Transgenic Models to Study Gonadotropin Function: The Role of Follicle-Stimulating Hormone in Gonadal Growth and Tumorigenesis

Abstract

The role of FSH in gonadal tumorigenesis and, in particular, in human ovarian cancer has been debated. It is also unclear what role the elevated FSH levels in the inhibin-deficient mouse play in the gonadal tumorigenesis. To directly assess the role of FSH in gonadal growth, differentiation, and gonadal tumorigenesis, we have generated both gain-of-function and loss-of-function transgenic mutant mice. In the gain-of-function model, we have generated transgenic mice that ectopically overexpress human FSH from multiple tissues using a mouse metallothionein-1 promoter, achieving levels far exceeding those seen in postmenopausal women. Male transgenic mice are infertile despite normal testicular development and demonstrate enlarged seminal vesicles secondary to elevated serum testosterone levels. Female transgenic mice develop highly hemorrhagic and cystic ovaries, have elevated serum estradiol and progesterone levels, and are infertile, mimicking the features of human ovarian hyperstimulation and polycystic ovarian syndromes. Furthermore, the female transgenic mice develop enlarged and cystic kidneys and die between 6-13 weeks as a result of urinary bladder obstruction. In a complementary 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-like syndrome by 12 weeks of age, only 30% of the double-mutant male mice lacking both FSH and inhibin die by 1 yr of age. The remaining double-mutant male 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 tumors, and 70% of these mice live beyond 17 weeks. The double-mutant mice demonstrate minimal cachexia in contrast to female mice lacking only inhibin, which develop highly hemorrhagic ovarian tumors, leading to cachexia and death by 17 weeks of age in 95% of the cases. The milder cachexia-like symptoms of the inhibin and FSH double-mutant mice are correlated with low levels 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 conclude that elevated FSH levels do not directly cause gonadal tumors. However, these results suggest FSH is an important trophic modifier factor for gonadal tumorigenesis in inhibin-deficient mice.

High levels of luteinizing hormone analog stimulate gonadal and adrenal tumorigenesis in mice transgenic for the mouse inhibin-α-subunit promoter/Simian virus 40 T-antigen fusion gene

“…Testosterone ( (Kumar et al, 1999). In contrast to previous data (Risma et al, 1995) indicating that there is no difference in circulating LH levels between the TG and WT males, we show in the present report that LH levels are elevated in male bLHb-CTP mice, at least at the age of 9-12 weeks, but the elevation is less marked than in females and could be explained by the different age groups analysed.…”

Follicle-stimulating hormone increases primordial follicle reserve in mature female hypogonadal mice

“…In comparison, ectopic FSH expression in the tg-hpg model independent of GnRH and LH (Allan et al 2004, Allan et al 2001, as well as preserved hormone responsiveness, allows further investigation of FSH in isolation or combined with other hormones. The confounding effects of supraphysiological FSH concentrations previously reported in tg-FSH mice (Kumar et al 1999) were not observed in this tg-FSH hpg model, since serum tg-FSH (4-5 IU/l) did not impede the fertility of young non-hpg females and was therefore within the limits compatible with physiological ovarian function (paper in preparation, Allan et al).…”

Inhibin, activin, follistatin and FSH serum levels and testicular production are highly modulated during the first spermatogenic wave in mice

“…The influence of inhibin B on adult spermatogenesis is not apparent, as mice that cannot produce inhibin B due to deletion of the gene encoding the b B subunit are fertile (Vassalli et al 1994, Kumar et al 1999. However, the chronic absence of inhibin in the Inha K/K mouse (Matzuk et al 1992) leads to development Figure 1 Development of the mouse testis and realtime PCR analysis of inhibin/activin subunits and follistatin mRNA.…”