The role of testosterone metabolites in nonhuman males

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In the 1960s, it was discovered that a testosterone metabolite, 5a-dihydrotesto-sterone, was formed from circulating testosterone in peripheral target organs like the prostate or seminal vesicle. The enzyme responsible for the transformation of testosterone into dihydrotestosterone, 5a-reductase, was found to be present in target tissues. Dihydrotestosterone has a higher affinity for the testosterone receptor than testosterone itself and it was soon suggested that testosterone was a pre-hormone and that it needed to be transformed into dihydrotestosterone before having any physiological effect (Wilson and Gloyna, 1970). It was quite logical to suppose that this would also be the case for the actions of testosterone within the central nervous system, particularly since 5a-reductase had been shown to be present in the brain (Jaffe, 1969). To the surprise of many scientists, this was not the case. Dihydrotestosterone turned out to be quite inefficient for the restoration of copulatory behavior in castrated male rats (McDonald et al., 1970). In addition, some studies had shown that androgen receptor antagonists failed to block male rat copulatory behavior while blocking testosterone actions in peripheral tissues such as prostate and seminal vesicle (Beach and Westbrook, 1968; Whalen and Edwards, 1969). These two lines of evidence made it possible to propose that stimulation of the androgen receptor within the central nervous system was not necessary for sexual behavior. At about the same time, another enzyme had been described, aromatase. This enzyme transforms testosterone into estradiol. Interestingly, aro-matase was found mainly in the brain, particularly in areas thought to be important for copulatory behavior (Ryan et al., 1972). It was already known that estradiol had some stimulatory effects on this behavior in castrated animals. In fact, estra-diol was known to efficiently stimulate mounting, but its effects on intromission were slight (Beach, 1942a; Davidson, 1969; Sodersten, 1973). The hypothesis that testosterone acts in the form of dihydrotestosterone in the periphery, maintaining the integrity of the penis and penile muscles, and in the form of estradiol in the brain, maintaining the integrity of the central nervous system processes necessary for sexual behaviors, was born from these two lines of evidence. Experimental support was soon obtained. It turned out that minute doses of estradiol combined with dihydrotestosterone was just as efficient as testosterone for the restoration of copulatory behavior in castrated rats (Baum and Vreeburg, 1973; Larsson et al., 1973). The pioneering observations were soon confirmed in an impressive amount of studies employing different techniques. For example, the effects of brain implants of testosterone, estradiol and dihydrotestosterone were evaluated in castrated male hamsters and it was found that testosterone was more efficient than estra-diol, while dihydrotestosterone was inactive with regard to stimulation of copula-tory behavior (Lisk and Bezier, 1980). Inhibitors of aromatase were shown to block the capacity of testosterone to stimulate this behavior in castrated male rats (Beyer et al., 1976; Morali et al., 1977) and an estrogen receptor antagonist was found to have similar effects (Luttge, 1975). Thus, it appears that the stimulation of androgen receptors alone is not sufficient for the activation of male sexual behavior in castrated male rats. This appears to be the case also in some other rodents. These observations led some scientists to consider that aromatization to estradiol was a requisite for all central nervous effects of androgens, at least as far as sexual behaviors are concerned. Furthermore, the notion was extended from rodents to other species and it appears in some textbooks as a general principle applicable to all mammals and also to birds.

Both the conclusion that all androgen actions are mediated by estradiol, and hence by the estrogen receptor, and its extension to non-rodent species may have been premature. I showed, in the early 1970s, that an androgen receptor antagonist efficiently blocked copulatory behavior in male rabbits (Agmo, 1975) and that dihydrotestosterone could activate that behavior in castrated males (Agmo and Sodersten, 1975). In addition, a non-aromatizable, synthetic androgen, fluoxymes-terone, was as efficient as testosterone for activating copulatory behavior in castrated rabbits (Agmo, 1977). Likewise, dihydrotestosterone was found efficiently to restore copulatory behaviors in castrated male guinea-pigs, either after peripheral administration (Alsum and Goy, 1974) or after implantation into the brain (Butera and Czaja, 1989). In mice, systemic dihydrotestosterone restores sexual behavior to precastrational levels in some strains while this androgen is inactive in others (Luttge and Hall, 1973). There are also rat strains that are responsive to dihydrotestosterone (Olsen and Whalen, 1984). This androgen also activates sexual behaviors in the rhesus monkey (Phoenix, 1974), while estradiol is ineffective in this primate (Michael et al., 1990). It seems safe to conclude that aromatization of androgens and consequent stimulation of estrogen receptors is of no importance for male sexual behavior in the rhesus monkey. In the crab-eating macaque, also called the long-tailed macaque or the cynomolgus monkey (Macaca fascicularis), the role or lack of a role of aromatization is less clear than in the rhesus. There are data showing that dihydrotestosterone is unable to restore sexual behavior in castrated males (Michael et al., 1986) and that the aromatase inhibitor fadrozole reduces this behavior in castrated males given testosterone replacement. Strangely enough, the behavioral deficits caused by fadrozole were not reliably reversed with concurrent treatment with estradiol (Zumpe et al., 1993, 1996), making it very difficult to understand by which mechanism fadrozole reduced sex behavior. This and other observations not mentioned here justify the conclusion that 'aromatiza-tion does not appear to be obligatory for the activation of male copulatory behavior' in the cynomolgus monkey (Wallen, 2005, p. 21).

Non-aromatizable androgens can also activate copulatory behaviors in rats (Morali et al., 2002). Furthermore, more recent rat data have convincingly shown that androgen receptor antagonists may have deleterious effects on male rat sexual behaviors. This assertion is based on a series of extremely interesting studies from Marilyn McGinnis laboratory at the Mount Sinai School of Medicine in New York. First they showed that systemic administration of an androgen receptor antagonist, OH-flutamide, efficiently blocks testosterone-induced restoration of copula-tory behaviors in castrated male rats and reduced the intensity of the behavior in intact males (McGinnis and Mirth, 1986). They then proceeded with intracerebral administration of the antagonist and found that it blocked testosterone-induced restoration of sex behavior when implanted into some hypothalamic sites. Implants into the septum were ineffective while medial amygdala implants produced a partial inhibition of testosterone's effects (McGinnis et al., 1996). The importance of androgen receptors at hypothalamic sites has been confirmed in later studies (Harding and McGinnis, 2004). It is important to point out that OH-flutamide does not bind to the estrogen receptor, so a blockade of estrogen effects cannot contribute to the actions of OH-flutamide.

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