Studies on men with spontaneous gene deletions

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There is one report of a man lacking a functional estrogen receptor because of a premature stop codon in exon 2 of the estrogen receptor gene (Smith et al., 1994). This man showed no response to administration of estradiol despite a large increase in blood estradiol concentration. The patient had normal male genitalia with bilateral descended testes, each with a volume of 20-25 ml, and a normal-sized prostate gland. Semen analysis showed a reduced sperm motility (viability of 18% against around 50% in normal men) with a normal sperm count of 25 million per millilitre. He indicated strong heterosexual interests and reported normal sexual functioning, including presence of morning erections and nocturnal emissions. From the clinical data reported, it is quite evident that the man lacked the estrogen receptor a. Although data from a single case study are far from sufficient for any firm conclusion, the evident lack of alterations of sexual behaviors in this man is remarkably different from the severe consequences of the absence of the estrogen receptor a in male mice. In addition to underlining possible crucial species differences, the data from the human aERKO, so to say, reinforce the notion that estrogens are not important for sexual behaviors in the human male.

Some men have an inactivating mutation in the gene coding for aromatase, CYP19. Up to 2005, seven cases have been identified and studied (Jones et al., 2006). This number is very low and any conclusion obtained from the studies of these seven men must be regarded as very uncertain. Nevertheless, sexual behaviors appear to be of normal intensity in all seven, although fertility may be reduced by the congenital lack of estrogens (Simpson, 2004). Plasma hormone concentrations are variable, with some men showing elevated testosterone concentrations (Morishima et al., 1995), while others have concentrations close to the lower end of the normal range (Carani et al., 1997). Obviously, estrogen is not found in the blood of these men. One case study suggests that estrogen treatment enhances sexual functioning above pretreatment levels (Carani et al., 1999), while another study fails to find this effect (Carani et al., 2005). However, the combined treatment with estradiol + testosterone was reported to increase masturbation, morning erections, erotic fantasies and 'libido' in one man. Actual copulatory behaviors were non-existent, because the patient was a catholic priest taking his faith seriously. In any case, these studies do not offer sufficiently clear results for any conclusion at all. Considering the previously mentioned modest or absent effects on sexual behaviors of estrogen receptor blockade and the apparently normal sexual behaviors in men lacking functional aromatase, I would suggest that activation of estrogen receptors is not a requisite for sexual behaviors in men. Here we have a nice example of a rather drastic species difference. While males of some mouse strains, like the 129 back-crossed into the C57/BL6, show a severely impaired sexual behavior if estrogen receptors are not stimulated, sexual behavior in the human male appears essentially independent of estrogen receptor activation.

The proposal of a modest or absent role for estrogen receptors in the control of human male sexual behavior is supported by additional observations. Most interestingly, just as in rodents there exist natural mutations in the androgen receptor gene that lead to a receptor that is entirely non-functional or that has a much reduced function. These rare mutations and their consequences were actually described in humans before similar mutations were found in other mammals. The most frequent of the human variant appears to be a point mutation in the androgen receptor gene localized on the long arm of the X-chromosome (Xq11-13). In addition to point mutations, several other kinds of errors in the androgen receptor gene have been described. In the case of a total loss of function, the complete androgen insensitivity syndrome appears. The affected individuals are born with female external genitalia, while having functional, non-descended testicles, producing amounts of androgens similar to those in a normal male. Since the fetal testicles secreted Müllerian inhibiting hormone they lack female internal genitalia, i.e. there are no fallopian tubes, no uterus and no upper vagina. Nevertheless, the external appearance is that of a female and therefore these genetic males are usually raised as girls. When androgen binding affinity is reduced but not absent, a conditioned called partial androgen insensitivity syndrome, the phenotype is most variable. It ranges from virilized female external genitalia (in its mildest form clitorimegaly without other anomalies) to almost normal male genitals, albeit with penile hypotrophy and/or hypospadia. For excellent summaries of both the complete and incomplete androgen insensitivity syndrome, the reader is referred to French et al. (1965) or to Patterson et al. (1994). Because of the large variability within the partial androgen insensitivity syndrome, I will concentrate the following discussion on the complete form.

It may be important to observe that what is now called androgen insensitivity syndrome was called testicular feminization for many years. The latter is the name found in most of the older literature and also in reports from non-human animals, as mentioned in the preceding section. Now and then the name Morris' disease (after the physician who first described it) is used.

Very few studies have investigated the psychosexual development in individuals suffering from complete androgen insensitivity syndrome, i.e. genetic males raised as females. This is in sharp contrast to the many reports of physiopathological aspects of the syndrome. In fact, there is only one study of psychosexual development satisfying elementary methodological criteria (Wisniewski et al., 2000). According to that study, individuals with complete androgen insensitivity show a normal female sexual behavior, have normal levels of 'libido' and normal levels of sexual satisfaction. Some cases required surgical intervention because of a shallow vagina and most individuals had had their testicles removed. Vaginoplasty as well as gonadectomy were usually performed during early adolescence. Some patients received estrogen treatment. Since compliance with estrogen therapy was low, this latter did not seem to be of major importance. These observations suggest that a functional androgen receptor is the sole source of masculinization. The androgen insensitive fetus must have been exposed to estradiol produced by aromatization from testosterone, so estrogen receptors do not seem to contribute to masculinization in the human. Interestingly, presence of a Y-chromosome, of testicles (at least until adolescence), of above normal body length etc. does not appear to affect psychosexual development as a female. It must be noted, though, that this study included only 13 subjects. As a curiosity it may also be mentioned that one of them displayed homosexual practices. Nevertheless, the results from this study coincide with the notion that the human brain differentiates in a female direction in the absence of testosterone actions.

It could, obviously, be argued that the assignment of a female gender at birth, and the subsequent up-bringing as a girl, is the cause of the female identity. However, there are cases where genetic males with functional androgen receptors and normal testicular androgen production have been assigned female gender and subjected to surgery to change the external genitalia to female shortly after birth. The cause for this has usually been insults causing irreparable damage to the penis. Many of these individuals show a male-like behavior during childhood, and at puberty they find females more attractive than males (reviewed in Diamond and Sigmundson, 1997). This is exactly the opposite to what was observed with men suffering from complete androgen insensitivity, and would suggest that the organizing and activating effects of testosterone in the human is dependent on the androgen receptor.

It should be observed that clinical studies of rare diseases are almost always limited to very few cases and results are influenced by a variety of uncontrolled and/or unknown factors. This makes the establishment of cause-effect relationships almost impossible and we should avoid the founding of vast hypotheses upon this kind of half-anecdotal observation.

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