Gynecomastia in children and adolescents

INTRODUCTION — This topic will focus on the evaluation of gynecomastia in children and adolescents. Gynecomastia in adults is discussed separately:

●(See "Epidemiology, pathophysiology, and causes of gynecomastia".)

●(See "Clinical features, diagnosis, and evaluation of gynecomastia in adults".)

●(See "Management of gynecomastia".)

DEFINITION AND CHARACTERISTIC FEATURES — Gynecomastia is the benign proliferation of glandular breast tissue in males. It differs from proliferation of breast tissue in females in that there is no terminal alveolar development in response to progesterone [1].

Gynecomastia is characterized by a mass or ridge of glandular tissue that is symmetrically distributed around the areolar-nipple complex (figure 1). It can generally be detected when the glandular tissue is >0.5 cm (0.2 inches) in diameter. Gynecomastia may be tender to palpation early in the course. It is usually bilateral, but some patients present with unilateral enlargement or bilateral enlargement with one side larger than the other or enlarging weeks to months before the other [2-4].

The distinct mass of glandular tissue, central location, and symmetrical shape distinguish gynecomastia from other causes of male breast enlargement in children and adolescents [1,5,6]. (See 'Mimics of gynecomastia' below.)

EPIDEMIOLOGY — In children and adolescents, gynecomastia is common during the neonatal period and during puberty (figure 2). Gynecomastia is uncommon in prepubertal males. The epidemiology of gynecomastia is discussed in detail separately. (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Epidemiology'.)

PATHOPHYSIOLOGY — Gynecomastia is presumed to be caused by a relative imbalance between androgens (testosterone and androstenedione) and estrogens (estradiol and estrone). The hormonal imbalance may be caused by an absolute increase in free estrogens, decrease in endogenous free androgens, a relative increase in the free estrogen-to-free androgen ratio, androgen insensitivity, or estrogen-like drug effects (table 1). (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Pathophysiology'.)

Transient neonatal gynecomastia is thought to result from placental transformation of dehydroepiandrosterone and dehydroepiandrosterone sulfate (derived from the fetus and mother) to estrone and estradiol, which enter the fetal circulation and stimulate glandular proliferation in the breast. (See "Epidemiology, pathophysiology, and causes of gynecomastia" and "Placental development and physiology", section on 'Steroid hormones'.)

The pathophysiology of pubertal gynecomastia is likely related to the transient estrogen/androgen imbalance caused by the earlier rise of serum estradiol than serum androgen concentrations to adult levels. However, most observational studies have not found differences in single point measurements of estradiol in males with and without pubertal gynecomastia [7-10]. In observational studies, males with gynecomastia have greater expression of aromatase in skin fibroblasts and higher concentrations of insulin-like growth factor-1 (IGF-1) than males without gynecomastia [10,11]. Aromatase locally converts androgen to estrogen, and IGF-1 is necessary for breast proliferation [10,11]. Additional studies suggest that changes in sex hormone-binding globulin levels (due to medications and illnesses such as liver disease) may impact estradiol levels [12]. (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Pubertal gynecomastia'.)

CAUSES OF GYNECOMASTIA

Physiologic gynecomastia — The majority of cases of gynecomastia in children and adolescents are physiologic (table 2) [2].

Neonatal breast hypertrophy — Neonatal breast hypertrophy (which occurs in both males and females) is presumably related to placental transformation of androgens to estrogens, which enter the fetal circulation and stimulate glandular proliferation (picture 1). (See "Epidemiology, pathophysiology, and causes of gynecomastia" and "Placental development and physiology", section on 'Steroid hormones'.)

Neonatal breast hypertrophy usually regresses spontaneously and completely within the first year of life. Approximately 5 percent of cases may be associated with galactorrhea [13]. (See "Breast masses in children and adolescents", section on 'Neonates and infants'.)

Pubertal gynecomastia — Pubertal gynecomastia is a physiologic enlargement of the glandular breast tissue that occurs in some males during puberty. In most studies, it occurs in >50 percent of male adolescents (range 4 to 69 percent) [1,3,12,14-16]. The wide range is related to differences in study population, diagnostic criteria, and observer technique [5].

The prevalence of pubertal gynecomastia peaks during mid-puberty, coinciding with peak height velocity at age 12 to 14 years, pubic hair sexual maturity rating (Tanner stage) 3 to 4 (picture 2), and testicular volumes of 8 to 10 mL bilaterally (figure 3) [3,5,10,14,15,17-19]. It is usually bilateral (64 percent of cases in the largest cross-sectional study) [3].

