The European Academy of Andrology has formulated a set of statements and clinical recommendations for the evaluation and management of gynaecomastia (GM). As per the guideline, GM is a common finding in infancy and puberty; however, GM of adulthood is associated with an underlying pathology in 50% of cases and warrants further evaluation. Watchful waiting and reassurance are recommended after the underlying pathology, or the administration/abuse of substances associated with GM has been excluded or treated.

Gynaecomastia (GM) is a benign proliferation of male breast tissue. Although, altered testosterone-estradiol ratios is a common cause of gynaecomastia, in most cases the disorder remains idiopathic. GM has to be distinguished from pseudo‐gynaecomastia (i.e., lipomastia), which is characterised by excess fat deposition without glandular proliferation.

GM shows three discrete peaks throughout a man's lifespan:

• The first peak is observed during infancy
• The second during puberty
• The third in middle‐aged and elderly men

The European Academy of Andrology (EAA) clinical practice guideline, provide recommendations regarding the evaluation and management of GM. A set of five statements and fifteen clinical recommendations has been formulated.

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Pathophysiology of Gynaecomastia

Statement 1. Gynaecomastia (GM) is a benign proliferation of glandular tissue of the breast in males.

The exact pathophysiology of GM is unknown; however, overt androgen deficiency or estrogen excess may be detected. Occasionally, the ratio between the hormones may be found to be abnormal, despite the presence of normal concentrations of both sex hormones. In rare cases, the activity of estrogen and androgen receptors might modify the hormonal signaling, leading to GM.

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Epidemiology of Gynaecomastia

Statement 2. GM of infancy is a common condition that usually resolves spontaneously, typically within the first year of life.

GM in newborns develops as a consequence of the persistent action of estrogens, progesterone, and mammotropic peptides that characterise the intrauterine milieu. The condition resolves spontaneously a few weeks after birth, coinciding with the withdrawal of maternal hormones from the neonate's circulation. In some cases, GM of the newborns may persist or even reappear in the first months of infancy (‘mini‐puberty’ period); however, GM of infancy is not associated with any sequels or aberrations of development. Typically, it does not persist after the first year of life.

Statement 3. GM of puberty is a common condition, affecting approximately 50% of mid‐pubertal boys; in more than 90% of cases, it resolves spontaneously within 24 months.

In adolescents, the peak prevalence of GM is observed during mid‐puberty, when the sex hormones surge, and growth and pubertal development are at the highest rate. The fundamental endocrinopathy is not detected in majority of cases; however, spontaneous regression can be expected within 24 months.

Statement 4. The prevalence of GM in adulthood increases with increasing age; proper investigation may reveal an underlying pathology in approximately 45–50% of the cases.

The incidence and prevalence of GM in elderly men are high and an underlying pathology may be observed in around 45–50% of adult men with GM. Systemic diseases, medical treatment, obesity, and endocrinopathies, including testosterone (T) deficiency are the most common causes for GM in this age group. If treatment of the underlying causes is feasible, GM may regress to some degree (based on size and duration). In cases which persists beyond a year, there is a high likelihood of development of fibrosis and hyalinisation, and in such cases, spontaneous regression is less likely even if the causative factor is removed.

Statement 5. Male breast cancer is rare; GM should not be considered a premalignant condition.

Male breast cancer is rarely observed. Klinefelter syndrome, a history of chest irradiation, and a family history of breast cancer are some risk factors for breast cancer in men. GM does not increase the risk of breast cancer.

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Causes of Gynaecomastia

Recommendation 1. The presence of an underlying pathology should be considered in GM of adulthood. Identification of an apparent reason for GM in adulthood, including the use of medication known to be associated with GM, warrants a detailed investigation.

