Aging-related premature luteinization of granulosa cells is avoided by early oocyte retrieval
Aging-related premature luteinization of granulosa cells is avoided by early oocyte retrieval
复制标题
DOI：
10.1530/joe-15-0246
复制
发表时间：
2015-09-01
影响因子：
4
通讯作者：
Gleicher, Norbert
中科院分区：
文献类型：
--
作者：
Wu, Yan-Guang;Barad, David H.;Gleicher, Norbert
为什么IVF怀孕率在43岁后急剧下降尚不清楚。在这项研究中，我们比较了年轻卵母细胞供体（n=31，年龄21-29），中年（n=64，年龄30-37）和老年不育患者（n=41，年龄43-47）的颗粒细胞（GC）功能。从卵泡液中收集的GCs中，通过实时荧光定量PCR和蛋白质印迹检测与促性腺激素活性、类固醇生成、凋亡和黄体化相关的基因表达。FSH受体（FSHR）、芳香化酶（CYP 19 A1）和17 β-羟基类固醇脱氢酶（HSD 17 B）表达随年龄增长而下调，LH受体（LHCGR）、P450 SCC（CYP 11 A1）和孕酮受体（PGR）表达随年龄增长而上调。在体外培养时，发现GC随着衰老表现出较低的增殖和增加的凋亡。而FSH在体外刺激GCs生长并阻止黄体化。这些观察结果表明GC中与年龄相关的功能下降，与过早黄素化一致。为了避免43岁以上妇女过早黄体化，我们在最大主导卵泡大小为16 mm（常规为19-21 mm）时给予人绒毛膜促性腺激素，以提前取卵。与同龄女性的正常周期相比，早期取出的患者仅表现出卵母细胞早熟的轻微增加，但表现出胚胎数量和质量的改善以及可观的临床妊娠率。过早的卵泡黄素化似乎有助于43岁后IVF妊娠机会的迅速下降，并且可以通过早期取卵来避免。
Why IVF pregnancy rates decline sharply after age 43 is unknown. In this study, we compared granulosa cell (GC) function in young oocyte donors (n=31, ages 21-29), middle-aged (n=64, ages 30-37) and older infertile patients (n=41, ages 43-47). Gene expressions related to gonadotropin activity, steroidogenesis, apoptosis and luteinization were examined by real-time PCR and western blot in GCs collected from follicular fluid. FSH receptor (FSHR), aromatase (CYP19A1) and 17 beta-hydroxysteroid dehydrogenase (HSD17B) expression were found down regulated with advancing age, while LH receptor (LHCGR), P450scc (CYP11A1) and progesterone receptor (PGR) were up regulated. Upon in vitro culture, GCs were found to exhibit lower proliferation and increased apoptosis with aging. While FSH supplementation stimulated GCs growth and prevented luteinization in vitro. These observations demonstrate age-related functional declines in GCs, consistent with premature luteinization. To avoid premature luteinization in women above age 43, we advanced oocyte retrieval by administering human chorionic gonadotropin at maximal leading follicle size of 16 mm (routine 19-21 mm). Compared to normal cycles in women of similar age, earlier retrieved patients demonstrated only a marginal increase in oocyte prematurity, yet exhibited improved embryo numbers as well as quality and respectable clinical pregnancy rates. Premature follicular luteinization appears to contribute to rapidly declining IVF pregnancy chances after age 43, and can be avoided by earlier oocyte retrieval.