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Developmental Programming: Deficits in Reproductive Hormone Dynamics and Ovulatory Outcomes in Prenatal, Testosterone-Treated Sheep¹

Departments of Pediatrics³ and Biostatistics,⁴ and the Reproductive Sciences Program,⁵ University of Michigan, Ann Arbor, Michigan 48109 Monash Institute of Medical Research,⁶ Monash University, Clayton, Victoria 3168, Australia School of Biological Sciences,⁷ The University of Reading, Reading RG6 6AJ, United Kingdom

ABSTRACT

Prenatal testosterone excess leads to neuroendocrine, ovarian, and metabolic disruptions, culminating in reproductive phenotypes mimicking that of women with polycystic ovary syndrome (PCOS). The objective of this study was to determine the consequences of prenatal testosterone treatment on periovulatory hormonal dynamics and ovulatory outcomes. To generate prenatal testosterone-treated females, pregnant sheep were injected intramuscularly (days 30–90 of gestation, term = 147 days) with 100 mg of testosterone-propionate in cottonseed oil semi-weekly. Female offspring born to untreated control females and prenatal testosterone-treated females were then studied during their first two breeding seasons. Sheep were given two injections of prostaglandin F_2alpha 11 days apart, and blood samples were collected at 2-h intervals for 120 h, 10-min intervals for 8 h during the luteal phase (first breeding season only), and daily for an additional 15 days to characterize changes in reproductive hormonal dynamics. During the first breeding season, prenatal testosterone-treated females manifested disruptions in the timing and magnitude of primary gonadotropin surges, luteal defects, and reduced responsiveness to progesterone negative feedback. Disruptions in the periovulatory sequence of events during the second breeding season included: 1) delayed but increased preovulatory estradiol rise, 2) delayed and severely reduced primary gonadotropin surge in prenatal testosterone-treated females having an LH surge, 3) tendency for an amplified secondary FSH surge and a shift in the relative balance of FSH regulatory proteins, and 4) luteal responses that ranged from normal to anovulatory. These outcomes are likely to be of relevance to developmental origin of infertility disorders and suggest that differences in fetal exposure or fetal susceptibility to testosterone may account for the variability in reproductive phenotypes.

fetal programming, infertility, ovulation

¹Supported by US Public Health Service grant P01 HD44232 (to V.P.), R01 HD 41098 (to V.P.), and the National Health and Medical Research Council of Australia GrantNet ID 334011 (to D.J.P.).

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

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