US Pharm. 2024;49(6):8-12.
ABSTRACT: Gynecomastia, a benign condition in which breast tissue in males is enlarged, can cause psychological distress and breast pain. Physiological gynecomastia, which occurs in neonates, adolescents, and older adults, is often self-limiting, involving an imbalance of estrogen and testosterone. Nonphysiological gynecomastia can be pathologic, pharmacologic, or idiopathic in nature. Management of this condition involves reversal of the underlying cause or causes; pharmacologic treatment, such as testosterone in hypogonadal men or the selective estrogen receptor modulator tamoxifen for partial reduction in size or pain; and surgery for gynecomastia that persists beyond 12 months.
Gynecomastia is a benign condition involving the proliferation of breast glandular tissue in males. The term gynecomastia is derived from gyneco, from the Greek word for woman or female, and mastos, the Greek word for breast.1 Although most cases of gynecomastia are asymptomatic, patients with this condition may experience breast pain and tenderness; psychological distress, including anxiety, depression, and body dysmorphic disorder; and, rarely, nipple discharge. The pain may be more pronounced in adolescents than in adults. Although gynecomastia is mostly bilateral, it is often asymmetrical and can occur unilaterally.2
Physiological gynecomastia has a trimodal age distribution, with incidence peaking in the neonatal period, puberty, and older age. Nonphysiological gynecomastia, including pathologic (due to a medical condition), pharmacologic (caused by a medication), and idiopathic (no underlying cause identified) etiologies, can occur at any age and has a wide variety of causes.2
Etiology
Breast enlargement in newborns can occur when high fetal levels of estradiol (E2) and progesterone generated by the mother result in transient proliferation of breast glandular tissue and, in some cases, nipple discharge. Neonatal gynecomastia usually resolves several weeks after birth.3
Pubertal gynecomastia can be detected clinically in up to 60% of boys by age 14 years, and it is more often bilateral and asymmetrical. Gynecomastia can develop in adolescents when the estrogen-to-androgen ratio is imbalanced, with E2 levels remaining high. Increased estrogen levels contribute to proliferation of breast glandular tissue, whereas androgens have antiproliferative effects. In addition, increased aromatase activity causing the conversion of circulating testosterone to E2 may be seen in boys with gynecomastia. Gynecomastia in adolescents generally resolves in about 6 months to 3 years.2,3
An estimated 36% to 57% of men older than age 60 years develop gynecomastia, with the wide range in reported prevalence attributed to variations in studies’ diagnostic criteria and selected populations. Gynecomastia in older men may result from decreased serum testosterone concentrations, increased aromatase activity related to increased body fat that leads to increased conversion of androgens to estrogen, and elevated luteinizing hormone (LH) concentrations. Increased serum sex hormone-binding globulin (SHBG) concentrations may also make estrogen more bioavailable than testosterone, further affecting the E2-to-testosterone ratio. Notably, gynecomastia is attributable to medications in 80% of cases in older men.3
Assessment
It is necessary to distinguish gynecomastia from other male breast conditions, such as pseudogynecomastia (also known as lipomastia) and breast cancer. Pseudogynecomastia, which involves excess adipose tissue without breast glandular tissue proliferation, is more commonly seen in males who are obese.2 Gynecomastia is in some cases a risk factor for male breast cancer, but gynecomastia itself is benign.4 Although gynecomastia should not be considered a premalignant condition, an evaluation should be performed to rule out other underlying breast pathologies.5,6 Male breast cancer is rare, as it constitutes approximately 0.2% of all male cancers. A breast examination is recommended in all male patients presenting with enlarged breast tissue, pain, or tenderness. Enlarged, palpable subareolar glandular tissue with a diameter of 2 cm or greater is indicative of gynecomastia.3 In the case of abnormal findings that are suspicious for breast cancer, further investigation (e.g., breast ultrasound, mammography, subsequent biopsy) may be indicated. TABLE 1 lists clinical features that can help clinicians differentiate between gynecomastia and male breast cancer.3
Men seeking medical attention for what appears to be gynecomastia should be evaluated for potential causes as well as for other conditions that mimic gynecomastia. Although there may be multifactorial causes, 25% of gynecomastia cases are idiopathic.7 In addition to the ruling out of pseudogynecomastia and breast cancer, men should be evaluated for testicular cancer and other causes of low testosterone that can affect the estrogen-androgen balance.6 A testicular examination as well as testicular ultrasound—if abnormalities exist—should be performed to determine the presence of a palpable testicular tumor or atrophy.
