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-Subunit
Department of Biochemistry, Molecular Biology, and Cell Biology, and Center for Reproductive Science, Northwestern University, Evanston, Illinois 60208
Address all correspondence and requests for reprints to: Kelly E. Mayo, Ph.D., Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208. E-mail: k-mayo{at}northwestern.edu
Inhibin and activin are structurally related dimeric peptide
hormones and are members of the TGF-ß superfamily of proteins. In the
accompanying paper, we describe transgenic mice that overexpress the
inhibin 
-subunit gene from a metallothionein-I promoter (MT-) and
examine the effects of the MT- transgene on gonadotropin levels and
fertility. To characterize the effects of increased inhibin -subunit
on gonadal morphology and function, in this report we investigate
gonadal histology, steroid hormone levels, and the basis of ovarian
cyst formation in MT- transgenic mice. MT- transgenic female mice
develop large fluid-filled ovarian cysts of follicular origin as early
as 3 months of age. By 12 months of age, more than 92% of female
MT- transgenic mice develop ovarian cysts compared with less than
25% of wild-type littermates. Ovarian cysts form unilaterally or
bilaterally, and cystic ovaries often have a greatly expanded bursal
sac. Additionally, the ovaries of MT- transgenic mice contain
polyovular follicles and have fewer mature antral follicles and corpora
lutea. MT- female mice exhibit abnormal steroid hormone production,
with increased serum T levels and reductions in serum E with
corresponding reductions in uterine mass. In the MT- transgenic
males, testis size was decreased by 20–40% compared with control
males, and there is a corresponding reduction in seminiferous tubule
volume. After a chronic treatment with a GnRH antagonist, MT- female
mice continued to develop ovarian cysts and bursal sac expansions,
although the cysts were markedly reduced in size. These results
indicate that the expression of the rat inhibin -subunit in mice
results in significant ovarian pathology, reduced testicular size, and
altered ovarian steroidogenesis. The antagonist studies are consistent
with a direct ovarian effect of the -subunit transgene product
mediated by changes in the inhibin-to-activin ratio in these
mice.
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