Gynecomastia

PROF:AKMAL JAMALFCPS;FRCSEd:

13 AUG 2011

Definition of Gynecomastia True Gynecomastia:

Rubbery or firm mass Extending concentrically Symmetrically from the nippleUsually bilateral but can be unilateral

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

Breast cancer: Hard or firm eccentric in location from the nippleMay be associated with skin dimpling Nipple retraction or dischargeAxillary lymphadenopathy

Hormonal control of breast development

estradiol stimulates glandular cells testosterone inhibits growth & differentiation GH,cortisol,IGF1,insulin act permissively thyroid hormones increase SHBG level cortisol & prolactin lower T levels

(hypothalamic & testicular effects)

Physiological vs pathological gynecomastia challenging common association with obesity psedogynecomastia pathological arbitrarily defined : palpable tissue > 4cm >2cm & tender >2cm & increasing

diagnosis of gynecomastia may be made

In the nonobese male, breast tissue measuring at least 2 cm in diameter must be present before a diagnosis of gynecomastia may be madedoes not predispose the male breast to cancer

Gynecomastia .

Physiologic gynecomastia: neonatal period, adolescence, and senescence. (excess of circulating estrogens in relation to circulating testosterone) .

The pathophysiologic mechanisms:

  I.   Estrogen excess states

   A.   Gonadal origin

    B.   Nontesticular tumors

  C.   Endocrine disorders

    D.  Diseases of the liver—nonalcoholic and alcoholic cirrhosis

    E.  Nutrition alteration states

   II.   Androgen deficiency states

   A.  Senescence

    B.  Hypoandrogen states (hypogonadism)

    C.   Renal failure

  III. Drug-related

  IV.  Systemic diseases with idiopathic mechanisms Therapy.

Simon classification of gynecomastia

Grade Enlargement Skin excess

I small absent

IIA moderate absent

IIB moderate present

III large present

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

Glandular Proliferation

Androgen ExposureEstrogen Exposure

Balance T &E2 =T/E2

Physiopathology of Gynecomastia

Glandular Proliferation

Androgen Exposure

1-Deficiency:

Genetic

Tumors

Drugs

2-Resistance:

AR mutation

Anti-androgens

Estrogen Exposure:

1- Excess of Production:

Tumors

Aromatization(age,obesity)

2-Exogenous E2:

E2

Aromatizable E2

3- Excess of Free E2

Thyrotoxicosis-Drugs(SHBG)

Physiopathology of Gynecomastia

Absolute increase in free estrogen

Direct secretion from: Maternal-placental-fetal unit Testes Adrenal glands

Extraglandular aromatization: Adipose, liver, skin, muscle, kidney and bone

Displacement from SHBG : SHBG higher affinity for andro.than estrogens

Enhanced sensitivity of breast tissue to circulating E2: via increased aromatization

Exogenous estrogen admininstration: drugs

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

Inhibitory

Estrogens

5 α -

androgens

Androgens

5 α - reduction

N

Aromatization of 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%

Gynecomastia and Thyrotoxicosis

Presenting manifestation (unusual) Occurs in 0-83% of patients* Onset during thyrotoxicosis Disappearance after euthyroidism occurs

* wide range probably indicates differences in examining technique

Drugs associated with Gynecomastia

Androgen Exposure1-Deficiency:

Gn-GH analogs

Spirolactone

Ketodanazole

Anti-androgens

Tumors,Drugs

2-Resistance:

Cimetidine

Siprolactone

Finesteride

Bicalutamide

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 ??

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

Adult men ;Multifactorial Increase body fat Decrease in T. By testes Increase in LH Polypharmacy.

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: Klinefelter’s 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

Testicular neoplasm Germ cell tumor (2.5-6%) =poor prognosis Leydig cell tumor (20-30%) These neoplasms produce estrogen/androgen inbalances

Specific Pathogeneses Hyperthyroidism due to Graves’ disease

As many as 25-40% have gynecomastia due to increase of SHBG and enhanced aromatization

Chronic renal failure and dialysis 50% develop gynecomastia due to Leydig cell dysfxn resulting

in low testosterone

Feminizing adrenocortical tumors Rare malignant tumors that have gynecomastia( 98%), palpable

tumor(58%), and testicular atrophy(50%).

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.

Androgen Insensitivity Syndromes Defects or absence of androgen receptors in target tissue

Excessive extraglandular aromatase activity X-linked recessive or sex-limited autosomal trait have many fold

increase in extraglandular conversion of plasma androstenedione to estrone.

Anabolic abuse

Evaluation whom to evaluate

how to evaluate

Candidates needing evaluation breast tenderness

rapid enlargement

eccentric, hard or irregular mass

lesion >4cm in diameter

Candidates not requiring evaluation

asymptomatic

stable

obese

<5cm

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

Examination : local presence or absence of breast disc diameter of breast disc to pinch the tissue between thumb &

forefinger lateral to nipple; ability to flip an edge of tissue at the interface of normal & glandular tissue signifies gynecomastia

comparison of consistency with abdominal fat or fat in the axillary line

tenderness

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

Laboratory Studies

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.

Biochemical investigations testosterone 17β estradiol DHEAS LH β hCG thyroid function test liver function test

proceed further according to lead

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

Complications Permanent numbness, compromise of blood supply,

irregular contour, hematoma, seroma, wound infection.