Endocrine alterations and signaling changes associated with declining ovarian function and advanced biological aging in follicle-stimulating hormone receptor haploinsufficient mice.
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 alpha (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.
Molecular Reproduction Research Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.
Natalia
N
Danilovich
Danesh
D
Javeshghani
Weirong
W
Xing
M Ram
MR
Sairam
D000375:Aging / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003338:Corpus Luteum / Q000378:metabolism; D004702:Endocrine Glands / Q000254:growth & development* / Q000502:physiology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000096:biosynthesis / Q000235:genetics; D018628:Gene Dosage; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006239:Haplotypes; D007150:Immunohistochemistry; D007265:Inhibins / Q000096:biosynthesis / Q000235:genetics; D007986:Luteinizing Hormone / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics; D010053:Ovary / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D010060:Ovulation / Q000187:drug effects; D021382:Protein Sorting Signals / Q000502:physiology; D011962:Receptors, FSH / Q000235:genetics* / Q000502:physiology*; D011974:Receptors, LH / Q000096:biosynthesis / Q000235:genetics; D012098:Reproduction / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*; D013256:Steroids / Q000097:blood
D006063:Chorionic Gonadotropin; D012739:Gonadal Steroid Hormones; D021382:Protein Sorting Signals; D011962:Receptors, FSH; D011974:Receptors, LH; D013256:Steroids; D007265:Inhibins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone