Abstract
SummaryIrregular menstrual cycles, reduced responses to exogenous hormonal treatments, and altered endocrine profiles (high FSH/high LH/low AMH) are observed in women with increasing age before menopause. In this study, because the granulosa cell‐specific Nrg1 knockout mice (gcNrg1KO) presented ovarian and endocrine phenotypes similar to older women, we sought to understand the mechanisms of ovarian aging and to develop a new strategy for improving fertility in older women prior to menopause. In the ovary of 6‐month‐old gcNrg1KO mice, follicular development was blocked in bilayer secondary follicles and heterogeneous cells accumulated in ovarian stroma. The heterogeneous cells in ovarian stroma were distinguished as two different types: (i) the LH receptor‐positive endocrine cells and (ii) actin‐rich fibrotic cells expressing collagen. Both the endocrine and fibrotic cells disappeared following long‐term treatment with a GnRH antagonist, indicating that the high levels of serum LH induced the survival of both cell types and the abnormal endocrine profile to reduce fertility. Moreover, follicular development to the antral stages was observed with reduced LH and the disappearance of the abnormal stromal cells. Mice treated with the GnRH antagonist regained normal, recurrent estrous cycles and continuously delivered pups for at least for 3 months. We conclude that endocrine and matrix alternations occur within the ovarian stroma with increasing age and that abolishing these alternations resets the cyclical release of LH. Thus, GnRH antagonist treatments might provide a new, noninvasive strategy for improving fertility in a subset of aging women before menopause.
Highlights
Female fertility declines with increasing age in humans and in other species including mice and livestock animals
The decline of fertility with increasing age is accelerated in gcNrg1KO mice In WT mice, the number of pups born per month decreased linearly from 9 to 15 months of age (Fig. 1A)
In the granulosa cell-specific Nrg1KO mice, the number of pups born per month was significantly lower than that in WT mice during all mating periods with linear decreases observed from 6 to 8 and 10 to 13 months of age after which very few pups were born (Fig. 1A)
Summary
Female fertility declines with increasing age in humans and in other species including mice and livestock animals. There are about 10 000 follicles in ovary of women over 40 years of age (Faddy et al, 1992) and woman beyond 40 years can get pregnant following hormone treatments used in assisted reproduction technology (ART) (Manson & Martin, 2001; Klipstein et al, 2005). These observations indicate that the decline in fertility in women over 40 years of age until menopause is related to the loss of follicles in ovary and to either abnormal hormone levels or abnormal responses to hormones in the hypothalamic–pituitary–gonadal axis. The development from secondary to antral follicles is dependent on the basal levels of serum FSH and LH that are regulated by hypothalamic release of GnRH as well as by ovarian factors, such as inhibin B, estradiol, and progesterone (Ling et al, 1987; Couse & Korach, 1999)
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