Sexual Differentiation of Steroid Metabolizing Enzymes in the Rat Liver. Further Studies on Predetermination by Testosterone at Birth

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Abstract
The role of neonatal androgen in sexual differentiation of hepatic enzymes metabolizing the steroid Δ4–3–keto group and 20—keto group in the rat was further investigated. Steroid metabolism was studied with cortisol–l,2–H3 as substrate in whole liver homogenates. In male rats, gonadectomy at birth completely prevented sexual differentiation of cortisol metabolism. The predominant metabolite formed was 3β–5α–tetrahydrocortisol (3α) while the formation of 3β–Satetrahydrocortisol (3β), 20β–dihydrocortisol (20β) and β–cortols (20β) was very low. However, male rats gonadectomized as soon as the 10th day of life differentiated their cortisol metabolism. In adult life, the formation of 3β and 20β was significantly higher and that of 3α significantly lower than in neonatally gonadectomized animals. Female rats differentiated their metabolism even when gonadectomized at birth. But when spayed and treated with 50 μg testosterone propionate (TP) at birth, they showed the male type of development: masculine changes came first to expression after the 30th day of life and differentiation was stable over a test period of 1.5 years. Administration of TP after the 15th day of life did not have such permanent effects. Cyproterone was able to inhibit the masculinizing effect of TP in neonatal females; when given during the first 6 days of life, the anti—androgen also significantly impaired masculine development in male rats. Neither masculine nor feminine differentiation of steroid metabolism was mediated by adrenocortical secretion. Estrogen treatment from the 45th to the 60th day of life permanently erased the masculine pattern. However, treatment of these animals, when adult, with TP restored permanent masculine differentiation. Estrogen treatment from day 12 to 32 had the same erasing effects, but in these animals subsequent TP treatment was unable to reinduce the masculine pattern. The present experiments further support the concept that the development of the specific pattern of enzymes metabolizing steroids in the male rat liver is an enzymic differentiation subjected to predetermination by a gonadal androgen in early postnatal life. At least some of the developmental processes initiated by androgenization at birth still seem to be evolving after the 12th day of life. (Endocrinology91: 374, 1972)

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