Adolescents with pubertal gynecomastia usually complain of a mass or lump behind the nipple [5]. The enlargement occurs gradually and should not exceed 4 cm (1.6 inches) in diameter. Palpable fibroglandular enlargement ≥4 cm (1.6 inches) in diameter or rapidly progressive glandular enlargement may be associated with an underlying disorder [5,20,21]. (See 'Pathologic gynecomastia' below.)

The breast may be tender for approximately six months after onset, but tenderness gradually resolves as the glandular tissue undergoes fibrosis and the inflammatory reaction and stretching of tissues diminish [5].

When left untreated, pubertal gynecomastia regresses substantially or resolves in >70 percent of patients after one year [2,14,15], although it may take up to three years for some patients [18,19]. Gynecomastia that persists for ≥1 year or after age 17 years is less likely to spontaneously regress [14,15,22].

Pathologic gynecomastia — Pathologic gynecomastia is rare in children and adolescents but may be associated with substantial morbidity (eg, testicular, adrenal, or pituitary tumors) (table 2). Pathologic gynecomastia usually is associated with other abnormalities on physical examination or clinical features that are not characteristic of physiologic gynecomastia, such as [5,6,20,23]:

●Occurrence outside the neonatal or pubertal age group

●Occurrence in prepubertal males who have no other secondary sexual characteristics (eg, testicular enlargement, pubic hair or axillary hair, axillary odor)

●Rapid progression

●Enlargement >4 cm (1.6 inches) in diameter [20]

●Persistence for more than one year or after age 17 years; persistent pubertal gynecomastia accounts for a large proportion of gynecomastia in young adults [6]

Pathologic gynecomastia has a number of causes including:

Drugs — The proportion of cases of gynecomastia in children and adolescents that are related to drugs is unknown. A variety of prescription, over-the-counter, and illicit drugs may be associated with gynecomastia (table 3), but the association is not necessarily causal [1,15,24-27].

Children and adolescents may be exposed to the following drugs/substances that have been associated with gynecomastia:

●Estrogens or substances that act like estrogens in medications (eg, oral contraceptive pills, digitalis) and cosmetics (lotions, lavender oil, and tea tree oil) [28-30] (see "Endocrine-disrupting chemicals")

●Drugs that enhance endogenous estrogen production (eg, gonadotropins, clomiphene)

●Drugs that inhibit testosterone synthesis and/or action (eg, ketoconazole, metronidazole, cimetidine); the effect is related to dose and duration of use

●Antiretroviral therapy for human immunodeficiency virus (HIV) (see "Overview of antiretroviral agents used to treat HIV", section on 'Non-nucleoside reverse transcriptase inhibitors (NNRTIs)')

●Drugs with other mechanisms (eg, hyperprolactinemia) of gynecomastia: isoniazid, calcium channel blockers, ACE inhibitors, amphetamines, diazepam, haloperidol, antipsychotics (especially risperidone), proton pump inhibitors, and tricyclic antidepressants [26,31,32]

●Alcohol and recreational or illicit drugs, including [1,20]:

•Marijuana, particularly if used ≥4 times per week [33-35]

•Anabolic steroids (see "Use of androgens and other hormones by athletes", section on 'Gynecomastia')

Hypogonadism — Primary (hypergonadotropic) hypogonadism accounts for approximately 8 percent and secondary (hypogonadotropic) hypogonadism accounts for approximately 2 percent of cases of gynecomastia in adult patients seeking consultation for gynecomastia [1]. It is not known how frequently hypogonadism causes gynecomastia in children and adolescents.

●Klinefelter syndrome, polysomy X, is the most common congenital cause of primary hypogonadism and often presents during adolescence. As many as 70 percent of patients with Klinefelter syndrome have gynecomastia (often bilateral), which usually is slowly progressive [5,36]. Although gynecomastia is common among patients with Klinefelter syndrome, in a small study, the incidence of gynecomastia in adolescents with Klinefelter syndrome was similar to that in chromosomally typical males [36]. Rapidly progressive gynecomastia in patients with Klinefelter syndrome may indicate an extragonadal human chorionic gonadotropin (hCG)-secreting tumor in the mediastinum; these malignant germ cell tumors occur in approximately 1 percent of patients with Klinefelter syndrome [37,38]. Other clinical features of Klinefelter syndrome include tall, thin body habitus; long arms and legs; learning, language, or behavioral difficulties; and small (<3 cm [1.2 inches] in length or 5 mL in volume), firm testes in pubertal-aged males. Patients with Klinefelter syndrome have an increased risk of breast cancer [39]. (See "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome' and 'Tumors' below and "Breast cancer in men", section on 'Alterations of the estrogen to androgen ratio'.)

