A novel transgenic model to characterize the specific effects of follicle-stimulating hormone on gonadal physiology in the absence of luteinizing hormone actions

Gonadal function is wholly reliant on the two pituitary-derived gonadotropi ns, FSH and LH. Identifying the specific effects of FSH has been difficult because of the intimate relationship between LH and FSH action and inherent limitations of classic research paradigms. We describe a novel transgenic model to characterize the definitive actions of FSH alone, distinct from LH effects, created by combining transgenic FSH expression with the gonadotro pin-deficient background of the hypogonadal (hpg) mouse. A tandem transgene construct encoding each alpha and beta -subunit of human FSH, under the ra t insulin II promoter, expressed biologically active heterodimers at serum levels, by immunoassay, equivalent to circulating FSH concentrations in fer tile humans (0.1-25 IU/liter). Transgenic mice were crossed into the hpg mo use genotype to obtain LH-deficient animals secreting FSH alone. Testis wei ghts of adult FSHxhpg mice were increased up to 5-fold, relative to nontran sgenic hpg controls (P < 0.001). However, only transgenic males with serum FSH levels more than 1 IU/liter showed testis weights increased relative to hpg controls, indicating a physiological FSH threshold for the testicular response. Histology of enlarged FSHxhpg testes revealed round spermatids an d sparse numbers of elongated spermatids, demonstrating that the testostero ne-independent FSH response targeting the Sertoli cell can facilitate compl etion of meiosis and minimal initiation, but not completion, of spermiogene sis. Transgenic FSH also induced inhibin B secretion in FSHxhpg mice, but s howed a distinct sexual dimorphism with only females exhibiting a strong FS H dose-dependent increase in serum inhibin B levels (r(2) = 0.84). In addit ion, ovaries of FSHxhpg females were enlarged up to 10-fold (P < 0.001), ch aracterized by increased follicular recruitment and development to type 7 a ntral follicles. Thus, these findings show that the transgenic FSHxhpg mous e provides a unique model for detailed investigations of the definitive in vivo actions of FSH alone.