Clinical Center of Endocrinology, Medical Faculty, Medical University of Sofia, 2, Zdrawe Street, Sofia, 1431, Bulgaria
GynecomastiaPubertyTesticular cancerKlinefelter syndromeAromataseAndrogensEstradiolHyperthyroidism
Gynecomastia is a benign enlargement of the male breast due to the proliferation of mammary glandular tissues . In contrast, pseudogynecomastia (adipomastia or lipomastia) represents increase of subareolar fat without proliferation of the breast glandular component [1, 2]. Gynecomastia occurs in males of all ages. The term, derived from the Greek words γυνη gyne (female) and μαστοζ mastos (breast), was first introduced by Galen in the second century AD .
Enlargement of the breast in males is not a disease. It is a sign of an underlying disturbance in hormonal physiology, mainly that of ste roids .
In three periods of life, male breast enlargement may be regarded as a normal developmental variant rather than a pathologic finding. These three forms are neonatal, pubertal (adolescent), and involutional gynecomastia and they occur shortly after birth, during puberty, and in old age, respectively . They correspond to times of hormonal changes  and are generally united under the name physiologic gynecomastia [4, 5]. Although not so adequate this term is used to underline their transient character and that not a strong pathologic process is the cause for these forms of gynecomastia.
Gynecomastia should be regarded as unusual in prepubertal children and men of reproductive age .
Normal Breast Development
In human embryo, bilateral mammary lines develop from the ectoderm during the first trimester and give rise to a single pair of placodes . Due to the epithelial/mesenchymal interactions , the placodes descent into the underlying mesenchyme and produce the ductal structure of the glands . Fat pad develops from subcutaneous mesenchymal cells. Parathyroid hormone-related protein secreted from the mammary epithelium seems to be involved in the bud formation, transition from budding to branching, as well as nipple generation . The precise mechanism for the formation of the ductal lumen is not clear, while nipple arises by modification of the skin and suppression of hair follicles during the fifth month of gestation [4, 7]. Mammary glands in males and females possess equal growth potential and have comparable structure with no clear-cut histologic or functional difference until the onset of puberty [2, 4]. At birth only a few small ducts are present and they have an open lumen. Estrogen and androgen receptors are present in both male and female breasts . The difference in the growth and proliferation of breast tissue in each sex is largely affected by the endocrine environment . Estrogens (estrone and mainly estradiol) strongly stimulate and androgens weakly inhibit mammary gland growth [2, 8].
It is the estrogen surge in prepuberty in girls that initiates the process of mammary development, the thelarche . There are two forms of the estrogen receptor , α and β, each encoded by a separate gen, ESR1 on chromosome 6q24-27 and ESR2 on chromosome 14q22-24, respectively . Estrogen receptor α seems to be more important for the ductal formations , but a study revealed a correlation between gynecomastia in adolescents and the estrogen receptor β gene polymorphisms . Female pubertal breast represents mammary tree with substantial number of blind-ended ductules, called acini . Estrogens not only stimulate growth, division, and elongation of the tubular duct system , but they contribute also to the development and maintenance of alveoli at the ends of the ducts .
Progesterone is required for the normal process of alveologenesis . In combination with prolactin, progesterone stimulates the differentiation of the alveoli, which synthesize and secrete milk during lactation .
Growth hormone (GH) through its receptor in stromal fibroblasts induces insulin-like growth factor 1(IGF1) which in turn signals to the mammary epithelium . Systematically produced IGF1 by the liver also acts in this regard at puberty . The observation that the appearance of pubertal gynecomastia coincides within a year of age of peak height velocity  further underlines the significant role of growth hormone for breast enlargement. Even when GH is present, no mammary development is possible in the absence of IGF 1 . On the other hand, the proliferative action of IGF1is inhibited by the insulin-like growth factor-binding protein-5, and this protein is linked to the involution of the mammary gland .
Insulin, thyroid hormones, leptin, and cortisol play also a role in mammogenesis. The presence of thyroid hormone receptor has been found in normal human breast . It was speculated that the GH/IGF 1 axis and thyroid hormones interact and influence breast enlargement in puberty .
