Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

Abstract

The ovarian follicle luteinizing hormone (LH) signaling molecules that regulate oocyte meiotic maturation have recently been identified. The LH signal reduces preovulatory follicle cyclic nucleotide levels which releases oocytes from the first meiotic arrest. In the ovarian follicle, the LH signal reduces cyclic nucleotide levels via the CNP/NPR2 system, the EGF/EGF receptor network, and follicle/oocyte gap junctions. In the oocyte, reduced cyclic nucleotide levels activate the maturation promoting factor (MPF). The activated MPF induces chromosome segregation and completion of the first and second meiotic divisions. The purpose of this paper is to present an overview of the current understanding of human LH signaling regulation of oocyte meiotic maturation by identifying and integrating the human studies on this topic. We found 89 human studies in the literature that identified 24 LH follicle/oocyte signaling proteins. These studies show that human oocyte meiotic maturation is regulated by the same proteins that regulate animal oocyte meiotic maturation. We also found that these LH signaling pathway molecules regulate human oocyte quality and subsequent embryo quality. Remarkably, in vitro maturation (IVM) prematuration culture (PMC) protocols that manipulate the LH signaling pathway improve human oocyte quality of cultured human oocytes. This knowledge has improved clinical human IVM efficiency which may become a routine alternative ART for some infertile patients.

Keywords: LH follicle signaling; Oocyte meiotic maturation; Oocyte quality.

Fig. 1

Human folliculogenesis, oogenesis, and oocyte meiotic maturation. a Gonadotropins regulate folliculogenesis, oogenesis, oocyte meiotic maturation, and oocyte competence. The first visible sign of meiotic progression is oocyte germinal vesicle breakdown (GVBD) followed by expulsion of the first polar body. The mid-cycle LH surge activates the oocyte maturation promoting factor (MPF) which initiates resumption of meiosis. The MPF activates the oocyte anaphase-promoting complex (APC) which promotes completion of the first meiotic division. MII oocytes remain arrested in metaphase II until fertilization induces completion of the second meiotic division. Oocyte meiotic maturation begins with the LH surge and ends at metaphase II. Competent oocytes support the subsequent development of blastocysts. b Human germinal vesicle (GV), MII oocyte (MII), and blastocyst

Fig. 2

Human model of LH regulation of oocyte meiotic maturation. The LH signal begins with mid-cycle LH activation of the mural granulosa cell LH receptor. The LH signal rapidly suppresses CNP/NPR2, activates the EGF/EGFR network, and inhibits gap junction activity. This reduces follicle and oocyte cGMP levels, activates oocytes phosphodiesterases, reduces oocyte cAMP levels, and activates the oocyte maturation promoting factor (MPF). The MPF initiates resumption of meiosis by protein phosphorylation of downstream proteins. The spindle assembly checkpoint (SAC) proteins are activated at the kinetochore to induce spindle formation and alignment. CDC20 activates the anaphase-promoting complex (APC) which initiates the transition from metaphase to anaphase by degrading securin releasing separase which degrades cohesin. This frees chromosomes to segregate to opposite poles. The first meiotic division is completed and the mature metaphase II oocyte remains arrested until fertilization. +, activation or stimulation; −, inhibition