Transgenic models to study gonadotropin function: The role of follicle-stimulating hormone in gonadal growth and tumorigenesis

The role of FSH in gonadal tumorigenesis and, in particular, in human ovari an cancer has been debated. It is also unclear what role the elevated FSH l evels in the inhibin-deficient mouse play in the gonadal tumorigenesis. To directly assess the role of FSH in gonadal growth, differentiation, and gon adal tumorigenesis, we have generated both gain-of-function and loss-of-fun ction transgenic mutant mice. In the gain-of-function model, we have genera ted transgenic mice that ectopically overexpress human FSH from multiple ti ssues using a mouse metallothionein-1 promoter, achieving levels far exceed ing those seen in postmenopausal women. Male transgenic mice are infertile despite normal testicular development and demonstrate enlarged seminal vesi cles secondary to elevated serum testosterone levels. Female transgenic mic e develop highly hemorrhagic and cystic ovaries, have elevated serum estrad iol and progesterone levels, and are infertile, mimicking the features of h uman ovarian hyperstimulation and polycystic ovarian syndromes. Furthermore , the female transgenic mice develop enlarged and cystic kidneys and die be tween 6-13 weeks as a result of urinary bladder obstruction. In a complemen tary loss-of-function approach, we have generated double-homozygous mutant mice that lack both inhibin and FSH by a genetic intercross. In contrast to male mice lacking inhibin alone, 95% of which die of a cancer cachexia-lik e syndrome by 12 weeks of age, only 30% of the double-mutant male mice lack ing both FSH and inhibin die by 1 yr of age. The remaining double-mutant ma le mice develop slow-growing and less hemorrhagic testicular tumors, which are noted after 12 weeks of age, and have minimal cachexia. Similarly, the double-mutant female mice develop slow-growing, less hemorrhagic ovarian tu mors, and 70% of these mice live beyond 17 weeks. The double-mutant mice de monstrate minimal cachexia in contrast to female mice lacking only inhibin, which develop highly hemorrhagic ovarian tumors, leading to cachexia and d eath by 17 weeks of age in 95% of the cases. The milder cachexia-like sympt oms of the inhibin and FSH double-mutant mice are correlated with low level s of serum estradiol and activin A and reduced levels of aromatase mRNA in the gonadal tumors. Based on these and our previous genetic analyses, we co nclude that elevated FSH levels do not directly cause gonadal tumors. Howev er, these results suggest FSH is an important trophic modifier factor for g onadal tumorigenesis in inhibin-deficient mice.