INDUCTION OF SPERMATOGENESIS BY ANDROGENS IN GONADOTROPIN-DEFICIENT (HPG) MICE

Using a new experimental model for studying the hormonal induction of spermatogenesis, the hpg mouse, which has congenital functional gonadotropin deficiency due to a major deletion in the GnRH gene, we investigated the roles of testosterone (T) and dihydrotestosterone (DHT) in the initiation of spermatogenesis. Weanling homozygous hpg male mice were implanted subdermally with SILASTIC brand implants of varying lengths (0-2 cm) filled with T or DHT, using phenotypically normal (N/N or N/hpg) and untreated hpg/hpg mice as positive and negative controls. After 8 weeks, both T and DHT equally stimulated (similar to 14-fold) testis size and induced qualitatively complete spermatogenesis despite low intratesticular androgen levels and undetectable circulating FSH. Stereological quantitation of Sertoli and germ cells demonstrated a dose-dependent rise in the absolute numbers of all germ cell types induced by both T and DHT. At maximal androgen doses, germ cell numbers expressed per Sertoli cell and homogenization-resistant elongated spermatids expressed per mg testis were increased to more than 80% of non-hpg control values. An in vitro fertilization assay confirmed that both T and DHT induced quantitatively normal fertilizing capacity of the sperm in hpg males. We conclude that androgens, acting through the androgen receptor without need for aromatization, initiate qualitatively complete spermatogenesis in the mouse, including fertile sperm despite low intratesticular androgen levels and the absence of blood FSH levels. The hpg mouse model is a useful new paradigm to study the molecular basis of the hormonal induction of spermatogenesis.