Hormonal basis of reproductive defects in athymic mice: reduced gonadotropins and testosterone in males.

We wished to determine if congenitally athymic nude male mice have the same reduction in circulating concentrations of gonadotropins and gonadal steroids observed in their female counterparts when compared to their normal heterozygous littermates. We therefore quantitated pituitary and circulating concentrations of gonadotropins and circulating levels of testosterone in 102 congenitally athymic mice and 101 of their heterozygous littermates ranging in age from 1 to 120 days. Although the developmental patterns observed for both circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were similar to those previously observed in rats and mice, the athymic mice had significantly reduced concentrations of both pituitary and serum LH and FSH in comparison to the heterozygotes. In general, the reduced secretion of gonadotropins was most marked prior to sexual maturation but persisted in adult athymic males. Circulating concentrations of testosterone were also markedly reduced in the adult athymic males. Histologically, the number of Leydig cells appeared reduced in testes from 20-day-old athymic mice. However, no differences could be detected in testes from 40-day-old animals, and spermatogenesis appeared normal. Thus, unlike athymic females, athymic male mice appear to have normal reproductive capacity despite these hormonal abnormalities.

The hormonal basis of reproductive defects in athymic mice: diminished gonadotropin concentrations in prepubertal females.

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.

Reduced gonadotropins in athymic mice: prevention by thymic transplantation.

The reduction in pituitary concentrations of gonadotropins observed in 20-day old congenitally athymic nude mice in comparison to their normal heterozygous littermates was completely prevented in females and partially prevented in males by thymic transplantation on the first day of life. Those athymic mice receiving transplants but in which no thymic tissue could be found at sacrifice had reduced pituitary gonadotropin concentrations equivalent to sham-operated athymic animals. From these data we infer that the reduced concentrations of gonadotropins seen in the athymic animals are causally related to the absence of the thymus and suggest that the thymus, directly or indirectly, is necessary for development of normal function of the hypothalamic-pituitary-gonadal axis in mice.