تغییرات در گیرنده های آندروژن، گیرنده استروژن آلفا، و رفتار جنسی با افزایش سن و تستوسترون در موش صحرایی نر

Reproductive aging in males is characterized by a diminution in sexual behavior beginning in middle age. We investigated the relationships among testosterone, androgen receptor (AR) and estrogen receptor alpha (ERα) cell numbers in the hypothalamus, and their relationship to sexual performance in male rats. Young (3 months) and middle-aged (12 months) rats were given sexual behavior tests, then castrated and implanted with vehicle or testosterone capsules. Rats were tested again for sexual behavior. Numbers of AR and ERα immunoreactive cells were counted in the anteroventral periventricular nucleus and the medial preoptic nucleus, and serum hormones were measured. Middle-aged intact rats had significant impairments of all sexual behavior measures compared to young males. After castration and testosterone implantation, sexual behaviors in middle-aged males were largely comparable to those in the young males. In the hypothalamus, AR cell density was significantly (5-fold) higher, and ERα cell density significantly (6-fold) lower, in testosterone- than vehicle-treated males, with no age differences. Thus, restoration of serum testosterone to comparable levels in young and middle-aged rats resulted in similar preoptic AR and ERα cell density concomitant with a reinstatement of most behaviors. These data suggest that age-related differences in sexual behavior cannot be due to absolute levels of testosterone, and further, the middle-aged brain retains the capacity to respond to exogenous testosterone with changes in hypothalamic AR and ERα expression. Our finding that testosterone replacement in aging males has profound effects on hypothalamic receptors and behavior has potential medical implications for the treatment of age-related hypogonadism in men.

In a variety of mammalian species including rats, monkeys and humans, there is an age-related decline in sexual performance that may be attributable to physiological or psychological changes (Chambers & Phoenix, 1983, Nicolosi et al., 2004 and Smith et al., 1992). Much of the loss of male sexual function with aging has been correlated with a decline in serum testosterone. This change has been shown in humans (Harman et al., 2001), rhesus monkeys (Downs and Urbanski, 2006), and rats, including Sprague–Dawley (Roselli et al., 1986, Wu et al., 2009 and Karpas et al., 1983), Wistar (Bernardi et al., 1998 and Taylor et al., 1996), Brown Norway (Chen et al., 1994 and Gruenewald et al., 2000), and Fischer 344 strains (Chambers et al., 1991 and Luine et al., 2007). However, not all studies show a clear relationship among testosterone, aging, and sexual behavior, a concept that is particularly important when considering the transitional life period of middle age. In fact, during this life stage, testosterone levels in rats may or may not differ from those in young animals depending on the absolute chronological age, strain, and/or other physiological, behavioral and experimental differences. Thus, whereas some studies have shown age-related declines in testosterone at middle age, others have not demonstrated such a loss (Gruenewald et al., 2000, Frankel & Mock, 1981 and Wu & Gore, 2009). Furthermore, testosterone replacement to castrated aging rats does not effectively reinstate sexual performance as it does in young rats (Chambers & Phoenix, 1984, Chambers & Phoenix, 1986, Chambers et al., 1991 and Sato et al., 1998), underscoring the point that absolute testosterone levels do not necessarily predict the capacity to perform sexual behavior, and that there are other changes to the aging brain that may explain this behavioral decline. Furthermore, much of this latter literature is primarily focused on old rats and information about effects of testosterone treatment to middle-aged rats is rather limited, raising the question of what hormonal and neurobiological changes may be occurring at this life stage. We hypothesized that the loss of sexual behavior with age may not be due to levels of testosterone per se but rather to age-related changes in the actions of testosterone on its androgen receptor (AR) in brain regions involved in the control of masculine sexual behaviors and the hypothalamic–pituitary–gonadal axis ( Vagell & McGinnis, 1998 and Portillo et al., 2006). Circulating testosterone levels regulate expression of the AR, as in young males, castration can eliminate, and testosterone replacement can restore, AR expression in the brain ( Iqbal et al., 1995, Lu et al., 1998, Lu et al., 1999 and Wood & Newman, 1993). In comparing young and old male Fischer 344 rats (4 and 26 months, respectively), Chambers et al. (1991) showed that nuclear AR binding is very low in castrated rats, and elevated by testosterone treatment in both ages, albeit to a greater extent in the young group. This suggests that the responsiveness of the aging brain to testosterone is diminished. We showed age-related increases in AR immunoreactive cells within several preoptic–hypothalamic regions between young and middle-aged rats ( Wu & Gore, 2009 and Wu et al., 2009). However, much more information is needed about the implications of this change at midlife. It is also important to consider that some actions of testosterone on masculine behaviors and physiology are due to its aromatization to estradiol and subsequent actions on estrogen receptors (ER) (Clancy et al., 2000, Larsson et al., 1973, Morali et al., 1977, Vagell & McGinnis, 1997 and Zumpe et al., 1993). Relatively little is known about the interactions among estradiol, aging, and behavior. Even the literature on serum estradiol is quite contradictory depending upon rat strain and absolute age: levels of estradiol have been reported to undergo no change (Goya et al., 1990 and Wu et al., 2009), decrease [an effect that was dependent upon prior sexual experience (Wu and Gore, 2009)], or increase (Fujita et al., 1990, Herath et al., 2001 and Luine et al., 2007). The hypothalamic ERα may also change with age, although evidence to date shows little change in ERα gene expression or protein immunoreactivity with aging (Bottner et al., 2007, Madeira et al., 2000, Wu & Gore, 2009 and Wu et al., 2009). Still, this question merits investigation in the context of sexual behavior and aging. In the current study, we investigated the effects of aging, testosterone treatment, and their interactions on sexual behavior and expression of AR and ERα in the hypothalamus, focusing on the transition between young and middle-aged rats. Together, these studies were intended to provide novel information about the potential roles of these hormone receptors, their regulation by testosterone, and their relationship to sexual behavior during reproductive aging.

We had initially hypothesized that the age-related behavioral decline in masculine behaviors may be due to changes in androgen and estrogen receptor numbers in the hypothalamus, and/or a diminished responsiveness of these receptors to testosterone treatment in animals of increasing age. The current results do not support that hypothesis, as both young and middle-aged castrated males responded similarly to testosterone replacement with an up-regulation of the AR and a down-regulation of the ERα. Therefore, we postulate that other neurotransmitter systems involved in the control of sexual behaviors in male rats are responsible for the pre-castration differences between the two age groups. In addition, other brain regions involved in the neural circuitry that controls masculine behaviors merit investigation. Future studies are necessary to delineate the nature of these circuits in middle-aged males.