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Fetal Programming: Prenatal Testosterone Excess Leads to Fetal Growth Retardation and Postnatal Catch-Up Growth in Sheep

Departments of Pediatrics (M.M., C.H., J.S.L., V.P.), Biostatistics (M.B.B., S.Y.), Obstetrics and Gynecology (D.L.F.), Ecology and Evolutionary Biology (D.L.F.), and Physiology (D.D.) and Reproductive Sciences Program (M.M., E.C., D.L.F., C.H., J.S.L., D.D., V.P.), University of Michigan, Ann Arbor, Michigan 48109

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

Alterations in the maternal endocrine, nutritional, and metabolic environment disrupt the developmental trajectory of the fetus, leading to adult diseases. Female offspring of rats, subhuman primates, and sheep treated prenatally with testosterone (T) develop reproductive/metabolic defects during adult life similar to those that occur after intrauterine growth retardation. In the present study we determined whether prenatal T treatment produces growth-retarded offspring. Cottonseed oil or T propionate (100 mg, im) was administered twice weekly to pregnant sheep between 30–90 d gestation (term = 147 d; cottonseed oil, n = 16; prenatal T, n = 32). Newborn weight and body dimensions were measured the day after birth, and postnatal weight gain was monitored for 4 months in all females and in a subset of males. Consistent with its action, prenatal T treatment produced females and males with greater anogenital distances relative to controls. Prenatal T treatment reduced body weights and heights of newborns from both sexes and chest circumference of females. Prenatally T-treated females, but not males, exhibited catch-up growth during 2–4 months of postnatal life. Plasma IGF-binding protein-1 and IGF-binding protein-2, but not IGF-I, levels of prenatally T-treated females were elevated in the first month of life, a period when the prenatally T-treated females were not exhibiting catch-up growth. This is suggestive of reduced IGF availability and potential contribution to growth retardation. These findings support the concept that fetal growth retardation and postnatal catch-up growth, early markers of future adult diseases, can also be programmed by prenatal exposure to excess sex steroids.

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