[Adam F]

NON-TUMOR CAUSES OF ESTROGEN EXCESS:

INCREASED AROMATASE ACTIVITY
Besides tumors, other conditions have been associated with excessive aromatization of testosterone and androgens to estrogen, which results in gynecomastia. For instance, a familial form of gynecomastia has been discovered, in which affected family members have an elevation of extragonadal aromatase activity. More recently, novel gain-of-function mutations in chromosome 15 have been reported to cause gynecomastia, possibly by forming cryptic promoters that lead to over expression of aromatase. As stated, obesity may cause estrogen excess through increased aromatase activity in adipose tissue. Furthermore, hyperthyroidism induces gynecomastia through several mechanisms, including increased aromatase activity.


DISPLACEMENT OF ESTROGENS FROM SHBG
Another cause of gynecomastia from estrogen excess includes steroid displacement from sex-hormone binding globulin (SHBG). SHBG binds androgens more avidly than estrogen. Thus, any condition or drug that can displace steroids from SHBG, will more easily displace estrogen, allowing for higher circulating levels of estrogen. Drugs can cause gynecomastia by numerous mechanisms besides displacement from SHBG.

DECREASED TESTOSTERONE AND ANDROGEN RESISTANCE
Breast development requires the presence of estrogen. Androgens, on the other hand oppose the estrogenic effects. Thus, equilibrium exists between estrogen and androgens in the adult male to prevent growth of breast tissue, whereby either an increase in estrogen or a decrease in androgen can tip the balance toward gynecomastia. Increased estrogen levels will increase glandular proliferation by several mechanisms. These include direct stimulation of glandular tissue and by suppressing LH, therefore decreasing testosterone secretion by the testes and exaggerating the already high estrogen to androgen ratio.

Besides increased estrogen production, decreased testosterone levels can cause an elevation in the estrogen to androgen ratio, producing gynecomastia. Primary hypogonadism, with its reduction in serum testosterone and increased serum LH levels increases testicular estradiol production and is associated with an increased estrogen to androgen ratio. Klinefelter's syndrome, occurring in 1 in 500 males who possess an XXY karyotype and primary testicular failure, features gynecomastia as well, again presumably secondary to decreased testosterone production, compensatory increased LH secretion, overstimulation of the Leydig cells and relative estrogen excess. In addition, any acquired testicular disease resulting in primary hypogonadism such as viral and bacterial orchitis, trauma, or radiation can also promote gynecomastia by the same mechanisms.

Lastly, enzyme deficiencies in the testosterone synthesis pathway from cholesterol also result in ***ressed testosterone levels and hence a relative increase in estrogen. Deficiency of 17-oxosteroid reductase, the enzyme that catalyzes the conversion of androstenedione to testosterone and estrone and estrone to estradiol, for example, will cause elevation in estrone and androstenedione, which is then further aromatized to estradiol.

Secondary hypogonadism, if severe enough, results in low serum testosterone and unopposed estrogen effect from increased conversion of adrenal precursors to estrogens. Thus, patients with Kallmann's syndrome, a form of congenital secondary hypogonadism with anosmia, also develop gynecomastia. In fact, hypogonadism from whatever cause constitutes most cases of gynecomastia.

The androgen resistance syndromes, including complete and partial testicular feminization (e.g. Reifenstein's syndrome) are characterized by gynecomastia and varying degrees of pseudohermaphroditism. Kennedy Syndrome, a neurodegenerative disease, is also associated with decreased effective testosterone due to a defective androgen receptor. The gynecomastia is the combined result of decreased androgen responsiveness at the breast level and increased estrogen levels as a result of elevated androgen precursors of estradiol and estrone. As such, androgens in these diseases are not recognized by the peripheral tissues including the breast and pituitary. Androgen resistance at the pituitary results in elevated serum LH levels and increased circulating testosterone. The increased serum testosterone is then aromatized peripherally, promoting gynecomastia. Thus, gynecomastia is the result of increased estradiol levels that arise due to unopposed androgen unresponsiveness.