BIOL30001 Reproductive Physiology 2024 PDF

Hypothalamus BIOL30001 Reproductive Physiology Pituitary Hypothalamo-pituitary- gonadal (HPG) axis Gonad Mark Green Reproductive organs  Reading and Resources Johnson (2013) Essential Repr...

Hypothalamus BIOL30001 Reproductive Physiology Pituitary Hypothalamo-pituitary- gonadal (HPG) axis Gonad Mark Green Reproductive organs  Reading and Resources Johnson (2013) Essential Reproduction (7TH Ed), Chapter 1,7,9, especially pp 12-19, 158-170, 124-127 Johnson and Everitt: Essential Reproduction (6thEd), Chapter 6 (& 4, 5) Austin and Short: Reproduction in Mammals, Book 3 (2nd Ed) Chapter 1 Most good endocrinology texts and physiology texts will have chapters on hypothalamo-pituitary-gonadal regulation. Wikipedia: – Hypothalamic Pituitary Axis http://en.wikipedia.org/wiki/Hypothalamic%E2%80%93pituitary%E2%80%93gonadal _axis – GnRH physiology https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone http://www.endotext.org/section/neuroendo/ How is the menstrual cycle regulated so precisely? Why do some men have breasts?  Outline Hypothalamus-pituitary axis – Anatomy and development – LH, FSH, Oxytocin, Prolactin Hypothalamic releasing factors – GnRH The GnRH pulse generator and gonadotrophin secretion Feedback effects at hypothalamus and pituitary – Steroids – testosterone, oestrogen, progesterone – Inhibin Prolactin and Dopamine  The Pituitary gland - Development “Master endocrine gland” regulates reproduction, metabolism, growth, stress response etc. – LH, FSH, Oxytocin, Prolactin – GH, TSH, ACTH, MSH …. Dual embryological origin – roof of the mouth, the pharynx (Rathke’s Posterior pituitary pouch) → anterior pituitary (adenohypophysis) – neural outgrowth → posterior pituitary (neurohypophysis) Anterior pituitary figure from Turner & Bagnara (1971)  Structure of the hypothalamus (b) (a) (c) Bilateral symmetry Forms walls, floor of 3rd ventricle 3rd ventricle contains cerebrospinal fluid supraoptic, paraventricular (PVN), arcuate, ventromedial (VMN), suprachiasmatic, medial preoptic & EssRep7 Figs 1.9, 1.11 medial anterior hypothalamic nuclei  Hypothalamic nuclei and pituitary anterior commissure 3rd ventricle (down midline) paraventricular nucleus preoptic area dorsomedial nucleus ventromedial nucleus suprachiasmatic nucleus mamillary body supraoptic nucleus arcuate nucleus optic chiasm median eminence anterior pituitary posterior pituitary sphenoid bone intermediate lobe The hypothalamus and pituitary interactions numerous Goes to posterior PG, interconnections with doesnt stop at Hypothalamic nuclei immenance. other brain areas parvocellular neurons (small cell bodies) magnocellular neurones (large cell bodies) Portal blood system Pituitary gland neural and oral ectoderm origin ectodermal → anterior pituitary (endocrine cells) neural → posterior pituitary (nerve terminals) EssRep7 Fig 1.10 Hypothalamo-pituitary axis  HPA: Nomenclature HPA: hypothalamo-pituitary axis HPG: hypothalamo-pituitary-gonadal axis Pituitary = hypophysis (pituitary ablation (removal) = hypophysectomy) Anterior pituitary = pars distalis Posterior pituitary = pars nervosa Intermediate lobe = pars intermedia Pituitary stalk = infundibulum Anterior Pituitary cells Gonadotroph → secretes LH and/or FSH Lactotroph → secretes prolactin  Hypothalamic nuclei and pituitary 3rd ventricle (down midline) para- ventricular nucleus Magnocellular neurons make oxytocin and vasopressin supraoptic nucleus large cell bodies in paraventricular and supraoptic nuclei axons run down pituitary stalk anterior terminate in posterior pituitary pituitary release oxytocin (OT) & VP sphenoid bone posterior pituitary  Posterior pituitary hormones Oxytocin (OT) & arginine vasopressin (AVP) related nonapeptides Oxytocin Cys-Tyr-Ile - Gln-Asp-Cys-Pro-Leu-Gly AVP Cys-Tyr-Phe-Gln-Asp-Cys-Pro-Arg-Gly Oxytocin stimulates luteolysis EssRep7 Fig 1.12 stimulates