Gynecomastia

• 1. Introduction

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  Gynecomastia is the non-cancerous growth of breast tissue in men, and about 35 percent of men are affected by it. The name is built from two Greek roots: gyné, meaning female, and mastós, meaning breast. The physician Galen coined the term. He knew that the male breast could swell through glandular growth, yet by his own reckoning that swelling was not the condition the word now describes. Physically, the condition is benign. That raises a puzzle, because it turns up in newborns, in teenagers and in men past fifty, three groups with little else in common. What tips the balance inside the body? Which pills and everyday products can set it off? How do doctors tell it from cancer? And why did a courtroom become part of its modern story?

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• 2. The Hormone Tug-of-War

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  In about one case in four, doctors never find the cause of gynecomastia. In the rest, the explanation is nearly always a matter of ratio. Estrogens push breast tissue to multiply, while androgens hold that growth back. Gynecomastia appears when estrogen action rises, when androgen action falls, or when both happen together. The ratio can tip even when each hormone sits within its normal range.

  Estrogen also works indirectly. By suppressing luteinizing hormone, it lowers the testicles' output of testosterone, which weakens the brake on the breast further. What a man or boy sees in the mirror may be glandular tissue, chest fat, extra skin, or, most often, a mixture of the three.

  The brake can also fail at the receiver. In androgen insensitivity syndromes, the androgen receptor cannot respond to testosterone. In the complete form, a person with testes fails to develop a penis and scrotum but does develop breasts. The minimal form may show up only as gynecomastia in adolescence, sometimes alongside infertility.

  Male breast tissue carries receptors for several other hormones, including prolactin, progesterone, luteinizing hormone and two insulin-like growth factors. How much each one matters is still not well understood. What is clearer is that the balance shifts naturally at three points in a human life.

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• 3. Three Windows in a Life

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  Between 60 and 90 percent of newborns, boys and girls alike, show breast development at birth or in the first weeks. The placenta is responsible. It converts the hormones DHEA and DHEA sulfate into the estrogens estrone and estradiol, and these pass into the baby's bloodstream. Some infants even leak a fluid from the nipples called neonatal milk, known in folk usage as "witch's milk". The swelling usually fades within two or three weeks.

  At age 10, some boys already begin to show it, and up to 65 percent of adolescents do at some point. Cases peak at ages 13 and 14. Early in puberty, the adrenal glands may supply less androgen, or more androgen may be converted into estrogen. Either shift raises the ratio. Between 75 and 90 percent of cases clear up without treatment, usually within one to three years, as rising testosterone shrinks the tissue. By age 17, only 10 percent of boys still have it.

  Between 24 and 65 percent of men aged 50 to 80 develop what is called senile gynecomastia. Aging lowers testosterone and adds fatty tissue, which is a major site of aromatase, the enzyme that turns androgens into estrogens. A blood protein called sex hormone binding globulin also climbs with age, and it grips estrogen less tightly than it grips androgens. Estimates that include men with no symptoms reach as high as 70 percent of those aged 50 to 69.

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• 4. The Medicine Cabinet

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  Cimetidine, ketoconazole and finasteride all appear on the list of drugs with good evidence linking them to gynecomastia. Medications and outside chemicals are thought to account for roughly 10 to 25 percent of all cases. They act in many ways. Some bind to estrogen receptors, some push the body to make more estrogen, and some supply raw material that can be converted into it. Others damage the testes, block testosterone production, interfere with androgen action, or pry estrogen loose from its carrier protein.

  The strongly implicated group is long. It includes gonadotropin-releasing hormone analogues, human growth hormone, human chorionic gonadotropin, dutasteride, certain estrogens used against prostate cancer, and the antiandrogens bicalutamide, flutamide and spironolactone. Evidence is weaker but still notable for the blood pressure drugs verapamil, amlodipine and nifedipine. The same goes for risperidone, olanzapine, anabolic steroids, alcohol, opioids, efavirenz, alkylating agents and omeprazole. Oral contraceptive pills are named as well.

  Prolactin offers a different route. High blood levels, caused by certain tumors or by some medications, can inhibit the release of gonadotropin-releasing hormone and lead to secondary hypogonadism.