●Other congenital causes of primary hypogonadism that may be associated with gynecomastia include:

•Cryptorchidism, including anorchia (testicular regression) (see "Undescended testes (cryptorchidism) in children: Clinical features and evaluation")

•Enzyme defects of testosterone production (see "Causes of primary hypogonadism in males", section on 'Disorders of androgen biosynthesis')

•Other genetic conditions, syndromes, or polymorphisms (examples can be found in the Online Mendelian Inheritance in Man [OMIM] database by searching on "gynecomastia")

●Acquired causes of primary hypogonadism in children and adolescents include infections that affect the testes (mumps, echovirus, group B arboviruses, leprosy), trauma (eg, testicular torsion), and radiation.

●Secondary hypogonadism may be congenital (eg, congenital gonadotropin-releasing hormone deficiency) or acquired (eg, pituitary tumor [40], hyperprolactinemia). (See "Causes of secondary hypogonadism in males".)

Tumors — A variety of tumors may cause gynecomastia by presumably altering the balance of androgens and estrogens. (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Causes of gynecomastia'.)

●Testicular tumors (Leydig or Sertoli cell tumors, germ cell tumors) occur predominantly in young men (15 to 35 years). The reported incidence of testicular tumors in men with gynecomastia is 3 percent [1,41]; gynecomastia may be the only clinical finding at the time of diagnosis [41-43].

A testicular mass may be palpable on examination. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Clinical manifestations'.)

The risk of testicular cancer is increased in patients with a history of cryptorchidism. (See "Undescended testes (cryptorchidism) in children: Management", section on 'Testicular cancer'.)

The risk of Sertoli cell tumors is increased in patients with Peutz-Jeghers syndrome, an autosomal dominant condition characterized by multiple hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation (picture 3A-C), and increased risk of gastrointestinal and nongastrointestinal cancer. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management", section on 'Testicular tumors'.)

●Feminizing adrenal tumors typically are aggressive and malignant; males with feminizing adrenal tumors may have testicular atrophy and decreased libido in addition to gynecomastia. (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Other rare causes' and "Clinical presentation and evaluation of adrenocortical tumors", section on 'Androgen and estrogen-secreting tumors'.)

●hCG-producing tumors may arise in the testes (germ-cell tumors), lungs, mediastinum, liver, kidneys, or brain.

Other pathologic causes

●Chronic liver or kidney diseases – Chronic liver or kidney diseases may be associated with gynecomastia [16]. Chronic liver disease affects sex hormone binding globulin levels, which alter the circulating levels of estradiol and testosterone. Kidney disease alters testosterone production from Leydig cells. There is also an increase in estradiol and luteinizing hormone. In addition, the effects of chronic disease on the hypothalamic-pituitary-testicular (HPT) axis, medications used in disease management, and declining nutrition contribute to the development of gynecomastia [44]. It is estimated that chronic disease accounts for approximately 8 percent of cases of gynecomastia in adult patients seeking consultation for gynecomastia [1]. It is not known how frequently chronic disease causes gynecomastia in children and adolescents.

●Malnutrition – Malnutrition suppresses the HPT axis leading to decreased testosterone production. However, during refeeding, the HPT axis re-engages. This increases production of testosterone and estradiol similar to that seen during physiologic puberty. (See 'Pubertal gynecomastia' above.)

●Hyperthyroidism – Hyperthyroidism is an uncommon cause of gynecomastia, estimated to cause approximately 1.5 percent of cases in adult patients evaluated for gynecomastia [1]; it is not known how frequently hyperthyroidism causes gynecomastia in children.

Other features of hyperthyroidism in children and adolescents include goiter, accelerated growth, ophthalmopathy (exophthalmos, stare, and lid lag), tachycardia, increased appetite without weight gain (or with weight loss), and tremor. However, gynecomastia may be the first manifestation of hyperthyroidism [45]. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

●Aromatase excess syndrome – Aromatase excess syndrome (also called familial prepubertal gynecomastia) is a heterogeneous autosomal dominant disorder characterized by accelerated early linear growth with low or normal final height, advanced bone age, prepubertal gynecomastia, and testicular failure [5,46]. It is caused by a gain-of-function mutation in the CYP19 (aromatase) gene [47-50].

