ABSTRACT

Gynecomastia is a relatively common disorder. Its causes range from benign physiological processes to rare neoplasms. To diagnose the etiology of the gynecomastia, the clinician must understand the hormonal factors involved in breast development. Parallel to female breast development, estrogen, growth hormone (GH), and IGF-1 are required for breast growth in males. Since a balance exists between estrogen and androgens in males, any disease state or medication that increases circulating estrogens or decreases circulating androgens, causing an elevation in the estrogen to androgen ratio, can induce gynecomastia. Due to the diversity of possible etiologies, including a neoplasm, performing a careful history and physical is imperative. Once gynecomastia has been diagnosed, treatment of the underlying cause is warranted. If no underlying cause is discovered, then close observation is appropriate. If the gynecomastia is severe and of recent onset, medical therapy can be attempted, and if ineffective, glandular tissue can be removed surgically. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

This chapter reviews the ontogeny and physiology of breast development; factors that influence breast enlargement in the male; the differential diagnosis of gynecomastia; the process of diagnostic investigation; and treatment of gynecomastia.

BREAST ONTOGENY AND DEVELOPMENT

Male breast development occurs in an analogous fashion to female breast development. At puberty in the female, a complex hormonal interplay occurs resulting in growth and maturation of the adult female breast.

In early fetal life, epithelial cells, derived from the epidermis of the area programmed to become the areola, proliferate into ducts, which connect to the nipple at the skin's surface. The blind ends of these ducts bud to form alveolar structures in later gestation. With the decline in fetal prolactin and placental estrogen and progesterone at birth, the infantile breast regresses until puberty (1).

During thelarche in females, the initial clinical appearance of the breast bud and growth and division of the ducts occur, giving rise to club-shaped terminal end buds, which then form alveolar buds. Approximately a dozen alveolar buds will cluster around a terminal duct, forming the type 1 lobule. The type 1 lobule will mature into types 2 and 3 lobules, called ductules. The number of alveolar buds increases to as many as 50 in type 2 and 80 in type 3 lobules. The entire differentiation process takes years after the onset of puberty and, if pregnancy is not achieved, may never be completed (2). On the contrary, there is usually no further development of breast because of the rising testosterone concentrations at puberty. Some peri-pubertal boys may transiently develop type 1 lobules that may undergo atrophy at a later stage.

HORMONAL REGULATION OF BREAST DEVELOPMENT

The initiation and progression of breast development involves a coordinated effort of pituitary and ovarian hormones, as well as local mediators (Figure 1).

Figure 1. 

Hormones affecting growth and differentiation of breast tissue.

ESTROGEN, GH AND IGF-1, PROGESTERONE, & PROLACTIN

Estrogen and progesterone act in an integrative fashion to stimulate normal adult female breast development. Estrogen, acting through its estrogen receptor (ER), promotes ductal growth, while progesterone, acting through its receptor (PR), promotes alveolar development (1). This is demonstrated by experiments in ER knockout mice that display grossly impaired ductal development, whereas PR knockout mice possess significant ductal development, but lack alveolar differentiation (3, 4).

Although estrogens and progestogens are vital to mammary growth, they are ineffective in the absence of anterior pituitary hormones (5). Thus, neither estrogen alone nor estrogen plus progesterone can sustain breast development without other mediators, such as GH and IGF-1. This was confirmed by studies involving the administration of estrogen and GH to hypophysectomized and oophorectomized female rats that resulted in breast ductal development. The GH effects on ductal growth are mediated through stimulation of IGF-1. This is demonstrated by studies of estrogen and GH administration to IGF-1 knockout rats that showed significantly decreased mammary development when compared to age-matched IGF-1- intact controls. Combined estrogen and IGF-1 treatment in these IGF-1 knockout rats restored mammary growth (6, 7). In addition, Walden et al. demonstrated that GH-stimulated production of IGF-1 mRNA in the mammary gland itself, suggesting that IGF-1 production in the stromal compartment of the mammary gland acts locally to promote breast development (8). Furthermore, other data indicates that estrogen promotes GH secretion and increases GH levels, stimulating the production of IGF-1, which synergizes with estrogen to induce ductal development. In a population-based study of healthy boys and adolescents, IGF-I levels were found to be elevated in boys with pubertal gynecomastia compared with boys without gynecomastia suggesting that the GH-IGF-I axis may be involved in the pathogenesis of pubertal gynecomastia (9). Indeed, dating back to 1950, it had already been reported that gynecomastia was found in a young patient with acromegaly (97).

