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

• Published in: Endocrinology (Philadelphia) 2004-02, Vol.145 (2), p.790-798
• Main Authors: Manikkam, Mohan, Crespi, Erica J, Doop, Douglas D, Herkimer, Carol, Lee, James S, Yu, Sunkyung, Brown, Morton B, Foster, Douglas L, Padmanabhan, Vasantha
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Anogenital; Biological and medical sciences; Biometry; Birth Weight; Embryonic and Fetal Development - drug effects; Female; Females; Fetal Growth Retardation - chemically induced; Fetuses; Fundamental and applied biological sciences. Psychology; Gestational Age; Growth; Growth rate; Insulin-Like Growth Factor Binding Protein 1 - blood; Insulin-Like Growth Factor Binding Protein 2 - blood; Insulin-like growth factor I; Insulin-Like Growth Factor I - analysis; Litter Size; Male; Males; Maternal-Fetal Exchange; Metabolism; Neonates; Offspring; Oils & fats; Postpartum period; Pregnancy; Pregnancy Outcome; Prenatal experience; Proteins; Sex Characteristics; Sex Ratio; Sheep; Steroid hormones; Testosterone; Testosterone - administration & dosage; Vertebrates: endocrinology; Weight Gain; Weight gain measurement
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0478

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.