W2 L2 Thu Hypothalamo-Pituitary-Gonadal Axis Flashcards
Pituitary Gland role and structure
- Pituitary gland: regulates reproduction, metabolism, growth + stress response
§ Hormones: LH/FSH (anterior pituitary), oxytocin (posterior pituitary), prolactin, GH (growth/development), TSH (regulates thyroid gland), ACTH (regulates adrenal gland), MSH - Develops in utero + has dual embryological origin
§ Roof of mouth/pharynx (Rathke’s pouch) forms the anterior pituitary (adenohypophysis)
§ Neural outgrowth forms the posterior pituitary (neurohypophysis) - Pituitary joined to hypothalamus by median eminence (contains portal veins)
- AP cells: gonadotrophs secrete LH +/or FSH, lactotrophs secrete prolactin
Hypothalamus
bilateral structure split by 3rd ventricle containing cerebrospinal fluid
§ Nuclei (11): clusters of neurons with the same function
* Coronal section through optic chiasm: paraventricular nucleus (PVN) on either side of 3rd ventricle, supraoptic, suprachiasmatic nuclei
* Coronal section through infundibulum + median eminence: ventromedial nucleus (VMN), arcuate nucleus
* Median eminence: no blood brain barrier, where neurons of hypothalamus terminate, capillary network that allows neuropeptides to drain from brain + be passed down into anterior/posterior pituitary
-Consist of 2 type of cell, Hormones are passed to posterior pituitary along axons via hypothalamo-hypophyseal tract
2 types of cells in hypothalamic nuclei Pavocellular
Ø Small cell bodies in preoptic area, PVN, ventromedial nucleus, arcuate nucleus
Ø Axons terminate at capillary beds in median eminence where factors are released
* Capillaries coalesce to form hypothalamo-pituitary portal vessels to anterior pituitary
* In anterior pituitary, GnRH stimulates gonadotrophs to release LH + FSH
Ø Produces various neuropeptide hormones incl. gonadotrophin (GnRH)
2 types of cells in hypothalamic nuclei Magnocellular neurons Magnocellular neurons::
Ø Large cell bodies in paraventricular nucleus + supraoptic nuclei
Ø Axons run down pituitary stalk (infundibulum) + terminate in posterior pituitary
Ø Produce oxytocin + vasopressin (related nonapeptides)
* Oxytocin: stimulates luteolysis, uterine contractions (myometrium), milk ejection in lactation, initiates nursing behaviour, stimulates contractions of seminiferous tubules + epididymis
* Vasopressin (AVP): water reabsorption, similar effect to oxytocin in high concentrations
HPG Axis Endocrinology Sequence
§ Hypothalamus releases GnRH to anterior pituitary which produces LH + FSH → systemic circulation to gonads
§ Sertoli cells produce inhibin which inhibits FSH secretion by pituitary gonadotrophs
§ Testosterone produced by gonads provide negative feedback to hypothalamus or pituitary (inhibits GnRH + LH/FSH)
Ø Testosterone injections suppress LH secretion (↓pulse frequency + amplitude of steroid release)
HPG Axis Endocrinology Experimental Models Rhesus Monkey
ovaries removed, hypothalamus lesioned + GnRH infused
Ø Pulsating GnRH: LH + FSH levels are high
Ø Continuous GnRH: LH + FSH levels drop (pituitary GnRH receptors downregulated by itself)
Portal blood system of Pituitary gland
- neural and oral ectoderm origin
- ectodermal anterior pituitary (endocrine cells)
- neural posterior pituitary (nerve terminals)
GnRH secretion is pulsatile
GnRH is a decapeptide
― 10 amino acids
― Rapidly broken down in blood
GnRH secreted in pulses
― § GnRH: secreted in pulses into portal system in median eminence = pulsatile release of FSH/LH
Ø Pulse generator in hypothalamus sets frequency of pulses
Ø Feedback from body regulates amplitude + frequency of pulses
Ø Pituitary is larger than hypothalamic nuclei so produces more LH which takes longer to break down
Ø Pulse frequency varies with species + reproductive state (ewe 1 pulse/2hr; rhesus monkey 1 pulse/hr)
Expiriment: gonadectomy
testes/ovaries removed = LH/FSH no effect = ↑GnRH = ↑LH/FSH
Hypophysectomy
remove pituitary gland = GnRH cannot bind + LH/FSH not produced to stimulate steroid production
Ø Spermatogenesis halted + accessory sex glands (ASG) regress
Ø Administer high dose testosterone = spermatogenesis resumed at ↓level + ASG re-develop
Antibodies experiment
bind hormones to remove its functionality (GnRH, inhibin, steroids)
Ø Anti-GnRH antiserum: binds GnRH = not effective in anterior pituitary + low levels of LH/FSH produced
§ Administrate exogenous FSH = partial spermatogenesis resumed (up to A3-4) + ASG regress
Ø Anti-LH antiserum: bind LH to prevent stimulation of Leydig cells + stops testosterone production
Pituatary stalk lesion exp
prevent GnRH from entering pituitary, investigate role of portal vessels + effects on LH/FSH
Neuroendocrine Control of Testis (Ram)
§ Non-breeding period: testis small, no testosterone produced due to low LH/FSH levels = no sperm produced
§ Onset of breeding: ↑frequent pulses of FSH + LH, some testosterone produced = sperm production + testes grow
§ Breeding period: small pulsatile FSH + LH levels, high testosterone = full sperm production + testes large
§ GnRH from hypothalamus → anterior pituitary release FSH/LH → gonads
Ø Testosterone/oestrogen: negative feedack for GnRH + therefore FSH/LH
Ø Inhibin (sertoli/granulosa cells): negative feedback on FSH
§ Castration: testosterone source removed = no negative feedback on GnRH = ↑FSH/LH levels
Ø Higher frequency + amplitude of pulses as system thinks T levels are too low + need more GnRH
HPG Axis (Ram)
§ Castrated rams (wethers): given T/DHT/E2 = ↓LH, ↓FSH, ↓GnRH pulse frequency
Ø Hormone treatment provides negative feedback to regulate GnRH + therefore LH/FSH
§ Hypothalamo-pituitary disconnected (HPD) wethers with GnRH pulses infused every 2 hours
Ø HPD disconnection = no GnRH reaches pituitary to stimulate LH/FSH release
Ø Adding T/DHT/E2 has little to no effect on LH/FSH levels as negative feedback cannot reach pituitary
§ Wether infused with testosterone results in ↓GnRH concentration, pulse frequency + pulse amplitude
Regulation of Ovarian Function
§ GnRH stimulates LH + FSH; oestrogen negative feedback on LH/FSH
§ Prior to ovulation, high levels of oestrogen build until LH surge
§ LH pulsatility varies duing menstrual cycle:
Ø Early follicular to mid-follicular phase: small LH ↑frequency
Ø Late follicular phase: LH pulse ↑frequency, ↑levels
Ø Ovulation: eventually pulses become so rapid + build up to 1 LH surge
Ø Luteal phase: ↓pulsatility, ↑amplitude (change in signal = produce progesterone)
§ For ovulation, ↑oestradiol + positive feedback occurs leading to LH/FSH surge
§ Post-menopausal: low oestradiol = no feedback + inhibition of LH/FSH release (pulse frequency change + high LH/FSH levels)