Antiprogesterone Treatment Rescues Fertility, by Overcoming Parturition Failure, in Ageing Transgenic FSH Female Mice.

Rising serum follicle-stimulating hormone (FSH) levels is one of the earliest signs of reproductive ageing in women and is considered to reflect ovarian follicle depletion. Whether rising serum FSH levels in ageing women actively contributes to declining fertility has been difficult to investigate, largely due to lack of specific in vivo models. We reported a transgenic (Tg) female mouse model with progressively rising serum human FSH with age, independent of ovarian follicle depletion, and unchanged serum LH, estradiol and progesterone (at diestrus). TgFSH females exhibited premature infertility with litter size rapidly declining from 20 weeks old (wo) relative to age-matched wt females. Despite accelerated reproductive failure, ageing TgFSH females maintained increased ovulation and embryo implantation, providing a unique model to study the effects of increased FSH independently of diminished follicle reserve. Analysis of pregnant 20-40 wo TgFSH females at term revealed declining fertility was due to a combination of increased embryo resorption and then parturition failure of remaining pups at term. To further determine the mechanism of reproductive failure, we examined the possibility that excessive FSH activity alters corpora lutea function and progesterone production. Analysis of pregnant females showed that serum progesterone levels at term or 21 days postcoitum (dpc) were elevated in 26 wo TgFSH mice relative to non-Tg controls (77.63 ± 19.48 vs 13.71 ± 5.23 nM, p < 0.05). Declining progesterone initiates the onset of parturition in rodents. To determine if full term in utero pups in ageing TgFSH females were viable, and whether FSH-driven parturition failure was related to elevated progesterone, we treated pregnant 26 wo TgFSH females that normally fail to deliver pups with the antiprogesterone mifepristone (RU486). Administration of 300 μg RU486 at 17:00 h on 18 dpc induced delivery of viable pups (6.86 ± 2.06 per female) from all treated TgFSH females (n = 7), whereas vehicle alone did not induce parturition (n = 5), within 12-21 hours of treatment (19 dpc). Age-matched non-Tg control females (n = 4) treated with RU486 (n = 4) or vehicle alone (n = 4) all delivered viable offspring within 21 hours of treatment (19 dpc) as expected. With the exception of some small litters (1-3 pups), which were cannibalized in the days following delivery, viable deliveries from all groups survived to weaning. Pups born to RU486-treated TgFSH dams (1.10 ± 0.03 g) were smaller (P < 0.0001) than pups delivered from RU486-treated wt dams (1.42 ± 0.03g). At weaning pups from transgenic dams (7.89 ± 0.18g) were still slightly smaller (P < 0.05) than from wt dams (8.54 ± 0.28g). While there was no significant difference between mean litter sizes of wt and TgFSH dams, the Tg dams exhibit significantly higher uterine embryo implantation sites with a large proportion of embryos resorbed after 14 dpc, which may contribute to reduced growth of surviving embryos and the decreased pup weights. In conclusion, our analysis reveals changes in the progesterone pathway play a key role in the parturition failure triggered by rising FSH levels in ageing TgFSH females.