Nonphysiological gynecomastia can have pathologic, pharmacologic, and idiopathic etiologies.2 Medical conditions that can cause gynecomastia include disorders resulting in testosterone deficiency, malnutrition associated with cirrhosis or chronic renal disease, and certain thyroid disorders, among others (TABLE 2).3,6,7
Up to 25% of gynecomastia cases can be attributed to medications, with one cohort study suggesting that medications are a contributing factor in 80% of older adults with gynecomastia.3,8 Medications associated with gynecomastia with the highest level of evidence include agents with antiandrogen activity (flutamide, bicalutamide, finasteride, dutasteride, spironolactone) and hormones that increase estrogen levels (estrogens, clomiphene citrate). See TABLE 3 for a list of medications that can cause gynecomastia.2,3,6
A thorough investigation is recommended in patients presenting with gynecomastia, as multifactorial etiologies may be involved. Approximately 10% of patients with gynecomastia may have more than one causative factor, and initial treatment is aimed at addressing the underlying cause or causes, if possible.6 It is also recommended to conduct a series of laboratory tests (e.g., E2, testosterone, human chorionic gonadotropin, SHBG, thyroid-stimulating hormone, prolactin, LH, follicle-stimulating hormone, liver and renal function tests) as part of the assessment for gynecomastia.6
Pharmacologic Management
For physiological cases of gynecomastia, such as with neonates and pubescent boys, watchful waiting is recommended because these cases often resolve on their own as hormone levels self-regulate. Most cases of pubertal gynecomastia resolve within 1 to 2 years, although in up to 20% of cases it can last until age 20 years.3,6
Initial management of gynecomastia focuses on identifying and managing the underlying pathologic cause. This includes discontinuing medications contributing to gynecomastia, if possible, and finding suitable alternatives when feasible. With discontinuation of an offending medication, improvement may be apparent within a month.3
If thyrotoxicosis (characterized by symptoms including unexplained weight loss and tachycardia) is identified, treatment with medications such as methimazole or propylthiouracil or with radioactive iodine and/or thyroidectomy may be indicated. In the presence of endocrinologic causes such as testicular germ, Leydig, or Sertoli cell tumors, surgical removal is required. Further treatment with chemotherapy may be necessary in the case of testicular germ cell tumors.9 Watchful waiting is recommended after discontinuing offending medications or substances or after treating underlying pathologic etiologies.6
Pharmacologic management may be considered in patients with severe gynecomastia of recent onset (less than 6 months), those with persistent gynecomastia after discontinuation of offending medications or substances, and those in whom an underlying cause has not been identified. Gynecomastia that persists beyond 6 months is unlikely to regress, owing to the presence of fibrotic tissue. In such cases, a breast examination is recommended every 3 to 6 months, with the goal being regression or stabilization.3
Three pharmacologic classes are available for the management of gynecomastia: androgens (testosterone, dihydrotestosterone, danazol), selective estrogen receptor modulators (SERMs; e.g., tamoxifen, clomiphene citrate, raloxifene), and aromatase inhibitors (letrozole, anastrozole).6 These medications have been used off-label in the United States, but results have been mixed, and as a rule they are not recommended for general management of gynecomastia.
