Centre for Rural Health and Community Development, University of South Australia, Adelaide 5000, South Australia.
J Biomed Sci. 2013 Dec 13;20(1):93. doi: 10.1186/1423-0127-20-93.
Infertility, spontaneous abortion and conception of trisomic offspring increase exponentially with age in mammals but in women there is an apparent acceleration in the rate from about age 37. The problems mostly commonly occur when the ovarian pool of follicles is depleted to a critical level with age but are also found in low follicular reserve of other etiologies. Since recent clinical studies have indicated that dehydroepiandrosterone (DHEA) supplementation may reverse the problem of oocyte quality, this review of the literature was undertaken in an attempt to find an explanation of why this is effective? In affected ovaries, oxygenation of follicular fluid is low, ultrastructural disturbances especially of mitochondria, occur in granulosa cells and oocytes, and considerable disturbances of meiosis occur. There is, however, no evidence to date that primordial follicles are compromised. In females with normal fertility, pre-antral ovarian theca cells respond to stimulation by inhibin B to provide androgen-based support for the developing follicle. With depletion of follicle numbers, inhibin B is reduced with consequent reduction in theca DHEA. Theca cells are the sole ovarian site of synthesis of DHEA, which is both a precursor of androstenedione and an essential ligand for peroxisome proliferator-activated receptor alpha (PPARα), the key promoter of genes affecting fatty acid metabolism and fat transport and genes critical to mitochondrial function. As well as inducing a plethora of deleterious changes in follicular cytoplasmic structure and function, the omega 9 palmitate/oleate ratio is increased by lowered activity of PPARα. This provides conditions for increased ceramide synthesis and follicular loss through ceramide-induced apoptosis is accelerated. In humans critical theca DHEA synthesis occurs at about 70 days prior to ovulation thus effective supplementation needs to be undertaken about four months prior to intended conception; timing which is also suggested by successful interventions to date. In humans and primates that undergo adrenarche, the adrenal zona reticularis (ZR) is the major site of DHEA production, however this is also reduced with age. Concomitant loss in function of the ZR might account for the acceleration in the rate of aging seen in humans in the late thirties' age group.
在哺乳动物中，不孕、自然流产和三体后代的受孕率随年龄呈指数增长，但在女性中，这种增长速度在大约 37 岁左右明显加快。这些问题主要发生在卵巢卵泡储备因年龄而减少到临界水平时，但也存在于其他病因的低卵泡储备中。由于最近的临床研究表明脱氢表雄酮（DHEA）补充可能逆转卵母细胞质量问题，因此进行了这项文献综述，试图找到为什么这种方法有效的解释？在受影响的卵巢中，卵泡液的氧合作用较低，颗粒细胞和卵母细胞中出现超微结构紊乱，减数分裂过程中出现相当大的紊乱。然而，迄今为止没有证据表明原始卵泡受到损害。在具有正常生育能力的女性中，窦前卵巢膜细胞对抑制素 B 的刺激做出反应，为发育中的卵泡提供雄激素支持。随着卵泡数量的减少，抑制素 B 减少，导致膜细胞 DHEA 减少。膜细胞是 DHEA 的唯一卵巢合成部位，DHEA 既是雄烯二酮的前体，也是过氧化物酶体增殖物激活受体-α（PPARα）的必需配体，PPARα 是影响脂肪酸代谢和脂肪转运的基因以及对线粒体功能至关重要的基因的关键启动子。除了诱导卵泡细胞质结构和功能的大量有害变化外，PPARα 活性降低会增加 omega 9 棕榈酸/油酸比值。这为增加鞘氨醇合成和通过鞘氨醇诱导的细胞凋亡加速卵泡丢失提供了条件。在人类中，排卵前约 70 天发生临界膜细胞 DHEA 合成，因此有效补充需要在预期受孕前四个月左右进行；这一时间也与迄今为止成功的干预措施相吻合。在经历肾上腺皮质增生的人类和灵长类动物中，肾上腺皮质网状带（ZR）是 DHEA 产生的主要部位，但随着年龄的增长，它也会减少。ZR 功能的同时丧失可能解释了人类在三十多岁后期年龄组中看到的衰老速度加快。