Due to the absence of sufficient quantities of estrogen and progesterone and because of the antimammary action of androgens in normal adult men, no breast tissue can be palpated. There are only histological remnants of the duct system .
The prevalence of pubertal gynecomastia varies between 4 and 69 % according to the criteria defined for diagnosis [2, 15]. It may not be as common as previously reported .
In the largest cross-sectional study performed to date on adolescent gynecomastia, breast enlargement was not found in boys younger than 10 years . A gradual increase was observed from 8 % at age 11.5 years to 43.8 % at age 13.5 years and peak incidence of 61.1 % occurring in 14-year-old boys . After this age the incidence gradually decreased. The gynecomastia was more frequent in children with pubic hair Tanner stage 3 and 4 and testicular volume between 5 and 10 mL . Pubertal gynecomastia coincides with peak height velocity usually at Tanner stage 3 for pubic hair . These findings suggest that gynecomastia is a mid-puberty event.
Etiology and Pathogenesis of Gynecomastia
The etiology still remains unclear. As estrogens stimulate the breast tissue proliferation and androgens suppress it, gynecomastia is regarded as a sign and consequence of disturbed balance between these two hormonal groups. As early as in 1941, it was suggested that gynecomastia is due to increased estrogen secretion or to decreased androgen production .
In normal men only about 15 % of the estradiol and 5 % of the estrone in blood circulation are secreted directly by the testes daily . The rest is produced in extragonadal tissues (fat, muscle, skin, bone, liver, kidneys) by the aromatase , the key enzyme for estrogen biosynthesis, from the precursors testosterone and androstenedione [18, 19]. There is also an interconversion between estradiol and estrone in the extragonadal tissues . Testosterone and estradiol bind to sex hormone-binding globulin (SHBG) and, to a lesser extent, to albumin, and a small quantity is unbound in circulation. Only this free fraction is capable to enter the target cells and exert its biologic action. SHBG has greater binding affinity to testosterone than to estradiol and estrone, and hence when serum levels of this globulin increase, relatively more estrogen is available than testosterone to the tissues which can stimulate male breast growth.
The imbalance in men between estrogens and androgens may result from:
· Increase in estrogens through
· Direct secretion from the testes or adrenals
· Extraglandular aromatization of testosterone and androstenedione
· Displacement of more estrogens than androgens from SHBG by certain factors
· Decreased or altered metabolism of estrogens
· Exposure to exogenous estrogens or estrogen-like substances
· Decrease of androgens , especially their free fractions in the circulation through
· Decreased secretion from the testes
· Altered metabolism of androgens
· Increased binding of androgens to SHBG
· Androgen receptor defects due to
· Mutations in the receptor
· Displacement of androgens from androgen receptor
· Enhanced sensitivity of breast tissues 
Pubertal gynecomastia can be explained with the different dynamics of the estradiol and testosterone in the course of puberty. During mid-puberty, relatively more estrogens may be produced by the testes and peripheral tissues before testosterone secretion reaches adult concentrations , and this temporary imbalance may result in gynecomastia. The reason for the differences in androgen and estrogen secretion is not clear. In most cases the alteration that lead to pubertal gynecomastia no longer exists when boys present for evaluation . Pubertal gynecomastia usually resolves spontaneously within 1–3 years  when adult estrogen/androgen ratios are achieved .
In a longitudinal study Biro et al. found that free testosterone levels and body weight were significantly lower and SHBG higher in boys with gynecomastia . Evaluation of 24-h profiles of steroid adrenal and gonadal hormones in eight boys with delayed puberty and 11 with pubertal gynecomastia showed that estradiol and estrone levels were higher relative to testosterone concentrations in the afternoon and evening (when testosterone levels normally are lowest) and that estradiol–testosterone ratio was significantly elevated in subjects with gynecomastia .
No relationship was found between gynecomastia and urban/rural areas of living and residences at different sea level, respectively , giving ground for assumption that these environmental factors may not play a role in breast development. No significant difference in incidence was observed when groups of fair-skinned and brunette (white) boys were compared .
