Don’t forget the men ! Gynaecomastia

1. Don’t forget the men ! Gynaecomastia Professor Philip J Drew

2. Gynaecomastia Giordano et al Cancer 2004 • “Man boobs” “Moobs” • Increasing • Actual • Patient Expectations • Male breast cancer • 1973 - 1998 • 0.86 – 1.08 / 100,000 men

3. Gynaecomastia Definition: Histologically: Benign proliferation of glandular tissue of the male breast Clinically: Rubbery firm mass extending concentrically from the nipple Pseudogynaecomastia: Fat deposition without glandular proliferation “lipomastia”

4. Gynaecomastia Pathophysiology: due to oestrogen / androgen imbalance Primary Secondary Decrease in androgen Actual / relative Increased binding to SHBG Receptor blockade Increase in oestrogen Direct / indirect (precursors)

5. Gynaecomastia Histology Early “florid” phase Oestrogen Ductal epithelial hyperplasia Ductal elongation and branching Proliferation periductal fibroblasts Later inactive senescent phase Dense fibrous tissue Breast enlargement may diminish Male / Female breast tissue Similar responsiveness No acinar development in men (progesterone) Wilson RL et al Adv Intern Med 1980

6. Gynaecomastia Aetiology Persistent pubertal gynaecomastia 25% Drugs 10-25% Idiopathic 25% Cirrhosis or malnutrition 8% Primary hypogonadism 8% Testicular tumours 3% Secondary hypogonadism 2% Hyperthyroidism 1.5%

7. Primary Gynaecomastia Prevalence: “Trimodal” Infants: 60% to 90% Pubertal: 30% to 60% Adults: 24% to 80% Wise et al J Am Coll Surg 2005

8. Gynaecomastia Pubertal gynaecomastia Bilateral 50-60% Midpuberty Nydick et al 1855 boy scouts 65% 14 yr olds 14% 16 yr olds Exact mechanism unknown Oestrogen increases before testosterone Most resolve spontaneously Moore DC J Clin Endocrinol Metab 1984 Nydick et al J Am Med Soc 1961

9. Gynaecomastia Marked pubertal breast development 10% endocrine abnormality Kleinfelter’s / XX maleness Primary testicular failure Androgen insensitivity Increase aromatase activity Autosomal dominant gene Sher ES et al Clinical Paediatrics 1998

10. Gynaecomastia Age related “senescent” gynaecomastia Increases in normal men after 44yrs (57%) Histologically only 7% active phase Bilateral >90% Peak 50-69yrs (72%) Decreases 70-89 yrs (47%) >80% if BMI>25 Nuttal FQ J Clin Endocrinol Metab 1979

11. Gynaecomastia Systemic Illness Liver disease Alcoholic cirrhosis Direct effect on hypothalamic-pituitary-testicular system SHBG increased – decreases free testosterone Thyrotoxicosis SHBG increased Increased peripheral aromatisation 25-40% men with Grave’s disease

12. Gynaecomastia Chronic renal failure Dialysis patients: 50% Leydig cell dysfunction HIV Antiretroviral therapy Inhibition of cytochrome P450 enzyme Malnutrition “Refeeding” gynaecomastia Second puberty Biglia A et al Clin Infect Diseases 2004 Holdsworth et al N Engl J Med 1977 Smith SR J Clin Endocrinol Metab 1975

13. Gynaecomastia Testicular neoplasms Germ cell tumours 2.5-6% gynaecomastia at presentation hCG Leydig cell dysfunction Inhibition of 17 alpha hydoxylase / 17,20 lyase enzymes Increased CYP450 aromatase activity Poor prognostic sign Same mechanism for other hCG producing tumours Leydig cell tumour 2% testicular neoplasms Testosterone and oestrodiol 6-10 yr olds Precocious puberty 26-35 yr olds Testicular mass, impotence 20-30% have gynaecomastia at presentation

14. Gynaecomastia Other tumours Prolactinoma 8% Hypogonadotrophichypogonadism Large cell calcifying Sertoli cell (sex-cord) tumours Increased aromatase activity Sporadic Autosomal dominant Peutz-Jehger’s syndrome Carney complex Feminising adrenocortical tumours 98% gynaecomastia 58% palpable adrenal tumour 50% testicular atrophy Pituitary / Hypothalamic tumours Braunstein GD Endocr Related Cancer 1999

