McTavish Kirsten J, Jimenez Mark, Walters Kirsty A, Spaliviero Jennifer, Groome Nigel P, Themmen Axel P, Visser Jenny A, Handelsman David J, Allan Charles M
ANZAC Research Institute, University of Sydney, Concord Hospital, New South Wales, 2139 Australia.
Endocrinology. 2007 Sep;148(9):4432-9. doi: 10.1210/en.2007-0046. Epub 2007 May 31.
Rising serum FSH levels is one of the earliest signs of human female reproductive aging. Whether or not elevated FSH remains a passive reflection of a diminishing ovarian follicle pool or actively contributes to declining female fertility with age has not been established. We therefore investigated female reproduction in mice expressing progressively rising serum levels of transgenic human FSH (Tg-FSH, 2.5-10 IU/liter) independently of follicle depletion. We show that serum LH and estradiol levels and uterine size remained normal in Tg-FSH females, whereas ovarian weight and corpora lutea number were significantly increased up to 1.3- and 5-fold, respectively. Furthermore, the monotrophic FSH rise produced a striking biphasic effect on female fertility. Tg-FSH females less than 22 wk old delivered increased litter sizes, then beyond 23 wk, litter sizes decreased rapidly culminating in premature infertility despite continued ovary follicle development, and increased ovulation and uterine embryo implantation sites as well as normal serum levels of anti-Mullerian hormone, a marker of ovarian follicle reserve. We found that rising circulating Tg-FSH produced premature infertility by increasing embryo-fetal resorption and parturition failure with age. Thus, our Tg-FSH mice present a novel paradigm to investigate selective contributions of elevated FSH to age-related female infertility, which revealed that rising FSH levels, despite no exhaustion of ovarian reserve, actively accelerates female reproductive aging primarily by postimplantation reduction of embryo-fetal survival.
血清促卵泡生成素（FSH）水平升高是人类女性生殖衰老的最早迹象之一。FSH升高究竟是卵巢卵泡池减少的被动反映，还是随着年龄增长对女性生育能力下降有积极作用，目前尚无定论。因此，我们研究了血清中转基因人FSH（Tg-FSH，2.5 - 10国际单位/升）水平逐渐升高且与卵泡耗竭无关的小鼠的雌性生殖情况。我们发现，Tg-FSH雌性小鼠的血清促黄体生成素（LH）和雌二醇水平以及子宫大小保持正常，而卵巢重量和黄体数量分别显著增加至1.3倍和5倍。此外，FSH的单调升高对雌性生育能力产生了显著的双相效应。22周龄以下的Tg-FSH雌性小鼠产仔数增加，然后在23周龄之后，产仔数迅速下降，最终导致过早不孕，尽管卵巢卵泡持续发育，排卵和子宫胚胎着床部位增加，且抗苗勒管激素（一种卵巢卵泡储备标志物）的血清水平正常。我们发现，循环中的Tg-FSH升高会随着年龄增长通过增加胚胎 - 胎儿吸收和分娩失败导致过早不孕。因此，我们的Tg-FSH小鼠为研究FSH升高对与年龄相关的女性不孕的选择性作用提供了一个新的范例，这表明FSH水平升高，尽管卵巢储备未耗尽，但主要通过植入后降低胚胎 - 胎儿存活率，积极加速了女性生殖衰老。