Sher et al. demonstrated that boys with idiopathic gynecomastia tended to be taller and heavier than average , whereas other authors found young men with breast enlargement to be heavier only . Obesity may be associated with increased peripheral conversion of androgens to estrogens and thus with higher prevalence of gynecomastia . It was shown that serum leptin levels were higher in boys with pubertal gynecomastia  and in other studies was found that leptin increased not only aromatase activity but also activated estrogen receptor α [rev. in 11]. In certain cases leptin receptor gene polymorphism may increase the susceptibility to gynecomastia . Obesity is associated with a significant reduction in SHBG but nevertheless with high incidence of gynecomastia . In contrast, one longitudinal study revealed that boys with pubertal gynecomastia are shorter and leaner . In accordance with the latter, the largest cross-sectional study found that adolescent boys with low BMI are more likely to develop gynecomastia . These both observations suggest that the idea according to which adipose tissue as the site of peripheral conversion of androgens to estrogens is positively correlated with the development of breast tissue in adolescents may not be true. The fact that it is easier to detect gynecomastia in lean boys may also be the cause of the above-described finding.
Approximately half of adolescents with breast enlargement have a positive family history  (Fig. 13.1).
A 14-year-old boy with gynecomastia. His father and grandfather have had bilateral gynecomastia too which had resolved within less than 1 year
Available images of Tutankhamun and his close relatives pharaohs Akhenaten and his father Amenhotep III represent them with enlarged breasts, which gives ground to assume familial gynecomastia in two or three generations , but this suggestion has not been proven yet . Tutankhamun died at around the age of 19 years ; therefore, his breast enlargement could be regarded as persistent pubertal gynecomastia (Fig. 13.2).
Statue of pharaoh Tutankhamun on a papyrus boat. Pronounced bilateral gynecomastia in the young ruler? (© exhibition TUTANKHAMUN HIS TOMB AND HIS TREASURES)
Pubertal gynecomastia is not always a harmless deviation of the norm. In many cases it is a manifestation of underlying medical problems or results from drug side effects and is denoted as pathologic gynecomastia [4, 21, 26].
Approximately half of nonmosaic and a third of mosaic patients with Klinefelter syndrome develop gynecomastia during puberty . It is associated with decreased testosterone production rates and enhanced peripheral aromatization . Gynecomastia may be found also in XX males. It can be a sign of the defects in testosterone biosynthesis due to deficiencies of enzymes involved in the conversion of cholesterol to testosterone . It was observed that breast enlargement correlates positively with varicocele at the ages at which gynecomastia is most prevalent (12–14 years); therefore, the suggestion arises that adolescent boys with left-sided varicocele are more likely to have gynecomastia  (Fig. 13.3). Varicocele can impair Leydig cell production of testosterone and by the resulting estrogen/androgen imbalance cause gynecomastia . In hypergonadotropic hypogonadism independently of the form, because of the absent or limited feedback by decreased testosterone, there is increased luteinizing hormone (LH) secretion and the remaining Leydig cells are stimulated to produce estradiol with the effects on the breast tissues . On the contrary, breast enlargement is not usual in hypogonadotropic hypogonadismbecause gonadotropins and sex steroids are low .
Prevalence of gynecomastia and varicocele according to pubic hair Tanner stages in boys of age 10–19 years. Data are expressed as percentages. (Reprinted from Kumanov Ph, Deepinder F, Robeva R, Tomova A, Li J, Agarwal A. Relationship of adolescent gynecomastia with varicocele and somatometric parameters: a cross-sectional study in 6200 healthy boys. J Adolescent Health. 2007; 41(2): 126–131. With permission from Elsevier)
The highest incidence of testicular neoplasms occurs after the end of puberty. Nevertheless they can be the cause of breast development in adolescents . Estradiol production can be stimulated by a human chorionic gonadotropin (hCG )-secreting tumor of gonadal or extra gonadal germ-cell origin (eutopic hCG production) or from lung, gastric, or renal carcinomas (ectopic hCG production) . As a result there is excessive estrogen and deficient androgen action on the breast tissue. Sertoli cell tumors may occur in association with multiple intestinal polyps and mucocutaneous pigmentation (Peutz–Jeghers syndrome ) .
