Aj gynecomastia 15 aug 2011

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Aj gynecomastia 15 aug 2011

  1. 1. Gynecomastia PROF:AKMAL JAMAL FCPS;FRCSEd: 13 AUG 2011
  2. 2. Definition of Gynecomastia <ul><li>True Gynecomastia : </li></ul><ul><ul><li>Rubbery or firm mass </li></ul></ul><ul><ul><li>Extending concentrically </li></ul></ul><ul><ul><li>Symmetrically from the nipple </li></ul></ul><ul><ul><li>Usually bilateral but can be unilateral </li></ul></ul><ul><li>Pseudogynecomastia : </li></ul><ul><ul><li>Fat deposition without glandular proliferation </li></ul></ul><ul><ul><li>On exam fingers will not meet any resistance  the nipple </li></ul></ul><ul><li>Breast cancer : </li></ul><ul><ul><li>Hard or firm eccentric in location from the nipple </li></ul></ul><ul><ul><li>May be associated with skin dimpling </li></ul></ul><ul><ul><li>Nipple retraction or discharge </li></ul></ul><ul><ul><li>Axillary lymphadenopathy </li></ul></ul>
  3. 3. Hormonal control of breast development <ul><li>estradiol stimulates glandular cells </li></ul><ul><li>testosterone inhibits growth & differentiation </li></ul><ul><li>GH,cortisol,IGF1,insulin act permissively </li></ul><ul><li>thyroid hormones increase SHBG level </li></ul><ul><li>cortisol & prolactin lower T levels (hypothalamic & testicular effects) </li></ul>
  4. 5. Physiological vs pathological gynecomastia <ul><li>challenging </li></ul><ul><li>common </li></ul><ul><li>association with obesity </li></ul><ul><li>psedogynecomastia </li></ul><ul><li>pathological arbitrarily defined : </li></ul><ul><li>palpable tissue > 4cm </li></ul><ul><li>>2cm & tender </li></ul><ul><li>>2cm & increasing </li></ul>
  5. 6. diagnosis of gynecomastia may be made <ul><li>In the nonobese male, breast tissue measuring at least 2 cm in diameter must be present before a diagnosis of gynecomastia may be made </li></ul><ul><li>does not predispose the male breast to cancer </li></ul>
  6. 7. <ul><li>Gynecomastia </li></ul><ul><li>. </li></ul><ul><li>Physiologic gynecomastia : neonatal period, </li></ul><ul><li>adolescence, and </li></ul><ul><li>senescence. (excess of circulating estrogens in relation to circulating testosterone) </li></ul><ul><li>. </li></ul>
  7. 8. <ul><li>The pathophysiologic mechanisms: </li></ul><ul><li>   I.   Estrogen excess states </li></ul><ul><li>   A.   Gonadal origin </li></ul><ul><li>    B.   Nontesticular tumors </li></ul><ul><li>  C.   Endocrine disorders </li></ul><ul><li>    D.  Diseases of the liver—nonalcoholic and alcoholic cirrhosis </li></ul><ul><li>    E.  Nutrition alteration states </li></ul><ul><li>    II.   Androgen deficiency states </li></ul><ul><li>   A.  Senescence </li></ul><ul><li>    B.  Hypoandrogen states (hypogonadism) </li></ul><ul><li>    C.   Renal failure </li></ul><ul><li>  III. Drug-related </li></ul><ul><li>  IV.  Systemic diseases with idiopathic mechanisms </li></ul><ul><li>Therapy. </li></ul>
  8. 9. Simon classification of gynecomastia Grade Enlargement Skin excess I small absent IIA moderate absent IIB moderate present III large present
  9. 10. Prevalence <ul><li>Gynecomastia has three peaks . </li></ul><ul><li>1. Infancy: 60-90% </li></ul><ul><ul><li>Transient maternal E2,regresses over 2-3 week </li></ul></ul><ul><li>2. Adolescence: </li></ul><ul><ul><li>4-69% (variation due to examiner) Onset 10-12y </li></ul></ul><ul><ul><li>Peaks 13-14. Normally regresses w/in 18mo </li></ul></ul><ul><ul><li>Persistence uncommon after 17y </li></ul></ul><ul><li>3. Older men : 24-65% </li></ul><ul><ul><li>Highest prevalence in the 50-80y </li></ul></ul>
