Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice

Targeted disruption of the receptor for glycoprotein hormone, FSH (FSH-R) c auses a gene dose-related endocrine and gametogenic abnormality in female m ice. The resulting FSH-R knockout (FORKO) mutants have disordered estrous c ycles, ovulatory defects, and atrophic uterus. The heterozygous animals tha t initially show reduced fertility undergo early reproductive senescence an d stop breeding altogether. Lack of FSH-R signaling in females causes sever e ovarian underdevelopment producing chronic estrogen deficiency. This was accompanied by increases in serum testosterone levels. Ovarian aromatase ge ne transcription and translation are unaltered in the mutants. Early loss o f estrogen in the null mutants leads to obesity and skeletal abnormalities that intensify with age producing (kyphosis), a hunchback appearance. Both these changes also become apparent in older heterozygous mice coincident wi th early reproductive senescence. The expression of nuclear estrogen recept or(s) alpha and beta genes and the corresponding proteins in the ovary and uterus of FORKO mice appear to be intact. The loss of ovarian estrogen crea tes an imbalance in A and B forms of the progesterone receptor in the uteru s of both heterozygotes and null mutants. Some of the changes we have docum ented here in FORKO mice are reminiscent of the ovarian dysfunction and oth er major symptoms that are usually associated with estrogen deficiency. In null mutants, estradiol-17 beta administration promptly induced uterine gro wth and reversed the accumulation of adipose tissue indicating that estroge n receptors are functional. Thus, the phenotypes evident in these genetical ly altered FSH-R mutants may provide an experimental system to explore the effects of estrogenic compounds on different targets including the ovary in a nonsurgical setting.