15. Gynaecomastia True hermaphroditism Testicular and ovarian tissue Excessive oestrogen production Direct affect Suppression of intratesticular cytochrome P450 Androgen insensitivity syndromes Defect or absence intracellular androgen receptor Spectrum Complete absence “testicular feminisation” Phenotypic females Complete / partial insensitivity Phenotypic males Quigley CA et al Endocr Rev 1995

16. Gynaecomastia Primary hypogonadism Congenital Klinefelter’s syndrome Lobular strutures 16 fold increase in breast cancer Acquired Trauma Infection Infiltration Vascular insufficiency Age Decrease in testosterone Increase in LH release Increase in aromatisation of testosterone to estradiol

17. Gynaecomastia Secondary hypogonadism Prostate cancer treatment Combined androgen blockade 50% LH-RH analogue alone 25% Orchidectomy alone 10% Combined drug + orchidectomy 1-24% Dicker AP Lancet Oncol 2003

18. Gynaecomastia • BPH • Finesteride • Type II 5 alpha – reductase inhibitor • Blocks testosterone to DHT conversion • Increase tesosterone – precursor to oestrodiol • Oestrodiol increase leads to gynaecomastia • But...increased risk of male (and female) breast cancer cannot be excluded • Total data (MHRA Dec 2009): • 90,000 pt/yr exposure, rate7.82 per 100,000 PYR • 80,000 placebo / yr exposure, rate 3.84 per 100,000 PYR • P=0.328

19. Gynaecomastia Anabolic steroids 52% gynaecomastia 57% testicular atrophy Self medicate with Tam or AI for gynaecomastia hCG for testicular atrophy Clomiphene / Nolvadex “PCT” Post cycle therapy

20. Gynaecomastia Other causes Diabetic mastopathy Not related to type of insulin Mimics gynaecomastia clinically Different histologically Occupational Morticians Very unusual causes Drinking female urine Vierhapper H Lancet 1999

21. Gynaecomastia Drug therapy Large number implicated Obvious association with hormonal agents Difficult to confirm for other agents Thompson & Carter Probable Ca channel blockers, chemotherapy, H2 blockers, ketoconazole, spirinolactone Inconclusive Digitalis, neuroleptic agents and marijuana Thompson DF & Carter JR Pharmacotherapy 1993

22. Gynaecomastia Assessment: Clinical Imaging - ? mammogram / ultrasound Tissue ? Core biopsy Not FNAC – C3 result

23. Gynaecomastia Clinical assessment History Age of onset Duration Family history Aromatase excesss syndrome Auto dominant Chromosome 15 Underlying disorders Hyperthyroidism Hepatic / Renal disease Loss of libido / impotence Drug history

24. Gynaecomastia Examination Swelling of the breast Tender Concentric Mobile Sinister findings Eccentric, unilateral, nipple retraction, skin dimpling, lymphadenopathy, nipple discharge Pseudogynaecomastia No resistance to apposition of fingers Abdominal / chest / ? testes examination

25. GYNAECOMASTIA – CLASSIFICATION • Simons et al ( 1973 ) I. Minor breast enlargement without skin redundancy

26. Gynaecomastia Investigation Teenager with otherwise normal examination Re-examine to establish whether persistent Adult or persistent/marked pubertal gynaecomastia BCP, Prolactin, LH, Oestrogen, Testosterone, hCG Consider genetic causes

27. Gynaecomastia

28. Gynaecomastia Imaging / biopsy Mammography Negative predictive value for malignancy: 99% Ultrasound +/- core biopsy Imaging for clinical gynaecomastia no longer supported by RCR Evans et al Am J Surg 2001

29. Gynaecomastia Primary gonadal failure “Hypogonadism” “Andropause” Consider endocrinology referral Testosterone Replacement Therapy? No mature data from large trials

30. Gynaecomastia TRT Potential benefits / drawbacks Bone density Cognition Muscle mass / body composition Mood Erythropoiesis Libido

