Molecular control of ovulation and luteinization in the primate follicle

Abstract

In recent years, significant progress was made, particularly through the use of the macaque monkey, in identifying three types of local factors that are induced by the midcycle LH surge and play a critical role in ovulation and/or luteinization of the primate follicle. The ovulatory gonadotropin surge increases prostaglandin (PTG, typically abbreviated PG) levels in follicles prior to rupture; although considerable attention has focused on LH stimulation of the "inducible" form of PG G/H synthase (PTGS2), other aspects of PG synthesis (notably a phospholipase A2, cPLA2, and a PGE synthase, PTGES) and metabolism (15-hydroxy PG dehydrogenase, HPGD) also appear LH-regulated and may control the timing of the PG rise in the ovulatory follicle. Local (intrafollicular) ablation and replacement of PGs suggests that PGE2 is essential for release of the oocyte; but not necessarily for follicle rupture, and not for luteinization. Novel PGE-regulated genes are being identified in macaque granulosa cells, including adipose differentiation-related protein (ADFP). Similar types of studies indicate that the rise in progesterone (P) synthesis, as well as the induction of the genomic P receptor in granulosa cells, is essential for both ovulation and luteinization of the primate follicle. Limited data suggest that P action controls cell cycle activity (via cyclin B1 and cyclin-dependent kinase inhibitor p27), cholesterol uptake and utilization (e.g., low density lipoprotein or LDL receptor), proteases and their inhibitors (matrix metalloproteinase or MMP1; tissue inhibitor of MMP or TIMP1) and cell health in the granulosa cell layer. Finally, members of two classes of angiogenic factors, originally proposed as important for embryonic and pathologic (tumorigenic) vasculogenesis, appear induced in the granulosa layer of the preovulatory follicle, i.e., vascular endothelial growth factor (VEGF) and angiopoietin (ANGPT). Local injection of antagonists to VEGF (soluble VEGF receptor) and ANGPT (the natural antagonist ANGPT2) into the preovulatory follicle suppressed ovulation and luteinization in monkeys, possibly by disrupting the structure-function of existing vessels or preventing angiogenesis in the avascular granulosa layer. Further studies using high-throughput genomic and proteomic analysis, particularly on specific cell types (e.g., granulosa, theca and microvascular cells) and distinct follicular regions (apex, base and cumulus-oocyte complex) of the dominant follicle in natural menstrual cycles, are needed. Such information is essential to advance our understanding of the cascade of events leading to ovulation and luteinization of the primate follicle, to unravel the causes of ovary-based infertility and to consider novel ovary-selective approaches to contraception.

A comparative study on oxidative and antioxidative markers of serum and follicular fluid in GnRH agonist and antagonist cycles

“…The effect of reduced ADA activity on follicular development is not clear. There is evidence that vasodilation and high vascular permeability play a curial role during the ovulatory event in humans, and also ADA activity diminishes the amount of adenosine, deteriorating its vascular effect during follicular phase [9,43]. However, a recent study evaluated follicular fluid adenosine concentration in women who undergoing ovarian stimulation indicated that there is no functional ADA in the follicular environment of mature oocyte [44].…”

Identification of protein kinases that control ovarian hormone release by selective siRNAs

“…Two positive controls were used at the same concentration as experimental siRNAs; one siRNA targeted GAPDH mRNA (Silencer GAPDH siRNA, Ambion) and the other targeted CDC2 mRNA (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA), whose presence in the ovary has been previously demonstrated (Sirotkin & Grossmann 2006, Stouffer et al 2007.…”

“…The stimulatory effects of these growth factors on maturation of the oocyte (Sirotkin et al 2000a,b,c), of Cumulus oophorus and embryo development (Makarevich et al 2000) are mediated through PKA. P 4 prevents apoptosis, maintains survival, and promotes proliferation of ovarian granulosa cells via the PKG-dependent (Peluso 2003) and CDK-dependent (Stouffer et al 2007) pathways.…”

Differential expression of matrix metalloproteinases during stimulated ovarian recrudescence in Siberian hamsters (Phodopus sungorus)

“…In mice and rhesus monkeys, MMPs are up-regulated during the transformation of follicular granulosa cells into functional luteal tissue, and again during luteal regression (Young and Stouffer, 2003;Liu et al, 1999). In addition to physical remodeling, the cleavage action of ovarian MMPs can release growth factors in vitro encouraging follicular development, and in turn, ovulation (Levi et al, 1996;Fowlkes et al, 1994;Gearing et al, 1995;Logan and Hill, 1992;Massova et al, 1998;Stouffer et al, 2007).…”