GnRH is a 10 amino acid peptide hormone secreted by the hypothalamus
cleaved from a 69 amino acid prohormone prior to release
amino acids 2-3 act in receptor binding and activation; amino acids 6-7 and 9-10 are sites of degradation
long-acting agonists and antagonists have D-amino acids at various positions
agonists
– D-amino acid at position 6 slows degradation; at positions 6, 10 enhance potency
antagonists
– D-amino acid at positions 1-3 bind receptor without activation (produces competitive inhibition)
Anatomy
Arcuate nucleus
– in mediobasal hypothalamus; contains cell bodies of GnRH-producing neurons
Tuberoinfundibular tract
– contains axons transporting hypothalamic hormones to the median eminance
Median eminence
– area where hypothalamic hormones are released into the pituitary portal circulation
Anterior pituitary
– contains gonadotroph cells that secrete FSH and LH in response to GnRH
Secretion of GnRH
– required for FSH synthesis and secretion; secretion is pulsatile and permissive
pulsitile
:
men: pulses every 2-4 hours
women: varies with menstrual cycle (2 per hour - 1 every 4 hours)
permissive
: necessary for the system to run, but not a necessary part of normal feedback and FSH/LH responses
Control of Secretion of GnRH
catecholamines
– norepinephrine stimulates GnRH secretion in rats; role in humans in unknown
dopamine
– both positive and negative stimulation
positive
– stimulates the pulse generator in the hypothalamus (dopamine antagonists
Þ ß pulse frequency)
negative
– LH levels during the late proliferative phase can be decreased with dopamine agonists
opioid peptides
(b -endorphins, dynorphin Þ morphone-like peptides) – provide tonic inhibition of GnRH secretion
help to mediate negative feedback of estradiol at the hypothalamus
estrogen inhibits opioids, alleviating inhibition of GnRH secretion – experiment that demonstrates this:
opioid antagonist (naloxone) administered to post-menopausal women
Þ no change in FSH/LH
estrogen treatment to lower FSH/LH, then naloxone
Þ Ý FSH/LH
Þ
conclusion: estrogen-induced opioid inhibition was present
gonadal steroids
:
testosterone
– slows pulses; reflected in the chronic slower LH pulses in men
progesterone
– slows pulses; most obvious during luteal phase (negative feedback on FSH/LH)
estradiol
– reduces GnRH impulse in gonadectomized individuals (positive and negative effects – see below)
Effects of GnRH
(1) upregulates its own receptor
on gonadotrophs (more receptors Þ Ý FSH/LH response)
Ca++-stimulated, protein synthesis dependant mechanism
(2)
Ý FSH/LH synthesis and storage – GnRH helps maximize rate of synthesis via internalization of receptor-hormone complex and PKC Þ upregulates transcription of FSH/LH precursors
(3)
Ý FSH/LH release – pulsatile Ca++-mediated vesicle release in response to GnRH
NOTE:
These effects of GnRH require pulsatile secretion at appropriate levels; excess, continuous (non-pulsitile) secretion, or an agonist will result in downregulation
initially loss of receptors on cell surface; eventually persistent desensitization (functional loss of ion channels?)
target of therapy for estrogen-dependant diseases
Other Factors that Affect Gonadotrophs
Estradiol
– major site of action is pituitary
low levels
–Ý a -chain, b -FSH, b -LH chain mRNA in gonadotrophsÞ Ý FSH/LH synthesis; ß FSH release; little effect on LH
high levels
– enhances ability of GnRH to upregulate GnRH receptors, increasing bioavailability of released GnRH
concentrations >200pg/ml for greater than 48 hrs cause LH surge (which causes FSH surge)
Progesterone
small increase
at mid-cycle amplifies positive feedback of estradiol Þ amplifies LH surge and FSH surge