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Gynecomastia Development Continued

PATHOLOGIC GYNECOMASTIA

INCREASED ESTROGEN

Since the development of breast tissue in males occurs in an analogous manner to that in females, the same hormones that affect female breast tissue can cause gynecomastia. The testes secrete only 6-10 mg of estradiol and 2.5 mg of estrone per day. Since this only comprises a small fraction of estrogens in circulation (i.e. 15% of estradiol and 5% of estrone), the remainder of estrogen in males is derived from the extraglandular aromatization of testosterone and androstenedione to estradiol and estrone, respectively (30). Thus, any cause of estrogen excess from overproduction to peripheral aromatization of androgens can initiate the cascade to breast development.

TUMORS

Testicular tumors can lead to increased blood estrogen levels by: estrogen overproduction; androgen overproduction with aromatization in the periphery to estrogens; and by ectopic secretion of gonadotropins which stimulate otherwise normal Leydig cells. Tumors causing an overproduction of estrogen represent an unusual but important cause of estrogen excess. Examples of estrogen-secreting tumors include: Leydig cell tumors, Sertoli cell tumors, granulosa cell tumors and adrenal tumors.

Interstitial cell tumors, or Leydig cell tumors constitute 1%-3% of all testis tumors. Usually, they occur in men between the ages of 20 and 60, although up to 25% of them occur prepubertally. In prepubertal cases, isosexual precocity, rapid somatic growth, and increased bone age with elevated serum testosterone and urinary 17-ketosteroid levels are the presenting features. In adults, elevated estrogen levels coupled with a palpable testicular mass and gynecomastia may develop. Though mostly benign, Leydig cell tumors may be malignant and metastasize to lung, liver, and retroperitoneal lymph nodes (38, 16).

Sertoli cell tumors comprise less than 1% of all testicular tumors and occur at all ages, but one third have occurred in patients less than 13 years, usually in boys under 6 months of age. Although they arise in young boys, they usually do not produce endocrinologic effects in children. Again, the majority is benign, but up to 10% is malignant. Gynecomastia occurs in one third of cases, presumably due to increased estrogen production (38).

Granulosa cell tumors, which occur very rarely in the testes, can also overproduce estrogen. In fact, only eleven cases have been reported with gynecomastia as a presenting feature in half of them (31).

Germ cell tumors are the most common cancer in males between the ages of 15 and 35. They are divided into seminomatous and nonseminomatous subtypes and include embryonal carcinoma, yolk sac carcinoma, choriocarcinoma and teratomas. Elevated a fetoprotein (AFP) and b HCG function as reliable markers in some tumors. As a result of the increased b HCG, acting analogously to LH to stimulate the Leydig cell LH receptor, testicular estrogen production is also increased, which, in turn, can cause gynecomastia. Although germ cell tumors generally arise in the testes, they can also originate extra-gonadally, specifically in the mediastinum. These extragonadal tumors also possess the capability of producing b HCG, but they must be differentiated from a multitude of other tumors such as large cell carcinomas of the lung which can synthesize ectopic b HCG (35).

Some neoplasms that overproduce estrogens also possess aromatase overactivity. Sertoli Cell tumors in boys with Peutz-Jegher syndrome, an autosomal dominant disease characterized by pigmented macules on the lips, gastrointestinal polyposis and hormonally active tumors in males and females, for instance, have repeatedly demonstrated aromatase overactivity, resulting in gynecomastia, rapid growth and advanced bone age as presenting features (20, 50, 12). Feminizing Sertoli cell tumors with increased aromatase activity can also be seen in the Carney complex, an autosomal dominant disease characterized by cardiac myxomas, cutaneous pigmentation, adrenal nodules and hypercortisolism. Other than sex-cord tumors, fibrolamellar hepatocellular carcinoma has also been shown to possess ectopic aromatase activity, causing severe gynecomastia in a 17-year-old boy (2). Furthermore, adrenal tumors can secrete excess dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS) and androstenedione that can then be aromatized peripherally to estradiol.

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 (5). 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. (43). 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 (42).

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. These drugs and their mechanisms will be addressed in a subsequent section.

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 (30). Lastly, enzyme deficiencies in the testosterone synthesis pathway from cholesterol also result in depressed 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 (7).

Secondary hypogonadism, if severe enough, results in low serum testosterone and unopposed estrogen effect from increased conversion of adrenal precursors to estrogens (30). 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 (42). 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.

OTHER DISEASES

Other disease states have also resulted in gynecomastia.

Men with end stage renal disease may have reduced testosterone, and elevated gonadotropins. This apparent primary testicular failure may then lead to increased breast development (18).