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Regular Article |
a Molecular Reproduction Research Laboratory, Clinical Research Institute of Montreal, Montreal, Quebec, Canada H2W 1R7
b Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3A 1A3
c Department of Medicine, Université de Montréal, Montreal, Quebec, Canada H3T 1J4
Reproductive aging in female mammals is characterized by a progressive decline in fertility due to loss of follicles and reduced ovarian steroidogenesis. In this study we examined some of the endocrine and signaling parameters that might contribute to a decrease in ovulation and reproductive performance of mice with haploinsufficiency of the FSH receptor (FSH-R). For this purpose we compared ovarian changes and hormone levels in FSH-R heterozygous (+/-) and wild-type mice of different ages (3, 7, and 12 mo). Hormone-induced ovulations in immature and 3-mo-old +/- mice were consistently lower. The number of corpora lutea (CL) were lower at 3 and 7 mo, and none were present in 1-yr-old +/- females. The plasma steroid and gonadotropin levels exhibited changes associated with typical ovarian aging. Plasma FSH and LH levels were higher in 7-mo-old +/- mice, but FSH levels continued to rise in both genotypes by 1 yr. Serum estradiol and progesterone were lower in +/- mice at all ages, and testosterone was several-fold higher in 7-mo-old and 1-yr-old +/- mice. Inhibin 
(Western blot) appeared to be lower in +/- ovaries at all ages. FSH-R (FSH* binding) declined steadily from 3 mo and reaching the lowest point at 1 yr. LH receptor (LH* binding) was high in the 1-yr-old ovary, and expression was localized in the stroma and interstitial cells. Our findings demonstrate that haploinsufficiency of the FSH-R gene could cause premature exhaustion of the gonadal reserves previously noted in these mice. This is accompanied by age-related changes in the hypothalamic-pituitary axis. As these features in our FSH-R +/- mice resemble reproductive failure occurring in middle-age women, further studies in this model might provide useful insights into the mechanisms underlying ovarian aging.
1 Supported by a grant from the Canadian Institutes of Health Research. N.D. and W.X. are the holders of a CIHR doctoral fellowship.
2 Correspondence: M. Ram Sairam, Molecular Reproduction Research Laboratory, Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, QC, Canada H2W 1R7. FAX: 514 987 5585; sairamm{at}ircm.qc.ca
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