What are the causes, genetic predisposition, pathophysiology, clinical features, comorbidities, hormonal influences, drug associations, diagnostic work‑up, and management options for gynecomastia?

Gynecomastia: Comprehensive Clinical Overview

Definition and Epidemiology

Gynecomastia is benign glandular breast tissue enlargement in males caused by an imbalance favoring estrogen over androgen action, affecting up to 65% of men asymptomatically during their lifetime. 1, 2 The condition presents bilaterally in approximately 50% of cases and manifests as a soft, rubbery, or firm mobile mass directly beneath the nipple-areolar complex. 3

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Pathophysiology

The fundamental mechanism involves disruption of the normal estrogen-to-androgen ratio through multiple pathways: 1, 4, 2

• Increased estrogen production – peripheral aromatization of androgens to estrogens, particularly in adipose tissue, or direct estrogen secretion from tumors 5, 4
• Decreased androgen production – primary testicular failure, secondary hypogonadism, or medication-induced suppression of testosterone synthesis 6, 4
• Enhanced estrogen sensitivity – increased breast tissue responsiveness to circulating estrogens 2
• Impaired estrogen clearance – hepatic dysfunction reduces metabolism of steroid precursors, allowing accumulation of estrogenic compounds 7

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Causes and Genetic Predisposition

Physiologic Gynecomastia (Age-Related)

• Neonatal period – transplacental transfer of maternal estrogens 6, 2
• Pubertal gynecomastia – occurs in 50% of adolescent males due to transient hormonal imbalance during sexual maturation; typically resolves spontaneously 8, 2
• Senescent gynecomastia – middle-aged to elderly men experience declining testosterone with preserved estrogen production 6

Genetic and Chromosomal Disorders

• Klinefelter syndrome (47,XXY) – carries a relative risk of 24.7 for gynecomastia and substantially elevates male breast cancer risk 5
• BRCA2 mutation carriers – significantly increased risk of both gynecomastia and male breast cancer 5
• Androgen resistance syndromes – defective androgen receptor function prevents normal masculinization 1

Endocrine Disorders

• Primary hypogonadism – testicular failure from trauma, infection, or congenital absence reduces testosterone production 3, 6
• Secondary hypogonadism – hypothalamic-pituitary dysfunction (tumors, infiltrative disease) lowers LH/FSH secretion 3, 6
• Hyperprolactinemia – prolactin-secreting pituitary adenomas suppress gonadotropin release and testosterone synthesis 3, 5
• Hyperthyroidism – increases sex hormone-binding globulin (SHBG), reducing free testosterone while enhancing peripheral aromatization 1, 6

Systemic Diseases

• Chronic liver disease/cirrhosis – impairs hepatic clearance of estrogen precursors and increases SHBG, creating a high estrogen-to-androgen ratio 5, 7, 1
• Chronic kidney disease – uremia disrupts hypothalamic-pituitary-gonadal axis 6

Neoplastic Causes

• Testicular tumors – germ cell tumors (especially choriocarcinoma) secrete human chorionic gonadotropin (hCG), stimulating testicular estrogen production 6
• Adrenal tumors – adrenocortical carcinomas may directly secrete estrogen 5
• Ectopic hCG-secreting tumors – lung, gastric, or hepatocellular carcinomas 6

Medication-Induced Gynecomastia

Numerous medications disrupt hormonal balance through diverse mechanisms: 1, 6

• Antiandrogens – flutamide, bicalutamide, nilutamide competitively block androgen receptors; prophylactic breast irradiation (8-15 Gy in 1-3 fractions) given 1-2 weeks before antiandrogen initiation prevents painful gynecomastia 9, 3
• 5α-reductase inhibitors – finasteride, dutasteride reduce dihydrotestosterone conversion 1
• GnRH agonists – leuprolide, goserelin suppress testosterone production 9
• Estrogens and estrogen-like compounds – diethylstilbestrol (DES), digoxin, phytoestrogens 9
• Cardiovascular medications – spironolactone (antiandrogen effect), calcium channel blockers, ACE inhibitors 1, 6
• Psychotropic drugs – tricyclic antidepressants, phenothiazines, benzodiazepines 1
• Chemotherapeutic agents – alkylating agents damage testicular tissue 5
• H2-receptor antagonists – cimetidine has antiandrogenic properties 1

Substance-Induced Gynecomastia

• Alcohol – dual mechanism: (1) alcohol-related liver disease impairs steroid clearance, and (2) direct suppression of testicular steroidogenesis and hypothalamic-pituitary function 7
• Cannabis – chronic use, especially when initiated during adolescence, may disrupt hormonal systems, though the association is less consistent than with alcohol 7
• Anabolic steroids – exogenous androgens undergo peripheral aromatization to estrogens; rebound gynecomastia occurs upon cessation 1
• Heroin, amphetamines, marijuana – various mechanisms of hormonal disruption 1