31. Gynaecomastia TRT Potential harm ?Cardiovascular disease Putative relationship Studies actually show favourable effect Prostate risks Mild increase in volume Theoretical cancer risk Snyder PJ J Clin Endocrinol Metab 2000

32. Treatment of Gynaecomastia Indications Pain Tenderness Embarrassment interfering with normal activity Options Medical Surgical

33. Gynaecomastia Non-surgical treatment Reassure and observe Painful for 6-12 months during florid phase Revue medication Correct obesity / lifestyle Medication Little good data End points difficult to assess Tends to resolve anyway Pain is self limiting

34. Gynaecomastia Medical therapy Clomiphene Danazol Tamoxifen Aromatase Inhibitors

35. Gynaecomastia Clomiphene 50-100mg day Evaluated in adolescents Unproven efficacy especially at 50mg May achieve up to 64% resolution Adverse effects rare Danazol 400mg day Evaluated in adolescents (200mg day) Objective response 20-76% Side effects common Weight gain, acne, abnormal LFT’s LeeRoith et al Acta Endocrinol 1980 Jones DJ et al Ann RCS Eng 1990

36. Gynaecomastia Tamoxifen Not evaluated in adolescents Generally poorly designed trials and audits Total of 136 patients in 5 trials Only 113 studied prospectively No randomised controlled studies Doses of 10, 20 & 40mg used From this “evidence” in adults Reduces pain: 70-100% May decrease lump: 50-80% Amoxifene 4-OH Tam gel No significant systemic level Trial in design stage (Hull / Cardiff) Plourde PV et al J Clin Endocrinol Metab 2004 Kahn HN, Blamey RW BMJ 2003

37. Gynaecomastia Aromatase Inhibitors One RCT in adolescents Pain reduced No effect on lump Theoretical risks Bone health LH increases leading to peripheral aromatisation Not use AI’s for male breast cancer

38. Gynaecomastia Prostate cancer therapy Bicalutamide Dose dependent response to Tamoxifen prohylaxis 8.8% on 20mg/day 96.7% placebo No increase in PSA Alternatives Low dose irradiation Fradet, Yves, Egerdie et al Europ Urol. 2007 52(1): 106-114

39. Gynaecomastia - Surgery Glandular enlargement with no/little excess skin ?liposuction alone – will not remove glandular element Ultrasound assisted Risk of thermal damage Minimally invasive gland excision +/- liposuction

40. USS Guided Intervention VABD Initially diagnostic Burbank, Parker, Fogarty Am J Surg 1996 Therapeutic Zannis, Aliano Am J Surg 1998

41. VABD Breast vacuum biopsy system Hand held Multiple sampling through a single incision Introduction of 8-gauge probe Therapeutic procedures

42. Mammotome® Technique

43. Gynaecomastia - VABD Hull Breast Unit Patients 59 men Mean age 38 (range 21-80) Grade Grade 1/2 14 unilateral

44. Gynaecomastia Complications Haematoma n=2 Spontaneously resolved (“Bruising” inevitable) Recurrence n=2 Re-mammotome Iwuagwu O et al Annals of Plastic Surgery 2004

45. Gynaecomastia Operating time 50 min (range 20-60 min) Patient satisfaction: 8-9/10 Cosmesis: 9-10/10

46. Gynaecomastia

47. Gynaecomastia - Surgery • Excess skin + • Consider staged operation • Liposuction • +/- skin excision • Periareolar breast reduction • Excess skin +++ • Consider Wise pattern, vertical scar etc. • Beware hypertrophic scars • Repeated periareolar operations

48. SURGICAL TECHNIQUE • Pre-operative markings – standing • Operative patient position : semi-sitting • Infiltrate breast with adrenaline solution ( 1 litre Ringers, 1ml 1: 1000 adrenaline , LA )

49. GYNAECOMASTIA ASSESSMENT – NIPPLE POSITION B A • A = ( 0.19 chest circumference ) + 2.192 cm • B = ( 0.12 height ) – 2.782 cm • Shulman et al PRS 2001

50. CIRCUMAREOLAR CONCENTRIC SKIN REDUCTION