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  1. 1. Hirsutism www.freelivedoctor.com
  2. 2. Outline • Introduction • Definition • Causes • Clinical evaluation • Investigations • Treatment • Conclusion www.freelivedoctor.com
  3. 3. Introduction www.freelivedoctor.com
  4. 4. Gynecological, Endocrinological, Cosmetic & Psychogenic: {great anxiety, nature of the disease, social acceptance} www.freelivedoctor.com
  5. 5. Incidence Not known Mediterranean> Asian American females: 10% European: 5% www.freelivedoctor.com
  6. 6. Cycle growth of hair Several months 2 weeks 3 months www.freelivedoctor.com
  7. 7. Types of hair Lanugo Fetal hair Vellus Short, fine, Unpigmented Before puberty Terminal Long, coarse, pigmented arises from vellus hair www.freelivedoctor.com
  8. 8. Non sexual Ambi-sexual Male sexual Sites Lower parts of the scalp, eye brow, lashes, fore-arms, lower legs Temporal & vertical parts of the scalp, axilla, lower pubic hair. Ears, nasal tip, chin, sternum, upper pubic triangle, back. Depend on Growth hormone from pituitary Androgen in low concentration from the adrenals & ovaries in females & adrenals in male Androgen in high concentration Sites of hair www.freelivedoctor.com
  9. 9. Androgen production Androstenedione Testosterone Adrenal DHEA Ovary DHEAS 50% 50% 50% 25% 25% 90% 10% 100% www.freelivedoctor.com
  10. 10. Androgen in the blood Male Normal female Hirsute female Free 3% 1% 2% Albumin 19% 19% 19% SHBG 78% 80% 79% www.freelivedoctor.com
  11. 11. Androgen at target cell (hair follicle) Testosterone (T) 5œ-reductase. Dihydrtestosterone (DHT) Androstanediol Glucuronide 3 alpha androstanediol glucuronide(3 alpha AG) www.freelivedoctor.com
  12. 12. Definitions www.freelivedoctor.com
  13. 13. Virilization: Defiminization: Atrophy of the breast & vagina Musculinization: Hirsutism, deepening of voice, temporal balding. Increase size of the clitoris, muscular mass & libido www.freelivedoctor.com
  14. 14. Hirsutism: Latin hirsutus = shaggy, hairy Excessive growth of terminal hair in male sexual sites. Excessive: Socially unacceptable to the patient F& G score >8 www.freelivedoctor.com
  15. 15. Hypertrichosis Excessive growth of Lanugo, vellus or terminal hair in non-sexual sites (James et al, 2005) •Cong Acquired •Localized Generalized Congenital hypertrichosis lanuginosaDrug-induced hypertrichosis www.freelivedoctor.com
  16. 16. Hirsutism: •Not an increase in the number of hair follicles but an alteration in their character. •An increase in the transformation of the vellus to terminal hair. {Androgens will convert lanugo & vellus hair to terminal hair}. www.freelivedoctor.com
  17. 17. Hirsutism is a consequence of several factors. An increase in: 1. Androgen production 2. The sensitivity of the androgen receptors at the level of the hair follicle. 3. The activity of 5œ-reductase. www.freelivedoctor.com
  18. 18. Causes www.freelivedoctor.com
  19. 19. A. Ovarian: .PCOS: 90% {hyperandrogenism, oligo-ovulation, PCO} .Virilizing ovarian tumors {arrhenoblastoma, hilus cell tumor, lipod cell tumor, granulosa cell tumor} .Luteoma of pregnancy { Not true tumor but an exaggerated reaction of ovarian stroma to chorionic gonadotropins. It is solid, usually unilateral & regress after labour} .Ovarian dysgenesis Turner’s syndromewww.freelivedoctor.com
  20. 20. B. Adrenal: •Cong adrenal hyperplasia •Tumors •Cushing syndrome Congenital adrenal hyperplasia www.freelivedoctor.com
  21. 21. C. PERIPHERAL •Idiopathic: Regular ovulation & normal androgen levels •Insulin resistance – HAIRAN syndrome: HyperAndrogenic Insulin-Resistant Acanthosis Nigricans – 5H syndrome acanthosis nigricans. www.freelivedoctor.com
  22. 22. •Aromatase deficiency •Glucocorticoid resistance •Hyperprolactinema can cause an increase in DHEAS. TT with bromocriptin: dec PRL & DHEAS www.freelivedoctor.com