Obesity and Pseudogynecomastia

• Obesity contributes through two pathways: (1) increased adipose tissue enhances peripheral aromatization of androgens to estrogens (true gynecomastia), and (2) fat deposition without glandular proliferation (pseudogynecomastia) 5, 4

Idiopathic Gynecomastia

• Up to 25% of cases remain idiopathic after comprehensive evaluation, likely representing subtle hormonal imbalances below detection thresholds 6, 4

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Clinical Features

Presentation

• Palpable findings – soft, rubbery, or firm mobile disc of tissue concentrically located beneath the nipple-areolar complex distinguishes true gynecomastia from pseudogynecomastia (fatty tissue only) 3, 1
• Pain – tenderness is common, especially in gynecomastia present less than 6 months (acute/proliferative phase) 3
• Laterality – bilateral in approximately 50% of patients; unilateral presentation warrants heightened suspicion for malignancy 3

Red Flags Suggesting Malignancy

Male breast cancer accounts for <1% of all breast cancers (median age 63 years) but must be excluded in suspicious presentations: 3

• Hard, fixed, or eccentric mass – not centered beneath the nipple 3
• Skin or nipple retraction – suggests invasive disease 3
• Bloody nipple discharge – highly suspicious for malignancy 3
• Axillary lymphadenopathy – indicates potential metastatic spread 3
• Rapid growth or ulceration – aggressive features 3

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Comorbidities and Associated Conditions

• Diabetes mellitus – men with diabetes have lower serum testosterone than age-matched controls; uncontrolled hyperglycemia further suppresses testosterone 3
• Cardiovascular disease – both a comorbidity and a consideration when prescribing testosterone replacement, which increases coronary artery plaque volume in older hypogonadal men 3
• Metabolic syndrome – obesity, insulin resistance, and dyslipidemia collectively promote estrogen excess 3, 5
• Peripheral neuropathy and nephropathy – diabetes complications that influence antihyperglycemic agent selection 3

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Hormonal Influences and Hormonal Therapy

Testosterone Therapy Considerations

• Measure serum estradiol in all testosterone-deficient patients presenting with breast symptoms or gynecomastia before starting testosterone therapy 3
• Men developing gynecomastia on testosterone treatment should undergo a monitoring period, as symptoms sometimes abate spontaneously 3
• Testosterone replacement in older hypogonadal men with diabetes increases coronary artery plaque volume, elevating cardiovascular risk 3

Estrogen Receptor Modulators

• Selective estrogen receptor modulators (SERMs) – tamoxifen may be considered for testosterone-deficient patients with low or low-normal LH levels 3
• Timing matters – medical therapy is most effective during the acute proliferative phase (first 6-12 months); gynecomastia persisting beyond 12 months becomes fibrotic and less responsive to pharmacotherapy 5, 1, 4

Fertility Preservation

• Men with gynecomastia interested in fertility should undergo reproductive health evaluation (testicular examination, FSH measurement) before treatment, as SERMs preserve fertility better than testosterone 3

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Diagnostic Evaluation

Clinical Assessment

Most men with breast symptoms can be diagnosed based on clinical findings without imaging. 3 The physical examination should systematically evaluate:

• Body habitus and BMI – calculate BMI or measure waist circumference to assess for obesity and metabolic syndrome 3
• Virilization status – examine body hair patterns in androgen-dependent areas (face, chest, pubic region) to evaluate for hypogonadism 3
• Testicular examination – assess testicular size, consistency, and presence of masses or varicocele 3
• Prostate assessment – digital rectal examination to evaluate size and morphology 3
• Visual field testing – bitemporal hemianopsia suggests pituitary pathology 3
• Breast palpation – differentiate true gynecomastia (glandular tissue beneath nipple) from pseudogynecomastia (diffuse fatty tissue) 3, 1

Medication and Substance History

• Temporal relationship – inquire about timing between medication initiation and gynecomastia onset 5, 1
• Substance use – alcohol, cannabis, anabolic steroids, heroin, amphetamines 7, 1

Laboratory Investigations

Biochemical testing should be tailored based on clinical suspicion: 3, 6

First-Tier Tests

• Morning total testosterone – use a reliable assay as the primary baseline test 3
• Serum estradiol – measure in all patients with gynecomastia, particularly before starting testosterone therapy 3, 7
• Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) – distinguish primary (high LH/FSH) from secondary (low/normal LH/FSH) hypogonadism 3, 6

Second-Tier Tests (If Indicated)

• Free testosterone – when total testosterone is borderline, assess by equilibrium dialysis or calculate using total testosterone, SHBG, and albumin 3
• Prolactin – if testosterone is low with low/normal LH, measure to exclude hyperprolactinemia 3, 6
• Human chorionic gonadotropin (hCG) – if testicular tumor suspected 6
• Thyroid function tests (TSH, free T4) – evaluate for hyperthyroidism 6
• Liver function tests – assess for cirrhosis 6
• Renal function tests – evaluate for chronic kidney disease 6

