Estrogenic induction of spermatogenesis in the hypogonadal mouse

Abnormal sperm production and reduced fertility have been reported in trans genic male mice lacking the alpha-subtype of the estrogen receptor (ER)alph a or aromatase. The aim of this study was to investigate the role of estrog en in male reproductive function, by determining the effect of estradiol on testicular function in hypogonadal (hpg) mice congenitally lacking gonadot ropin; and thus, sex steroid production. hpg mice were treated, at 23 month s of age, with slow-release estradiol implants, which achieved circulating estradiol concentrations of approximately 40 pg/ml. Treatment for 35 days r eliably induced a 4- to 6-fold increase in testicular weight, compared with the vestigial testes in the untreated or cholesterol-treated controls. The degree of testicular growth after 35 days was similar to that in hpg mice receiving an intrahypothalamic graft of preoptic area tissue taken from neo natal mice on the day of birth, a procedure known to induce testicular deve lopment in hpg mice by activation of the pituitary gland. Histological anal ysis revealed that the testes contained elongated spermatids after 35 days of estradiol treatment, whereas germ cell development never progressed beyo nd the pachytene stage in control hpg mice. Treatment for 70 days induced f ull qualitatively normal spermatogenesis in hpg mice. Testis weight increas ed 8-fold, reflecting a B-fold increase in total seminiferous tubule volume and a 4- to 8-fold increase in the total volume of the seminiferous epithe lium. In all experiments, spermatogenesis proceeded in the absence of measu rable androgen concentrations, but circulating FSH concentrations were slig htly (but significantly) elevated, relative to cholesterol-treated control hpg mice. This stimulatory action of estradiol on FSH secretion was unexpec ted, particularly because identical estradiol treatments significantly decr eased serum FSH levels in wild-type littermates. These results indicate tha t estrogens may play a role in spermatogenesis, via stimulatory effects on FSH secretion. An alternative or complementary explanation, given the recen t identification of estrogen receptors (ER alpha and ER beta) and aromatase within various cell types in the testis, is that estrogens exert paracrine actions within the testis to promote spermatogenesis. The identification o f effects of estradiol on testicular function provides a conceptual basis t o reexamine the speculative link between increased exposure to environmenta l estrogens and reduced fertility in man.