Neuroendocrinology

Developmental Programming: Impact of Prenatal Testosterone Excess on Pre- and Postnatal Gonadotropin Regulation in Sheep

Abstract
The goal of this study was to explore mechanisms that mediate hypersecretion of LH and progressive loss of cyclicity in female sheep exposed during fetal life to excess testosterone (T). Our working hypothesis was that prenatal T excess, by its androgenic action, amplifies GnRH-induced LH (but not FSH) secretion and thus hypersecretion of LH in adulthood and that this results from altered developmental gene expression of GnRH and estradiol (E₂) receptors, gonadotropin subunits, and paracrine factors that differentially regulate LH and FSH synthesis. We observed that, relative to controls, females exposed during fetal life to excess T, and the non-aromatizable androgen dihydrotestosterone (DHT), exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. LH hypersecretion was more evident in adults than prepubertal females and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal T excess induced developmental changes in gene expression of pituitary GnRH and E₂ receptors, and paracrine modulators of LH and FSH synthesis in a manner consistent with subsequent amplification of LH release. Together these series of studies suggest that prenatal T excess, by its androgenic action, amplifies GnRH-induced LH response leading to LH hypersecretion and acyclicity in adulthood and that this programming involves developmental changes in expression of pituitary genes involved in LH and FSH release.

Key words: Neuroendocrinology • Pituitary • Activin • Developmental biology • Gonadotropin-releasing hormone receptor

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