Steroidogenic factor 1 (SF1) is essential for pituitary gonadotrope function

Knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (S F1) exhibit a complex endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and absence of t he ventromedial hypothalamic nucleus (VMH). These multiple defects complica te efforts to delineate primary versus secondary effects of SF1 deficiency in different tissues, such that its direct role in gonadotropes remains unc ertain. To define this role, we have expressed Cre recombinase driven by th e promoter region of the common alpha subunit of glycoprotein hormones (alp ha GSU), thereby inactivating a loxP-modified SF1 locus in the anterior pit uitary gland. Although pituitary-specific SF1 knockout mice were fully viab le, they were sterile and failed to develop normal secondary sexual charact eristics. Their adrenal glands and VMH appeared normal histologically, but their testes and ovaries were severely hypoplastic, alpha GSU-Cre, loxP mic e had normal levels of most pituitary hormones, but had markedly decreased expression of LH and FSH. Treatment with exogenous gonadotropins stimulated gonadal steroidogenesis, inducing germ cell maturation in males and follic ular and uterine maturation in females - establishing that the gonads can r espond to gonadotropins, The pituitary-specific SF1 knockout mice are a nov el genetic model of hypogonadotropic hypogonadism that establishes essentia l role(s) of SF1 in pituitary gonadotropes.