  The cause can also be a bottle in the bathroom. Lavender and tea tree oil in personal care products have been linked to gynecomastia in boys before puberty, because of their estrogen-like and anti-androgen effects. The supplements dong quai and Tribulus terrestris have been associated with it too.

  Some researchers suspect the condition has grown more common in recent years. Proposed drivers include anabolic steroids and estrogen-mimicking chemicals in cosmetics, organochlorine pesticides and industrial compounds, though the epidemiology remains poorly understood.

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• 5. Illness and Recovery

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  Men returning home from prison camps after World War II developed gynecomastia once they went back to a normal diet. Doctors called the pattern refeeding gynecomastia. Malnutrition and heavy loss of body fat suppress the signals that drive the gonads, causing hypogonadism. When food returns, those signals restart, and for a time the estrogen and androgen balance resembles puberty. The swelling clears by itself in one to two years.

  Dialysis can set off a similar sequence. About half of chronic kidney disease patients on dialysis develop gynecomastia. High urea levels already suppress testosterone and damage the testes. Dialysis then lets formerly malnourished patients eat more and regain weight, and the condition resolves within one to two years.

  The liver plays its own part. In cirrhosis or liver failure, the body handles estrogen poorly. Cirrhosis brings more of the adrenal hormone androstenedione, more of it converted to estrogens, and more binding protein to tie up free testosterone. Alcoholic liver disease adds risk, since ethanol may directly disrupt testosterone synthesis and alcoholic drinks contain plant-derived estrogens. Cystic fibrosis and ulcerative colitis, which impair absorption, can also contribute.

  Between 10 and 40 percent of men with Graves' disease, a common form of hyperthyroidism, develop gynecomastia. Higher aromatase activity, more binding protein, and extra testosterone and estradiol output driven by luteinizing hormone are all involved. Treating the thyroid problem can resolve it.

  Primary hypogonadism damages the testes, through radiation, chemotherapy, infection or injury, or through the chromosomal makeup seen in Klinefelter syndrome. About 80 percent of people with Klinefelter syndrome have gynecomastia, and their risk of male breast cancer is 20 to 50 times higher than normal. Secondary hypogonadism stems from damage to the hypothalamus or pituitary. Rare inherited conditions, including spinal and bulbar muscular atrophy and aromatase excess syndrome, account for a small share.

  Tumors can bring on gynecomastia quickly. Leydig cell tumors, Sertoli cell tumors seen in Peutz-Jeghers syndrome, and hCG-secreting choriocarcinoma all overproduce estrogen. Adrenal tumors, pituitary prolactinomas and even lung cancer can send hormonal signals that tilt the balance.

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• 6. The Examination

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  Three possibilities worry doctors most when a man presents with enlarged breasts: gynecomastia, pseudogynecomastia and breast cancer. Pseudogynecomastia is extra fat or skin in the male chest with no true glandular growth, common in obesity, and a physical exam can rule it in or out. True gynecomastia feels like a soft, rubbery, movable mass under the nipple and the skin around it. It may be symmetrical or lopsided, with tender breasts, sensitive nipples or a wider areola.

  Some findings point elsewhere. Skin dimpling, nipple discharge and a retracted nipple are not typical, and milky discharge suggests a prolactin-secreting tumor. The physician also checks the genitals, looks for testicular masses, and notes the pattern of pubic and underarm hair.

  First-round blood tests look at liver enzymes called aspartate transaminase and alanine transaminase, at serum creatinine for kidney damage, and at thyroid-stimulating hormone. If those find nothing, the next panel covers total and free testosterone, luteinizing hormone, follicle stimulating hormone, estradiol, beta human chorionic gonadotropin and prolactin. An abnormally high beta-hCG calls for an ultrasound of the testicles. When every test comes back clear, the case is labeled idiopathic, meaning the cause is unclear.

