Progesterone: The Forgotten Hormone?

PROGESTERONE: THE FORGOTTEN HORMONE? DARRELL W. BRANN* Introduction The female ovulatory cycle is characterized by a remarkable sequence of events, which ultimately culminates in the ovulation of a mature egg for fertilization. During this cycle, the central event that precedes and serves to initiate ovulation is the precisely timed preovulatory surge of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The preovulatory gonadotropin surge is, itself, regulated and initiated by the ovary, predominantly through the production and secretion of steroid hormones [1, 2]. Of the steroid hormones secreted by the ovary, estradiol has been given the preeminent role in the regulation of the events leading to the preovulatory surge of gonadotropins and ovulation. The other prominent steroid of the ovary, progesterone, has typically been assigned a "secondary" and relatively insignificant role in these events, since only small changes in serum levels of progesterone have been reported prior to the surge of gonadotropins. However, many investigators believe that preovulatory progesterone may be critically involved in the regulation of the surge and subsequent ovulation, and the question remains widely debated. Progesterone has been ascribed a significant role in the facilitation of implantation and in the maintenance of pregnancy [3, 4]. This critical influence of progesterone is most likely due to the well-known ability of progesterone to inhibit uterine contractility and to suppress the immune response to the fetus [5, 6]. These ascribed roles of progesterone in implantation and in pregnancy have received further verification recently , through the use of the antiprogestin compound, RU486. Furthermore , recent studies utilizing the antiprogestin RU486 have proThis paper was submitted to the 1991 Dwight J. Ingle Writing Award competition for young authors. *Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, Georgia 30912.© 1993 by The University of Chicago. All rights reserved. 003 1-5982/93/3604-0820$0 1 .00 642 Darrell W. Brann ¦ Progesterone vided new insights and clarification of the possible role of preovulatory progesterone in regulating the preovulatory surge of gonadotropins and ovulation. Therefore, the purpose of the present article is to reexamine this issue, through a detailed analysis of the literature in the area, with the goal of clarifying the role of preovulatory progesterone in the regulation of preovulatory gonadotropin secretion and ovulation. It will become readily apparent, and the treatise will be advanced by this author, that progesterone plays a much more critical role in the events leading to the preovulatory gonadotropin surge and ovulation than previously thought. Furthermore, a corollary tenet of this treatise will be advanced, holding that the adrenal gland, through the secretion of adrenal progesterone , acts in concert with the ovary to initiate, synchronize, potentiate, and finally to limit the expression of the preovulatory surge of gonadotropins to a narrow, precisely timed event, thus ensuring a full and optimal ovulatory quotient. Evidence That Estradiol Is Not the Sole Regulator of the Preovulatory Gonadotropin Surge In the rat and the human, serum estradiol levels rise precipitously on the days preceding the preovulatory LH and FSH surge [I]. This rise in estradiol is essential for the expression of the preovulatory gonadotropin surge and subsequent ovulation. This conclusion is supported by studies demonstrating that if the elevation of estradiol is prevented by ovariectomy, then the preovulatory gonadotropin surge fails to occur [1, 7-9]. Similarly, administration of agents that block estradiol's action (i.e., estradiol antagonists or estradiol antibodies) results in a corresponding block of the preovulatory surge of gonadotropins and ovulation [10, H]. While these studies clearly demonstrate that estradiol is essential for expression of the preovulatory surge of gonadotropins, they do not conclusively show that estradiol is the actual factor responsible for induction of the surge. Estradiol could be acting in a supportive role, which while essential, could still be left to another factor to actually induce the preovulatory gonadotropin surge. Hence, experiments were performed to determine whether estradiol could reproduce the preovulatory gonadotropin surge in an animal model in which the influence of other ovarian steroids and factors could be eliminated. The long-term ovariectomized rat allowed for such an elimination of ovarian steroids and thus was utilized for these studies. The administration of estradiol to the ovariectomized rat caused an initial suppression...