The following are the pathological causes of GM:

1. Low androgen concentrations
   1. Primary testosterone deficiency - Primary testicular failure leads to low testosterone (T) production, which, in turn, evokes an elevation of Luteinizing hormone (LH). The increased LH concentration enhances the activity of aromatase, resulting in an increased estrogen‐to‐androgen balance.
   2. Secondary testosterone deficiency – In this, the production of T decreases due to reduced secretion of gonadotropin‐releasing hormone (GnRH), LH, or both resulting in a decrease of the inhibitory effect of androgens on the breast tissue.
   3. Hyperprolactinemia - Prolactin causes GM by suppressing GnRH secretion at the level of the hypothalamus, leading to secondary hypogonadism.
   4. Renal disease - Both gonadal and hypothalamic/pituitary dysfunction can be induced by renal disease, resulting in Τ deficiency. Additionally, chronic renal failure is found to be commonly associated with hyperprolactinemia.
2. Combination of high estrogen and androgen concentrations
   1. Kennedy syndrome - Clinical signs of mild androgen deficiency such as GM are combined with both high T and LH concentrations, implying partial resistance to androgens.
   2. Androgen insensitivity syndrome - In this rare syndrome, a genetic defect in the androgen receptor leads to decreased sensitivity for T.
   3. Hyperthyroidism and hypothyroidism - Increased thyroid hormone concentrations lead to increased production of sex hormone‐binding globulin (SHBG). In some cases a direct stimulating effect of thyroid hormones on the activity of aromatase enzyme is also suggested. In the hypothyroid state, the reduced T concentration due to an elevation of prolactin as a (result of enhanced thyroid‐releasing hormone (TRH) stimulation) is held responsible.
   4. Leydig and Sertoli cell tumors
   5. Germ cell cancer, particularly those that contain choriocarcinoma components.
   6. Abuse of anabolic androgenic steroids (AAS)
3. High estrogen concentrations is found in following cases
   1. Cannabis abuse
   2. Unintentional exposure to oestrogens
   3. Obesity
   4. Liver disease
   5. Alcohol abuse
4. Other causes of GM include
   1. Drug‐induced GM - Anti‐androgens, Antibiotics, Anti‐ulcer drugs, Cancer chemotherapeutics, Psychoactive drugs, Cardiovascular drugs, drugs of abuse and hormones
   2. Re‐feeding syndrome
5. Non‐gonadal tumors
   1. Adrenal tumors
   2. Androgen ablation therapy for prostate cancer

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Clinical Evaluation of Gynaecomastia

Recommendations 2. Initial screening might be performed by a general practitioner or another non‐specialist.

Recommendations 3. In cases where a thorough diagnostic workup is warranted, it should be performed by a specialist.

The authors emphasise that initial evaluation of GM may be carried out by a general practitioner, adequately trained to rule out lipomastia, breast cancer, or testicular cancer (that warrant further evaluation by a specialist).

The primary goal of the initial evaluation should be to confirm the presence of palpable glandular tissue and rule out the suspicion of malignant breast tumor or testicular tumor by palpation.

A thorough diagnostic workup (by a specialist) is recommended only on individuals with adult‐onset GM, provided that they are not in androgen ablation therapy (AAT) or are abusing AAS. Exclusion of the presence of a testicular tumor may be sufficient.

Recommendations 4. The medical history should include information on the onset and duration of GM, sexual development and function, and administration or abuse of substances associated with GM.

The medical history should focus on the onset and duration of GM as well as its previous occurrences. Persistence during adolescence or a new and rapidly developing condition may warrant further workup.

Andrological history should include:

• Cryptorchidism
• The onset of puberty
• Fertility status
• Symptoms of T deficiency (including sexual functioning)

Information on general illness, use of medications (both prescription and over‐the‐counter), use of AAS, alcohol, cannabis, and drug abuse should also be noted.

Recommendations 5. The physical examination should detect signs of under‐virilisation or systemic disease.

The physical examination includes:

• Anthropometric measurements (e.g., height, weight, body mass index, waist circumference, waist‐to‐hip ratio) to quantify obesity
• Assessment of body proportions to document eunuchoidism (arm span, and upper and lower body segment measurement) is recommended in younger patients
• Signs of under‐virilisation (face and body hair pattern, loss of muscle mass) should also be described
• Palpation of the thyroid gland and identification of signs of hyper‐ or hypothyroidism, hepatic or renal failure, and Cushing's disease.

Recommendations 6. Breast examination should confirm the presence of palpable glandular tissue to discriminate GM from lipomastia (pseudo‐gynaecomastia) and rule out the suspicion of malignant breast tumor.

