Definition of Gynecomastia

True Gynecomastia:
Rubbery or firm mass Extending concentrically Symmetrically from the nipple Usually bilateral but can be unilateral

Pseudogynecomastia:
Fat deposition without glandular proliferation On exam fingers will not meet any resistance the nipple

Breast cancer:
Hard or firm eccentric in location from the nipple May be associated with skin dimpling Nipple retraction or discharge Axillary lymphadenopathy

Prevalence

Gynecomastia has three peaks. 1. Infancy: 60-90%

Transient maternal E2,regresses over 2-3 week

2. Adolescence:

4-69% (variation due to examiner) Onset 10-12y Peaks 13-14. Normally regresses w/in 18mo Persistence uncommon after 17y

3. Older men: 24-65%

Highest prevalence in the 50-80y

Physiopathology of Gynecomastia
Glandular Proliferation

Estrogen Exposure

Androgen Exposure

Balance T &E2 =T/E2

Physiopathology of Gynecomastia
Glandular Proliferation
Estrogen Exposure: 1- Excess of Production: Tumors Aromatization(age,obesity) 2-Exogenous E2: E2 Aromatizable E2 3- Excess of Free E2 Thyrotoxicosis-Drugs(SHBG) Androgen Exposure 1-Deficiency: Genetic Tumors Drugs 2-Resistance: AR mutation Anti-androgens

Absolute increase in free estrogen

Direct secretion from:

Maternal-placental-fetal unit Testes Adrenal glands Adipose, liver, skin, muscle, kidney and bone SHBG higher affinity for andro.than estrogens via increased aromatization drugs

Extraglandular aromatization:

Displacement from SHBG :

Enhanced sensitivity of breast tissue to circulating E2:

Exogenous estrogen admininstration:

Decreased endogenous free androgens

Decreased secretion by testes and adrenals Increased metabolism via aromatization Increased binding to SHBG Congenital defects in A.R. structure or function Displacement of androgens from receptor

Aromatization of Androgens
Aromatization N
Androgens Estrogens

Inhibitory

55 - reduction

androgens

Etiologies of Gynecomastia

Drugs: No detectable abnormality Persistent pubertal gynecomastia Cirrhosis or malnutrition Primary hypogonadism Testicular tumors Secondary Hypogonadism Hyperthyroidism Chronic renal insufficiency

10-25% 25% 25% 8% 8% 3% 2% 1.5% 1%

Drugs associated with Gynecomastia

Estrogen Exposure:
1- Excess of Production: HCG Aromatizable Androgens 2-Exogenous E2: E2 Digoxin Marijuana 3- Excess of Free E2 Spirolactone Aromatizable E2 ACE,CCB ??

Androgen Exposure
1-Deficiency: Gn-GH analogs Spirolactone Ketodanazole Anti-androgens Tumors,Drugs 2-Resistance: Cimetidine Siprolactone Finesteride Bicalutamide

Specific Pathogeneses

Puberty

During puberty, E2 rise to adult levels before the T. Transient increase in E2 at onset of puberty T.-E2-Estrone- Gonadotropins: No difference Increase body fat Decrease in T. By testes Increase in LH Polypharmacy.

Adult men ;Multifactorial

Specific Pathogeneses

Drugs

Increase E2 Act as Antiandrogens by binding receptors and displacing androgens. Increase aromatization of T. To E2 Decrease T. Production Displace T. From SHBGincreasing its metabolic clearance

Cirrhosis

Increase Androstenedione and its conversion to Estrone & E2 Elevated SHBG levels, reducing free T.

Malnutrition

Decrease androgen with normal Estrogen production. Refeeding mimics normal puberty hormone pattern.