  10. 11. Glandular Proliferation Androgen Exposure Estrogen Exposure Balance T &E2 =T/E2 Physiopathology of Gynecomastia
  11. 12. Pathophysiologic Causes for Gynecomastia <ul><li>The basic mechanisms of gynecomastia include a decrease in androgen production, an increase in estrogen production, or increased availability of estrogen precursors for peripheral conversion to estrogen. </li></ul><ul><li>Androgen receptor blockade and increased binding of androgen to sex-hormone binding globulin (SHBG). </li></ul><ul><li>Estrogen-like or antiandrogen effects of Drugs </li></ul>
  12. 13. <ul><li>Glandular Proliferation </li></ul><ul><li>Androgen Exposure </li></ul><ul><li>1-Deficiency: </li></ul><ul><li>Genetic </li></ul><ul><li>Tumors </li></ul><ul><li>Drugs </li></ul><ul><li>2-Resistance: </li></ul><ul><li>AR mutation </li></ul><ul><li>Anti-androgens </li></ul>Physiopathology of Gynecomastia Estrogen Exposure: 1- Excess of Production: Tumors Aromatization(age,obesity) 2-Exogenous E2 : E2 Aromatizable E2 3- Excess of Free E2 Thyrotoxicosis-Drugs(SHBG)
  13. 15. Absolute increase in free estrogen <ul><li>Direct secretion from: </li></ul><ul><ul><li>Maternal-placental-fetal unit </li></ul></ul><ul><ul><li>Testes </li></ul></ul><ul><ul><li>Adrenal glands </li></ul></ul><ul><li>Extraglandular aromatization : </li></ul><ul><ul><li>Adipose, liver, skin, muscle, kidney and bone </li></ul></ul><ul><li>Displacement from SHBG : </li></ul><ul><ul><li>SHBG higher affinity for andro.than estrogens </li></ul></ul><ul><li>Enhanced sensitivity of breast tissue to circulating E2: </li></ul><ul><ul><li>via increased aromatization </li></ul></ul><ul><li>Exogenous estrogen admininstration: </li></ul><ul><ul><li>drugs </li></ul></ul>
  14. 16. Decreased endogenous free androgens <ul><li>Decreased secretion by testes and adrenals </li></ul><ul><li>Increased metabolism via aromatization </li></ul><ul><li>Increased binding to SHBG </li></ul><ul><li>Congenital defects in A.R . structure or function </li></ul><ul><li>Displacement of androgens from receptor </li></ul>
  15. 17. Aromatization Inhibitory Estrogens 5 α - androgens Androgens 5 α - reduction N Aromatization of Androgens
  16. 18. Etiologies of Gynecomastia <ul><li>Drugs: </li></ul><ul><li>No detectable abnormality </li></ul><ul><li>Persistent pubertal gynecomastia </li></ul><ul><li>Cirrhosis or malnutrition </li></ul><ul><li>Primary hypogonadism </li></ul><ul><li>Testicular tumors </li></ul><ul><li>Secondary Hypogonadism </li></ul><ul><li>Hyperthyroidism </li></ul><ul><li>Chronic renal insufficiency </li></ul>10-25% 25% 25% 8% 8% 3% 2% 1.5% 1%
  17. 19. Gynecomastia and Thyrotoxicosis <ul><li>Presenting manifestation (unusual) </li></ul><ul><li>Occurs in 0-83% of patients* </li></ul><ul><li>Onset during thyrotoxicosis </li></ul><ul><li>Disappearance after euthyroidism occurs </li></ul>* wide range probably indicates differences in examining technique
  18. 20. Drugs associated with Gynecomastia <ul><li>Androgen Exposure </li></ul><ul><li>1-Deficiency: </li></ul><ul><li>Gn-GH analogs </li></ul><ul><li>Spirolactone </li></ul><ul><li>Ketodanazole </li></ul><ul><li>Anti-androgens </li></ul><ul><li>Tumors,Drugs </li></ul><ul><li>2-Resistance: </li></ul><ul><li>Cimetidine </li></ul><ul><li>Siprolactone </li></ul><ul><li>Finesteride </li></ul><ul><li>Bicalutamide </li></ul>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 ??
