lecture 6: HPG axis

Question 1

summary of hypothalamo-pituitary gonadal axis?

Answer 1

• start off where the CNS feeds into the hypothalamus
• gives signals which lead to the release of factors
• these factors regulate the pituitary
• regulates, through LH and FSH, the ovary and testis
• hormones from these gonads affect the accessory sex organs
• so on

Question 2

how does the pituitary develop?

Answer 2

• dual embryological origin
  
  • roof of pharynx → anterior pituitary
  • neural outgrowth → posterior pituitary
  • therefore part epithelial in origin and part neural in origin
• “master endocrine gland” regulates reproduction, metabolism, growth, stress response etc etc
  
  • LH, FSH, Oxytocin, Prolactin
  • GH, TSH, ACTH, MSH…

Question 3

What is the structure of the hypothalamus?

Answer 3

• bilateral symmetry
• forms walls, floor of 3rd ventricle
• 3rd ventricle contains cerebrospinal fluid
• lateral, supraoptic, paraventricular, arcuate, ventromedial, suprachiasmatic, medial preoptic and medial anterior hypothalamic nuclei
• brain originates embryologically as a tube of neural tissue
• floor of the tube is the thalamus
• hypothalamus below the thalamus
• complicated structure
• cavity in the middle of the hollow tube stays as the third ventricle – midline
• optic chiasm right at the front of the hypothalamus

Question 4

What are the interactions between the hypothalamus and the pituitary?

Answer 4

hypothalamic nuclei

• tracts of nerves that run from them
• parvocellular neurons (small cell bodies)
  
  • neurons from arcuate nucleus that terminate on a capillary plexus
  • another group in the preoptic area terminating on the capillary bed
• magnocellular neurons (large cell bodies)
  
  • paraventricular nucleus
  • terminals in posterior pituitary
  • cell bodies not in posterior pituitary
• different sorts of functions

portal blood system

• supplied by arteries running into the hypthalamus
• beautiful capillary bed
• when the capillary outflow coalesces into a series of vessels that come down into the pituitary abd make another capillary bed
• carries neurosecretory neurons released by parvocellular neurons straight the anterior pituitary where they can have an action
• the HPA

pituitary gland

• neural and oral ectoderm origin
• ectodermal – anterior pituitary
• neural – posterior pituitary (cell terminals)

numerous interconnections with other brain areas

Question 5

What are some of the key nuclei?

Answer 5

• paraventricular nucleus
• preoptic area
• supraoptic nucleus
• ventromedial nucleus
• arcuate nucleus
• median eminence (bulge on the midline)
  
  • capillary beds come together here in the start of the HPA
• anterior pituitary
• posterior pituitary

Question 6

What is the HPA?

Answer 6

hypothalamo-pituitary axis

Question 7

what is HPG?

Answer 7

hypothalamo-pituitary-gonadal axis

Question 8

What is the hypophysis?

Answer 8

pituitary

(pituitary ablation (removal) = hypophysectomy)

Question 9

What is pars distalis?

Answer 9

anterior pituitary

Question 10

What is the pars nervosa?

Answer 10

posterior pituitary

Question 11

What is the pars intermedia?

Answer 11

intermediate lobe

Question 12

What is the infundibulum?

Answer 12

pituitary stalk

Question 13

What are the anterior pituitary cells?

Answer 13

• Gonadotroph secretes LH and/or FSH
• Lactotroph secretes prolactin

Question 14

What are the magnocellular neurons?

Answer 14

• make oxytocin and vasopressin
• large cell bodies in paraventricular and supraoptic nuclei
• axons run down pituitary stalk
• terminate in posterior pituitary
• release oxytocin (OT) and VP

Question 15

What is oxytocin?

Answer 15

• uterine contractions
• mammary milk ejection
• maternal behaviour
• luteolysis: made in the CL
• neurohormone
• released from posterior pituitary
  *

Question 16

What are the parvocellular neurons?

Answer 16

• make GnRH and other releasing factors
• small cell bodies in several nuclei
• axons terminate at capillary beds in median eminence, where they release factor
• capillaries coalesce to form hypothalamo-pituitary portal vessels that connect to capillary beds in anterior pituitary
• in anterior pituitary GnRH stimulates gonadotrophs to release LH and FSH
• if not in this system it wouldn’t be produced in high enough concentrations to act on the cells in the pituitary, and also would be broken down by proteolytic enzymes in the body before it could act properly

Question 17

What kind of molecule is GnRH?

Answer 17

• decapeptide
• 10 amino acids
• rapidly broken down in the blood

Question 18

How is GnRH secreted?

Answer 18

• In pulses
• pulse generator in hypothalamus sets frequency of pulses
• GnRH in portal blood is pulsatile
• LH secretion is also pulsatile and coincides with GnRH pulses
• pulse frequency varies with species/reprod
  
  • ewe 1 pulse/2 hours
  • Rhesus monkey 1 pulse / hour
• looks like GnRH pulses drive LH pulses
• pulse frequency isn’t constant
• use sheep because much easier to access sheep skull surgically
• pulsatile GnRH → LH and FSH release
• continuous GnRH → basal LH and FSH release
  
  • pituitary GnRH receptors down regulated
  • GnRH regulates its own receptor
  • receptors internalised and can no longer respond
• GnRH pulse generator is a central regulator of reproductive activity
• Experimental model: Rhesus monkey
  
  • ovariectomised
  • hypothalamus lesioned;
  • given GnRH by infusion
  • LH and FSH go down when continuous GnRH, go up when pulsatile

Question 19

What are experimental models for HPA?