  23. 23. Hirsutism Anabolic steroids Danazol Metoclopramide Methyldopa Phenothiazines Progestins Reserpine Testosterone Hypertrichosis Cyclosporine Diazoxide Hydrocortisone Minoxidil Penicillamine Phenytoin Psoralens StreptomycinHunter, 2003 D. Drugs www.freelivedoctor.com
  24. 24. Clinical evaluation www.freelivedoctor.com
  25. 25. Primary objective: Confirm diagnosis Determine degree Exclude life threatening diseases www.freelivedoctor.com
  26. 26. History .Virilization, psychological .Onset & duration: Rapidly progressive virilization: androgen secreting tumors .Menstrual history: PCOS, Pregnancy .Family history: Hair patterns are similar in families .Drug intake www.freelivedoctor.com
  27. 27. Examination .General: Thyroid disease, Cushing syndrome, Signs of virilization, Signs of insulin resistance e.g. acanthosis nigricans. www.freelivedoctor.com
  28. 28. .Breast: Galactorrhea {Hyperprolactinaemia can be accompanied by increase in adrenal androgen} .Pelvic: mass www.freelivedoctor.com
  29. 29. Degree of hirsutism Photography or scoring systems a. Ferriman & Gallwey(1961): 9 areas upper lip, chin, chest upper abdomen, lower abdomen, upper arm, thighs, upper back, lower back/buttocks minimal=1, mild=2, moderate=3, severe=4 >8 = hirsutismwww.freelivedoctor.com
  30. 30. Degree of hair growth (Ferriman & Gallwey,1961) www.freelivedoctor.com
  31. 31. www.freelivedoctor.com
  32. 32. b. Macnight (1964): divided the body into 7 areas: Face Neck Shoulders Chest Abdomen back www.freelivedoctor.com
  33. 33. Investigations www.freelivedoctor.com
  34. 34. Initial laboratory investigation (Speroph,2005) 1.Total testosterone: measures the ovarian & adrenal activity. 2.17 OHP: an intermediate metabolite in steroidogensis in the adrenals. DHEAS: Good marker of Adrenal A production Not essential www.freelivedoctor.com
  35. 35. •DHES is not essential (Speroff,2005) 1. If 17 OHP is normal: adrenal enzyme defect can be excluded . 2. Moderate elevations of DHES can be suppressed by suppression of ovulation. 3. DHES > 700 ug/dl is rare & is associated with high levels of T 4. Imaging of the adrenals is more cost-effective than measuring DHES. www.freelivedoctor.com
  36. 36. Testosterone (ng/dl) >200 <200 U/S of the ovary Anovulation (PRL, endom biopsy) Adenxal mass Nothing Laparotomy CT of the adrenala & ovaries Laparotomy www.freelivedoctor.com
  37. 37. Free testosterone •Good correlation with total production rate (= secretion rate + peripheral conversion rate) Good correlation with degree of virilization •Free androgen index(FAI)= TX 100 / SHBG if > 4.5: PCOS •Not done routinely in presence of hirsutism www.freelivedoctor.com
  38. 38. 3 alpha androstanediol glucuronide •Metabolite of DHT •Good marker of peripheral androgen action •Inc {increased activity of 5 alpha reductase} {end organ hypersensitivity} •Not done routinely: 1. No change in diagnosis & treatment, 2. Values overlap in 20% www.freelivedoctor.com
  39. 39. Ovarian tumors should be suspected 1. Rapid onset of virilization 2. Unilateral adenxal mass 3. Testosterone >200 ng/dl. •TVS, CT or MRI. www.freelivedoctor.com
  40. 40. Screening for late onset adrenal hyperplasia •Incidence: 1-5% •Clinical indication of ACTH stimulation test: Strong family history Severe hirsutism from puberty Flatness of the breast Hypertension Short stature www.freelivedoctor.com
  41. 41. 17 oh P(ng/dl) morning < 200 > 200 Rules out adrenal hyperplasia ACTH stimulation test (0.25 21-hydroxylase deficiency mg ACTH I.V.& 17 oh P at time zero & after 1 hour) Normal Abnormal Rules out adrenal hyperplasia Adrenal hyperplasiawww.freelivedoctor.com
  42. 42. Screening for Cushing syndrome •Rare •Indications: Centripetal obesity, buffalo hump Moon face, Virilization Pigmented stria, Hypertension www.freelivedoctor.com
  43. 43. Dexamethazone suppression test ( 1 mg orally at bed time) Free cortisol (ug/dl > 6 < 6 long term dexamethazone test Normal www.freelivedoctor.com
