Estrogen Deficiency, Obesity, and Skeletal Abnormalities in Follicle-Stimulating Hormone Receptor Knockout (FORKO) Female Mice**This investigation was supported in part by the Canadian Institutes of Health Research.

Abstract

Targeted disruption of the receptor for glycoprotein hormone, FSH (FSH-R) causes a gene dose-related endocrine and gametogenic abnormality in female mice. The resulting FSH-R knockout (FORKO) mutants have disordered estrous cycles, ovulatory defects, and atrophic uterus. The heterozygous animals that initially show reduced fertility undergo early reproductive senescence and stop breeding altogether. Lack of FSH-R signaling in females causes severe ovarian underdevelopment producing chronic estrogen deficiency. This was accompanied by increases in serum testosterone levels. Ovarian aromatase gene transcription and translation are unaltered in the mutants. Early loss of 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 with early reproductive senescence. The expression of nuclear estrogen receptor(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 creates an imbalance in A and B forms of the progesterone receptor in the uterus of both heterozygotes and null mutants. Some of the changes we have documented here in FORKO mice are reminiscent of the ovarian dysfunction and other major symptoms that are usually associated with estrogen deficiency. In null mutants, estradiol-17beta administration promptly induced uterine growth and reversed the accumulation of adipose tissue indicating that estrogen receptors are functional. Thus, the phenotypes evident in these genetically 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.

Blocking FSH induces thermogenic adipose tissue and reduces body fat

“…This clinical phenotype has often been documented in rodents post-ovariectomy, as well as in chronic hypoestrogenemic models, such as in female Erα −/− , aromatase −/− and Fshr −/− mice 4, 16–18 , although in our hands, female Fshr −/− mice are not obese. While in female mice, genetic Fshr deficiency does not seem to protect against the pro-adiposity effects of severe chronic hypoestrogenemia, we questioned whether acute suppression of Fsh by an Fsh Ab can, through parallel mechanisms, not only attenuate bone loss 6 , but also reduce body fat and improve energy homeostasis.…”

Establishment of a Mouse Model of Premature Ovarian Failure Using Consecutive Superovulation

“…Currently, mouse models of female reproductive aging are divided into two categories: genetic mutation animal models, such as the follitropin receptor knockout animal model [4, 5] and the dioxin/aryl hydrocarbon receptor knockout animal model [6, 7]; and poison damage models, such as the 4-vinylcyclohexene diepoxide-induced female reproductive aging model [8, 9] and the D-galactose-induced female reproductive aging model [10-12]. Although these animal models show an increase in follicular consumption or even depletion, the resulting estrous cycle disorders, decreased sex hormone secretion and decrease in or loss of fertility may indicate one or more pathological states and thus do not simulate the real pathophysiological condition of ovarian aging [8, 13].…”

Iron deficiency induces female infertile in order to failure of follicular development in mice

“…We also observed herein that the FSH concentration in the serum of the mice was not affected by the LFD feeding for 3 weeks, suggesting that iron restriction for 3 weeks influences peripheral tissues (including the ovaries) but not the pituitary gland. In addition, since a previous study using Fshr gene target disruption mice showed reduced concentrations of LH [29] and progesterone [30] in the serum, we suspected that the LFD feeding also had an adverse effect on the ovulatory stage as was observed in the Fshr knockout mice, which may have resulted in a reduction of the oocyte's ability to develop to the blastocyst stage in this study.…”