  19. 22. Specific Pathogeneses <ul><li>Puberty </li></ul><ul><ul><li>During puberty, E2 rise to adult levels before the T. </li></ul></ul><ul><ul><li>Transient increase in E2 at onset of puberty </li></ul></ul><ul><ul><li>T.-E2-Estrone- Gonadotropins: No difference </li></ul></ul><ul><li>Adult men ;Multifactorial </li></ul><ul><ul><li>Increase body fat </li></ul></ul><ul><ul><li>Decrease in T. By testes </li></ul></ul><ul><ul><li>Increase in LH </li></ul></ul><ul><ul><li>Polypharmacy. </li></ul></ul>
  20. 23. Specific Pathogeneses <ul><li>Drugs </li></ul><ul><ul><li>Increase E2 </li></ul></ul><ul><ul><li>Act as Antiandrogens by binding receptors and displacing androgens. </li></ul></ul><ul><ul><li>Increase aromatization of T. To E2 </li></ul></ul><ul><ul><li>Decrease T. Production </li></ul></ul><ul><ul><li>Displace T. From SHBG  increasing its metabolic clearance </li></ul></ul><ul><li>Cirrhosis </li></ul><ul><ul><li>Increase Androstenedione and its conversion to Estrone & E2 </li></ul></ul><ul><ul><li>Elevated SHBG levels, reducing free T. </li></ul></ul><ul><li>Malnutrition </li></ul><ul><ul><li>Decrease androgen with normal Estrogen production. </li></ul></ul><ul><ul><li>Refeeding mimics normal puberty hormone pattern. </li></ul></ul>
  21. 24. Specific Pathogeneses <ul><li>Male hypogonadism </li></ul><ul><ul><li>Primary hypogonadism: </li></ul></ul><ul><ul><li>Klinefelter’s </li></ul></ul><ul><ul><li>enzymatic defect in the T. </li></ul></ul><ul><ul><li>testicular trauma </li></ul></ul><ul><ul><li>infection </li></ul></ul><ul><ul><li>infiltrative disorders </li></ul></ul><ul><ul><li>vascular insufficiency aging : decrease in T. with increase in E2 </li></ul></ul><ul><ul><li>Secondary hypogonadism : low T.- increase in E2 precursors </li></ul></ul><ul><li>Testicular neoplasm </li></ul><ul><ul><li>Germ cell tumor (2.5-6%) =poor prognosis </li></ul></ul><ul><ul><li>Leydig cell tumor (20-30%) </li></ul></ul><ul><ul><li>These neoplasms produce estrogen/androgen inbalances </li></ul></ul>
  22. 25. Specific Pathogeneses <ul><li>Hyperthyroidism due to Graves’ disease </li></ul><ul><ul><li>As many as 25-40% have gynecomastia due to increase of SHBG and enhanced aromatization </li></ul></ul><ul><li>Chronic renal failure and dialysis </li></ul><ul><ul><li>50% develop gynecomastia due to Leydig cell dysfxn resulting in low testosterone </li></ul></ul><ul><li>Feminizing adrenocortical tumors </li></ul><ul><ul><li>Rare malignant tumors that have gynecomastia( 98%), palpable tumor(58%), and testicular atrophy(50%). </li></ul></ul>
  23. 26. Specific Pathogeneses <ul><li>Ectopic production hCG </li></ul><ul><ul><li>Precocious puberty in boys with hepatoblastomas </li></ul></ul><ul><ul><li>In adults, large cell CA of lung, gastric CA, renal cell Ca, and occasionally hepatomas. </li></ul></ul><ul><li>True Hermaphroditism </li></ul><ul><ul><li>Harbor both testicular and ovarian tissue. Increased estrogen activity can suppress testosterone production by testes. </li></ul></ul><ul><li>Androgen Insensitivity Syndromes </li></ul><ul><ul><li>Defects or absence of androgen receptors in target tissue </li></ul></ul><ul><li>Excessive extraglandular aromatase activity </li></ul><ul><ul><li>X-linked recessive or sex-limited autosomal trait have many fold increase in extraglandular conversion of plasma androstenedione to estrone. </li></ul></ul>