Usually adrenal tumors secrete large amounts of androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS) which are then aromatized to estradiol in peripheral tissues. It is also possible that adrenal tumors secrete excessive amounts of estradiol and estrone because of enormous expression of aromatase in the tumor cells . Feminizing adrenocortical tumors are typically malignant .
Prolactin receptors are present in male breast tissue , but hyperprolactinemia usually is not accompanied by gynecomastia. However, in men with gynecomastia, milk is rarely secreted because progesterone is not high enough for breast acinar development to occur .
Thyroid hormones alter the estrogen/androgen ratio by two mechanisms: by direct stimulation of peripheral aromatase and consequently estrogen production and also by increasing hepatic SHBG synthesis and hence decrease of free testosterone levels relative to free estrogen concentrations [rev. in 6]. About 30 % of young men with hyperthyroidism develop clinically apparent breast enlargement . However, it resolves with treatment that restores euthyroidism .
In liver diseases hepatic extraction of androstenedione is decreased, and thus there is an increase availability of this substrate for estrogen synthesis . Moreover, in hepatic cirrhosis, serum levels of SHBG are increased . Both alterations have as a consequence male breast enlargement.
The cause of gynecomastia as well as of the testicular dysfunction in patients with chronic renal failure is not clear. Breast enlargement in such situation does not respond to treatment . Gynecomastia can develop on several mechanisms in individuals with acquired immunodeficiency syndrome (AIDS) [3, 8].
Familial or sporadic aromatase excess syndrome manifests itself around the adrenarche and is characterized with prepubertal onset of gynecomastia and incomplete virilization by the end of puberty as well as with accelerated growth in childhood but reduced final height [20, 36]. Mutations in aromatase gene CYP19 which is located on chromosome 15q21.2  can increase aromatase activity resulting in hyperestrogenism and subsequently gynecomastia may arise [38, 39].
During starvation and weight loss, the hypothalamic-pituitary-gonadal axis is suppressed. With sufficient feeding and normalization of the weight, the gonadal function will be restored (“second puberty”), and like in normal puberty, there is a possibility for transient disturbance in estradiol/testosterone ratio in favor of estradiol with inducing gynecomastia . Male breast may enlarge on the same mechanism during recovery from chronic illness.
Testosterone, an aromatizable androgen, and androgenic anabolic steroids are widely used for muscle mass and better sport achievements. They not only diminish testosterone production by suppressing gonadotropin secretion but are substrates for peripheral conversion to estrogens with the resulting altered estrogen/androgen balance and breast enlargement in men .
Environmental influence of estrogens or estrogen-like substances may induce gynecomastia. It has been reported that lavender and tea tree oils might be the factor of gynecomastia in prepubertal boys due to their antiandrogenic and weak estrogenic activities .
Substantial number of drugs, although most of them are rarely used in adolescent years, may cause breast enlargement. Among them besides the estrogens and antiandrogens are also metronidazole, ketoconazole, spironolactone, cimetidine, ranitidine, omeprazole, alkylating agents, vinca alkaloids, cardiovascular drugs, theophylline and some psychoactive agents . Spironolactone and ketoconazole displace steroids from SHBG with estrogens released more easily . Moreover, spironolactone blocks the biosynthesis of testosterone and also inhibits the binding of testosterone and dihydrotestosterone to androgen receptor . Thus, at least on three different mechanisms, spironolactone can cause gynecomastia.
Alcohol increases metabolism and clearance of androgens . Alcohol abuse is associated with elevated levels of SHBG. It has direct toxic effects on the testes . Marijuana and heroin also have been linked to the development of gynecomastia [8, 15].
In some patients there is no alteration in estradiol/testosterone ratio in systemic circulation. It has been proposed that the changes are only local, e.g., enhanced aromatization of androgens in subareolar adipose tissue, resulting in elevated estrogen concentration in the breast . Alternatively, enhanced susceptibility of breast tissue to estrogens could also be considered. No identified cause is found in 25 % of patients with gynecomastia [18, 26] and therefore it is signed as idiopathic.