●Partial androgen insensitivity syndrome – Partial androgen insensitivity syndrome (PAIS) is an X-linked disorder caused by mutations in the androgen receptor (AR) gene that is associated with gynecomastia, decreased virilization, and a small phallus in males. In a retrospective case series, 14 of 14 male patients with PAIS developed gynecomastia at puberty [51]. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Partial androgen insensitivity (PAIS)'.)

Partial androgen insensitivity occurs in X-linked spinal and bulbar muscular atrophy (also known as Kennedy disease), which may present with gynecomastia in adolescence or before puberty [52-54]. Associated clinical features may include muscle fasciculations, weakness, muscle cramps, and calf hypertrophy. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Spinobulbar muscular atrophy'.)

●Congenital adrenal hyperplasia – Various forms of congenital adrenal hyperplasia, including 11-beta-hydroxylase deficiency [55,56], 3-beta hydroxysteroid dehydrogenase deficiency [57], and late-onset 21-hydroxylase deficiency [58], on rare occasion, present with gynecomastia due to increased production of estrogen precursors [59-61]. (See "Uncommon congenital adrenal hyperplasias" and "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●Ovotesticular differences of sex development – Ovotesticular differences of sex development (previously called "true hermaphroditism") are characterized by the presence of both ovarian follicular and testicular tubular tissue in the same individual. Associated clinical features may include hypospadias and cryptorchidism [62]. (See "Causes of differences of sex development", section on 'Gonadal overproduction of androgens'.)

MIMICS OF GYNECOMASTIA — Mimics of gynecomastia in infants include:

●Mastitis – In infants younger than two months, unilateral or bilateral breast enlargement may be caused by mastitis (cellulitis or abscess of the breast). Associated clinical features include swelling, erythema, warmth, tenderness, and induration of the breast with or without purulent nipple discharge. Gynecomastia is not warm, indurated, or associated with purulent nipple discharge. (See "Mastitis and breast abscess in infants younger than two months", section on 'Introduction'.)

●Galactocele – Galactocele (a benign milk-filled cystic lesion, which may be associated with milky nipple discharge) is a rare cause of unilateral or bilateral breast enlargement in infants [63,64].

Mimics of gynecomastia in children and adolescents include:

●Pseudogynecomastia – Pseudogynecomastia is fatty infiltration of the breast (also called lipomastia). It is a common finding, especially in adolescents who are overweight (body mass index [BMI] ≥85^th and <95^th percentile for age) or obese (BMI ≥95^th percentile for age). The lack of a discrete mass or ridge of glandular tissue distinguishes pseudogynecomastia from gynecomastia (figure 1). On palpation, pseudogynecomastia feels similar to adjacent adipose tissue in the anterior axillary fold [37]. In pubertal males, transition from gynecomastia to lipomastia is common [50,65].

●Breast carcinoma and other tumors – Breast carcinoma is extremely rare in male children and adolescents [66,67]; <1 percent of breast cancer occurs in males, with a median age of 67 years [68,69]. Risk factors for breast cancer in males include Klinefelter syndrome, gonadal failure, obesity, radiation exposure, and positive family history of BRCA2 gene mutations [70,71]. Other primary or metastatic tumors may present with breast masses including rhabdomyosarcoma, angiosarcoma, lymphoma, leukemia, and neuroblastoma [72].

In contrast to gynecomastia, breast carcinoma and other tumors usually are eccentrically located and fixed to the chest wall (figure 1). Breast carcinoma may be associated with skin dimpling, nipple retraction, and nipple bleeding, or discharge [73], none of which is typical of gynecomastia. Breast carcinoma usually is not associated with tenderness, which may occur in the early development of gynecomastia.

●Other breast masses – Other masses that may occur in the male breast include lipomas, hemangiomas, hematomas, neurofibromas, lymphangiomas, and dermoid cysts [16,74]. Unlike gynecomastia, these often are unilateral and tend to be eccentrically located.

APPROACH TO DIAGNOSIS — The history and examination of children and adolescents with gynecomastia focus on clinical features of pathologic causes of gynecomastia (table 2). Laboratory and imaging studies usually are not necessary in adolescents with clinical features typical of physiologic gynecomastia.

