Reproductive Aging is Associated With Altered Gene Expression in Human Luteinized Granulosa Cells

Abstract

Declining reproductive success with aging is attributable to qualitative and quantitative deterioration in oocytes, which are nurtured by granulosa cells (GCs). This prospective study assesses whether reproductive aging is accompanied by differential gene expression in luteinized GCs from in vitro fertilization (IVF) patients. Women with nonovarian infertility etiologies were categorized as younger (< or =30, n = 3) or older (> or =40, n = 3). During oocyte retrieval, mural GCs were isolated; messenger RNA (mRNA) was extracted and transcribed for complementary DNA (cDNA) microarray analysis. Differential gene expression was confirmed by real-time polymerase chain reaction (PCR). Analysis revealed 120 genes were differentially expressed. Three genes were upregulated and 117 were downregulated (including interleukin [IL]-1beta, IL-1R2, and IL-6R) in GCs of older versus younger patients. Our data provide evidence of downregulation in IL-1 and IL-6 gene families in luteinized GCs with advancing age. Given previously recognized roles for the IL gene family in folliculogenesis and ovulation, our findings may partly explain ovulatory and luteal dysfunctions associated with reproductive aging.

Aging-related premature luteinization of granulosa cells is avoided by early oocyte retrieval

“…A likely explanation for this result is that here investigated GCs were exposed to hCG in vivo. As shown by us and others (Murphy 2000, Hurwitz et al 2010, Jeppesen et al 2012, McReynolds et al 2012, hCG administration causes luteinization of GCs, and a changing physiological and molecular signatures. Therefore, it is possible that hCG administration changes cell sensitivity of the FSH response.…”

“…Although numerous studies have documented the relationship between poor oocyte quality and GC abnormalities in human and animals (Buccione et al 1990, Senbon et al 2003, Assou et al 2012, Huang & Wells 2012, Matsuda et al 2012, effects of age on physiological function and molecular signature of GCs have so far been only sparsely investigated. Indeed, to our knowledge, they have never before been performed in such distinct age groupings (Hurwitz et al 2010, McReynolds et al 2012.…”

Granulosa cell function and oocyte competence: Super-follicles, super-moms and super-stimulation in cattle

“…Although granulosa cells for these two studies were obtained from superstimulated follicles (by-passing the natural selection process), they still provide some useful insights about the cellular mechanisms in maternal reproductive aging. Likewise, down-regulation of IL-1 and IL-6 gene families in luteinized granulosa cells from patients of advancing age (Hurwitz et al, 2010) may partly explain the age-associated luteal dysfunctions.…”

Age-associated changes in bovine oocytes and granulosa cell complexes collected from early antral follicles

“…Oocyte growth is supported by surrounding granulosa cells [17], and a deterioration in the characteristics of these granulosa cells derived from full-grown antral follicles have been observed in aged women and cows [18][19][20][21]. Result from real time RT-PCR experiments have revealed that the expression of some genes including those that encode for antioxidants in mouse ovary was affected by aging [22].…”