Nuclear Receptor Coactivator Function in Reproductive Physiology and Behavior1

Gonadal steroid hormones act throughout the body to elicit changes in gene expression that result in profound effects on reproductive physiology and behavior. Steroid hormones exert many of these effects by binding to their respective intracellular receptors, which are members of a nuclear receptor superfamily of transcriptional activators. A variety of in vitro studies indicate that nuclear receptor coactivators are required for efficient transcriptional activity of steroid receptors. Many of these coactivators are found in a variety of steroid hormone-responsive reproductive tissues, including the reproductive tract, mammary gland, and brain. While many nuclear receptor coactivators have been investigated in vitro, we are only now beginning to understand their function in reproductive physiology and behavior. In this review, we discuss the general mechanisms of action of nuclear receptor coactivators in steroid-dependent gene transcription. We then review some recent and exciting findings on the function of nuclear receptor coactivators in steroid-dependent brain development and reproductive physiology and behavior. behavior, hypothalamus, neuroendocrinology, steroid hormone receptors ROLE OF STEROID HORMONES IN BRAIN DEVELOPMENT AND REPRODUCTIVE BEHAVIOR Organizational Effects of Steroid Hormones Steroid hormones have profound effects on development, growth, and reproduction. Most of these effects can be classified as organizational and activational effects. Organizational effects occur prior (or just after) birth and are usually permanent, while activational effects occur long after birth (usually in adulthood) and are often transient. Reproductive physiology and behavior in adults require the appropriate hormone-dependent development of reproductive organs and specific neural substrates. A classic example of hormonal influences on sexual differentiation of the brain is the development of the sexually dimorphic nucleus 1Grant support by NIH R01 DK61935 and NSF IBN-0080818 (M.J.T.) and NIMH T32MH47538 (H.A.M.). 2Correspondence: Marc J. Tetel, Department of Biology and Neuroscience Program, Skidmore College, 815 North Broadway, Saratoga Springs, NY 12866. FAX: 518 580 5071; e-mail: [email protected] Received: 14 May 2003. First decision: 3 June 2003. Accepted: 9 July 2003. Q 2003 by the Society for the Study of Reproduction, Inc. ISSN: 0006-3363. http://www.biolreprod.org of the preoptic area (SDN-POA), a hypothalamic region involved in the control of adult sexual behavior in rodents [1]. In males, this nucleus is three to four times larger in volume and contains a greater density of cells than in females [1]. Castration of male rats on the day of birth reduces the size of the SDN [2]. Testosterone (T) administration to female rat pups during the first week of life will increase the volume of this nucleus to that of normal males [2]. A variety of studies have revealed that these effects of testosterone on the SDN-POA are due to the conversion of T to estradiol (E) by the enzyme aromatase [3, 4]. Aromatase is found in a variety of brain areas, including the POA [5], which is the primary neural structure that controls male sexual behavior in rodents [6, 7]. The T surge in males just after birth also suppresses the development of female sexual behavior in adulthood [8, 9]. This suppression of female sexual behavior is due to E, aromatized from T, binding to ER [10]. In addition, the development of masculine sexual behavior in the adult male rat is dependent on this T surge and is mediated by androgen receptors [11, 12]. In adult male rats that were castrated and treated with either T or E, no differences were found in the number of mounts or intromissions. Interestingly, rats receiving T ejaculated more frequently than those treated with E [13, 14]. These findings suggest that while E does not elicit full male sexual behavior alone, many of the effects of T on brain and behavior are mediated by its conversion to E. Activational Effects of Steroid Hormones The ovarian steroid hormones E and progesterone (P) act in the brain to regulate female sexual behavior in rodents [15]. During the 4–5-day rat estrous cycle, follicle stimulating hormone acts at the ovaries to induce an estrogen peak on the day of proestrus [16, 17]. This peak in E is followed by a rise in luteinizing hormone (LH), which causes ovulation [16, 17]. Approximately 48 h after the E peak, the corpus luteum begins to produce P, and estrous behaviors begin [18, 19]. In rodents, E is necessary for sexual receptivity, which is characterized by the lordosis posture [20, 21]. This welldefined posture consists of the female arching the back and raising the head and hindquarters in response to mounting by a male [22]. Ovariectomy eliminates lordosis, while administration of E, followed by P, to mimic the estrous cycle, induces the expression of lordosis [20, 21, 23]. One physiological function of E is to induce progestin receptors (PR) in the brain and other reproductive tissues [24–28].