The following points should be noted while performing a breast examination:

• Initial examination is performed with the patient in the sitting or lying position
• Breast palpation should be performed by squeezing the breast between the thumb and forefinger of the examiner to locate the rim that distinguishes the outer limits of the gland to evaluate its size.
• The examination should conclude with the patient in supine position with his hands clasped beneath his head – this step facilitates palpation of the axillary regions
• Breast carcinoma is typically felt like a non‐tender unilateral hard mass mostly located outside the areolar area, occasionally accompanied by skin changes (peau d'orange, ulceration), nipple retraction or bleeding, and possible axillary lymphadenopathy; signs of carcinoma should prompt further investigations
• Breast tenderness is a sign of recent hormone stimulation
• Evaluation of the size of GM should be based on the five breast stages described by Tanner (Stage 1 - normal male breast, whereas stage 5 - the mature breast of an adult female)
• Gland location, size, galactorrhea and whether the condition is unilateral or bilateral should also be documented

Recommendations 7. Physical examination should include examination of the genitalia to rule out the presence of a palpable testicular tumor and to detect testicular atrophy.

Recommendations 8. As the detection of a testicular tumor by palpation has low sensitivity, genitalia examination should be done by testicular ultrasound.

The genital examination should include evaluation of pubic hair, penile size, scrotal development, testicular size, consistency, and surface. Testicular volume should be evaluated by a Prader orchidometer and by scrotal ultrasound scan.

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Laboratory Evaluation of Gynaecomastia

Recommendations 9. Evaluations may include T, estradiol (E2), SHBG, LH, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin, human chorionic gonadotropin (hCG), alpha‐fetal protein (AFP), and liver and renal function tests.

As low total T concentrations are not always indicative of T deficiency, measurement of SHBG in addition to total T and, in equivocal cases, assessment of free testosterone (fT) should be carried out. fT should be measured directly by assays including equilibrium dialysis or calculated indirectly by using one of the available accurate formulas. For E2 measurement, liquid chromatography–tandem mass spectrometry (LC‐MS/MS) should be preferred.

Broad screening, including the screening of other organ systems should be performed to increase the diagnostic sensitivity.

Recommendations 10. When the clinical examination is equivocal, breast imaging should be performed for clarification.

Recommendations 11. If the clinical picture is suspicious for a malignant lesion, core needle biopsy should be performed.

Breast imaging may be useful in obese men where it is difficult to differentiate breast examination and lipomastia or in cases with fibrosis/hyalinisation. For the detection of malignancy, mammography has been shown to be the most sensitive and ultrasound, the most specific technique. In cases suspicious of a malignant lesion, a core needle biopsy should be performed.

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Management of Gynaecomastia

Any underlying pathology should be treated. If a medication is suspected to be the cause, it should be changed or discontinued. In the case of AAS abuse, cessation of the substance is recommended.

Recommendations 12. Watchful waiting is recommended after treatment of underlying pathology or discontinuation of the administration/abuse of substances associated with GM.

Watchful waiting is particularly important in cases of GM of puberty or GM of adulthood with negative physical and hormonal investigations. There are chances that the condition may resolve spontaneously (especially if it is of recent onset).

Recommendations 13. T treatment should be offered only to men with proven testosterone deficiency.

Recommendations 14. The use of selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or non‐aromatisable androgens is not recommended in the treatment of GM in general.

T treatment in eugonadal men is reported to aggravate or produce GM due to aromatisation of excessive T to estradiol. Hence, T treatment should be offered only to men with unequivocally confirmed T deficiency.

Limited data from randomised controlled trials is available for the use of SERMs and DHT in the treatment of idiopathic GM. Tamoxifen can be used in painful GM of recent onset as it offers rapid relief from pain, regardless of the magnitude of response. Low‐dose prophylactic radiotherapy (PRT) is an option for GM patients with prostate cancer undergoing AAT. Even though PRT is less effective, it is a more practical option, as only a few short‐term applications are required.

Recommendations 15. Surgical treatment is only recommended for patients with long‐lasting GM, which does not regress spontaneously or following medical therapy. The extent and type of surgery depend on the size of breast enlargement, and the amount of adipose tissue.

Surgery should not be offered until an observation period has been allowed; in pubertal GM, the observation period may be extended up to two years of persistence. Surgical treatment is justified in cases where GM causes considerable cosmetic and psychological distress.