Congenital estrogen deficiency in men: a new syndrome with different phenotypes; clinical and therapeutic implications in men

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Abstract

The report focuses on the role of estrogens in human male, dealing with two human models of congenital estrogen deficiency: estrogen resistance and aromatase deficiency. Similarities and differences of clinical phenotypes of these models are described and progresses of estrogen treatment of aromatase-deficient men are reported. Finally, the putative use of estrogen in men and the use of aromatase inhibitors and antiestrogen for male disorders are discussed.

Introduction

Until now, only few naturally occurring inactivating mutations have been documented in both estrogen receptor (ER) α and aromatase gene in humans. These findings allowed to define the clinical phenotype of congenital lack of estrogens in men. Anyhow the comprehension of estrogen physiology in human male is far from being exhaustive (Faustini-Fustini et al., 1999, Grumbach and Auchus, 1999).

These recent advances rise some questions of whether estrogen treatment will be promising for the future not only for aromatase-deficient men, but also for men's health in some particular pathological circumstances. The issue concerning the use of aromatase inhibitors as therapeutics in men is also discussed.

Section snippets

Human models of estrogen deficiency in men

At present, two reported different conditions causing congenital estrogen deficiency in the human male have been described: (1) a complete defect of ER α, and (2) the congenital absence of aromatase activity. Till now, only one adult man with a defect of ER α and three adult men with aromatase deficiency have been described (Smith et al., 1994, Morishima et al., 1995, Carani et al., 1997, Bilezikian et al., 1998, Murata et al., 2001, Maffei et al., 2001a). Preliminary data concerning the third

Estrogen replacement therapy in males with aromatase deficiency

The beneficial effects of estrogen treatment in aromatase-deficient men have been well documented in two of the three patients affected, while in the unique man with the complete defect of α-ER, estrogen supplementation has been demonstrated to be useless (Smith et al., 1994).

In aromatase-deficient men, estrogen treatment was effective in obtaining a complete bone maturation by promoting both epiphyseal closure and bone mineralization (Bilezikian et al., 1998, Carani et al., 1997), while

Estrogen treatment: future perspectives

Traditionally estrogen therapy has been used in men for the treatment of prostate cancer and in male to female transsexuals (Table 4).

Before the development of LHRH analogs, estrogen treatment was used in the past for the treatment of prostate cancer in men. High doses of estrogens suppresses gonadotropin secretion (Rochira et al., 2001a, Rochira et al., 2001b, Hayes et al., 2000) and consequently lowers androgen production from the testis (Lippman, 1998). At present estrogen treatment is

Aromatase inhibitors and antiestrogens in the human male: clinical implications

The development of a new generation of aromatase inhibitors (Seralini and Moslemi, 2001) is opening new interesting perspectives concerning their possible clinical use alone or in combination with growth hormone for the treatment of male growth disorders (e.g. growth hormone (GH) deficiency, idiopathic short stature) (Table 5). Evidences do exist that aromatase inhibitors are efficacious in delaying bone maturation in boys. Recently, in fact, anastrazole was effective in slowing cartilage

Conclusions

Several lines of evidence support the view that estrogens are required and mediate part of the actions of androgens on bone tissue at puberty and regulate bone homeostasis during adulthood in men. Thus estrogens seem to be the main sex steroids involved in the final phases of skeletal maturation (e.g. achievement and maintenance of peak bone mass, epiphyseal closure).

The improvement of our knowledge of the natural history of congenital estrogen deficiency together with further progress in the

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