Endocrine Abstracts

In primates: (a) the midcycle surge of gonadotropins (particularly LH) is essential for ovulation and luteinization of the dominant follicle, and (b) the pulsatile release of LH during the subsequent luteal phase is required for the normal functional lifespan of the corpus luteum during the menstrual cycle. However, information on the cellular and molecular actions of LH, outside of promoting steroidogenesis, remains limited. This presentation will summarize evidence that steroids (notably progesterone, P) and angiogenic factors (i.e., vascular endothelial growth factor, VEGF, and angiopoietin, ANG) produced in response to LH act locally to promote ovulation and development of luteal structure-function in monkeys. First, the midcycle gonadotropin surge increases P production and P receptor expression early (less than 12 hr) in the ovulatory cascade. Steroid ablation (using a steroid synthesis inhibitor) and replacement established the requirement for P to assist LH in eliciting follicle rupture and corpus luteum development. Subsequent studies revealed that P has important actions to prevent atresia and promote luteinization of the ovulatory follicle; tissue remodeling is regulated by P including the expression of certain proteases and their inhibitors (e.g., MMP-1 and TIMP-1) and angiogenic factors (ANG-1, but not ANG-2). Second, the gonadotropin surge increases the expression of angiogenic (VEGF-A and ANG-1) factors, but not angiolytic factors (ANG-2) in the granulosa layer of the ovulatory follicle. Injection of a VEGF antagonist (sVEGFR-1) into the preovulatory follicle caused a dose-dependent suppression of ovulation (50%) and decreased P levels during the subsequent luteal phase. More remarkably, intrafollicular injection of the endogenous ANG antagonist, ANG-2 totally blocked ovulation and eliminated the luteal phase; morphologic evidence indicated rapid degeneration of the preovulatory follicle. Thus, alterations in the timely, local production or actions of steroids or angiogenic factors disrupts cyclic ovarian function, and possibly fertility. HD20869, U54 HD18185, WHO/RF96020, RR00163.