uterine contractions during labour acts on smooth muscle (myometrium) of uterus milk ejection during lactation initiates nursing behaviour in mothers stimulates contractions of seminiferous tubules and epididymis  Hypothalamic nuclei and pituitary para- Parvocellular neurons ventricular 3rd ventricle nucleus (down midline) make gonadotrophin (GnRH) preoptic and other releasing factors area small cell bodies in several ventromedial nucleus nuclei arcuate axons terminate at capillary beds nucleus in median eminence, where they median release factor eminence capillaries coalesce to form hypothalamo-pituitary portal anterior vessels that connect to capillary pituitary beds in anterior pituitary in anterior pituitary GnRH sphenoid stimulates gonadotrophs to bone release LH and FSH hypothalamo-pituitary posterior pituitary portal vessels  GnRH secretion is pulsatile GnRH is a decapeptide ― 10 amino acids GnRH ― Rapidly broken down in blood LH GnRH secreted in pulses ― pulse generator in Portal hypothalamus sets frequency of pulses ― GnRH in portal blood is pulsatile LH secretion is pulsatile ― GnRH and LH pulses coincide Pulse frequency varies with species / reproductive state ― ewe 1 pulse / 2 hr ― Rhesus monkey 1 pulse / hr (Johnson & Everitt Fig 6.6 after Clarke and Cummins 1982)  GnRH pulses needed for LH release Experimental model: Rhesus Monkey ovariectomised, Pulsatile GnRH → LH & FSH hypothalamus lesioned; release give GnRH by infusion Continuous GnRH → basal LH & FSH release – pituitary GnRH receptors down regulated – GnRH regulates its own receptor Too much of a good thing. GnRH pulse generator is a central regulator of reproductive activity  Experimental Models Gonadectomy (ovariectomy, castration) +/- gonadal hormones → effects on LH/FSH (& feedback) Hypophysectomy (lesions, ablate the nuclei) +/- exogenous GnRH → effects on gonads Antibodies (act as blockers) → GnRH, inhibin, steroids Pituitary stalk lesion (prevent the GnRH from getting to the pituitary) +/- GnRH pulses → role of portal vessels → effects on LH/FSH Regulation of testis function - ram Onset of Non-breeding breeding Breeding  Neuroendocrine control of the testis Testosterone = negative feedback GnRH GnRH testosterone LH FSH testosterone LH FSH Intact castrate – about 10ng/ml, pulses every hour to 14 ng/ml Castrated intact about 1 ng/ml- pulses every 2 h to 4 ng/ml Testosterone but not DHT can be converted to oestrogens OH OH Androgens→AR O O H Testosterone Dihydrotestosterone (DHT) Aromatase OH Oestrogens→ER HO Oestradiol  HPG axis in ram GnRH Castrated rams (wethers) + T, DHT, E2 compared to control All hormone treatments:  LH,  FSH T, DHT, E2 or oil LH FSH  GnRH pulse frequency GnRH infusion Hypothalamo-pituitary (HPD) disconnected wethers with GnRH pulses infused every 2 h LH FSH All hormone treatments: have little or no effect on LH T, DHT, E2 or oil or FSH; negative feedback occurs on hypothalamus GnRH Castrated wethers ± testosterone treatment - portal blood samples for GnRH Effect of T:  GnRH concentrations T or oil LH FSH  GnRH pulse frequency  GnRH pulse amplitude based on Tilbrook AJ, et al. (1991) Endocrinology 129:3080-92  Regulation of ovarian function - rat Stimulates LH GnRH and FSH Needed for ovulation – release LH of ovum Increases follicle FSH growth & oestrogen oestrogen Increases LH How is the menstrual cycle (ovulation) regulated so precisely? High levels of oestrogen LH surge  LH secretion pattern in menstrual cycle LH pulsatility varies during the menstrual cycle- increases during follicular phase (day 4 vs day 8) Pre-ovulation LH pulse frequency steady but LH levels rise (day 8 vs day 13) Luteal phase decreased pulsatility, increased amplitude OV = ovulation E2 = oestrogen P = progesterone Johnson & Everitt Fig 6.14  LH & FSH secretion in women – changes in cycle Early follicular Post-menopausal For ovulation oestradiol is increased (200% or more) positive