History — Important aspects of the history in children and adolescents with gynecomastia include:

●Breast enlargement – The size, timing of onset, and duration of breast enlargement: Breast size ≥4 cm and rapid progression may indicate greater hormone imbalance and a pathologic cause [5]

●Pubertal status and age – Beyond the neonatal period, prepubertal gynecomastia is always pathologic; pubertal gynecomastia is most common during mid-puberty (eg, age 12 to 14 years, during peak height velocity, or at sexual maturity rating [Tanner stage] 3 to 4 (figure 3)) [5,10,17-19]

●Associated symptoms – Mild pain is normal during the early development of physiologic gynecomastia, and may also occur with mastitis, but is unusual in breast carcinoma; galactorrhea may indicate hyperprolactinemia

●Review of systems – Symptoms of a previously undiagnosed endocrine abnormality or chronic illness, particularly [6]:

•Hypogonadism – Atypical genitalia, undervirilization

•Hyperthyroidism – Goiter, tachycardia, tremor, increased appetite without weight gain, accelerated linear growth

•Aromatase excess syndrome – Early accelerated linear growth

•Liver disease – Anorexia, nausea, vomiting, acholic stools, edema, jaundice, spider angiomata

•Renal disease – Anorexia, nausea, vomiting, edema, changes in urination, hematuria

•Human chorionic gonadotropin (hCG)-producing tumor – Rapid and significant virilization with only slightly enlarged testes, headache

•Prolactinoma – Headache, galactorrhea

●Family history – Family history of gynecomastia or hypogonadism (table 4), testicular cancer, and liver or kidney disease (see 'Pathologic gynecomastia' above)

●Medications/drugs – Exposure to medications, including over-the-counter drugs, marijuana, dietary supplements, and herbal products that are associated with gynecomastia (table 3) (see 'Drugs' above)

●Psychosocial effects – The degree to which gynecomastia affects school or social life (may have bearing on management and follow-up) (see 'Management' below)

Physical examination — Important aspects of the physical examination of children and adolescents with gynecomastia include:

●Breast – Proper examination of the breast differentiates gynecomastia from pseudogynecomastia (lipomastia) and other causes of breast enlargement. The patient is examined in the supine position with their hands beneath their head (figure 1) [6].

Galactorrhea may indicate hyperprolactinemia. Overlying skin changes (skin dimpling), nipple bleeding or discharge, or axillary adenopathy may be associated with breast carcinoma (extremely rare in children and adolescents).

●Genitalia

•Sexual maturity rating – Physiologic gynecomastia typically occurs at pubic hair sexual maturity rating (Tanner stage) 3 to 4 (picture 2); pathologic causes of gynecomastia should be considered if the sexual maturity rating is stage 1 or 5.

•Testes – Physiologic gynecomastia typically occurs at testicular volumes of 8 to 10 mL bilaterally (figure 3).

Testes that are small (<2.5 cm [1 inch] in length or <5 mL in volume (picture 4)), atrophied, or absent suggest that the patient is prepubertal or has hypogonadism, and additional evaluation is warranted. Small, firm testes may suggest Klinefelter syndrome. A testicular mass may indicate testicular cancer.

•Scrotum and phallus – A bifid scrotum and/or hypospadias may indicate partial androgen insensitivity or other causes of congenital hypogonadism.

●Other aspects of the physical examination – Other aspects of the physical examination may suggest a pathologic cause or mimic of gynecomastia:

•Body mass index – Body mass index (BMI) ≥85^th percentile may indicate pseudogynecomastia rather than gynecomastia, although it does not definitively exclude gynecomastia [4]; weight loss (or lack of gain) may indicate hyperthyroidism or malignancy.

•Height – Early accelerated linear growth in prepubertal males may suggest aromatase excess syndrome or hyperthyroidism; tall stature with long extremities may suggest Klinefelter syndrome.

•Thyroid – Palpable goiter suggests hyperthyroidism; other signs of hyperthyroidism include ophthalmopathy (exophthalmos, stare, and lid lag), tachycardia, and tremor.

•Abdomen – An abdominal mass may indicate an adrenal tumor or extragonadal germ cell tumor. Hepatomegaly may indicate a hCG-secreting tumor or chronic liver disease.

•Virilization – Undervirilization may indicate hypogonadism, partial androgen insensitivity, congenital adrenal hyperplasia (3-beta hydroxysteroid dehydrogenase deficiency), or an ovotesticular difference of sex development. Rapid or precocious virilization may indicate an hCG-secreting tumor.

•Skin – Perioral pigmentation (ie, dark blue to dark brown macules around the mouth or on the buccal mucosa (picture 3A-B)) may indicate Peutz-Jeghers syndrome, which is associated with an increased risk of Sertoli cell tumors. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management", section on 'Extra-intestinal cancers' and "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management", section on 'Genital tract cancers'.)

Jaundice and spider angiomata may indicate liver disease.

Edema may indicate renal disease. (See "Chronic kidney disease in children: Clinical manifestations and evaluation", section on 'Clinical manifestations'.)