Progesterone has minimal effects on breast development without concomitant anterior pituitary hormones, indicating that progesterone also interacts closely with pituitary hormones. For example, prolonged treatment of dogs with progestogens such as depot medroxyprogesterone acetate or with proligestone was associated with increased GH and IGF-1 levels, suggesting that progesterone may stimulate GH secretion (10). In addition, clinical studies have correlated maximal cell proliferation to specific phases in the female menstrual cycle. For example, maximal proliferation occurs not during the follicular phase when estrogens reach peak levels and progesterone is low (less than 1 ng/mL [3.1nmol/mL]), but rather, it occurs during the luteal phase when progesterone reaches concentrations of 10-20 ng/mL (31- 62 nmol/mL) and estrogen concentrations are two to three times lower than in the follicular phase (11). Furthermore, immunohistochemical studies of ER and PR showed that the highest percentage of proliferating cells, found almost exclusively in the type 1 lobules, contained the highest percentage of ER and PR positive cells (2). Similarly, there is immunocytological presence of ER, PR, and androgen receptors (AR) in gynecomastia and male breast carcinoma. ER, PR and AR expression was observed in 100% (30/30) of gynecomastia cases (12). Given these data and the fact that PR knockout mice lack alveolar development in breast tissue, it seems that progesterone, analogous to estrogen, increases GH secretion and acts through the PR on mammary cells to enhance breast development and alveolar differentiation (13, 4).

Prolactin is another anterior pituitary hormone integral to breast development. Prolactin is not only secreted by the pituitary gland but may be produced by normal mammary tissue epithelial cells and breast tumors (14, 15). Prolactin stimulates epithelial cell proliferation only in the presence of estrogen and enhances lobulo-alveolar differentiation only with concomitant progesterone. Gynecomastia is seen rarely in hyperprolactinemia, possibly because of the low estrogen levels due to suppression of LH secretion. Previously, receptors for LH/ human chorionic gonadotropin (hCG) have been found in male and female breast tissues, but their functional roles remain to be determined (16).

ANDROGEN AND AROMATASE

Estrogen effects on the breast is the result of circulating estradiol levels or locally produced estrogens. Aromatase P450 catalyzes the conversion of the C19 steroids-- androstenedione, testosterone, and 16- α- hydroxyandrostenedione-- to estrone, estradiol-17β and estriol. As such, an overabundance of substrate (e.g., testosterone) or an increased enzyme activity (aromatase) for estrogen production can increase serum and breast estrogen concentrations and initiate the cascade to breast development in females and males. For example, in the more complete forms of androgen insensitivity syndromes in genetically male (XY) patients, excess androgen is aromatized into estrogen that results in gynecomastia and an overall phenotypic female appearance. Furthermore, the loss of the anti-proliferative effect of androgens on breast also contributes significantly to breast development in XY individuals with complete androgen insensitivity. Likewise, the biologic effects of over-expression of the aromatase enzyme in female and male mice transgenic for the aromatase gene result in increased breast proliferation. In female transgenics, over-expression of aromatase promotes the induction of hyperplastic and dysplastic changes in breast tissue. Over-expression of aromatase in male transgenics causes increased mammary growth and histological changes similar to gynecomastia, increased estrogen and progesterone receptors, and increased downstream breast growth factors such as TGF-beta and βFGF (17). Interestingly, treatment with an aromatase inhibitor leads to involution of the mammalian gland phenotype (18). Thus, although androgens do not stimulate breast development directly, they may do so if they aromatize to estrogen. This occurs in cases of androgen excess or in patients with increased aromatase activity.

PHYSIOLOGIC GYNECOMASTIA

Gynecomastia, breast development in males, can occur normally during three phases of life. The first occurs shortly after birth in both males and females. This is partly caused by the high fetal blood levels of estradiol and progesterone (produced by the mother) that stimulate breast tissue in the newborn. Another mechanism is the increased conversion of steroid hormone precursors to sex steroids and increased aromatization of androgen as a result of neonatal surge of luteinizing hormone (LH). Neonatal gynecomastia may persist for several weeks after birth and may be associated with a milky breast discharge called "witch's milk" (2).

