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Developmental Programming: Exogenous Gonadotropin Treatment Rescues Ovulatory Function But Does Not Completely Normalize Ovarian Function in Sheep Treated Prenatally with Testosterone¹

Departments of Pediatrics,³ Biostatistics,⁴ and the Reproductive Sciences Program⁵, University of Michigan, Ann Arbor, Michigan 48109-0404 Division of Animal and Veterinary Sciences,⁶ West Virginia University, Morgantown, West Virginia 26506-6108

ABSTRACT

Prenatal testosterone treatment leads to LH excess as well as ovarian follicular and ovulatory defects in the adult. These disruptions may stem from LH excess, abnormal FSH input, compromised ovarian sensitivity to gonadotropins, or intrinsic ovarian defects. To determine if exogenous gonadotropins rescue ovarian and ovulatory function of testosterone-treated sheep, the release of endogenous LH and biopotent FSH in control and prenatal testosterone-treated sheep was blocked with a GnRH antagonist during the first two breeding seasons and with LH/FSH coadministered in a manner approximating natural follicular phase. An acidic mix of FSH was administered the first 36 h at 2-h intervals and a less acidic mix for the next 12 h at 1-h intervals (different FSH preparations were used each year), and ovulation was induced with hCG. Circulating FSH and estradiol responses to gonadotropins measured in 2-h samples differed between treatment groups in Year 1 but not in Year 2. Ovarian follicular distribution and number of corpora lutea (in ewes that ovulated) tracked by ultrasonography and luteal progesterone responses were similar between control and prenatal testosterone-treated females but differed between years. Furthermore, hCG administration induced large cystic and luteinized follicles in both groups of females in Year 2, although the growth rate differed between control and prenatal testosterone-treated females. Our findings provide evidence that 1) ovulatory response in prenatal testosterone-treated females can be rescued with exogenous gonadotropins, 2) resultant follicular response is dependent on the nature of gonadotropic input, and 3) an abnormal follicular milieu may underlie differences in developmental trajectory of cystic follicles in prenatal testosterone-treated females.

follicle-stimulating hormone, follicular cysts, follicular development, FSH heterogeneity, gonadotropins, ovarian follicles, ovary, ovulation, ovulatory cycle

¹This study was supported by USPHS grants R01-HD 41098 and P01-HD44232 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