ICI-176334

Diagnosis and Management of Gynecomastia for Urologists

Lee Baumgarten1 • Ali A. Dabaja1

Ⓒ Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Our aim is to review the steps of diagnosis and management of gynecomastia with a special focus on treatment of gynecomastia associated with androgen deprivation therapy for prostate cancer.
Recent Findings Recent studies investigating tamoxifen and radiation therapy for both therapy and prophylaxis of bicalutamide- induced gynecomastia are reviewed.
Summary Gynecomastia is a common clinical problem, affecting between one and two thirds of middle-aged men. Diagnosis is typically made by history and physical exam. Common causes include chronic medical conditions and medications; however, unexplained gynecomastia should prompt laboratory work-up, followed by appropriate imaging studies to evaluate for hormone producing cancers. For patients taking bicalutamide for treatment of prostate cancer, tamoxifen or radiation therapy for gyneco- mastia are excellent options.
Keywords Gynecomastia . Prostate cancer . Tamoxifen . Androgen deprivation therapy

Introduction

Gynecomastia, commonly described as enlargement of the male breast tissue, is the most common breast alteration in men [1]. There is a trimodal age distribution, with prevalence rates of 60–90% in newborns, 50–60% in adolescents, and up to 60% of men aged 50–70 years [1]. Patients often present complaining of painful or bothersome breast enlargement; however, gynecomastia is also associated with major psycho- social consequences, including depression, anxiety, disor- dered eating, body dissatisfaction, and reduced self-esteem [2, 3]. In addition, gynecomastia can be an incidental finding on physical exam. The initial evaluation of a male with breast enlargement should include careful history and physical ex- amination. Chronicity of breast enlargement, associated pain, skin changes, and nipple discharge should be assessed. Any cancer history and all medication use should be evaluated. On physical exam, there is an important distinction between
gy neco ma stia an d p se udog yne comastia. Pseudogynecomastia is an accumulation of fat without glan- dular proliferation. True gynecomastia is characterized by marked proliferation of ductal epithelium, periductal edema and inflammation, and increased subareolar fat [4]. Therefore, on physical examination in gynecomastia, there is a palpable, firm, and rubbery mound of tissue concentrically expanding from the nipple-areolar complex. In pseudogynecomastia, no such disk of tissue is palpable.
In any male presenting with breast complaints, underlying breast cancer must be ruled out. Although rare, risk factors for breast cancer in males include BRCA germline mutations and Klinefelter’s syndrome, which poses a 20–50 times higher risk of breast cancer than the general male population [5]. If the rubbery mound or disk is non-concentric around the nipple, there should be suspicion for primary breast malignancy. Breast pain is uncommon in malignancy, however often oc- curs during the first 6 months of breast enlargement due to

gynecomastia. Skin dimpling, nipple retraction, and nipple

This article is part of the Topical Collection on Men’s Health

* Ali A. Dabaja [email protected]

1 Henry Ford Health System, 2799 W. Grand Blvd, Detroit, MI 48202, USA
discharge or bleeding are all suggestive of breast cancer [6]. When the diagnosis is in question or there is a suspicion for breast cancer, the patient should undergo diagnostic mam- mography, which has a 90% sensitivity and specificity for differentiating benign and malignant breast pathology [7, 8].