Androgens: Testosterone treatment may be considered for hypogonadal men with proven testosterone deficiency; it is not recommended for all patients with gynecomastia, however. This treatment should be avoided in eugonadal men, as testosterone can have negative effects, including aggravating or inducing gynecomastia through aromatization or catalyzing the conversion of testosterone to E2. Dihydrotestosterone, a nonaromatizable androgen, is available in some countries outside the U.S. and has been used in patients with pubertal gynecomastia. Danazol is a weak androgen that has been used for gynecomastia, albeit with mixed success.6
SERMs: The most-studied SERM is tamoxifen, with a partial response expected for pubertal gynecomastia. The recommended dosing for tamoxifen is 10 mg twice daily or 20 mg daily for 3 to 6 months. Tamoxifen may be particularly helpful for patients with painful gynecomastia due to rapid enlargement, despite its modest effect on reducing breast size.3,6 Clomiphene citrate, a weak estrogen and moderate antiestrogen, produced a partial response in a cohort study, with an observed response rate of 64%. Although raloxifene has been used to treat pubertal gynecomastia, there is more evidence supporting tamoxifen for gynecomastia, and the efficacy of raloxifene remains unclear.3,6 Tamoxifen or radiation therapy may be used to treat gynecomastia in prostate cancer patients who develop gynecomastia from antiandrogen therapies. These therapies include gonadotropin-releasing hormone analogues, goserelin, leuprolide, triptorelin, histrelin, and degarelix.7,10
Aromatase Inhibitors: It has been theorized that aromatase inhibitors such as anastrozole and letrozole decrease the estrogen-to-androgen ratio by blocking estrogen synthesis; however, they are typically not recommended owing to a lack of efficacy data from clinical trials.3,6,7 In men with idiopathic and acute gynecomastia of less than 6 months’ duration, conservative management with pharmacotherapy is typically used only short-term, for up to 6 months.3
Nonpharmacologic Management
Gynecomastia that does not resolve spontaneously or with medical treatment may persist into the fibrotic stage after 12 months. In late adolescence or older age, surgical intervention may be indicated.7 The type and extent of surgery are dependent on the severity of breast enlargement and the amount of adipose tissue present.6 In addition, pain, psychological distress, and cosmetic distortion factor into the decision to undergo surgical intervention.7
The focus of surgical procedures is to remove hypertrophic fibrotic glandular tissue and reestablish the shape of the male breast. Surgery historically has been limited to mastectomy, liposection, or a combination of both procedures. Nipple-sparing subcutaneous mastectomy involves the removal of glandular tissue and helps maintain blood flow and prevent nipple retraction. Suction lipectomy is used to shape the breast. In more severe cases, skin resection may be used in combination with transposition of the nipple-areola complex. Reduction mammoplasty to remove fibrotic glandular tissue is considered in more severe cases. Surgical complications may include nipple numbness and adherence of the areola to the pectoral muscle.3,6,7
The Pharmacist’s Role
When a male patient presents with abnormal breast enlargement or symptoms such as pain or tenderness, evaluation for potential underlying causes of gynecomastia or causes other than gynecomastia is essential for determining the best course of action. Pharmacists can inquire about medications or substances, including prescription and OTC medications, supplements, alternative medicines, marijuana, or chronic alcohol use. Determining a temporal relationship with a new medication may be helpful, as once the offending medication is discontinued, gynecomastia regression may be noticeable after 1 month. Knowing the duration of gynecomastia is also helpful in assessing its potential reversibility, as the presence of breast enlargement beyond 12 months is unlikely to be reversible.
Management includes referral of the patient to a primary care provider for a thorough evaluation. The assessment may include a breast examination, relevant laboratory tests that can reveal potential causes, the discontinuation of any offending medications, and subsequent follow-up visits to determine whether pharmacologic treatment (e.g., testosterone for hypogonadism or tamoxifen for pain relief associated with rapid enlargement) or surgical referral for severe, persistent gynecomastia is needed.
REFERENCES
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4. Fentiman IS. Risk factors for male breast cancer. Am J Transl Res. 2023;15(12):6918-6925.
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6. Kanakis GA, Nordkap L, Bang AK, et al. EAA clinical practice guidelines—gynecomastia evaluation and management. Andrology. 2019;7(6):778-793.
7. Baumann K. Gynecomastia—conservative and surgical management. Breast Care (Basel). 2018;13(6):419-424.
8. Batteux B, Llopis B, Muller C, et al. The drugs that most frequently induce gynecomastia: a national case-noncase study. Therapie. 2020;75(3):225-238.
9. Mohammadnia N, Simsek S, Stam F. Gynecomastia as a presenting symptom of Graves’ disease in a 49-year-old man. Endocrinol Diabetes Metab Case Rep. 2021;2021(1):20-0181.
10. Gonadotropin releasing hormone (GnRH) analogues [updated March 20, 2018]. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
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