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.
Danilovich
Natalia
N
Molecular Reproduction Research Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.
Javeshghani
Danesh
D
Xing
Weirong
W
Sairam
M Ram
MR
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