Familial gynecomastia with increased extraglandular aromatization of plasma carbon19-steroids.

Abstract

We evaluated a family in which gynecomastia occurred in five males in two generations. In each affected subject, gynecomastia and male sexual maturation began at an early age. The ratio of the concentration of plasma estradiol-17#6 to that of plasma testosterone was elevated in each affected subject. In the three siblings with gynecomastia, the transfer constant of conversion of androstenedione to estrone (i.e., the fraction of plasma androstenedione that was converted to estrone as measured in the urine) was 10 times that of normal persons. The transfer constant of conversion of testosterone to estradiol-170 in the one subject studied also was 8-10 times that of normal men, whereas the transfer constants of conversion of estrone to estradiol-17j0 and of estradiol-17,6 to estrone were normal.Despite the elevation in extraglandular aromatase activity, there was a normal response of the hypothalamic-pituitary axis to provocative stimuli. This is the second documentation of gynecomastia that is associated with increased extraglandular aromatase activity, and the first time that the defect was found to be familial with a probable X-linked (or autosomal dominant, sex limited) mode of inheritance.

Aromatase and gynecomastia.

“…The authors hypothesized that the syndrome was the result of a failure in the normal decline in expression of both P450 arom and sulfokinase enzyme activities after birth (Hemsell et al 1977). Subsequently, several families with this syndrome have been described with apparent autosomal dominant and X-linked recessive or sex-linked autosomal dominant modes of inheritance described (Berkovitz et al 1985, Leiberman & Zachmann 1992, Stratakis et al 1998. Males exhibit heterosexual precocity with gynecomastia, accelerated height and bone age in childhood and adolescence and shortened final adult height, while females have isosexual precocity and macromastia.…”

Gynecomastia: Pathomechanisms and Treatment Strategies

“…Obesity [13], liver disease [14], testicu lar feminization [10], and Klinefelter's syndrome [15], all may result in increased peripheral aromatization. Prima ry aromatase excess, possibly due to persistence of fetal aromatase, is another condition which may cause gyneco mastia through increased peripheral aromatization of an drogens to estrogens [16], This condition may result in extremely high estrogen levels and subsequent prolifera tion of breast tissue. Pathological increases in estrogen levels may also be seen in conditions such as Leydig cell tumors and feminizing adrenocortical neoplasms.…”

Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment

“…MacDonald and his colleagues described originally a feminized, prepubertal adopted boy in whom large amounts of estrone and estradiol were produced by extraglandular aromatization of plasma androstenedione (Hemsell et al, 1977). Five families were subsequently described in which several members had estrogen excess as a result of increased extraglandular aromatization inherited in an autosomal dominant fashion (Berkovitz et al, 1985;Leiberman and Zachmann, 1992;Stratakis et al, 1998;Martin et al, 2003;Shozu et al, 2003b).…”