•Musculoskeletal – Muscle fasciculations, weakness, and calf hypertrophy may indicate X-linked spinal and bulbar muscular atrophy, which is associated with partial androgen insensitivity.

Initial laboratory evaluation and management

Drug or medication exposure — If the patient has been exposed to a drug (eg, marijuana), medication, or herbal therapy that is known to be associated with gynecomastia (table 3), the agent should be discontinued. Improvement (decreased tenderness and softening of the glandular tissue) within one month of discontinuation supports the agent as the cause [6]. However, drug-induced gynecomastia of >12 months' duration is unlikely to regress because of fibrosis.

Other cause suggested by history or examination — Targeted laboratory and imaging studies should be performed if the initial evaluation suggests an underlying cause other than drug/medication exposure (table 5) [5].

Prepubertal gynecomastia — Gynecomastia in prepubertal males without any other secondary sexual characteristics (eg, increased testicular volume, pubic hair) is usually pathologic and should prompt a search for an underlying etiology [75]. If the initial evaluation and/or the targeted evaluation do not suggest a cause, we suggest obtaining an early morning blood sample to measure serum hCG, estradiol, testosterone, luteinizing hormone (LH), and dehydroepiandrosterone sulfate (DHEAS) [5]. An early morning sample is recommended because serum testosterone concentration varies during the day and is highest in the morning. Referral to a pediatric endocrinologist is recommended [5,16]. Although a specific cause is rarely identified [76], evaluation is necessary because of the potential morbidity associated with the various causes. (See 'Indications for referral' below and 'Pathologic gynecomastia' above.)

The interpretation of initial laboratory studies is discussed below. (See 'Laboratory interpretation and additional evaluation' below.)

Pubertal gynecomastia

●Typical pubertal gynecomastia – Laboratory studies generally are not necessary for adolescents with clinical features typical of pubertal gynecomastia [1,16,19,37,77]:

•Tender gynecomastia with onset at mid-puberty (ie, age 12 to 14 years, pubic hair sexual maturity rating [Tanner stage] 3 or 4, testicular volume 8 to 10 mL)

•History and physical examination not suggestive of a pathologic cause

Management of physiologic pubertal gynecomastia typically entails reassurance and observation. The majority of cases resolve spontaneously within one to three years of onset [14,15,18,19]. (See 'Physiologic gynecomastia' below.)

●Pubertal gynecomastia with atypical features – Clinical features that are not typical of physiologic pubertal gynecomastia include rapid progression, diameter ≥4 cm (1.6 inches), rapid and/or precocious virilization, and persistence for ≥24 months or after age 17 years [18,78]. Consensus regarding the laboratory evaluation of adolescents with asymptomatic, atypical pubertal gynecomastia is lacking [18,79]. Our evaluation typically includes early morning measurement of serum hCG, estradiol, testosterone, LH, and DHEAS [1,5].

The interpretation of initial laboratory studies is discussed below. (See 'Laboratory interpretation and additional evaluation' below.)

Laboratory interpretation and additional evaluation — The results of the laboratory tests direct additional laboratory or imaging studies (table 6). Laboratory results must be interpreted in the context of age and pubertal status (eg, low testosterone is normal for a prepubertal male but abnormal for a pubertal-aged adolescent).

Increased hCG — Elevated hCG (regardless of the other results) suggests an hCG-secreting tumor (testicular germ cell, extragonadal germ cell tumor, or hCG-secreting nontrophoblastic tumor).

Additional evaluation typically includes testicular ultrasonography for testicular mass.

●A testicular mass in a patient with elevated hCG suggests a testicular germ cell tumor. Referral to a pediatric urologist or oncologist is warranted.

●In the absence of a testicular mass, imaging of the chest and abdomen (and possibly other sites [eg, brain]) is warranted to look for an extragonadal germ cell tumor or hCG-secreting nontrophoblastic tumor. If found in the anterior mediastinum, a karyotype is mandatory to assess for Klinefelter syndrome. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum" and "Intracranial germ cell tumors".)

Increased estradiol — Elevated estradiol in a child or adolescent with gynecomastia may indicate a Leydig or Sertoli cell testicular tumor, feminizing adrenal tumor, increased extraglandular aromatase activity, congenital adrenal hyperplasia, or ovotesticular differences of sex development (table 6 and algorithm 1).

Increased testosterone — Increased testosterone and increased LH may indicate androgen resistance or hyperthyroidism (table 6 and algorithm 2).

