Definition Gynecomastia is a common disease of the male breast where there is a benign glandular enlargement of that breast at some time in the male's life. It usually consists of the appearance of a flat pad of glandular tissue beneath a nipple which becomes tender at the same time. The development may be unilateral or bilateral. There is rarely a continued growth of the breast tissue; ordinarily the process is of brief duration and stops short of the production of permanent enlargement of the breast. Causes A great number of patients who suffer from this disease have a disturbance in the proper ratio of androgen and estrogen levels. The normal ratio of the two hormones in plasma is approximately 100:1. "The etiology of gynecomastia in patients with a known documented cause appears to be related to increased estrogen stimulation, decreased testosterone levels, or some alteration of the estrogens and androgen so that the androgen-estrogen ratio is decreased"(Williams 373). From this information it was discovered that there is also a lower ratio of weaker adrenal androgens (delta 4-androstenedione and dehydroepiandrosterone) found in youths with this disease. It was once believed that there was an imbalance in the ratios of testosterone to estrogen or estradiol, but this is now know to be untrue. There are three areas the can be attributed to the cause of gynecomastia: physiologic, pathologic and pharmacologic. "Enlargement of the male breast can be a normal physiologic phenomenon at certain stages of life or the result of several pathologic states."(Isselbacher, 2037) In the case of physiologic gynecomastia the disease can occur in a newborn baby, at puberty or at any time in a man's life. In the newborn, transient enlargement of the breast is due to the action of maternal and/or placental estrogens. The enlargement usually disappears within a few weeks. Adolescent gynecomastia is common during puberty with the onset at the median age of 14. It is often asymmetrical and frequently tender. It regresses so that by the age of 20 only a small number of men have palpable vestiges of gynecomastia in one or both the breasts. Gynecomastia of aging also occurs in otherwise healthy men. Forty percent or more of aged men have gynecomastia. One explanation is the increase in age in the conversion of androgens to estrogens in extra-glandular tissues. Drug therapy and abnormal liver functioning can also be causes of gynecomastia in older men. When the disease is pathologic, the patient can have increased estrogen secretions, increased conversion of androgens to estrogens, or decreased androgen activity due to a failure in protein receptors. Increased estrogen secretions are found in such diseases and disorders as Hermaphroditism, Kleinfelter's syndrome, congenital adrenal hyperlasia, and adrenal carcinoma or testicular tumors. In the second case some examples are adrenal carcinoma, liver disorders, malnutrition and thyroidtoxicosis. Decreased androgen activity can be found in complete testicular feminization, incomplete testicular feminization and Reifenstein's syndrome. Many drugs can cause gynecomastia by several mechanisms. The drugs can either act directly as estrogens or cause and increase in plasma estrogen levels. "Boys and young men are particularly sensitive to estrogen, and can develop gynecomastia after the use of dermal ointments containing estrogen or after the ingestion of milk or meat from estrogen-treated animals."(Isselbacher, 2038) Some examples of drugs that may have cause gynecomastia include Cannabinoids (methane and marijuana), Psychotropics (pheno-thiazine, butyrophenone and reserpine), Antihypertensives (reserpine, alpha-methyldopa and spironolactone), Cardiac (digitalis), Gastrointestinal (cimetidine, metoclopramide and domperidone), Antituburculous (isoniazid), Cytoxic (cyclophospha-mide, mustine, vincristine and mitotane) and Hormonal (sex steroids, gonadotropins and antiandrogens). Use of these drugs, however, will rarely cause gynecomastia. In some instances, the feminization is due to effects of drugs on liver functions. Signs and Symptoms There are very few signs and symptoms that are associated with this disease. Signs may appear at any time in a male's life, although the most common time of onset is during puberty. At the first indication of the disease the patient will feel pain and tender-ness in the breast area due to the rapid development of the breast. The breasts grow because of the enlargement of the glandular tissue. "The concentric arrangement of the connective tissue around the ducts is a characteristic feature of the active phase of gynecomastia."(Delany, 67) The enlargement of the breast is usually bilateral but some cases have unilateral enlargement. In the case of unilateral enlargement, "Induration, fixation, or bloody discharge should raise the possibility of carcinoma."(Wyngaarden, 1450) Carcinoma is a cancerous growth of the epithelial tissues. It may be hard to distinguish true breast tissue from masses of adipose tissue without true enlargement (lipomastia). In such cases, a real case of gynecomastia can be distinguished by mammography or by sonography. Early gynocomastia is characterized by "proliferation of both the fibrobalstic stroma and the duct system, which elongates, buds, and duplicates. As the disease progresses, fibrosis and hyalinization are associated with the regression of epithelial proliferation." Eventually the number of ducts decreases, resolution occurs by reduction in size of epithelial content leaving temporary hyaline bands behind. (Isselbacher, 2037) Diagnosis A satisfactory diagnosis can be made in only half or less of patients referred for gynecomastia. This is a result of insufficient diagnostic techniques, causes that are still undefined and/or difficult to diagnose, or in some instances, gynecomastia may be normal rather than due to a pathologic state. This disease should only be worked up only if there is a negative drug history, if the breast is tender (indicating rapid growth), or if the breast mass is larger than 4 cm in diameter. A decision to perform an endocrine evaluation depends on the clinical context. An example would be gynecomastia associated with signs of under androgenization. Obesity can often be confused with gynecomastia. To prevent this, the doctor can palpate the breast to see if there is a lack of glandular elements that would indicate only obesity. Once the signs become evident, the doctor needs to assess the patient with a number of test to give a proper diagnosis since many other diseases and disorders are commonly involved. This can be done with a physical examination. The head and