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Developmental Programming: Excess Weight Gain Amplifies the Effects of Prenatal Testosterone Excess On Reproductive Cyclicity—Implication for Polycystic Ovary Syndrome

Departments of Pediatrics (T.L.S., C.H., V.P.), Obstetrics and Gynecology (V.P.), and Molecular and Integrative Physiology (V.P.) and the Reproductive Sciences Program (V.P.), University of Michigan, Ann Arbor, Michigan 48109; Reproductive Medicine and Infertility Associates (D.A.D.), Woodbury, Minnesota 55125; and National Primate Research Center, University of Wisconsin, Madison, Wisconsin 53715

Address all correspondence and requests for reprints to: Vasantha Padmanabhan, Department of Pediatrics and Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1109 SW, Ann Arbor, Michigan 48109-0404. E-mail vasantha{at}umich.edu.

Sheep exposed to testosterone (T) during early to midgestation exhibit reproductive defects that include hypergonadotropism, functional hyperandrogenism, polycystic ovaries, and anovulatory infertility, perturbations similar to those observed in women with polycystic ovary syndrome. Obesity increases the severity of the phenotype in women with polycystic ovary syndrome. To determine whether prepubertal weight gain would exaggerate the reproductive disruptions in prenatal T-treated sheep, pregnant sheep were injected with 100 mg T propionate (1.2 mg/kg) im twice weekly, from d 30–90 of gestation. Beginning about 14 wk after birth, a subset of control and prenatal T-treated females were overfed to increase body weight to 25% above that of controls. Twice-weekly progesterone measurements found no differences in timing of puberty, but overfed prenatal T-treated females stopped cycling earlier. Detailed characterization of periovulatory hormonal dynamics after estrous synchronization with prostaglandin F₂ found 100% of controls, 71% of overfed controls, 43% of prenatal T-treated, and 14% of overfed prenatal T-treated females had definable LH surges. Only one of seven overfed prenatal T-treated female vs. 100% of control, 100% of overfed control, and seven of eight prenatal T-treated females exhibited a luteal progesterone increase. Assessment of LH pulse characteristics during the anestrous season found both overfeeding and prenatal T excess increased LH pulse frequency without an interaction between these two variables. These findings agree with the increased prevalence of anovulation observed in obese women with polycystic ovary syndrome and indicate that excess postnatal weight gain amplifies reproductive disruptions caused by prenatal T excess.

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