Gynecomastia (male breast development) is a common clinical problem. The patient’s concerns are: discomfort, aesthetic impact, and suspicion of cancer. The physician’s concern is whether it is the initial manifestation of an insidious tumor or the clinical manifestation of a serious disease and whether it is idiopathic, physiologic or pathologic gynecomastia. It is generally considered abnormal for men to have palpable breast tissue in their lifetime, except for three cases (transient mastopexy in newborns, enlarged mammary glands in adolescence and occasional mastopexy in older men). Zhang Mei, Department of Two Gland Surgery, Shandong Province Qianfo Mountain Hospital
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. A small amount of white discharge may be seen when the nipple is squeezed in a few patients. 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 causes gynecomastia and is histologically indistinguishable from other causes of gynecomastia. Therefore, it can be assumed that all gynecomastia is due to an increase in estrogen production or a decrease in the androgen/estrogen ratio. Excessive estrogen is the main cause of gynecomastia, and the 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. Etiological classification of gynecomastia.
Etiology.
The growth of the female mammary gland is dependent on the action of estrogen. Estradiol has the same growth-promoting effect on the male breast as it does on the female. The administration of estrogen to males also results in mammary gland development and is histologically indistinguishable from other causes of mammary gland development.
Plasma prolactin levels are usually normal in all causes of gynecomastia. Those with persistently elevated plasma prolactin levels following 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 elevated prolactin levels, but this is a consequence of hyperestrogenemia.
Pathological gynecomastia Mainly diseases or certain drugs that cause insufficient testosterone production, or its diminished action, or excessive estrogen production.
(1) Low androgen production or receptor insensitivity to androgens: Patients with Klinefelter syndrome, anencephaly, and 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, contributing to 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 and alcoholism. The degradation of estrogen is weakened due to decreased liver function. 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 cause an increase in TeBG (more bound testosterone and less free testosterone 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 increase in the ratio of Leydig cells with decreased function. (iii) Chronic renal failure. The accumulation of toxic substances inhibits testicular function and reduces testosterone levels, while LH and FSH are elevated along with increased prolactin. ④Malnutrition. The synthesis of androgens can be decreased and the synthesis and secretion of pituitary gonadotropins can be inhibited. When nutrition improves, this inhibition disappears.
(4) Increased estrogen production: This is seen in 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.
The secretion of testosterone is depressed.
(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: The main causes are: (1) estrogens and their analogs – estrogen application for certain diseases (e.g. prostate cancer) or exposure to estrogens in industrial production, consumption of estrogen-containing foods and even use of estrogen-containing cosmetics can lead to this disorder. In addition, digitalis also has a mild estrogenic effect. (ii) Chorionic gonadotropin. HCG increases 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 enzymes). 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 (Maryland), calcium antagonists, ACE inhibitors, phenytoin sodium, tricyclic antidepressants, penicillamine, diazepam (Valium), marijuana, 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 normal limits and PRL levels are normal. PRL is not a growth hormone of the mammary gland and has no direct effect on the development of the male breast.
Diagnosis: The first step is to determine if the tissue is true mammary gland tissue. Mammary gland development in men should be a firm palpable subareolar breast tissue with a free base and a diameter of >2 cm. Lipomastia is common in obese men and resembles mammary gland development in appearance, but there is no glandular tissue. If careful palpation is not possible, mammography or ultrasonography can differentiate between fat and breast tissue. The next step is to rule out breast cancer, which is very rare in men. The frequency of cancer in men with gynecomastia is slightly higher than in normal men, with an incidence of about 0.4%. If the surface of breast tissue is not smooth, irregular in growth and hard in texture, it is often indicative of early cancer, while local ulcers or enlarged adjacent lymph nodes are signs of advanced breast cancer.
Laboratory tests
1. Gonadotropin measurement and gonadotropin measurement. They are useful for diagnosing primary or secondary testicular function
Hypogonadism.
2. Liver and kidney function tests. Help diagnose liver and kidney failure.
3. Cortisol and ACTH, 17-OHP, 17-ketosteroids and 17-ketogenic solid ketones are measured. May evaluate congenital and congenital adrenal cortical hyperplasia.
Other ancillary tests.
1. Breast ultrasound, mammogram. This can differentiate between fat and breast tissue and exclude breast cancer in time.
2. Histopathological examination of the breast to further confirm the diagnosis.
Differential diagnosis
A thorough history of the patient’s medications can help identify drug-induced gynecomastia. Careful physical examination, including secondary sexual characteristics, testes and body type, together with sex hormone and gonadotropin assays help to diagnose primary or secondary hypospadias. Liver and renal function tests help to diagnose liver and renal failure. Cortisol and ACTH, 17-OHP, 17-ketosteroid and 17-ketogenic solid ketone assays can evaluate congenital adrenocortical hyperplasia. If all of these tests are normal, the diagnosis of idiopathic gynecomastia can be made.
Treatment options
1. 200 mg of dihydrotestosterone enanthate was administered intramuscularly every 3 to 4 weeks. One group reported a 67%-78% reduction in breast size after 3 months of treatment, with elevated plasma DHT and suppressed LH, FSH, T and E2 levels during treatment. At present, it is still in the trial stage, and no DHT formulation is available.
2. Tamoxifen (triamcinolone) can bind to estrogen receptors in target tissues and block the effect of estrogen. It is commonly used at a dose of 20 mg/d, divided into oral doses. It has been reported that the breast gland shrinks significantly after 1 month of administration, and the dose can be increased if the effect is not significant.
3. Clomiphene The mechanism of action is similar to that of tamoxifen (triamcinolone). It is given orally at 50-100mg/d, and about 70% of patients have different degrees of efficacy.
Testosterone lactone inhibits aromatase and blocks the conversion of testosterone to E2 in the periphery. 450mg/d orally in divided doses has been reported to have significant efficacy. No adverse effects were found. After taking the drug, △4A level increased significantly, T, DHEA and E1 increased slightly, and △4A/E1 ratio increased, but LH, PRL and E2 levels did not change significantly.
5. Chinese medicine Chinese medicine believes that male breast development is caused by liver qi stagnation, phlegm and dampness, so the treatment should use agents that dredge the liver and regulate qi, and strengthen the spleen and resolve phlegm. Some people have reported that the efficiency of prolotherapy can reach 90%, but unfortunately there is a lack of control.
The mammaplasty is still an important means of treating this disease due to the irreversibility of the long-term delay of mammary gland development in men. If the subcutaneous glands of mammary gland development are large, a curved incision below the mammary gland can be considered to remove the mammary gland tissue.