Puberty marks the second period when gynecomastia can occur physiologically. In fact, up to 60% of boys have clinically detectable gynecomastia by age 14. Although it is mostly bilateral, it is often asymmetrical and can occur unilaterally. Pubertal gynecomastia usually resolves within 3 years of onset (2). In early puberty, the pituitary gland releases gonadotropins at night and stimulates testicular production of testosterone during the very early morning hours. Serum estradiol concentration, however, remains elevated above prepubertal concentrations throughout the day. Compared with boys who do not develop gynecomastia, boys with pubertal gynecomastia have a decreased androgen to estrogen ratio (19, 100). Furthermore, another study showed increased aromatase activity in the skin fibroblasts of boys with gynecomastia (103). Thus, the mechanism by which pubertal gynecomastia occurs may be due to either decreased production of androgens or increased aromatization of circulating androgens, thus increasing the estrogen to androgen ratio (20).

The third age range in which gynecomastia is frequently seen is during older age (>60 years). The reported prevalence varies from 36 to 57%, possibly because of different selected populations and different diagnostic criteria (101). Although the exact mechanisms by which this occurs have not been fully elucidated, evidence suggests that it may result from increased peripheral aromatase activity secondary to increased total body fat, relatively elevated LH concentrations, and decreased serum testosterone concentrations associated with male aging. For instance, investigators have shown increased urinary estrogen concentrations in obese individuals and have demonstrated aromatase expression in adipose tissue (21). Thus, like the gynecomastia of obesity, the gynecomastia of aging may partly result from increased aromatase activity, causing increased conversion of androgens to estrogens (22). Moreover, not only does total body fat increase with age, but there may be an increase in aromatase activity in the adipose tissue already present, further increasing circulating estrogens. Serum sex hormone binding globulin (SHBG) concentrations increase with age in men. Because SHBG binds estrogen with less affinity than testosterone, the bioavailable estradiol to bioavailable testosterone ratio may increase in older men. Lastly, elderly patients may take multiple medications associated with gynecomastia. One cohort study suggests medications play a role in 80% of gynecomastia in older men (23).

PATHOLOGIC GYNECOMASTIA

Pathologic gynecomastia is due to an increase in the circulating and/or local breast tissue ratio of estrogen to androgen.

MALE BREAST CANCER

Male breast cancer is rare and comprises only 0.2% of all male cancers. The overall prevalence of invasive carcinomas was 0.11% and of in situ carcinomas was 0.18% in in a 20-year national registry study of surgically excised breast specimens with the diagnosis of gynecomastia (55). Although male breast cancer is rare and gynecomastia is not considered a premalignant condition (101), men with gynecomastia, especially elderly, worry about breast cancer and often seek medical advice (56) and it is important to differentiate male breast cancer from gynecomastia (Table 4). Of note, men with Klinefelter syndrome have a 20- to 50-fold increased risk of breast cancer. Other risk factors include hyperestrogenic conditions like obesity, alcohol, exogenous estrogen exposure (e.g., gender reassignment), and testicular disorders. It is unclear if these are specific risks for breast cancer are linked to the stimulatory process responsible for gynecomastia (57). Old age, working in environment with high temperature, exhaust emissions, radiation to chest, and liver damage are also risk factors for male breast cancer (58). Family history should always be explored. In particular, a family history of BRCA2 positive breast cancer significantly increases the risk of male breast cancer in carriers of mutation (59).

PATIENT EVALUATION

Laboratory Evaluation

All patients who present with gynecomastia should have serum testosterone, estradiol, LH, and hCG measured (93) (using an assay that detects all forms of hCG) (Fig 2). Further testing should be tailored according to the history, physical examination and the results of these initial tests. An elevated beta hCG or hCG or a markedly elevated serum estradiol suggests neoplasm and a testicular ultrasound is warranted to identify a testicular tumor. However, non-testicular tumors can also secrete beta hCG or hCG and therefore further imaging such as CT thorax and abdomen is indicated if ultrasound does not show a testicular mass. A low testosterone level, with an elevated LH indicates primary hypogonadism. If the history suggests Klinefelter syndrome, then a karyotype should be performed for definitive diagnosis. Low testosterone and low LH indicate secondary hypogonadism, and hypothalamic or pituitary causes should be sought. If testosterone and LH are elevated, then the diagnosis of androgen resistance should be considered. In case of estrogen-secreting tumor, LH is usually suppressed with low or low normal testosterone concentrations and negative pituitary imaging. Estradiol concentrations are high. Liver, kidney and thyroid function should be assessed if clinically indicated. Furthermore, if examination of breast tissue suggests malignancy, a biopsy should be performed. This is of particular importance in patients with Klinefelter syndrome, who have an increased risk of breast cancer. On the other hand, if the examination finding is compatible with breast abscess, then fine needle aspiration for microscopy and culture is warranted (60). Acid-fast bacilli and tuberculosis culture can be done if there is risk factor(s) for tuberculosis.

