Neonatal testosterone suppresses a neuroendocrine pulse generator required for reproduction

Abstract

The pituitary gland releases hormones in a pulsatile fashion guaranteeing signalling efficiency. The determinants of pulsatility are poorly circumscribed. Here we show in magnocellular hypothalamo-neurohypophyseal oxytocin (OT) neurons that the bursting activity underlying the neurohormonal pulses necessary for parturition and the milk-ejection reflex is entirely driven by a female-specific central pattern generator (CPG). Surprisingly, this CPG is active in both male and female neonates, but is inactivated in males after the first week of life. CPG activity can be restored in males by orchidectomy or silenced in females by exogenous testosterone. This steroid effect is aromatase and caspase dependent, and is mediated via oestrogen receptor-a. This indicates the apoptosis of the CPG network during hypothalamic sexual differentiation, explaining why OT neurons do not burst in adult males. This supports the view that stereotypic neuroendocrine pulsatility is governed by CPGs, some of which are subjected to gender-specific perinatal programming.

Puberty in Mice and Rats

“…412 The axons of ARH neurons, which are suspected of playing a role in mediating estrogen and testosterone negative feedback 410,[413][414][415] and in the control of pulsatile GnRH secretion, 405,414 first reach the MEPO at P12 and only achieve their final distribution by the end of the infantile period in both males and females, 416,417 when circulating FSH levels dramatically rise 140,276,280,282 (Figures 30.2 and 30.3) and estrogen-negative feedback starts to operate in females. 416 Intriguingly, analogous to the critical period during neonatal life when sex steroids may specify sexually dimorphic patterns of development in the mammalian forebrain, 382,418,419 it has been shown over the past decade that the establishment of at least some of the projections of ARH neurons (e.g., the projections of the POMC and NPY/ AgRP neurons) is also determined by metabolic hormones (e.g., leptin, ghrelin, and insulin) during a second critical period of postnatal development. 417 Efferents from other nuclei of the tuberal region of the hypothalamus that are functionally connected with GnRH neurons, 98,100 such as the VMH and DMH, also develop postnatally but are seen to reach the preoptic region earlier than ARH fibers.…”

Frank Beach Award Winner: Steroids as neuromodulators of brain circuits and behavior

“…This suppression occurs even in spinally transected newts (Lewis and Rose, 2003), consistent with an interaction with a CPG (the exact neural locus is currently undefined). Second, a CPG that governs oxytocin release from the hypothalamus is responsive to long-term steroid actions, and these actions appear to drive sex differences in the bursting membrane properties of oxytocinergic neurons (Israel et al, 2014). Circulating androgens can also exert long-term actions on the electric organ that controls social signals in electric fishes, although the involvement of a CPG is not yet clear (Few and Zakon, 2001; Liu et al, 2008).…”

Insights into the Development of the Adult Leydig Cell Lineage from Stem Leydig Cells

“…This CPG is active in both male and female neonates, but is inactivated in males after the first week of life by the neonatal testosterone pulse. This suggests that the neonatal LCs are important for gender-specific perinatal programming (Israel et al, 2014). …”