Endocrinology Referral

• Mandatory referral for all patients with elevated baseline estradiol measurements 3, 5

Imaging

When to Image

• No imaging is routinely recommended for men with clinical findings consistent with gynecomastia or pseudogynecomastia 3
• Imaging is indicated if differentiation between benign disease and breast cancer cannot be made clinically, or if presentation is suspicious (unilateral, hard, fixed, eccentric mass, bloody discharge, skin/nipple retraction) 3

Imaging Algorithm

For men younger than 25 years with indeterminate or suspicious findings:

• Ultrasound is the initial recommended imaging study due to extremely low breast cancer incidence in young males 3
• If ultrasound shows suspicious features, proceed to mammography or digital breast tomosynthesis (DBT) before biopsy, as gynecomastia can appear suspicious on ultrasound but benign on mammography 3

For men 25 years and older with indeterminate or suspicious findings:

• Bilateral diagnostic mammography or DBT is the initial exam, with sensitivity 92-100%, specificity 90-96%, and negative predictive value 99-100% 3
• Follow with ultrasound if mammogram is indeterminate or suspicious 3

Biopsy Technique

• Image-guided core needle biopsy is superior to fine-needle aspiration in sensitivity, specificity, and histological grading 3
• Ultrasound guidance is preferred for lesions visible on ultrasound due to real-time visualization, patient comfort, and absence of ionizing radiation 3
• Stereotactic guidance for lesions visible only on mammography 3
• DBT guidance for lesions visible only on tomosynthesis 3
• Post-biopsy marker clip placement confirms tissue sampling and aids correlation 3
• Imaging should precede biopsy as post-biopsy changes confuse image interpretation 3

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Treatment Protocol and Management Steps

Step 1: Identify and Address Underlying Cause

• Discontinue offending medications if possible, or substitute with alternatives 1, 4
• Substance cessation – reduce or stop alcohol, cannabis, or anabolic steroid use 7
• Treat underlying endocrine disorders – thyroid replacement for hypothyroidism, dopamine agonists for hyperprolactinemia, testosterone replacement for hypogonadism (after measuring estradiol) 3, 6
• Optimize glycemic control in diabetic patients, as uncontrolled diabetes further reduces testosterone 3
• Weight loss for obese patients reduces peripheral aromatization 4

Step 2: Observation for Physiologic or Recent-Onset Gynecomastia

• Spontaneous resolution occurs in up to 50% of cases with non-cyclical breast symptoms, particularly pubertal gynecomastia 3, 8
• Reassurance is appropriate for adolescents with pubertal gynecomastia and adults with mild, asymptomatic disease 1, 4
• Monitor testosterone-treated patients who develop gynecomastia, as symptoms sometimes abate without intervention 3

Step 3: Medical Therapy for Persistent, Painful Gynecomastia

Medical therapy is most effective during the acute proliferative phase (first 6-12 months): 5, 1, 4

• Tamoxifen (selective estrogen receptor modulator) – trial for up to 3 months in acute gynecomastia 6, 4
• Consider SERMs for testosterone-deficient patients with low or low-normal LH, particularly those wishing to preserve fertility 3
• Over-the-counter analgesics for breast pain 3

Step 4: Prophylactic Measures for High-Risk Patients

• Breast irradiation (8-15 Gy in 1-3 fractions) given 1-2 weeks before initiating antiandrogen therapy prevents painful gynecomastia 9, 3

Step 5: Surgical Intervention for Long-Standing or Refractory Gynecomastia

For gynecomastia persisting beyond 12 months, surgical excision is the treatment of choice: 1, 4, 8

• Combination approach – liposuction plus subcutaneous mastectomy (adenectomy) provides excellent results with low complication rates 4, 8
• Grade-dependent technique selection – mild cases may require liposuction alone, while severe cases need excision with skin reduction 1, 4
• Fibrotic tissue in chronic gynecomastia does not respond to medical therapy and requires surgical removal 5, 1

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Common Pitfalls and Caveats

• Failing to distinguish true gynecomastia from pseudogynecomastia – palpation for glandular tissue beneath the nipple is essential, especially in obese patients 3, 5
• Unnecessary imaging in clear cases leads to additional unnecessary benign biopsies without improving outcomes 3, 5
• Delaying evaluation in unilateral or suspicious presentations – male breast cancer, though rare, must be excluded 3
• Starting testosterone therapy without measuring estradiol – baseline estradiol guides monitoring and intervention 3
• Attempting medical therapy for chronic (>12 months) gynecomastia – fibrotic tissue is unresponsive to pharmacotherapy 5, 1, 4
• Ignoring cardiovascular risk when prescribing testosterone to older hypogonadal men, particularly those with diabetes 3
• Overlooking medication history – many commonly prescribed drugs cause gynecomastia, and temporal correlation is key 5, 1