Gynecomastia (male breast development) is a common clinical problem. It is generally considered abnormal when breast tissue is palpable in men during their lifetime except for 3 conditions (transient gynecomastia in newborns, breast enlargement during puberty and occasionally in older men). Men present with unilateral or bilateral palpable breast tissue in the form of disc-shaped nodules or diffuse enlargement, sometimes accompanied by enlarged nipples and areolas. Localized discomfort or tenderness may be felt, and in a few patients, a small amount of white discharge is seen when the nipple is squeezed. Epidemiology: The incidence of gynecomastia varies. It varies from 5% to 36%. The majority of these are young and elderly, with inactive and discontinued growth being more common in men with mastopexy, at 32% to 48%. Symptoms and signs: Men present with unilateral or bilateral palpable breast tissue in the form of disc-shaped nodules or diffuse enlargement, sometimes accompanied by enlarged nipples and areolas. Localized discomfort or tenderness may be felt, and in a few patients, a small amount of white discharge is seen when the nipple is squeezed. Pathological gynecomastia caused by organic disease also has clinical manifestations of the original disease. Etiology of the disease: The growth of the female breast is dependent on the action of estrogen. The administration of estrogen to men also leads to gynecomastia and is histologically indistinguishable from other causes of gynecomastia. Therefore, it can be assumed that all gynecomastia is due to increased estrogen production or a decrease in the androgen/estrogen ratio. Excessive estrogen is the main cause of gynecomastia, and administration of exogenous estrogen preparations to men, such as estrogen therapy for prostate cancer patients, long-term estrogen use in transsexual men, and excessive estrogen secretion from adrenal or testicular tumors can lead to gynecomastia. Pathophysiology: The growth of the female breast is dependent on the action of estrogen. Estradiol has a growth-promoting effect on the male breast as it does on the female breast. The administration of estrogen to males can also lead to breast development and is histologically indistinguishable from other causes of mammary gland development. In all causes of gynecomastia, plasma prolactin levels are usually normal. Those with persistently elevated plasma prolactin levels after antipsychotic use and the vast majority of men with pituitary prolactinomas do not develop mastocytosis. Therefore, prolactin does not play a direct role in the development of this disease. This is consistent with the fact that prolactin does not play a direct role in mammary gland development. A small number of male patients with pituitary prolactinomas and hyperprolactinemia develop mastocytosis by mechanisms such as pituitary tumor compression stimulation or high prolactin levels directly affecting gonadotropin secretion and developing secondary hypogonadism. Some patients with mastocytosis may have mildly increased prolactin levels, but this is a consequence of hyperestrogenemia. 1. Physiological male breast hyperplasia: There are several stages of mammary gland development that occur during a man’s life that are physiological in nature. ① Neonatal mastopexy. About 50% or more of newborns are born with enlarged mammary glands, which are caused by estrogen from the mother or placenta entering the fetal circulation and acting on the breast tissue. It usually subsides within a few weeks, with individual cases lasting a little longer. ②Mastocytosis in adolescent males. Transient mastocytosis can occur in normal males during the pubertal stage, with an incidence of about 39% (up to 50% to 70% has also been reported, with some other statistics being lower). In most boys, the degree of breast enlargement is asymmetrical on both sides, with one side larger than the other, and the time of appearance of the enlargement may not be the same on both sides. The majority of the hyperplastic mammary glands subside spontaneously before the age of 20, and only a few boys have permanent residual breast tissue on one or both sides of the breast that cannot subside completely. In a very small number of boys, one or both mammary gland enlargement can be more pronounced, resembling a teenage breast (adolescent gigantism) and can persist into adulthood. The exact cause of adolescent breast enlargement is not known. Plasma estradiol concentrations reach adult levels before boys reach adult levels of plasma testosterone, resulting in an increased estrogen/androgen ratio. Some studies have found higher mean plasma estradiol levels in boys with mastocytosis. Thus, boys with mastocytosis have lower plasma testosterone to estradiol ratios and adrenal androgen to estrone ratios. In addition, increased local aromatase action in the mammary gland during the pubertal stage and increased local estrogen formation lead to adolescent mastocytosis. Geriatric male breast hyperplasia, which can occur in healthy older men, can also be a manifestation of some disease, but it is important to first rule out the possibility of organic disease. The incidence of mastocytosis in elderly men is high, with a group of elderly men with autopsy findings of 40%. Another report was as high as 72% in hospitalized men aged 50 to 69 years. However, older men often have various diseases such as cardiovascular disease, liver disease, kidney disease, and often take a variety of medications, all of which may cause mastocytosis. The causes of mastocytosis in elderly men are explained as follows: most elderly men have different degrees of decreased testicular function, the metabolism of estrogen and androgen has changed, including a decrease in plasma total testosterone, a decrease in plasma free testosterone, an increase in plasma testosterone-binding globulin, an increase in the fat content of body tissues in the elderly, an increase in the aromatase action in peripheral tissues, a decrease in the ratio of androgens to estrogens, and a decrease in plasma LH and FSH. Plasma LH and FSH are elevated, and the circadian rhythm variation of plasma testosterone disappears or is diminished. The above changes that occur in the elderly are sufficient to change the ratio of testosterone to estradiol in the breast tissue, thus causing hyperplasia of the breast tissue. 