neck area may show signs of a pituitary tumor or goiter which is found in Graves disease. The skin and abdomen may reveal signs of liver failure and the testes should be examined for asymmetric enlargement in Klinefelter's syndrome. The doctor may consider liver function tests of a karyotype if Kleinfelter's is suspected. Other diseases related to gynecomastia include: testicular tumors, hypo and hyperthyroidism, Cushing's disease, cirrhosis, spinal cord lesions, Hodgkin's disease, enzymatic defects in androgen synthesis and androgen resistance syndromes, and many others. The evaluation of patients with gynecomastia should include a careful drug history, measurement and examination of the testes, evaluation of liver function and endocrine evaluation to include measurement of serum androstenedione or 24-h urinary 17-keto-steriods, plasma estradiol and hCG, and plasma luteinizing hormone (LH) and testosterone. If LH is high and testosterone is low, the diagnosis is usually testicular failure. If LH and testosterone are both low, the diagnosis is usually increased estrogen production. If they are both high, the diagnosis is either an androgen-resistance state or a gonadotropin -secreting tumor. In true gynecomastia these tests would prove to be unnecessary because the symptoms would regress. Treatment When the primary cause can be identified and corrected, breast enlargement usually diminishes until it usually disappears. For example, "androgen replacement therapy may produce dramatic improvement in men with testicular insufficiency. However, if the gynecomastia is of long duration (and fibrosis has replaced the original ductal hyperplasia), correction of the primary defect may not be followed by resolution." (Isselbacher, 2038) In this case, surgery would be the only effective treatment. Candidates for surgery include those with several psychologic and/or cosmetic problems, continued growth, or a suspected malignancy. The treatment selected for this disease is related to how the patient was affected by the disease. The treatment for a person who contracted the disease through certain drug use will be treated different from a person who is affected from a related disease. If gynecomastia is contracted through drug use, the patient will needs to discontinue the medications that are associated with the disease. The only exception is when there is a life threatening illness involved, and there is no alternative medication available. For those suffering from gynecomastia, the doctor may prescribe antiestrogens such as clomiphene citrate or tamoxiten to eliminate tenderness of the breast. "The non-aromatizable androgen dihydrotesosterone also has been reported to reduce gynecomastia by reducing testicular secretion of estradiol, by decreasing peripheral conversion of precursors to estradiol and by increasing circulating levels of androgen."(Kohler, 295) In patient with painful gynecomastia and who are not candidates for other therapy, treat-ments with antiestrogens such as tamoxifen may be used. When other related diseases are the cause for the onset of gynecomastia, treatment of these diseases will often cure gynecomastia, too. The removal of a sex steroid produc-ing tumor or treatment of thyroidtoxicosis are two examples. Testosterone treatment of androgen deficiency will also cause great improvement in this condition. "Prophylactic radiation of the breasts prior to the institution of diethylstilbestrol therapy is effective in preventing gynecomastia and has a low complication rate in elderly men."(Isselbacher, 2039) In most cases of true gynecomastia, the signs and symptoms should regress in about a year. However, in the case of severe gynecomsatia where the breast has an increase of fibrous tissue stroma the patient will require a surgical reduction mammo-plasty. Once this has been done the tissue is sent to a lab to be examined. The results should show elongated circular ducts imbedded in cellular fibrous tissue with a rubbery fatty quality. From these laboratory tests it can be determined if there is any cribiform epithelial hyperlasia or a case of carcinoma. Although the relative risk of carcinoma of the breast is increased in men with gynecomastia, it is rare nevertheless. Statistical Data Gynecomastia is found only in males, and the signs can appear any time in a male's lifetime. It is the leading breast disorder in males and it accounts for 60% of all disorders of the male breast. About 85% of male breast masses are due to gynecomastia. Forty percent of the cases affect pubescent boys occurring most often between the ages of 14 to 15.5. Approximately 40% of normal men and up to 70% of hospitalized men have palpable breast tissue. Active gynecomastia in autopsy data is between 5 and 9%. "More than 80% of their hospitalized patients with a body mass index of 25 kg/m2 or greater had gynocamastia."(Williams, 373) About 70% of pubertal males required no treatment. "If the threshold for judging that the breast is enlarged is set at 2.0cm in diameter, the incidence is 32-36% in normal aged men 17-58 years."(Williams, 340) A bloody discharge is present in about 60% of patients, while a milky discharge is present in about 1% of patients. Recent Research In the Wilford Hall USAF Medical Center a set of experiments were done to see if there is a connection between 3B-HSD deficiency and gynecomastia. The researchers tested a male who had developed right side gynecomastia at the age of twenty-four. When a series of tests were run, no other underlying conditions were evident. He was found only to have a deficiency of 3B-HSD. The patient also had abnormally high ratios of estradiol, estrogen and aldosterone and other serums. This showed the presence of adrenal sex steroid production on the right side of his body. This is not to say that all males patients with a deficiency of 3B-HSD will develop gynecomastia. Other patients with the same deficiency showed no signs, and still others with normal 3B-HSD levels have also been found to have reduced breast tissue. Researchers, however, do believe that the deficiency of 3B-HSD later in life is quite possibly a frequently unrecognized cause of new-onset gynecomastia. There are so many causes and factors that lead to the disease gynecomastia that it is very difficult for researchers to try to agree upon one main factor. So many of the cases differ from one another, and, perhaps, no one cause will ever be agreed upon as the leading factor of the disease. As long as there is no other underlying disease or disorder, gynecomastia is not a life threatening disease. Experimentation with hormone therapy is the main research being tested at this time.