This brief survey indicates that all male patients with breast enlargement should undergo complete evaluation.
Histology of Gynecomastia
In gynecomastia of recent onset, the histologic findings include hyperplasia of the ductal epithelium, infiltration of the periductal tissue with inflammatory cells, and increased subareolar fat . When gynecomastia lasts long without or still under hormonal influences, there is progressive fibrosis and hyalinization and regression of epithelial proliferation . Inflammatory reaction wanes . The number of ducts decreases, they disappear but the fibrosis usually remains even when the cause of the gynecomastia is no more active . Hence, pathologic changes correlate with the duration and not with the causes of gynecomastia. The histological appearance of gynecomastia is the same regardless of the cause .
Unilateral breast enlargement should be regarded as a stage in the development of the gynecomastia .
Recently onset gynecomastia is usually accompanied with pain or sensitiveness to clothing. Pubertal gynecomastia has a negative impact on the self-esteem of adolescent boys. In all ages it can lead to psychological distress, decreased participation in social activities, and to depression.
It has not been established that gynecomastia predisposes to breast cancer. Klinefelter syndrome , often associated with breast enlargement, does carry a higher risk for mammary malignancy . However, this malignancy is rare in men .
Diagnosis aims to solve two problems:
· To differentiate true gynecomastia from:
· Breast cancer
· Other processes in breast area: neurofibroma, lymphangioma, hematoma, lipoma, and dermoid cyst 
· To determine if the breast enlargement is caused by an underlying disorder or it is idiopathic 
A careful medical history should be obtained from the patients and, when necessary, from their parents. The breast should be carefully inspected and palpated. The normal male breast is relatively flat with certain degree of fullness around the nipple-areola complex . The true gynecomastia can be distinguished from breast adiposity simply by palpation. With the patient supine on his back with his hands clasped beneath his head, the examiner grasps the breast between the thumb and forefinger and gradually moves the digits toward the nipple [15, 20]. In case of gynecomastia freely mobile disk of tissue will be palpated concentrically under the nipple and areola [8, 20]. According to some authors, gynecomastia is present when the subareolar disk is about 0.5 cm in diameter [17, 25], and others recommend acceptance of gynecomastia when the diameter is 2 cm . Macrogynecomastia is referred to excessive breast enlargement (>4 cm) . Another method for evaluation of gynecomastia is the use of Tanner stages for breast development in girls during puberty (see Chap. 4, Fig. 4.1). Due to excessive fat and/or connective tissue, the glands can be significantly prominent . In cases of macrogynecomastia, the areola and nipple form a secondary mound over the dome-shaped breast as in Tanner stage 4 female breast development . Obesity may disturb the accurate assessment of the size of gynecomastia. Glandular breast tissue has rubber consistence and is firmer than the surrounding adipose tissue. Gynecomastia of recent onset (less than 6 months’ duration) is in most cases tender on palpation . In patients with pseudogynecomastia on the contrary, no such subareolar disk of glandular tissue is palpated [15, 20]. Gynecomastia is usually bilateral and more or less symmetric. Estrogens darken the areolae and therefore some patients with gynecomastia may have change in areolar pigmentation .
Physical examination should include height and weight, pubertal development stage, testes size, and palpation of possible testicular masses . Renal and liver function tests should be done along with the assessment of serum levels of LH, testosterone, estradiol, prolactin, DHEAS, and thyreostimulating hormone (TSH) [4, 15]. If both testes are small (testes volumes less than 6 mL), karyotype should be evaluated , and in case of asymmetrical gonads, ultrasound of the testes is indicated and the serum levels of tumor markers hCG and α-fetoprotein should be assessed. Elevated levels of hCG and normal findings on testicular ultrasonography are indication for searching for extragonadal hCG secreting tumor . A constellation of accelerated linear growth, high estradiol, low LH, and normal gonadal and adrenal imaging is typical for the increased peripheral aromatase activity (aromatase excess syndrome) [21, 36]. Breast ultrasound is useful for differentiation between adipomastia and gynecomastia . At ultrasound examination, homogenous hypoechoic glandular tissue beneath the nipples may be found or nonhomogenous and hyperechogenic tissue is present with increased amount of adipose and fibrous tissues .
