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This Article Full Text Full Text (PDF) All Versions of this Article: 79/1/154    most recent biolreprod.108.067702v1 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 Google Scholar Articles by Abbott, D. H Articles by Tarantal, A. F PubMed PubMed Citation Articles by Abbott, D. H Articles by Tarantal, A. F Agricola Articles by Abbott, D. H Articles by Tarantal, A. F

Endocrine Antecedents of Polycystic Ovary Syndrome in Fetal and Infant Prenatally Androgenized Female Rhesus Monkeys¹

Departments of Neurobiology and Physiology,⁷ Northwestern University, Evanston, Illinois 60208 Departments of Pediatrics, Obstetrics and Gynecology, Molecular and Integrative Physiology, and Reproductive Sciences Program,⁸ University of Michigan, Ann Arbor, Michigan 48109 Reproductive Medicine and Infertility Associates,⁹ Woodbury, Minnesota 55125 Department of Biology,⁶ University of Alaska-Southeast, Sitka, Alaska 99835 Departments of Pediatrics and Cell Biology and Human Anatomy and the California National Primate Research Center,¹⁰ University of California, Davis, California 95616 Wisconsin National Primate Research Center,³ Department of Obstetrics and Gynecology,⁴ and Endocrinology-Reproductive Physiology Program,⁵ University of Wisconsin, Madison, Wisconsin 53715

ABSTRACT

Experimentally induced fetal androgen excess induces polycystic ovary syndrome-like traits in adult female rhesus monkeys (Macaca mulatta). Developmental changes leading to this endocrinopathy are not known. We therefore studied 15 time-mated, gravid female rhesus monkeys with known female fetuses. Nine dams received daily s.c. injections of 15 mg of testosterone propionate (TP), and six received injections of oil vehicle (control) from 40 through 80 days of gestation (term, 165 days; range, ±10 days). All fetuses were delivered by cesarean section using established methods at term. Ultrasound-guided fetal blood sample collection and peripheral venous sample collection of dams and subsequent infants enabled determination of circulating levels of steroid hormones, LH and FSH. The TP injections elevated serum testosterone and androstenedione levels in the dams and prenatally androgenized (PA) fetuses. After cessation of TP injections, testosterone levels returned to values within the reference range for animals in these age groups, whereas serum androstenedione levels in PA infants were elevated. The TP injections did not increase estrogen levels in the dams or the PA fetuses or infants, yet conjugated estrogen levels were elevated in the TP-injected dams. Serum levels of LH and FSH were elevated in late-gestation PA fetuses, and LH levels were elevated in PA infants. These studies suggest that experimentally induced fetal androgen excess increases gonadotropin secretion in PA female fetuses and infants and elevates endogenous androgen levels in PA infants. Thus, in this nonhuman primate model, differential programming of the fetal hypothalamo-pituitary unit with concomitant hyperandrogenism provides evidence to suggest developmental origins of LH and androgen excess in adulthood.

androgen excess, early development, environment, fetal programming, LH hypersecretion, LH negative feedback, luteinizing hormone, testosterone

¹Supported by National Institutes of Health grants P50 HD044405, U01 HD044650, P51 RR000167 (Wisconsin National Primate Research Center [WNPRC] base operating grant), and RR00169 (California National Primate Research Center base operating grant) and partly conducted at a facility (WNPRC) constructed with support from Research Facilities Improvement Program grants RR15459-01 and RR020141-01.

Correspondence: ²David H. Abbott, Department of Obstetrics and Gynecology and Wisconsin National Primate Research Center, University of Wisconsin, 1223 Capitol Court, Madison, WI 53715. FAX: 608 263 3524; e-mail: abbott{at}primate.wisc.edu