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The development of visible breasts in males has fascinated human culture for millennia, at least since Pharaoh Amenhotep IV (Akhenaten) and his family ruled Egypt; medical journals still discuss whether or not his son, Tutankhaten (Tutankhamun), had gynecomastia (1). There is no question that a breast for “male” activities was at least as impractical as the Amazons had discovered—they underwent right mastectomy so that they could use their bows or throw their javelin better—and that femininity (at least in the eyes of culture) depended on the presence of breast, as Saint Agatha of Sicily found when she underwent bilateral mastectomy as part of her faith-defending torture. The medical term we use today, “gynecomastia,” is indicative of these cultural assumptions; it defines the presence, in a male, of “μαστóς” (breast in Greek) as if he were a “γυναíκα” (female in Greek).

Be that as it may, but is gynecomastia a sign of disease? As we all know today, the answer is yes, but only in rare cases (2). Most gynecomastia in growing boys is a transient and almost normal phenomenon (3); however, in prepubertal children and in adults who have never had visible breast previously, the development of breast is a clinical sign of abnormality. In the vast majority of cases, it reflects the lack of androgens (4, 5), the exposure to estrogen or estrogen-like compounds (6, 7), or an inability to metabolize these compounds properly (8, 9). In other cases, gynecomastia may be the result of abnormal expression, excessive, ectopic, or both, of a fascinating enzyme (10) that was first suspected in the 1930s (11), was proven to exist in the 1950s (12, 13), was further elucidated in the 1960s (14, 15), and was shown to be expressed widely beyond the expected estrogen-forming tissues of the ovaries and the placenta in the 1970s (16). Of particular importance was the finding that aromatase was expressed within breast carcinoma tissues (17, 18), which made the development of inhibitors of its action essential for chemotherapy of breast cancer. It was this need that led to the development of testolactone (19), a first-generation aromatase inhibitor (AI) and ancestor of today's potent AIs (anastrozole, letrozole, and others). These studies were done without actually having the pure enzyme at hand; the human aromatase cytochrome P450 enzyme (P450arom; the product of the CYP19A1 gene) was purified in the 1980s (20), and the CYP19A1 cDNA followed soon thereafter (21). The identification of the gene sequence led to the description of CYP19A1-inactivating mutations (22, 23) that were the molecular cause of aromatase deficiency (AD), a syndrome that was first suggested to exist in humans in 1978 in the case of a primigravida woman who had low urinary estrogen excretion and lacked placental aromatase activity in vitro (24). This was conclusively demonstrated for the first time in a severely virilized pregnant mother, who gave birth to a severely virilized newborn girl with a mutated CYP19A1 gene, as a consequence of aromatase-deficient placenta that is genetically fetal tissue (25, 26). Androgens of fetal adrenal origin could not be aromatized and cleared by aromatase-deficient placenta and thus virilized both the female fetus and her mother (25).

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Editorial > Editorials
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