  Mammography is reserved for cases where cancer is suspected. A painless, fixed, irregular lump with skin changes raises the alarm. A clear mammogram usually ends the imaging. A doctor must also exclude mastitis, lipoma, sebaceous cysts, dermoid cysts, hematoma, fat necrosis and hamartoma. Under the microscope, early tissue shows lengthened ducts, inflammation and more fibroblasts. Chronic tissue shows more fibrosis and less inflammation. Whether examining tissue removed from adolescents is worthwhile has recently been questioned, because breast cancer is so rare in that group.

  Severity is graded from one to four. Grade I is minor enlargement with no excess skin. Grade IV is marked enlargement with excess skin.

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• 7. Medicine and the Knife

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  Albucasis described a surgical operation for gynaecomastia in his second book of Kitab al-Tasrif. Modern medicine still treats surgery as the final answer, but only after a waiting period. If swelling has not gone away within two years, treatment is warranted, and drugs work best when they begin within those two years.

  Tamoxifen is the most effective of the medications. Raloxifene and clomifene belong to the same class, called selective estrogen receptor modulators, and clomifene seems the weakest of the three. None is approved by the Food and Drug Administration for this use. Aromatase inhibitors such as anastrozole have been tried off-label in puberty cases and work less well. A few patients with aromatase excess syndrome or Peutz-Jeghers syndrome have responded to them. Testosterone itself can be converted into estradiol, so doctors may turn instead to a topical androgen that cannot be, dihydrotestosterone, also called androstanolone.

  For prostate cancer patients about to start androgen deprivation therapy, radiation therapy and tamoxifen can help prevent gynecomastia and breast pain. They work best given in advance.

  When drugs fail, surgeons remove the glandular tissue. The American Board of Cosmetic Surgery calls it the "most effective known treatment for gynecomastia." Surgery is considered when swelling lasts more than 12 months, causes distress, and has reached the fibrotic stage. Adolescents should wait until puberty is complete, at Tanner stage V. Methods include subcutaneous mastectomy, liposuction-assisted mastectomy, laser-assisted liposuction and laser-lipolysis without liposuction. Possible complications include hematoma, wound infection, asymmetry, changed sensation, tissue death in the areola or nipple, seroma, painful scars and contour deformities.

  In 2019-24,123 men in the United States underwent the operation, a 19 percent increase since 2000. Thirty-five percent were aged 20 to 29, and 60 percent were under 29. The average surgeon's fee was $4,123, making it the 11th most costly male cosmetic surgery that year. In 2020, the American Society of Plastic Surgeons counted just over 18,000 such procedures, down 11 percent from 2019.

  Many American insurers deny coverage, classing male breast reduction as cosmetic.

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• 8. Stigma and Verdicts

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  Research has mostly asked what causes gynecomastia and how to treat it, and has rarely asked what it does to a person's mind. The few studies that exist point to a heavy load. Adolescents face it just as their bodies mature and their sense of self forms. Reported effects include body image disturbance, negative attitudes toward eating, low self-esteem, social withdrawal, anxiety and shame. Some men look anxious or stressed because they worry about appearance and about breast cancer. Particular studies link the condition to depression, anxiety and disordered eating. Support groups exist to help affected people rebuild their self-esteem.

  Culture supplies its own labels. "Moob," a blend of man and boob, is a popular term for male breasts. In bodybuilding communities, where anabolic steroid use can cause the condition, a cruder slur is also used.

  The condition also reached a courtroom. In Murray v. Janssen Pharmaceuticals, the plaintiff, Murray, had been prescribed risperidone at age nine and developed male breasts. In November 2015, a jury ruled in his favor and awarded $1.75 million for "disfigurement and mental anguish." That sum was later reduced to $680,000.

  A second phase of the bifurcated trial asked a harder question. The plaintiffs sought to prove that the companies knew of evidence linking risperidone to gynecomastia in young males and deliberately disregarded it. They also alleged that the drug was promoted off-label and sold without disclosure of the side effects. The jury sided with the plaintiffs and awarded $8 billion in punitive damages. Judge Kenneth Powell Jr. later reduced that amount to $6.8 million. A 12-person Philadelphia jury made the $8 billion award in 2019.

  Risperidone is an atypical antipsychotic first approved to treat psychosis. Over the last two decades, its use has grown among children, including those diagnosed with autism spectrum disorder, ADHD and schizophrenia.

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