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Molecular Reproduction Research Laboratory, Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7, Canada
Address all correspondence and requests for reprints to: M. Ram Sairam, Ph.D., Molecular Reproduction Research Laboratory, Clinical Research Institute of Montréal, 110 Pine Avenue West, Montréal (Québec), H2W 1R7, Canada. E-mail: sairamm{at}ircm.qc.ca
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) 
and ß
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-17ß 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.
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