Additional evaluation includes thyroid function tests (free thyroxine, total tri-iodothyronine, and thyroid-stimulating hormone [TSH]):

●Increased free thyroxine and/or tri-iodothyronine and decreased TSH indicate hyperthyroidism. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

●Androgen resistance (eg, partial androgen insensitivity) should be considered if free thyroxine, total tri-iodothyronine, and TSH are normal. (See "Diagnosis and treatment of disorders of the androgen receptor".)

Decreased testosterone — Decreased testosterone in a pubertal-aged male may indicate primary or secondary hypogonadism or hyperprolactinemia (table 6 and algorithm 2).

●Decreased testosterone with increased LH indicates primary hypogonadism. (See "Causes of primary hypogonadism in males" and "Clinical features and diagnosis of male hypogonadism".)

●Decreased testosterone with normal or decreased LH may indicate secondary hypogonadism or hyperprolactinemia, possibly due to a prolactin-secreting pituitary tumor (even in the absence of galactorrhea).

Additional evaluation includes measurement of serum prolactin.

•Elevated prolactin (hyperprolactinemia) may indicate the presence of a prolactin-secreting pituitary tumor; additional evaluation may include magnetic resonance imaging of the head. (See "Clinical manifestations and evaluation of hyperprolactinemia", section on 'Laboratory/imaging tests'.)

•Normal prolactin suggests other causes of secondary hypogonadism. (See "Causes of secondary hypogonadism in males".)

MANAGEMENT — The management of gynecomastia is discussed in detail separately. (See "Management of gynecomastia".)

Physiologic gynecomastia — Although the majority of cases of physiologic pubertal gynecomastia resolve spontaneously within a year of onset, management decisions are individualized according to the degree of psychosocial distress.

Given the usual natural history, many patients can be managed with reassurance and observation. Adjunctive psychotherapy may be beneficial for adolescents with psychosocial consequences of gynecomastia (eg, bullying and decreased self-esteem) [78].

The frequency of follow-up varies with the degree of psychosocial distress and the clinical setting. Primary care providers may monitor pubertal gynecomastia every three to six months (often in conjunction with follow-up of other adolescent health issues), particularly if gynecomastia affects the patient's school or social life [1,6,16,23]. Less frequent follow-up, or no follow-up, may be appropriate for patients who are not bothered by gynecomastia provided that the gynecomastia regresses as expected over the next 12 months. Although referral to a pediatric endocrinologist for patients with typical pubertal gynecomastia is not necessary, patients whose diagnosis of pubertal gynecomastia has been confirmed by a pediatric endocrinologist should follow up as recommended by the specialist.

We do not routinely suggest pharmacologic therapy for pubertal gynecomastia in adolescents. Evidence supporting the efficacy of pharmacologic therapy for pubertal gynecomastia in adolescents is limited to case reports and uncontrolled studies [5,80], and the US Food and Drug Administration (FDA) has not approved any drug for this indication. Nonetheless, pharmacologic therapy may be warranted for select patients (eg, those with physiologic gynecomastia that is >4 cm [1.6 inches] in diameter [which is unlikely to spontaneously regress], rapidly progressive, or associated with embarrassment that interferes with normal daily activities). Pharmacologic therapy is most effective during the proliferative phase of breast development, which lasts approximately 12 months. Pharmacologic therapy for gynecomastia is discussed separately. (See "Management of gynecomastia", section on 'Pharmacologic therapy'.)

Surgical therapy may be warranted for adolescents with physiologic gynecomastia that is >3 cm (1.2 inches) in diameter, unresponsive to medical therapy, persists for more than two years or after age 16 years, or is associated with embarrassment that interferes with normal daily activities [18,77,81,82]. Before surgery is performed, biochemical evaluation (early morning human chorionic gonadotropin [hCG], estradiol, testosterone, luteinizing hormone [LH], dehydroepiandrosterone sulfate [DHEAS]) may be warranted (if not already performed) to avoid delaying diagnosis of a pathologic condition that has clinical implications (eg, requires specific directed treatment, affects fertility) [16]. When surgery is performed in adolescents, we suggest that tissue be sent for histology, given rare reports of incidental breast carcinoma [5,83]. Surgical management of gynecomastia is discussed separately. (See "Management of gynecomastia", section on 'Surgery'.)

Pathologic gynecomastia — Management of pathologic gynecomastia depends upon the underlying cause. In general, gynecomastia resolves with discontinuation of the offending medication/environmental exposure or treatment of the underlying condition. These measures should be undertaken before pharmacologic or surgical therapy, which are discussed separately. (See "Management of gynecomastia".)

