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This Article Full Text Full Text (PDF) All Versions of this Article: 78/4/648    most recent biolreprod.107.063347v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Manikkam, M. Articles by Padmanabhan, V. PubMed PubMed Citation Articles by Manikkam, M. Articles by Padmanabhan, V. Agricola Articles by Manikkam, M. Articles by Padmanabhan, V.

Developmental Programming: Impact of Prenatal Testosterone Excess on Pre- and Postnatal Gonadotropin Regulation in Sheep¹

Departments of Pediatrics,⁴ Psychiatry,⁵ and Molecular and Integrative Physiology,⁶ the Reproductive Sciences Program,⁷ and the Center for Statistical Consultation and Research,⁸ University of Michigan, Ann Arbor, Michigan 48109

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. Our working hypothesis was that prenatal testosterone 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 testosterone, as well as the nor-aromatizable androgen dihydrotestosterone, exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. Luteinizing hormone hypersecretion was more evident in adults than in prepubertal females, and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal testosterone 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, this series of studies suggests that prenatal testosterone 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.

activin, developmental biology, estradiol receptor, follistatin, FSH, gonadotropin-releasing hormone receptor, inhibin, LH, neuroendocrinology, pituitary, pituitary responsiveness

³Current address: Department of Psychiatry, University of Cincinnati, Cincinnati, OH 45267.

¹Supported by USPHS Grants P01-HD44232 and R01 HD41098 to V.P.

Correspondence: ²Vasantha Padmanabhan, Department of Pediatrics and Reproductive Sciences Program, University of Michigan, 300 N. Ingalls Bldg., Rm. 1109 SW, Ann Arbor, MI 48109-0404. FAX: 734 936 8620; e-mail: vasantha{at}umich.edu

This article has been cited by other articles:

				A. Veiga-Lopez, W. Ye, D.J. Phillips, C. Herkimer, P.G. Knight, and V. Padmanabhan Developmental Programming: Deficits in Reproductive Hormone Dynamics and Ovulatory Outcomes in Prenatal, Testosterone-Treated Sheep Biol Reprod, April 1, 2008; 78(4): 636 - 647. [Abstract] [Full Text] [PDF]