  24. 27. Anabolic abuse
  25. 28. Evaluation <ul><li>whom to evaluate </li></ul><ul><li>how to evaluate </li></ul>
  26. 29. Candidates needing evaluation <ul><li>breast tenderness </li></ul><ul><li>rapid enlargement </li></ul><ul><li>eccentric, hard or irregular mass </li></ul><ul><li>lesion >4cm in diameter </li></ul>
  27. 30. Candidates not requiring evaluation <ul><li>asymptomatic </li></ul><ul><li>stable </li></ul><ul><li>obese </li></ul><ul><li><5cm </li></ul>
  28. 31. Work-up <ul><li>History </li></ul><ul><ul><li>Onset </li></ul></ul><ul><ul><li>Bilateral/unilateral </li></ul></ul><ul><ul><li>Pain </li></ul></ul><ul><ul><li>Change in size </li></ul></ul><ul><ul><li>Nipple discharge </li></ul></ul><ul><ul><li>Drugs/medications </li></ul></ul><ul><ul><li>Family history </li></ul></ul>
  29. 32. Work-up <ul><li>Complete Physical Exam </li></ul><ul><ul><li>Look for signs of liver and kidney disease </li></ul></ul><ul><ul><li>Evaluate for hyperthyroidism </li></ul></ul><ul><ul><li>Seek for signs hypogonadism: eg. Impotence, decreased libido, strenght, and change in testicular size </li></ul></ul><ul><ul><li>Check for abdominal mass and testicular mass </li></ul></ul><ul><ul><li>Careful breast exam </li></ul></ul>
  30. 33. Examination : local <ul><li>presence or absence of breast disc </li></ul><ul><li>diameter of breast disc </li></ul><ul><li>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 </li></ul><ul><li>comparison of consistency with abdominal fat or fat in the axillary line </li></ul><ul><li>tenderness </li></ul>
  31. 34. <ul><li>Physiologic gynecomastia :no further evaluation </li></ul><ul><li>Further evaluation is necessary in the following: </li></ul><ul><ul><li>Breast size greater than 5 cm (macromastia) </li></ul></ul><ul><ul><li>A lump that is tender, of recent onset , progressive, unknown duration </li></ul></ul><ul><ul><li>Signs of malignancy (eg, hard or fixed lymph nodes or positive lymph node findings) </li></ul></ul><ul><li>Evaluation for renal or liver disease </li></ul><ul><li>Free or totalT.,LH,E2,DHAS :patient with possible feminization syndrome </li></ul><ul><li>TSH and FT4 if hyperthyroidism is suspected </li></ul>Laboratory Studies
  32. 35. Work-up <ul><li>Labs if gynecomastia of recent onset, persistent, or painful/tender and has no clear physiologic etiology. </li></ul><ul><ul><li>TSH, LH, FSH, hCG, Prolactin, Estradiol, Testosterone, Androstenedione </li></ul></ul><ul><li>Imaging? US and mammogram for any eccentric or discrete mass. </li></ul>
  33. 36. Biochemical investigations <ul><li>testosterone </li></ul><ul><li>17 β estradiol </li></ul><ul><li>DHEAS </li></ul><ul><li>LH </li></ul><ul><li>β hCG </li></ul><ul><li>thyroid function test </li></ul><ul><li>liver function test </li></ul>proceed further according to lead
