Congenitally nude athymic female mice are known to have severe deficiencies in reproductive function, including reduced ovarian weight, increased follicular atresia, decreased fertility, and premature ovarian failure, in comparison to their phenotypically normal heterozygous littermates. To determine the hormonal basis for these reproductive defects, pituitary and circulating concentrations of gonadotropins and circulating levels of gonadal steroids were quantitated in 132 congenitally athymic mice and 126 of their normal heterozygous littermates, ranging in age from 1-120 days. Although prepubertal increases in both circulating LH and FSH, which were maximal at 10 days of age, were observed in both athymic and heterozygous females, the concentrations were reduced significantly in the athymic animals (P less than 0.01). Dramatic increases in the pituitary concentrations of both LH and FSH followed at 20 days, with the concentrations in heterozygotes being 3-fold greater than those in the athymic mice (P less than 0.01 for LH; P less than 0.001 for FSH). These abnormalities in pituitary gonadotropin concentrations in the athymic mice were followed by a 2- to 3-fold reduction in the secretion of estrone but not estradiol in athymic females 30 days and older. Serum androgen levels were also reduced. From these data we infer that the reduced gonadotropin concentrations observed in the athymic animals are responsible for their increased follicular atresia and premature ovarian failure and that the thymus gland appears to be essential for normal development of the hypothalamic-pituitary-ovarian axis.