One-sided gynecomastia should always be differentiated from breast cancer. The latter is usually very hard on palpation and eccentrically located from the nipple and areola . Pain is less common with breast cancer than with gynecomastia . Skin dimpling and nipple retraction may be present as well as bloody nipple discharge; these signs can be observed in breast carcinoma but never in gynecomastia [20, 35]. Lymphadenopathy is also suspicious for malignancy . Mammography (Fig. 13.4) is fairly accurate in differentiating between malignant and benign male breast diseases, and this method reduces the need for biopsies .
Mammography of a gynecomastia in a 13-year-old boy
No guidelines are still available for the management of gynecomastia .
In general, the decision to treat gynecomastia depends on the patient’s preferences and on the impact of gynecomastia on his quality of life . Underlying pathological condition should be treated. If the enlargement of the breast is drug induced, discontinuation of the drug is advisable.
Reassurance and watchful waiting are regarded as the mainstay of treatment, given that the breast enlargement is usually a self-limiting condition [22, 30]. If pubertal gynecomastia causes anxiety and embarrassment that are not relieved by explanations and reassur ance, it should be treated .
Medical therapy is indicated during the initial phase of gynecomastia. It aims to correct the estrogen/androgen imbalance by either blocking the effects of estrogens on the breast with estrogen-receptor modulators or by inhibiting estrogen production with anastrozole or testolactone . Aromatase inhibitors would reduce estrogen effect in all tissues. On the contrary, selective estrogen-receptor modulators tamoxifen and raloxifene have antagonist effect only on breast tissue .
The selective estrogen-receptor modulator tamoxifen (10 or 20 mg orally once or twice a day for 3 months) is effective in pain and size reduction of pubertal and adult gynecomastia of recent onset [30, 41, 42]. Adverse events seem to be uncommon . It has been shown that the selective estrogen-receptor modulator raloxifene (60 mg once daily) for 3 months reduces the size of gynecomastia in boys [20, 30]. In a comparative study, they both appeared to be safe and effective in reducing persistent pubertal gynecomastia, with a better response to raloxifene than to tamoxifen .
Using the aromatase inhibitor testolacton e in a dosage of 150 mg three times daily, Mahoney has found it less effective than tamoxifen in reducing pubertal gynecomastia . In a randomized, double-blind, placebo-controlled study on boys aged 11–18 years, the aromatase inhibitor anastrozole 1 mg daily for 6 months showed no significant difference as compared to placebo in the percentage of patients with breast volume reduction . Since aromatization of androgens is a prerequisite for breast enlargement in many cases, it is not clear why such discouraging results are obtained with aromatase inhibitors . This would suggest that gynecomastia, at least some cases of this heterogeneous abnormality, results not from the altered estradiol/testosterone ratio but from other signaling pathways .
Despite some promising observations, no pharmacological agents have been approved for the treatment of gynecomastia .
Breast enlargement of longer than 1 year duration is not responsive to medical treatment because of substantial stromal fibrosis. Such cases should undergo surgical removal of the breast tissue and subareolar fat [2, 18, 35]. The available data suggest that the first surgical attempt was undertaken in the seventh century AD by the byzantine physician Paulus Aegineta . After many modifications surgery remains the most effective overall method in treating gynecomastia . The goals should be restoration of adequate male chest shape with limited scar extensions . Complications include skin retraction, scars as well as hematoma and insufficient resection but they all are seldom when the surgeons are experienced .
Gynecomastia is not a separate disease. In many cases and in all ages, it may reflect severe underlying conditions. Gynecomastia is often asymptomatic and in adolescents usually resolves spontaneously within 1–3 years. Nevertheless a pathologic process, environmental exposure, or abuse of some substances must be ruled out also in this period of life as well as in preadolescent boys. Due to insufficient studies, there is no consensus recommendation for the treatment of gynecomastia.
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