Objective: The purpose of this review is to present the complex underlying pathophysiology that can form the basis of this common condition.
Methods: More than 20 years of clinical experience in endocrinology and plastic surgery and a review of the Englishlanguage literature were used to form the basis of this review.
Results: While idiopathic and physiologic causes are frequent, there are multiple, significant, underlying disorders that can result in gynecomastia, including chronic illness, cancer, medications, syndromes, and a variety of endocrinopathies.
Conclusion: Both history and physical examination are frequently sufficient to make an appropriate diagnosis. In patients who do not have a definitive etiology of their gynecomastia, a screening battery of laboratory tests is sufficient to rule out significant pathophysiology, although these tests may be difficult to interpret in children and adolescents. An endocrinology consultation is suggested whenever an abnormal screening laboratory test occurs or if there are any other suggestions of underlying endocrinopathy.
Gynecomastia refers to the condition of breast development in a male. It can occur in boys and men of all ages and is most common in infancy and adolescence and in middle-aged to older men. The pathophysiology of gynecomastia is felt to be an imbalance of estrogens and androgens, with a decreased testosterone-to-estradiol ratio.1 This imbalance can occur through many mechanisms and directly affects breast tissue.2 Transient gynecomastia is estimated to occur in 60% to 90% of male infants secondary to high estrogen state during pregnancy.3,4 Pubertal gynecomastia has a peak prevalence of nearly 65% and occurs at about 14 years of age.3,5 Older men also develop involutional gynecomastia, with a prevalence of 40% to 55%, seen at autopsy.6 Frequently, the etiology of gynecomastia is evident when a thorough history and physical examination are performed. When the etiology is not apparent, then a series of laboratory tests should be performed to rule out significant underlying pathophysiology.
The physician should treat the specific condition causing gynecomastia, if one is identified. Medications that cause gynecomastia should be discontinued. Softening of the glandular tissue along with decreased tenderness will usually occur by 1 month. However, if breast development has been present for more than 1 year, it rarely regresses substantially because of fibrosis. Hypogonadism of various causes can be treated with testosterone, and regression of gynecomastia should occur if the condition is short term. Although medical therapy with estrogen antagonists has not been approved for the treatment of gynecomastia, various researchers have shown different levels of effectiveness for the regression of both the pain and size of the breast tissue. A retrospective analysis comparing danazol with tamoxifen was done on 43 patients with idiopathic gynecomastia, ranging in age from 13 to 82 years (mean = 39.5 years).18 The median size of the breast tissue was 3 cm and the median duration of gynecomastia was 3 months.
Of the 23 patients who were treated with tamoxifen, complete resolution occurred in 18 (78.2%), whereas 8 of the 20 (40%) who were treated with danazol had complete resolution. A decrease in pain occurred in 82% of the patients in the tamoxifen group and 75% in the danazol group. However, 5 patients in the tamoxifen cohort developed recurrences of the breast mass. There was progressive enlargement in 1 patient in each of the groups undergoing medical treatment.
No adverse effects were seen except for 1 male developing calf muscle pain, which was shown not to be due to thrombosis. A prospective study on the use of tamoxifen in physiologic gynecomastia was conducted in 36 men who were classified as having either lump or fatty gynecomastia.19 Lump gynecomastia was defined as a single palpable solid lesion in the retroareolar region and was observed in 20 men. Sixteen men had fatty gynecomastia, referring to those presenting with breast enlargement and no palpable solid lump. The patients ranged in age from 18 to 64 years (mean = 31 years), and the mean duration of gynecomastia was 4 months. Pain and tenderness were characterized in 25 cases. The patients took tamoxifen for a mean of 12 weeks (duration = 4–24 weeks). Resolution of the mass occurred in 83.3% of the total patients, 100% in the lump group and 62.5% in the fatty group. Tenderness decreased in 84% of the total patients, 100% in the lump group and 69% in the fatty group. There was only 1 recurrence after 7 months.
There were no major adverse effects except for a deep vein thrombosis in a 23-year-old man who sustained major lower limb trauma. Aretrospective chart reviewcompared 38 patients with persistent pubertal gynecomastia assigned to either tamoxifen or raloxifene treatment group.20 The mean agewas 14 years, and the mean duration of gynecomastia was 28.3 months. Tamoxifen is an antiestrogen that has estrogenic effects in all tissues other than the breast. Raloxifene is a nonsteroidal antiestrogen that shows estrogenic effects for skeletal and lipid tissues and antiestrogenic effects for the breasts and the uterus. The mean diameter of breast nodules decreased by 2.1 cm after tamoxifen treatment and 2.5 cm after raloxifene treatment. Improvement was noted in 86% of the tamoxifen-treated group and 91% in the raloxifene-treated group.
No adverse effects were seen in either group. Thus, in spite of the relatively long duration of gynecomastia prior to treatment, a high percentage of patients responded to both treatment modalities. However, because there was no follow-up in untreated patients, the final assessment is murky regarding treatment versus observation alone. In addition, although no treated patients complained of a recurrence, 40% went for surgery because the medical treatment did not completely solve the problem. Anastrozole, another nonapproved treatment for gynecomastia, was evaluated in a randomized, double-blinded, placebo-controlled study of 80 male adolescents over a 3-month period.21 Anastrozole is a potent aromatase inhibitor that decreases estrogen levels and increases testosterone concentration.
A response was defined as 50% or more reduction in the calculated volume of both breasts by using ultrasonography. In the anastrozole group, there was a 38.5% response versus a 31.4% response in the placebo group. This was not significant. Similarly, a randomized placebo-controlled study comparing tamoxifen with anastrozole was evaluated for the prevention of bicalutamide-induced gynecomastia in 93 men with prostate cancer.22,23 Men receiving tamoxifen had a significantly reduced risk of gynecomastia compared with the anastrozole-treated group in which the risk was similar to the placebo-treated group. These studies suggest that selective estrogen antagonists may be the pharmacologic treatment of choice for most patients with gynecomastia.
Gynecomastia is usually a physiologic condition that may regress over time. The etiology is often determined as a result of both thorough history and physical examination. However, an atypical presentation can signify a pathologic state and the surgeon should be aware of associated problems. If the gynecomastia involves breast tissue of 5 cm or more or if there is an atypical presentation, a hormonal and sometimes radiologic workup should be performed. Suspicious breast lesions should be biopsied. Hormonal studies are frequently difficult to interpret and are based on age and Tanner staging in the adolescents and children. When there is a screening laboratory abnormality or if the etiology is in doubt, an endocrinologist should be consulted. Medical treatments of gynecomastia are currently being studied, and antiestrogens may become the pharmacologic treatment of choice within certain presentations and conditions.