  34. 40. Treatment Options <ul><li>Watchful Waiting </li></ul><ul><li>Medications </li></ul><ul><li>Surgery </li></ul>
  35. 41. A major factor that should influence the initial choice of therapy <ul><li>Pubertal gynecomastia :resolves spontaneously within several weeks to 3 years in approximately 90% </li></ul><ul><li>Breasts greater than 4 cm in diameter may not completely regress. </li></ul><ul><li>the duration of 12 mo or longer(late fibrotic stage): unlikely that any medical therapy will result in significant regression </li></ul>
  36. 42. Treatments <ul><li>Watchful waiting </li></ul><ul><ul><li>In healthy adolescent ; normal genital exam, reevaluate in 6 months </li></ul></ul><ul><ul><li>Gynecomastia attributed to a medication should be stopped and patient reassessed after stopping medication </li></ul></ul><ul><ul><li>Regression will occur in 85% of patients with gynecomastia due to various causes </li></ul></ul>
  37. 43. Treatments <ul><li>Medications </li></ul><ul><ul><li>May be indicated in patients with persistent gynecomast.; </li></ul></ul><ul><ul><ul><li>Later puberty with severe pain </li></ul></ul></ul><ul><ul><ul><li>tenderness, </li></ul></ul></ul><ul><ul><ul><li>psychosocial issues of embarrasment </li></ul></ul></ul><ul><ul><li>Consider that current medications have only been studied in small sizes that have been unblinded and uncontrolled </li></ul></ul><ul><ul><li>Three types of medical therapy </li></ul></ul><ul><ul><ul><li>Androgens, antiestrogens and aromatase inhibitors </li></ul></ul></ul><ul><ul><ul><li>None are FDA approved for gynecomastia </li></ul></ul></ul>
  38. 44. Androgens <ul><li>Testosterone </li></ul><ul><ul><li>Not more effective than placebo and can be aromatized exogenously </li></ul></ul><ul><ul><li>Reduce the prevalence of gyne. in patients with cirrhosis </li></ul></ul><ul><li>Dihydrotestosterone (nonaromatizable androgen) </li></ul><ul><ul><li>Decrease in breast volume in 75% </li></ul></ul><ul><ul><li>Resolution in 25%. No noted side effects </li></ul></ul><ul><li>Danazol </li></ul><ul><ul><li>Complete resolution , in 23%(12% in placebo ) </li></ul></ul><ul><ul><li>well tolerated </li></ul></ul><ul><ul><li>S.E: edema, weight gain, acne, nausea , muscle cramps. </li></ul></ul>
  39. 45. Antiestrogens <ul><li>Clomiphen </li></ul><ul><ul><li>Dose=50-100 mg  6 mo ;Response rates of 36-95% </li></ul></ul><ul><li>Tamoxifen </li></ul><ul><ul><li>significant reduction in pain and breast size , none had complete remission. </li></ul></ul><ul><ul><li>S.E. :no major side effects, except for occassional epigastric distress and nausea. </li></ul></ul>
  40. 49. Surgery <ul><li>Should be considered in patients who do not respond to medical therapy or who have long standing gynecomastia. </li></ul><ul><li>Options Include </li></ul><ul><ul><li>Liposuction </li></ul></ul><ul><ul><li>Direct surgical excision, or both </li></ul></ul><ul><li>Complications </li></ul><ul><ul><li>Permanent numbness, compromise of blood supply, irregular contour, hematoma, seroma, wound infection. </li></ul></ul>

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