Another role highlighted for estrogens in the male: sexual behavior.

M of lack of estrogen representation, whether they be failure of synthesis or insensitivity of response, have provided new, and in some respects counterintuitive, insights into the roles of estrogens in both males and females. Among the natural mutations, there is currently 1 man identified with a mutation of the estrogen receptor a (ERa) and up to 10 individuals with mutations of the gene encoding aromatase, the enzyme responsible for estrogen biosynthesis. Of these, 2 are men. In addition, there are various mouse models involving targeted gene disruption. These include knock-outs of the ERa (aERKO; ref. 1) and ERb (bERKO; ref. 2) genes as well as the double ERa and ERb (abERKO; ref. 3) knockout, in addition to the aromatase knockout (ArKO; refs. 4–6) mice. Analysis of the phenotypes resulting from these mutations has revealed various degrees and types of infertility in both male and female, depending on the mutation involved. Lipid and carbohydrate phenotypes involving increased adiposity with insulin resistance, hyperlipidemia and hyperleptinemia as well as disturbances in behavior patterns, both social and sexual, have also been described (6–8). These studies reveal that estrogens have more extensive roles in physiology than was previously thought, and moreover these are frequently of a non-sexually dimorphic nature. Indeed the traditional concepts of the terms estrogen and androgen are now challenged because the role of estradiol in the regulation of spermatogenesis (3, 9) is one that would more properly be classified as androgenic. Another important concept that has emerged in recent years is that in postmenopausal women, as well as in men, estrogens function primarily as paracrine or even intracrine factors (10, 11). Thus, following menopause, when the ovaries cease to produce estradiol and circulating estrogen levels are extremely low, estrogen is produced in a variety of extragonadal sites and acts locally to stimulate adjacent cells or even the cells in which it is produced. These sites include osteoblasts and chondrocytes of bone (12), where it plays a key role in the maintenance of bone mineralization in both males and females; adipose tissue, particularly of the breast, which is the major site of formation of estrogen driving breast cancer development in the postmenopausal woman (reviewed in ref. 13); and also numerous sites in the brain, where it serves key roles in the regulation of reproduction, behavior, and perhaps also cognitive function. Both estrogen receptors, namely ERa and ERb, which bind to estradiol with similar affinity, have been identified in numerous sites in the brain (14, 15). For example, both are present in the arcuate nucleus and the preoptic area of the hypothalamus, while ERa is present in the ventromedial nucleus and ERb in the paraventricular nucleus. These regions of the hypothalamus are important in reproduction, sexual behavior, thermoregulation, and feeding behavior. Both receptors also appear to be present in the amygdala and hippocampus, where they may be involved in short-term memory and emotion. ERb has also been identified in the cerebellum and in cortical regions. The article by Ogawa and colleagues in this issue of PNAS (16) deals with the effect on male sexual behavior of targeted disruption of both ERa and ERb in mice (the abERKO mice). Previous studies by this group in mice that lack the gene for either ERa (aERKO) or ERb (bERKO) individually have shown that male sexual behaviors are partially disrupted or virtually normal. aERKO mice, although they rarely ejaculated and were infertile, manifested almost normal frequency of mounts but reduced numbers of intromissions (17). In contrast, all three components of sexual behavior were present and robust in bERKO males (18). However, in ArKO male mice, sexual behavior is severely compromised, including a marked reduction in mount frequency and prolonged mount latency (ref. 5; K. M. Robertson and M. E. E. Jones, personal communication; Table 1). However male ArKO mice are fertile at least until the age of 14–20 weeks (9). No detailed analysis of ArKO ejaculatory or intromission behavior has yet been reported. These results suggest either that ER activation may be only partially responsible for the induction of male sexual behavior or else in aERKO and bERKO mice the one missing ER gene is compensated for by the other. In contrast to sexual behavior, aggressive behavior is greatly reduced in aERKO male mice (16, 19). In particular, male typical offensive attacks were almost abolished in both gonadally intact and testosterone-treated gonadectomized aERKO mice, whereas lunge and bite attacks, which are considered to represent mild and short-lasting aggressive behaviors, were still present. In bERKO male mice on the other hand, aggressive behavior was not reduced but rather was elevated, depending on age and social experience (17).§ These findings suggest that ERb might be inhibitory of male aggressive behavior, which is facilitated by action of the androgen receptor, ERa, or both. So again the question arises, How might the deletion of both ERa and ERb gene function affect male aggressive behavior? To answer these questions, Ogawa et al. (16) used double-knockout mice lacking both ERa and ERb genes, namely the abERKO mice. Aggressive behaviors and sexual behaviors were evaluated in male abERKO mice, and results were compared with those of single-knockout (aERKO and bERKO) as well as wildtype littermates. Sexual behavior was studied in the male mice by placing a female in the male’s own cage. The females were ovariectomized and injected s.c. with estradiol benzoate and progesterone to ensure high sexual receptivity. For