E/P ratio becomes > 1
i. P inhibition of uterine contractions now limited
c. oxytocin receptors (OT-R) to rise in the uterus ® labor begins
i. at night
d. increased neural feedback from the cervix and uterus
i. stimulates increased production of OT & PGF2a
1) OT stimulates uterine PGF2a production
2) nocturnal OT increases over final 30 days
(humans)
ii. begins the neuroendocrine reflex
2. OT & PGF2a stimulate uterine contractions
a. progressive neuroendocrine reflex
i. positive feedback loop
1) stronger and stronger contractions