Answer 19

• Gonadectomy
  
  • +/– gonadal hormones → effects on LH/FSH and feedback
• Hypophysectomy
  
  • +/– exogenous GnRH → effects on gonads
• Antibodies
  
  • → GnRH, inhibin, steroids
• Pituitary stalk lesion
  
  • +/- GnRh
  • → role of portal vessels
  • → effects on LH/FSH

Question 20

What is the neuroendocrine control of the testis?

Answer 20

• testes putting out testosterone and inhibin
• feedback on the hypothalamus and pituitary
• regulate GnRH pulses
• GnRH pulses control LH pulses
• if we take out the testes:
  
  • no testosterone and inhibin produced by testes
  • GnRH levels increase
  • LH and FSH levels go up
  • reduction of negative feedback

Question 21

Can DHT be converted to oestrogens?

Answer 21

• no
• T but not DHT can be converted to oestrogens
• T to DHT is a one way conversion

Question 22

What was seen in the HPG axis in a ram?

Answer 22

• castrated rams (wethers) + T, CHT, E2 or control
• all treatments: ↓ LH, ↓ FSH, ↓ pulse frequency
• hypothalamo-pituitary (HPD) disconnected wethers with GnRH pulses infused every 2 h
• all treatments: no effect on LH or FSH
• therefore both androgen and oestrogen receptors in the hypothalamus responsible for some of that feedback
• wethers: portal blood samples for GnRH ± testosterone
  
  • effect of T:
    
    • ↓ GnRH conc
    • ↓ GnRH pulse frequency
    • ↓ GnRH pulse amplitude

Question 23

How are LH and FSH secreted in women?

Answer 23

• feedback control
  
  • oestradiol and inhibin
• post menopausal
  
  • release from oestradiol feedback
  • pulse frequency changed
  • LH and FSH levels reversed
  • inhibin effect?
• if oestradiol increased (200% or more)
  
  • +ve feedback occurs leading to LH, FSH surge

Question 24

Can steroids directly affect pituitary?

Answer 24

• rhesus monkey with lesions in MBH that blocked GnRH secretion, given exogenous GnRH pulses
• large dose of oestradiol benzoate
• initial suppression of FSH and LH
• if E2 remains high enough for long enough → LH surge

Question 25

What is the LH secretion pattern in menstrual cycle?

Answer 25

* LH pulsatility varies during the ovulatory cycle * Pre-ovulation LH pulse frequency steady but LH levels rise * early follicular phase: relatively small, frequenct LH pulses * early luteal: progesterone high, oestradiol small, infrequenty but large pulses

Question 26

What does inhibin regulate?

Answer 26

* FSH * rabbit infused with either normal rabbit serum (NRS) or an inhibin antiserum in the late follicular phase * note the large rise in FSH when inhibin is inactivated

Question 27

* response to oestradiol injection is a huge surge in LH but in male only small surge (virtually nothing) * female and male profile in mokeys are almost the same in response to oestradiol challenge * positive feedback system potentially different in male's and females * neonatal androgen exposure prevents response to E2 in adult rat * neonatal androgen does not masculinise hypothalamus in monkeys

Question 28

What is the role of prolactin in reproduction?

Answer 28

* protein hormone * secreted by lactotrophs of anterior pituitary gland * circadian pattern of release * levels go up at night time * promotes lactation * luteotrophin in some species (e.g. rat and mouse → pseudopregnancy after infertile mating) * versatile hormone * in rats prolactin surges with GnRH before ovulation * in human no clear cycle

Question 29

How is prolactin secretion controlled?

Answer 29

* released from the pituitary gland * regulated by factors from the hypothalamus * unlike FSH and LH * the main control is inhibitory * short-loop feedback * negative feedback, increases dopamine turnover and release into portal capillaries to inhibit further prolactin secretion * pituitary disconnection increases Prl * prolactin inhibitory facotr (PIF) * Dopamine * GABA * GnRH-associated peptide (GAP) * prolactin releasing factors * vasoactive intestinal polypeptide (VIP) * thyrotropin releasing hormone (TRH) * oestrogen * Prl short loop feedback * Prl-R on tuberoinfundibular dopamine associated neurons * Prl inhibits its own release * Oestrogen * stimulates Prl synthesis and release by lactotrophs

Question 30

What is the prolactin inhibitory factor?

Answer 30

* dopamine * dopamine and D2 receptor agonists (bromocriptine) inhibit Prl * D2 receptor antagonists (haloperidol, domperidone) increase Prl

Question 31

What happens if you have hyperprolactinaemia?

Answer 31

* in women * amenorrhoea and decreased libido * no pulsatile release of LH * reduced response to GnRH * no +ve feedback * in men * no pulsatile release of LH * decreased testosterone and libido * erectile dysfunction * infertility * treatment * drugs like bromocriptine * surgery (tumours)

Question 32

What are the posterior pituitary hormones?

Answer 32

* oxytocin (OT) and anginine vasopressin (AVP) * related nonapeptides