2. Pathological gynecomastia: Mainly diseases or certain drugs that cause insufficient testosterone production, or its weakened effect, or excessive estrogen production. (1) Low androgen production or receptor insensitivity to androgens: Patients with Klinefelter’s syndrome, orchidrosis, androgen insensitivity syndrome, for example, have low androgens, which increase pituitary gonadotropin or androgen insensitivity to receptors and imbalance the ratio of estrogen to androgen, prompting mastocytosis. (2) Clonal karyotype abnormalities: Some male breast development is due to clonal karyotype abnormalities, such as 12p deletion, chromosome 9, 17, 19 and 20 monosomy, and some patients have benign or malignant tumors of the breast. (3) Imbalance of estrogen balance: mainly seen in: ① Cirrhosis of the liver, alcoholism. Decreased liver function and reduced estrogen degradation. At the same time, the aromatization of androgens is enhanced, resulting in a relative increase in estrogen. ② Hyperthyroidism. About 10% of men with hyperthyroidism have mammary gland development. Thyroid hormones can cause an increase in TeBG (more bound testosterone and more free testosterone reduction than free E2) and also have a facilitative effect on peripheral aromatase, which increases the conversion of testosterone to E2. In addition, hyperthyroidism causes an increased ratio to decreased Leydig cell function. (iii) Chronic renal failure. The accumulation of toxic substances inhibits testicular function and reduces testosterone levels, while LH and FSH are elevated with elevated prolactin. ④Malnutrition. Androgen synthesis can be decreased, and pituitary gonadotropin synthesis and secretion are inhibited. When nutrition improves, this inhibition disappears. (4) Increased estrogen production: ① Testicular tumors. Some testicular tumors (such as choriocarcinoma, teratoma and a few seminoma) can produce HCG, which can increase the synthesis of testosterone and estradiol in residual testicular tissues. Also, due to the increased concentration of aromatase in cancerous tissues, it can cause excessive conversion of androgens into estrogens. (ii) Adrenal tumors. For example, some adrenal carcinomas can produce large amounts of estrogen or its precursor, androstenedione, which in turn can be converted into estradiol by aromatase in the surrounding tissues. At the same time, pituitary gonadotropin secretion is suppressed and testosterone secretion is reduced in patients with this disease. (5) Hyperthyroidism or hypothyroidism: Occasionally, hyperthyroidism is associated with gynecomastia, the cause of which is unknown and disappears after treatment with antihyperthyroid drugs. Breast development in polyneuropathy – tissue hypertrophy – endocrinopathy – M proteinopathy – skin damage syndrome (POEMS syndrome) is also mainly related to hypothyroidism. (6) Exogenous drug effects: Main causes: ① Estrogen and its analogs – Estrogen application for certain diseases (e.g. prostate cancer) or exposure to estrogen in industrial production, consumption of estrogen-containing foods and even estrogen-containing cosmetics can lead to this disorder. In addition, digitalis also has a mild estrogenic effect. (ii) Chorionic gonadotropin. HCG can increase the secretion of estradiol and testosterone by the testes and can cause breast development with long-term use. (iii) Androgen antagonists. For example, cyproterone and flutamide can inhibit the binding of testosterone to receptors. In addition, cimetidine and spironolactone also have similar effects (cimetidine and spironolactone may also inhibit the synthesis of testosterone by inhibiting 17,20 cleavage chain enzyme). ④ Long-term use of androgens. They can be converted into estrogen by aromatase, so long-term use of androgens can also cause mammary gland development. ⑤ Other drugs, such as isoniazid, reserpine, leucovorin (Marilan), calcium antagonists, ACE inhibitors, phenytoin sodium, tricyclic antidepressants, penicillamine, diazepam (Valium), cannabis, heroin, etc. The mechanism of action of these drugs is unknown. In addition, radiotherapy and chemotherapy may impair testicular function and cause a decrease in testosterone production, which can also cause gynecomastia. Gynecomastia caused by different etiologies has the same histological changes. Early stages are characterized by hyperplasia of the glandular duct system, with lengthening of the ducts, the appearance of new bracts and branches, and proliferation of fibroblasts in the stroma. In the late stage (after several years) there is proliferative degeneration of the epithelium, progressive fibrosis and hyaline degeneration, reduction in the number of glandular ducts, and infiltration with mononuclear cells. When the disease progresses to the stage of extensive fibrosis and hyaline degeneration, complete regression of the mammary gland is not possible. Except for some pathological gynecomastia, hormone levels are within the normal range and PRL levels are normal. PRL is not a growth hormone of the breast and has no direct effect on gynecomastia.