feedback occurs leading to LH, FSH surge Feedback control Oestradiol and inhibin Post menopausal release from oestradiol feedback pulse frequency changes LH & FSH levels higher Purification for ovarian stimulation Johnson & Everitt Fig 6.8  Steroids can directly affect pituitary Rhesus monkey with lesions in the MBH that blocked GnRH secretion, given exogenous GnRH pulses large dose of oestradiol benzoate (EB) initial suppression of FSH and LH if E2 remains high enough for long enough → LH surge via action on Pituitary in monkeys! Johnson & Everitt Fig 6.9 MBH = medial basal hypothalamus Based on Nakai et al (1978) Endocrinology 102:52 Regulation of steroid production - pituitary GnRH – hypothalamus LH & FSH - anterior pituitary FSH - ovary (growing follicle secretes increasing amounts of oestrogen, E2) Oestrogen rise triggers LH surge (positive feedback) by increasing response to GnRH Oestrogen induces and maintains GnRH receptors in pituitary GnRH pulses also change expression of GnRH receptors (can downregulate itself) AFTER ovulation, oestrogen has a negative feedback effect on FSH/LH  Sexual dimorphism in the HPG Axis Neonatal androgen exposure prevents Neonatal androgen exposure does response to E2 in adult not masculinise hypothalamus Johnson & Everitt Fig 6.20 Johnson & Everitt Fig 6.21 Oestradiol (OB) challenge in Oestradiol challenge in a male monkey male & female rats  In rats prolactin surges with Prolactin in reproduction GnRH before ovulation Protein hormone (PRL) In human no clear cycle Secreted by lactotrophs of anterior pituitary gland Circadian pattern of release Promotes lactation Luteotrophin in some species (e.g. rat and mouse → pseudopregnancy after infertile mating) Very high PRL decreases oestrogen and testosterone Johnson & Everitt Fig 6.24,25  Control of Prolactin secretion Pituitary disconnection increases prolactin, so ‘suppression’ from hypothalamus Prolactin inhibitory factors (PIF) Dopamine (DA) GABA GnRH-associated peptide (GAP) Prolactin releasing factors vasoactive intestinal polypeptide (VIP) thyrotrophin releasing hormone (TRH) oestrogen Oestrogen Prolactin short loop feedback +ve prolactin receptors on tuberoinfundibular dopamine associated neurons (TIDA) prolactin inhibits its own release Short-loop feedback Oestrogen (-ve feedback) stimulates prolactin synthesis and release by lactotrophs EssRep7 Fig 1.12  Dopamine is the prolactin inhibitory factor (PIF) Dopamine and D2 receptor agonists (e.g. bromocriptine) inhibit prolactin D2 receptor antagonists (haloperidol, domperidone) increase prolactin Johnson & Everitt Fig 6.22  Hyperprolactinaemia – elevated serum prolactin Reduced dopamine levels or excess production from a pituitary gland adenoma tumour- in men and women In women amenorrhoea and decreased libido no pulsatile release of LH reduced response to GnRH no positive feedback In men no pulsatile release LH decreased testosterone and libido erectile dysfunction Hyperprolactinaemic man infertility Treatment drugs like bromocriptine to block prolactin surgery (tumours)  Summary Parvocellular neurons synthesise GnRH & release it into the hypothalamo-pituitary portal blood vessels Hypothalamic GnRH secretion pulsatile so LH, FSH secretion pulsatile GnRH pulse generator in the anterior hypothalamus In females Ovarian oestrogen, progesterone control GnRH, LH & FSH via –ve feedback Oestrogen acts on pituitary & hypothalamus to induce LH surge via +ve feedback In males Testosterone controls GnRH, LH & FSH via –ve feedback on pituitary & hypothalamus Testosterone acts via AR or is aromatised to oestrogen in pituitary & hypothalamus, binds ER LH surge mechanism present in male primates, absent most species Prolactin controlled by dopamine → lactation; luteotroph in some species; hyperprolactinaemia causes infertility Oxytocin from posterior pituitary → milk let-down; uterine contractions; maternal behaviour