REPRODUCTIVE BIOLOGY

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REPRODUCTIVE BIOLOGY 2008 Neuroendocrine control
of reproduction II Dr. David Hazlerigg
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Neuroendocrine control of reproduction
Males
Essential Reproduction, Johson Everitt,
Blackwell Science
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Neuroendocrine control of reproduction
Females
Follicular phase
Luteal phase
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STRUCTURE OF LECTURES

• Discussion of how this control is turned on and
  off by specific environmental signals
• Puberty
• Nutrition
• Social cues
• Photoperiod
• Puberty
• ? growth spurt development of secondary sex
  characteristics (i.e., pubic hair, breasts,
  gonadal development)
• In neuroendocrine terms reactivation of
  gonadotrophin secretion

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GnRH pulse frequency increase at puberty
PUBERTY
Plant, 2001 Frontiers in Neuroendocrinology 22107
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GnRH priming of Gonadotroph responsiveness
PUBERTY
Plant, 2001 Frontiers in Neuroendocrinology 22107
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PUBERTY

• Central control of puberty
• GnRH neurones present and express GnRH from early
  fetal life through the post natal perod
• Episodes of increased gonadotrophin secretion
  occur during fetal and postnatal development -
  but do not lead to reproductive activation
• System appears to be kept in quiescent state -
  although neuroendocrine architecture is all in
  place
• WHY?

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PUBERTY
What triggers the re-activation of GnRH pulses?
Juvenile hiatus
Plant, 2001 Frontiers in Neuroendocrinology 22107
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Experimental approaches

• Agonadal animals
• Agonadal animals with steroid replacement
  (steroid clamp or hypophysiotropic clamp)

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Gonadostat Hypothesis
-
Hypothalamic pulse generator
GnRH
LH
LH
PD
Gonadal steroids
Pubertal / adult
Juvenile
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Gonadostat Hypothesis
Prepuberty Initiation of puberty Gonadal
hormones Low Unchanged Feedback Operative De
creasing Sensitive in sensitivity Gonado
trophins Low Increasing
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Feedback control in monkeys and rams
Tilbrook and Clarke, 2001 Biol Reprod 64735
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Juvenile hiatus is partly a steroid-independent
property of the GnRH system
Hypothalamic control
Plant, 2001 Frontiers in Neuroendocrinology 22107
Trigger for puberty must be sought in the CNS!
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Defining hypothalamic mechanisms controlling
pubertal activation

• Mutant genotypes showing abnormal reproductive
  phenotype
• Hypothalamic gene expression changes in relation
  to reproductive state
• Central administration of neuropeptides to
  demonstrate causality

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regulators of the GnRH system
RF-amide family of neuropeptides
..ArgPheNH2

• See Kriegsfeld, 2006 Hormones Behaviour 50655

Clam Macrocallista nimbosa
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.ancient signalling molecules with diverse
functions
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Mutant phenotypes
Loss of the orphan G-protein coupled receptor,
Gpr54 blocks reproductive activation in mice
humans
et al
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Gpr54 is the cognate G-protein coupled receptor
for KISSPEPTIN
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Kisspeptin acts in the hypothalamus
Gpr54 (blue) GnRH (brown) double labelling
kisspeptin
?-galactosidase
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Kisspeptin expression in the hypothalamus
The missing link in feedback control of steroids
on GnRH secretion?
Soay sheep
SP
oestrus
OVXestrogen
Intact
OVX
anoestrus
Sense control
1mm
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Kisspeptin infusion drives LH release
Gpr54 mediates response to KISSPEPTIN in mice
KISSPEPTIN stimulates LH pulses in sheep
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Kisspeptin
Popa et al. 2007 Annu. Rev. Physiol 2008 70
14.1-14.26
Kiss1-expressing neurons may relay positive and
negative feedback effects of sex steroids on GnRH
secretion
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Gonadotrophin-inhibiting hormone
RFamide-related peptides RFRP-1,-3
Sagittal mouse brain
Preoptic area (POA) and arcuate nucleus (ARC) are
regions where GnRH expression is found
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Gonadotrophin-inhibiting hormone
GnIH inhibits LH secretion in Syrian hamsters
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Gonadotrophin-inhibiting hormone
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Dual control of GnIH Kisspeptin
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Timing of puberty
From Ebling, 2005
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Reference list
Popa et al (2007) The role of kisspeptins and
GPR54 in the neuroendocrine regulation of
reproduction Annual Review Of Physiology 70
213-238 Ebling (2005) The neuroendocrine timing
of puberty. Reproduction 129 675-83 Kriegsfeld
et al. (2006) Driving reproduction RFamide
peptides behind the wheel. Hormones Behaviour
50 655-66 Messager (2005) Kisspeptin directly
stimulates gonadotropin- releasing
hormone release via G protein-coupled
receptor 54. PNAS 102 1761-66 Plant (2001)
Neurobiological bases underlying the control of
the onset of puberty in the rhesus monkey a
representative higher primate. Frontiers in
Neuroendocrinology 22107-39 Roux et al. (2003)
Hypogonadotropic hypogonadism due to loss
of function of the KiSS1-derived peptide
receptor GPR54. PNAS 100
10072-6 Tilbrook Clarke (2001) Negative
feedback regulation of the secretion and actions
of gonadotropin-releasing hormone in males.
Biology of Reproduction 64 735-42