Progesterone and progestin receptors in the brain: the neglected ones.

Progesterone and1 progestin receptors each have a checkered past. As Frank Beach described in “Historical origins of modern research on hormones and behavior” (1), in the 1930s, William C. Young’s group was mocked for their finding that the physiological pattern of hormone treatment that induces feminine sexual behavior in rats and guinea pigs with ovaries removed was estradiol followed a day or two later by progesterone and their heretical suggestion that this was the pattern necessary during the estrous cycle (2–5). Because sexual behavior is expressed before ovulation and, hence, before formation of the corpus luteum, and progesterone was believed to come only from the corpus luteum, how could progesterone be involved? That is, how could progesterone do something before it was secreted? Because the field was certain that there was no progesterone released before ovulation, this may have been the origin of the secondclass status of progesterone contrasted with estradiol. However, with the development of the first progesterone assays in the late 1960s (6, 7) followed by RIA (8, 9), Young’s group was proved correct; there was apparently another source of progesterone besides the corpus luteum, and in fact, there was a quite sizable preovulatory surge of progesterone. This progesterone surge was later learned to be essential for the facilitation of feminine sexual behavior. Because two prototypical, brain-regulated, physiological events, ovulation (10) and feminine sexual behavior (11), each can be induced in ovariectomized rats without progesterone in some circumstances, progesterone took a back seat to estradiol for a long time. Many experiments were performed to test hypotheses of how estradiol alone induces, for example, feminine sexual behavior, despite the fact that the physiologically relevant means of inducing sexual behavior, as occurs during the estrous cycle of several rodent species, is by estradiol followed a day or two later with progesterone. Likewise, although progesterone is secreted before ovulation, because LH surges can be induced with estradiol alone, the role of progesterone in the initiation and/or maintenance of the LH surge has often been neglected. Progestin receptors in the brain have a similar sketchy history. Up until the mid-1970s, it was widely held that whereas the actions of estradiol in the brain were mediated by cell nuclear estrogen receptors, those of progesterone were not. To make that long story short, it was discovered in the late 1970s and early 1980s that the brain does in fact synthesize progestin receptors and that these receptors are essential for the effects of progesterone on sexual behavior. Nevertheless, progestin receptors took a back seat to estrogen receptors in most research on steroid hormone mechanisms in the brain. It is noteworthy that in some of the early experiments on steroid receptors in peripheral reproductive tissues, the brain was used as a negative control tissue. Although the role of estrogen receptors in the brain was accepted early in the development of the field, the role of progestin receptors was initially met with some skepticism, perhaps because early attempts to identify them were negative. Much progress has now been made on the roles of progestin receptors, perhaps the prototypical protein induced by estradiol action, in the brain. Some recent progress on the forgotten receptor, the progestin receptor, is summarized by Shaila Mani (12) in her review of the role of different forms of the receptor in the brain. For several decades, the vast majority of studies on steroid hormone influences on sexual differentiation of the brain focused primarily on the actions of estrogens and estrogen receptors (13), but only recently has attention turned to the role of the progestin receptor. In her minireview, Christine Wagner (14) summarizes recent work suggesting a role for this receptor in sexual differentiation of the brain. Although the de novo synthesis of progestin precursors has been known for nearly 20 yr (15), most researchers have neglected to look at the brain as a source of progesterone until quite recently. The current state of work on the synthesis and effects of progesterone in the developing brain (16), as well as the adult brain (17), is summarized in a pair of minireviews. The absence of consideration of progesterone can be found in a good deal of the human literature as well. Despite the fact that progesterone is secreted before ovulation (18), as it is in many rodent species (11), experiments typically focus on the role of estrogens alone or estrogens concurrently with progestins, but seldom if ever estradiol followed by progesterone (19). Likewise, in most studies, synthetic progestins are administered rather than the endogenous hormone, progesterone. In recent years, an increasing amount of research on steroid hormones and the brain has focused on the role of progesterone and progestin receptors, as demonstrated by these four minireviews. However, in many cases, work on steroid hormone action in peripheral tissues continues to neglect the important influences that the sex steroid horFirst Published Online