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Pathophysiology

Following diagnosis, the distinction between physiologic and pathologic gynecomastia dictates further management. Physiologic gynecomastia occurs secondary to an elevated ratio of estradiol to testosterone (E2/T). Male breast tissue has both androgen receptors which inhibit tissue proliferation and estrogen receptors which promote it [9]. In physiologic neonatal gynecomastia, transplacental transfer of maternal es- trogens can cause gynecomastia. Treatment or evaluation of gynecomastia in an infant should be avoided until 1 year of age. Pubertal gynecomastia occurs due to an increase in estra- diol, which precedes the pubertal surge of testosterone. This form typically regresses in 1–2 years; however, reassurance is often needed for these patients as there can be significant psychosocial burden [1].
Pathologic processes and medications can also affect the E2/T ratio on many levels due to complex hormonal regula- tion. Approximately 15% of a male’s estradiol and most of the testosterone is secreted directly from the testes. These bind to sex hormone-binding globulin (SHBG), produced by the liver, and travel to target organs through the bloodstream. The un- bound sex hormones enter target tissues, where the aromatase enzyme complex converts testosterone to estradiol. Multiple processes can alter these pathways, resulting in pathologic gynecomastia from an enhanced estrogen or a diminished an- drogen effect on the breasts [6].
Testicular secretion of estradiol can be increased patholog- ically due to Sertoli cell or Leydig cell tumors. Pathologic human chorionic gonadotropin (hCG) secretion also leads to stimulation of testicular estradiol secretion. Examples of hCG producing tumors include gonadal or extra-gonadal germ-cell tumors, large-cell lung, gastric, and renal cell carcinomas. Adrenal neoplasms may produce the weak androgen andro- stenedione, which is converted to estrogens in peripheral tis- sues. Finally, pathologic increases in aromatase activity in peripheral tissues are associated with multiple disease process- es including thyrotoxicosis, Klinefelter syndrome, as well as with aging and increasing body fat [6]. Decreased body tes- tosterone can occur due to primary and secondary hypogonadism. Hyperprolactinemia causes gynecomastia via multiple mechanisms including secondary hypogonadism and hampering the androgen-mediated inhibition of breast tissue growth [1]. Other medical diseases, such as chronic kidney and liver disease can cause gynecomastia. In advanced liver disease, increased SHBG reduces the bioavailable testoster- one, whereas chronic kidney disease causes impaired testicu- lar secretion of testosterone [10, 11].
Many medications increase the risk of gynecomastia by altering the balance of estrogen and testosterone. Exogenous steroid use, particularly performance-enhancing drugs, cause gynecomastia due to conversion of the androgenic steroids to estrogens [1]. Although spironolactone is primarily an
aldosterone antagonist, it can also increase unbound estrogens by decreasing the binding of estrogens to SHBG. Clomiphene citrate and testosterone replacement therapy of all forms in- creases the risk of gynecomastia due to conversion of testos- terone to estradiol. Several other medications have also been associated with gynecomastia, including cimetidine, phenyto- in, metoclopramide, and highly active antiviral therapies for HIV, but the cause and effect relationship is unclear [12]. Lastly, bicalutamide used in prostate cancer treatment is known to block the androgen effects on the breast, leading to gynecomastia in many patients.

Management

After diagnosing gynecomastia, if medications, physiologic gynecomastia, chronic liver, and kidney disease are excluded as the underlying cause for gynecomastia, further work-up is indicated. Endocrine laboratory tests should be performed, including serum testosterone, serum estradiol, SHBG, lutein- izing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) measurements. Free thyroxine (T4) and thyroid-stimulating hormone (TSH) are measured to exclude hyperthyroidism. Serum estradiol and hCG concentrations should be measured to investigate gynecomastia associated with an underlying malignancy, and if elevated, a testicular ultrasound must be performed. Further imaging may be re- quired to search for adrenal or other extratesticular tumors [13•].
If a medical cause for the gynecomastia, for instance, hypogonadism or hyperthyroidism, is identified and reversed, the breast enlargement and tenderness will resolve in approx- imately 1 month [14]. When hypogonadism is treated appro- priately with testosterone replacement therapy, the E2/T ratio normalizes with subsequent improvement in gynecomastia [1]. Hyperprolactinemia should be evaluated for a pituitary cause, but does not by itself cause gynecomastia. However, elevated prolactin can lead to hypogonadism, altering the E2/ T ratio, leading to gynecomastia [14].
Unfortunately, if the gynecomastia has been present for over 1 year, it is unlikely to regress spontaneously with resto- ration of hormonal balance, and consultation with a breast or plastic surgeon is recommended. In these cases, subcutaneous mastectomy, ultrasound-assisted liposuction, and suction- assisted lipectomy have been shown to be successful treat- ments [15].
In cases of idiopathic gynecomastia or when the causative medication should not be discontinued, for instance when treating prostate cancer with antiandrogens, medical treatment aimed at symptom management is necessary. For idiopathic gynecomastia, medical treatment with tamoxifen has shown to be effective in several small trials resulting in partial

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regression of gynecomastia in approximately 80% of patients and complete regression in about 60% [6, 16].