INDICATIONS FOR REFERRAL — Indications for referral in children or adolescents with gynecomastia include:

●Prepubertal gynecomastia – Refer to a pediatric endocrinologist to evaluate for an endogenous or exogenous source of estrogen and other endocrine abnormalities [5,16,18].

●Breast enlargement that is not gynecomastia – Referral to a pediatric surgeon may be warranted for children and adolescents with breast enlargement that is not characteristic of gynecomastia (eg, eccentric enlargement, fixed mass, etc) [18].

●Endocrine abnormality (primary or secondary hypogonadism, hyperthyroidism, androgen resistance, increased extraglandular aromatase activity) – Refer to a pediatric endocrinologist.

●Testicular mass on testicular ultrasonography – Refer to a pediatric urologist/oncologist.

●Other tumor (adrenal, extragonadal germ cell, pituitary) suspected on imaging – Refer to a pediatric oncologist.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topics (see "Patient education: Gynecomastia (male breast development) (The Basics)")

●Beyond the Basics topics (see "Patient education: Gynecomastia (breast enlargement in males) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Gynecomastia is the benign proliferation of glandular breast tissue in males and is characterized by a mass or ridge of glandular tissue that is symmetrically distributed around the areolar-nipple complex (figure 1). These features distinguish gynecomastia from other causes of male breast enlargement in children and adolescents. (See 'Definition and characteristic features' above and 'Mimics of gynecomastia' above.)

●Epidemiology and pathophysiology – In the pediatric age range, gynecomastia is common in the neonatal period and during puberty. (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Epidemiology'.)

Gynecomastia is thought to be caused by a relative imbalance between androgens (testosterone and androstenedione) and estrogens (estradiol and estrone) (table 1). (See 'Pathophysiology' above.)

●Physiologic gynecomastia – Physiologic pubertal gynecomastia typically occurs during mid-puberty. Adolescents complain of a mass or lump behind the nipple. The breast may be tender for approximately six months after onset. Pubertal gynecomastia regresses spontaneously in the majority of adolescents but is unlikely to regress if it persists for ≥1 year or after age 17 years. (See 'Pubertal gynecomastia' above.)

●Pathologic gynecomastia – Clinical features suggestive of pathologic gynecomastia include:

•Occurrence outside the neonatal or pubertal age range

•Occurrence in prepubertal males

•Rapid progression

•Enlargement >4 cm (1.6 inches) in diameter

•Rapid and/or precocious virilization

Pathologic causes of gynecomastia include drugs/medications (table 3), hypogonadism, tumors, and endocrinologic abnormalities (table 2). (See 'Causes of gynecomastia' above and 'Pathologic gynecomastia' above.)

●Approach to diagnosis – The history and examination of children and adolescents with gynecomastia focuses on the clinical features of pathologic causes of gynecomastia, including drugs/medications; age and pubertal status; family history; associated symptoms; growth parameters; palpation of the breasts; and evaluation of the testicles for size, masses, and consistency (table 2). (See 'History' above and 'Physical examination' above.)

•The initial laboratory evaluation and management depend on whether a cause is suggested by the history and examination:

-If the patient has been exposed to a medication or herbal therapy associated with gynecomastia (table 3), the agent should be discontinued. Clinical improvement within one month of discontinuation supports the agent as the cause. (See 'Drug or medication exposure' above.)

-If the history and examination suggest a cause other than drug/medication exposure, targeted laboratory and imaging studies should be performed (table 5). (See 'Other cause suggested by history or examination' above.)

-In prepubertal males, if the history and examination do not suggest a cause, we suggest obtaining an early morning blood sample to measure serum human chorionic gonadotropin (hCG), estradiol, testosterone, luteinizing hormone (LH), and dehydroepiandrosterone sulfate (DHEAS). (See 'Prepubertal gynecomastia' above.)

-In adolescents with clinical features of typical pubertal gynecomastia, laboratory studies generally are not necessary. Initial management usually consists of reassurance and observation. (See 'Pubertal gynecomastia' above.)

-Clinical features that are not typical of physiologic pubertal gynecomastia include rapid progression, diameter ≥4 cm (1.6 inches), and persistence for ≥12 months or after age 17 years. Our evaluation for such patients consists of early morning measurement of serum hCG, estradiol, testosterone, LH, and DHEAS. (See 'Pubertal gynecomastia' above.)

•The results of the initial laboratory tests direct additional laboratory and imaging studies (table 6 and algorithm 1 and algorithm 2). (See 'Laboratory interpretation and additional evaluation' above.)