Figure 2. 

Algorithm for investigation of gynecomastia.

TREATMENT

Treatment of the underlying endocrinologic or systemic disease that has caused gynecomastia is appropriate when possible. Testicular tumors, such as Leydig cell, Sertoli cell, or granulosa cell tumors should be surgically removed. In addition to surgery, germ cell tumors are further managed with chemotherapy involving cisplatin, bleomycin, and either vinblastine or etoposide (25, 26). Should underlying thyrotoxicosis, renal, or hepatic failure be discovered, appropriate therapy should be initiated. Medications that cause gynecomastia should also be discontinued whenever possible based on their role in management of the underlying condition. The improvement should be apparent within a month after discontinuation of the culprit drug (61). If the gynecomastia has been present for more than six months, regression is unlikely because of the presence of less reversible fibrotic tissues (62). Of course, if a breast biopsy indicates malignancy, then mastectomy should be performed.

If no pathologic etiology is detected, then appropriate treatment is close observation. A careful breast exam should be done initially every 3-6 months until the gynecomastia regresses or stabilizes, after which a breast exam can be performed yearly. It is important to remember that most cases of pubertal gynecomastia may resolve spontaneously within one to two years, around 20% of patients have residual gynecomastia at the age of 20 (63). An information sheet about gynecomastia is available for those patients who are interested to know more about their conditions (64).

PREVENTION OF GYNECOMASTIA IN MEN WITH PROSTATE CANCER

Because androgen deprivation is one of the commonly used treatment modalities for advanced prostate cancer, its possible role in the development of gynecomastia is of particular concern to clinicians. Up to 80% of patients receiving non-steroidal anti-androgen therapy may develop gynecomastia, usually 6-9 months after hormonal treatment. Some patients may have painful and disfiguring gynecomastia (81). Preventive options include tamoxifen, radiation therapy, or aromatase inhibitors.

Tamoxifen is the most effective preventive therapy for gynecomastia due to anti-androgen therapy for treatment of prostate cancer. Tamoxifen is superior to radiotherapy in preventing gynecomastia in patients receiving bicalutamide (Casodex) for prostate cancer in a randomized controlled trial (82). Tamoxifen is superior to aromatase inhibitor to prevent gynecomastia in patients with prostate cancer. For instance, Boccardo, et al. showed that 10% patients in the tamoxifen group (20 mg daily dose) developed gynecomastia, whereas 51% in the anastrozole group and 73% in the placebo group had gynecomastia over a period of 48 weeks (74). Fradet, et al. showed tamoxifen reduced the incidence of breast events (gynecomastia and/or breast pain) in patients with prostate cancer receiving bicalutamide in a dose-dependent manner (83). Likewise, it has been shown that low dose weekly tamoxifen (20 mg/week) is inferior to the usual dose daily regimen (20mg/day) in terms of the prevention and treatment of gynecomastia (84). Current data suggests tamoxifen 10-20 mg per day is the optimum dose required for prophylaxis of gynecomastia in patients with prostate cancer receiving androgen deprivation therapy (83, 84, 85). Low dose prophylactic irradiation has been reported to reduce the rate of gynecomastia but not breast pain in men receiving estrogens or anti-androgens for prostate cancer (11, 86, 87). Compared with tamoxifen, irradiation seems to be less effective for prevention and treatment of gynecomastia but it is usually well-tolerated (94).

Some studies suggest that the new generation of anti-androgen drugs such as abiraterone acetate, enzalutamide, apalutamide, and darolutamide might be associated with less gynecomastia (88, 95); More recently, it has been reported that 36.6% of patients receiving enzalutamide develop gynecomastia; this incidence seems to be lower than reported in patients who were treated with older anti-androgens such as bicalutamide (99).

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