Gynecomastia and Androgen Deprivation Therapy for Prostate Cancer

Androgen deprivation therapy (ADT) is recommended for many patients with prostate cancer, including asymptomatic patients with high risk, locally invasive disease, as well as long-term adjuvant therapy, alone and in conjunction with radiation therapy, for node positive disease. Surgical or med- ical castration with LHRH agonist is recommended for meta- static disease. Antiandrogen treatment, most commonly the nonsteroidal antiandrogen bicalutamide is recommended in conjunction with LHRH agonist [17].
Gynecomastia is a common side effect in patients receiving ADT, with a cumulative prevalence as high as 70%, leading to discontinuation of therapy in up to 16% of patients, and there is a documented decrease in quality of life from gynecomastia [17, 18]. Gynecomastia associated with prostate cancer treat- ment can be effectively treated with medications or radiation [19•].
Medications aimed at preventing or treating gynecomastia include the selective estrogen-receptor modulator tamoxifen and the aromatase inhibitor anastrozole. Tamoxifen blocks the estrogenic effect on breast tissue and anastrozole reduces pe- ripheral conversion of androgens to estrogens [20]. Although not approved for this indication, tamoxifen has been shown to be effective in treating gynecomastia in several recent meta- analyses, whereas anastrozole has little therapeutic benefit [21••, 22]. Radiation can also prevent or treat gynecomastia by inducing hypoplasia or aplasia of the irradiated tissue and reducing the number of ducts in the breast [23].
Tamoxifen is effective in preventing and treating gyneco- mastia in men receiving monotherapy with high doses of bicalutamide for prostate cancer. In a randomized, double- blind, placebo-controlled trial involving men receiving bicalutamide, gynecomastia occurred in 10% of patients who received tamoxifen at a dose of 20 mg daily, but it oc- curred in 51% of those who received anastrozole at a dose of 1 mg daily and in 73% of those who received placebo, over a period of 48 weeks. Mastalgia, or breast pain without enlarge- ment, occurred in 6, 27, and 39% of these patients, respective- ly [24].
Serreta et al. compared tamoxifen given therapeutically versus prophylactically. One hundred and seventy-six patients receiving bicalutamide for prostate cancer were randomized to tamoxifen therapy, 20 mg daily for 1 month at the onset of breast symptoms, or tamoxifen prophylaxis, 10 mg daily starting simultaneously with bicalutamide. Seventy-eight per- cent of men in the therapeutic group developed symptoms, whereas 35% of the prophylaxis group experienced
gynecomastia. Gynecomastia was of lower intensity and no patients discontinued bicalutamide in the prophylaxis group, whereas 4% of patients in the therapy group discontinued bicalutamide due to breast complaints. The authors concluded that tamoxifen prophylaxis is safe and effective for prevention of gynecomastia in this setting [21••].
At this time, tamoxifen is an off-label medication for gy- necomastia. However, it is well-studied in women with breast cancer and its cardiotoxicity in this population is documented. Wibowo et al. identified 14 randomized controlled trials for men taking tamoxifen. From a total of 1645 subjects, less than 5% discontinued tamoxifen treatment due to side effects. Although few male patients discontinued tamoxifen treat- ment, men offered tamoxifen to block bicalutamide-induced gynecomastia should be advised about the more common side effects, such as cardiovascular and gastrointestinal events. Some of the tamoxifen side effects, especially the cardiovas- cular events, are consistent with tamoxifen blocking the role of estradiol in men [25••].
For patients at elevated risk of cardiovascular events or who refuse tamoxifen, radiation therapy is an effective man- agement option for gynecomastia, although it is less effective than prophylactic tamoxifen [26•]. Ozen et al. reduced gy- necomastia to 15.8%, compared to a control group with an incidence of 50%. Side effects following radiation were pres- ent in one third of the patients, but these were usually mild and short-lived [27].

Conclusion

Gynecomastia is a common problem in the urologist’s clinic. Diagnosis is typically made by history and physical exam; however, mammography should be used judiciously if breast cancer cannot be ruled out. Medications and known medical diseases are often the cause; however, unexplained gyneco- mastia should prompt an endocrine work-up, followed by ap- propriate imaging studies to search for testicular and other cancers. For patients with idiopathic gynecomastia or who cannot discontinue the causative medication, especially pa- tients taking bicalutamide for treatment of prostate cancer, tamoxifen or radiation therapy for prophylaxis or treatment of gynecomastia are excellent options.

Compliance with Ethical Standards

Conflict of Interest Lee Baumgarten declares no potential conflicts of interest. Ali A. Dabaja is a section editor for Current Urology Reports.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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