Specific Pathogeneses

Male hypogonadism

Primary hypogonadism: Klinefelters enzymatic defect in the T. testicular trauma infection infiltrative disorders vascular insufficiency aging: decrease in T. with increase in E2 Secondary hypogonadism : low T.- increase in E2 precursors
Germ cell tumor (2.5-6%) =poor prognosis Leydig cell tumor (20-30%) These neoplasms produce estrogen/androgen inbalances

Testicular neoplasm

Specific Pathogeneses

Hyperthyroidism due to Graves disease

As many as 25-40% have gynecomastia due to increase of SHBG and enhanced aromatization 50% develop gynecomastia due to Leydig cell dysfxn resulting in low testosterone Rare malignant tumors that have gynecomastia( 98%), palpable tumor(58%), and testicular atrophy(50%).

Chronic renal failure and dialysis

Feminizing adrenocortical tumors

Specific Pathogeneses

Ectopic production hCG

Precocious puberty in boys with hepatoblastomas In adults, large cell CA of lung, gastric CA, renal cell Ca, and occasionally hepatomas.

True Hermaphroditism

Harbor both testicular and ovarian tissue. Increased estrogen activity can suppress testosterone production by testes.
Defects or absence of androgen receptors in target tissue X-linked recessive or sex-limited autosomal trait have many fold increase in extraglandular conversion of plasma androstenedione to estrone.

Androgen Insensitivity Syndromes

Excessive extraglandular aromatase activity

Anabolic abuse

Work-up

History

Onset Bilateral/unilateral Pain Change in size Nipple discharge Drugs/medications Family history

Work-up

Complete Physical Exam

Look for signs of liver and kidney disease Evaluate for hyperthyroidism Seek for signs hypogonadism: eg. Impotence, decreased libido, strenght, and change in testicular size Check for abdominal mass and testicular mass Careful breast exam

Laboratory Studies

Physiologic gynecomastia :no further evaluation Further evaluation is necessary in the following:

Breast size greater than 5 cm (macromastia) A lump that is tender, of recent onset, progressive, unknown duration Signs of malignancy (eg, hard or fixed lymph nodes or positive lymph node findings)

Evaluation for renal or liver disease Free or totalT.,LH,E2,DHAS :patient with possible feminization syndrome TSH and FT4 if hyperthyroidism is suspected

Work-up

Labs if gynecomastia of recent onset, persistent, or painful/tender and has no clear physiologic etiology.

TSH, LH, FSH, hCG, Prolactin, Estradiol, Testosterone, Androstenedione

Imaging? US and mammogram for any eccentric or discrete mass.

Treatment Options

Watchful Waiting Medications Surgery

A major factor that should influence the initial choice of therapy

Pubertal gynecomastia :resolves spontaneously within several weeks to 3 years in approximately 90% Breasts greater than 4 cm in diameter may not completely regress. the duration of 12 mo or longer(late fibrotic stage): unlikely that any medical therapy will result in significant regression

Treatments

Watchful waiting

In healthy adolescent ; normal genital exam, reevaluate in 6 months Gynecomastia attributed to a medication should be stopped and patient reassessed after stopping medication Regression will occur in 85% of patients with gynecomastia due to various causes

Treatments

Medications

May be indicated in patients with persistent gynecomast.;

Later puberty with severe pain tenderness, psychosocial issues of embarrasment

Consider that current medications have only been studied in small sizes that have been unblinded and uncontrolled Three types of medical therapy

Androgens, antiestrogens and aromatase inhibitors None are FDA approved for gynecomastia

Androgens

Testosterone

Not more effective than placebo and can be aromatized exogenously Reduce the prevalence of gyne. in patients with cirrhosis

Dihydrotestosterone (nonaromatizable androgen)

Decrease in breast volume in 75% Resolution in 25%. No noted side effects

Danazol

Complete resolution , in 23%(12% in placebo ) well tolerated S.E: edema, weight gain, acne, nausea , muscle cramps.

Antiestrogens

Clomiphen

Dose=50-100 mg 6 mo ;Response rates of 36-95%

Tamoxifen

significant reduction in pain and breast size , none had complete remission. S.E. :no major side effects, except for occassional epigastric distress and nausea.

Surgery

Should be considered in patients who do not respond to medical therapy or who have long standing gynecomastia. Options Include

Liposuction Direct surgical excision, or both Permanent numbness, compromise of blood supply, irregular contour, hematoma, seroma, wound infection.

Complications