Biology of Reproduction Summers |
Endocrinology Homeostasis/Feedback Adult Female Steroid Production Ovulation |
 |
Adult Male Gonadal Axis Regulation Sexual Differentiation Sexual Behavior Puberty |
Reproductive Cycling Estrous Cycles Menstrual Cycle Menopause Fertilization |
Fertilization Systems Gamete Interaction Pregnancy Labor and Parturition Lactation |
Sexual Response & Behavior Pheromones STDs text: Human Reproductive Biology4th Edition- RE Jones & KH Lopez,: pp 10-21 Acronyms/Abbreviations end |
XI. Gonadal Axis regulation
A. GnRH release is pulsatile
1. pulses are not driven by a single molecule
a. complex hypothalamic pulse generator
2. GnRH neurons are controlled by
a. trans-synaptic and glial inputs
i. glial transmitters - Glu
b. major excitatory - Glu + NE + Kisspeptins
c. inihitory - GABA + End/Enk + Kisspeptin neurons
B. Kisspeptin 1 gene
1. RF-amide superfamily
a. kisspeptins, GnIH (Gonadotropin Inhibiting Hormone),
26/43RFa, RF-releasing peptides (RFRP)
2. Metabolic peptides
a. NPY (Neuropeptide Y), Nesfatin 1
3. Tachykinins
a. NKB (Neurokinin B)
5. Kisspeptins all derive from the KISS1/Kiss1 gene
a. inhibit metastasis (originally called metastin)
b. Kisspeptin 54 - binds GPR54 receptor (= Kiss-R)
i. GPR54 has partial similarity to galanin receptors
1) 7 transmembrane a-helical proteins
2) Gp/q/11 ® PLC ® PIP2 ® IP3 ®Ca++
a) PLC ® PIP2 ® DAG® PKC
b) PKC ® RAS® RAF1 ® ERK1/2/p38
i) b-arrestin2 ® ERK1/2/p38
3) desensitization on continuous ligand exposure
a) rapid internalization
via clathrin after Kiss54 binding
c. Two distinct sets of KISS1/Kiss1 neurons
C. Kp54 ® GPR54 ® Ý GnRH
1. GPR54 on GnRH cells
a. Kp54 ® Ý GnRH neuron depolarization
2. Kiss1/Kp54 neurons in avPV promote postive feedback (1 type)
a. Puberty ® Ý Kiss1 neurons
i. Seasonal Reproduction ® Ý Kiss1 neurons
b. avPV Kp54 neurons are activated prior to ovulation
3. Kp54/Dyn/NKB neurons in ARC promote negative feedack (2nd type)
a. Kp54/Dyn/NKB neurons promote GnRH pulse generation
D. GnRH (pulsatile) ® LH (pulsatile) ® T - - - ® E2
1. GnRH stimulates the release of both LH and FSH
a. pulsatile GnRH release necessary
for gonadotropin secretion
2. pulsatility maintains [GnRH-R]
3. autopriming: LH/FSH release 4-6x higher
on 2nd dose (pulse) of GnRH
E. mechanism of pulsatile GnRH release
1. GnRH neurons have intrinsic oscillatory capacity
a. enhanced and paced by extra-ARC transmitters
i. Kp54 ® Ý GnRH
1) Glu ® Ý NMDA ® Ý Kp54 burst firing
ii. NE, NPY, GABA pulse synchronously with GnRH
1) NPY + GABA are transmitters used
for timing by SCN
2) Kp54/Dyn/NKB ® Ý GnRH pulse generation
a) Glu/NMDA ® Ý burst firing?
2. GnRH 2nd messengers are Gs ® AC ® cAMP or
IP3 ® Ca++ ® calmodulin
3. autocrine +feedback control
a. pacemaker/pulse generator ® Ý Kp54? ®
® V gated Ca++ ®+ exocytosis ®+ GnRH
b. GnRH ®+ GnRH-R (autoreceptors) ®+ IP3/Ca++
i. Ca++ ®+ NOS ®+ NO ®+ (more) GnRH
c. ultrashort negfeedback inhibits spontaneous pulsatility
during 2nd phase (habituation of autoreceptor action?)
F. T or E2/P feed back to regulate GnRH and LH levels
1. carried by binding proteins (SBP) in the blood (for Long-Loop fb)
2. manner of feedback determines manner of release
a. + vs -
modified by activin, inhibin, leptin, galanin, b-endorphin
G. Endocrine Positive Feedback
1. in females E2 is monitored by anterior hypothalamus (APS/avPV)
2. E2 stimulates avPV Kp54 neurons
a. few Kp54 synapses on GnRH neurons
i. very little needed - 100 fmol
b. E2 determines Kp54 circadian rhythm
3. Circadian rhythm timed by SCN
a. regulated by AVP and VIP
b. AVP ® Ý Kp54
4. Thresholds Reached (2 coordinated thresholds)
a. at E2 threshold
i. Kp54 and ® Ý GnRH maximum stimulation
b. at circadian/daytime threshold ® Ý Kp54 stimulation
5. E2 threshold adds Glu to NE stimulation
a. Glu/NMDA ® Ý Kp54
b. Glu stimulates VIP in SCN too
6. at E2 & daytime thresholds ® Ý GnRH surge stimulated
H. Inhibin/Activin
1. small polypeptides
2. made in Sertoli and Granulosa cells
a. also found in Antral fluid
3. feeds back to regulate FSH levels
a. selectively inhibits (inhibin)
or stimulates (activin) FSH
I. Leptin
1. produced by adipose (fat) cells
2. stimulates GnRH, but only indirectly
3. Leptin ® Ý Kp54
a. by binding to obRb-R
i. on ARC Kp54 neurons
J. galanin (Gal)
1. colocalized in GnRH neurons,
and stimulates GnRH release (with NPY)
2. released with GnRH,
also stimulates LH (but not FSH)
K. Androgen Target Cells
1. Secondary Sex Characteristics
(facial hair, rooster comb, phallus development)
5a-reductase
a. T --------® 5a-DHT
i. intracellular conversion at target tissue
b. DHT binds to cytoplasmic/nuclear receptors (A-R)
2. muscle has no 5a-reductase
a. although A-R have a higher affinity for 5a-DHT,
T may bind when concentrations are high enough
3. Brain (and other adipose tissue)
aromatase
a. T -------® E2
i. bind to E-R