  44. 44.  PCOS  T LH/FSH  usually inc 2/1  Late-onset CAH 17-OH-P >200 ng/dL  Androgen-secreting ov tumor Total T >200 ng/dL  Androgen-secreting ad tumor DHEAS  >700 g/dL  Cushing syndrome Cortisol Increased  Exogenous androgen use Toxicology  screen Increased www.freelivedoctor.com
  45. 45. Treatment www.freelivedoctor.com
  46. 46. I. General II. Specific III. Local IV. Surgery www.freelivedoctor.com
  47. 47. I. General •Reassurance: •explain the condition, treatment regimen & the time required •Stop smoking •Weight reduction: {Inc SHBG: Dec FT} Keep BMI around 21 kg / m2 Dec the risk of DM & CVD www.freelivedoctor.com
  48. 48. II. Specific I. Ovarian suppression: 1. OCPs 2. Progestagen 3. GnRha II. Adrenal suppression: Corticosteroids III. Antiandrogens: 1. Spironolactone 2. Cyproterone acetate   3. Flutamide 4. Ketoconazole IV. 5 alpha reductase inhibitors: Finasteride V. Insulin sensitizer: Metforminwww.freelivedoctor.com
  49. 49. I. Ovarian suppression: 1. Oral contraceptive pills The first line of therapy Mechanism: P: suppress ov steroidogenesis E: inc SHBG: dec FT www.freelivedoctor.com
  50. 50. Best type: Avoid OCs containing norethisterone or levonorgestrel less androgenic, high estrogen Diane (cyproterone acetate), Gynera (gestodene), Marvelon (desogestrel), Cilest (norgestimate). Effect: 1. Dec T after 1-3 mo. 2. Additional benefits www.freelivedoctor.com
  51. 51. 2. Progestins Indication: If pills is contraindicated or unwanted Mechanism: inhibit ov steroidogenesis, inc clearance of androgen, inhibit 5 alpha reductase dec SHBG:inc FT Dose: DMPA: 150 mg IM / 3 mo. MPA: 30 mg PO / d Effect: comparable to OCPs www.freelivedoctor.com
  52. 52. 3. Gn Rh analogue Indications: Failure of usual management Overweight with severe hirsutism Dose: leuprolide acetate depot: IM / mo. The initial stimulatory effect can be avoided by starting therapy in the luteal phase when Gnt are already suppressed by elevated progesterone levels. Once maximal response has been obtained OCP or antiandrogen for long term suppression of hair growth. Treatment should be limited to 6 mo. www.freelivedoctor.com
  53. 53. Mechanism of action: Side effects: of estrogen deficiency Use with OCPs: {avoid problems associated with E deficiency & add benefits} Effects: highly effective & better than OCP alone www.freelivedoctor.com
  54. 54. II. Adrenal suppression: Glucocorticoids Indication: 1.High not moderate elevation of DHEAS (Sperof,2005) 2. CAH Mechanism: inhibit ACTH dependant androgen www.freelivedoctor.com
  55. 55. Dose: Nocturnal {maximal suppression of the CNS adrenal axis that peaks during sleep} Dexamethazone: 0.3 mg or 0.25 mg/ other evening Prednisone: 3 mg Adrenal hyperplasia: higher doses Effects: 1. No cortisol suppression 2. No Cushingoid side effects www.freelivedoctor.com
  56. 56. III. Antiandrogens: 1. Spironolactone (Aldactone) Dose: 100-200 mg/d remission: dec dose to 25-50 mg 100-200 mg/d from D1-D21 Mechanism : on receptor ovary & adrenals Liver kidney www.freelivedoctor.com
  57. 57. Side effects: minimal. Mens irregularities, mastalgia, feminization of male fetus, transient diuresis, hyperkalemia, ? carcinogenic Use with OCP: 1. Dramatic effect, but not impressively better 2. Prevent feminization of male fetus 3. Regular menstruation Effects: maximal by 6mo Cessation : relapse www.freelivedoctor.com
  58. 58. 2. Cyproterone acetate (androcure) Dose: 50-100 mg from D5 to D15 & EE2: 30-50 ug from D5 to D25. Dec dose after remission Mechanism: on receptors Progestational effect Weak corticosteroid effectwww.freelivedoctor.com
  59. 59. Side effects: mens irregularities, mastalgia, feminization of male fetus, loss of libido, fatigue, edema, weight gain, decrease HDLP & cholesterol, glucose intolerance. Use with EE2 or OCPs Effects: maximal by 3mo improvement in 60-90% Cessation: relapse www.freelivedoctor.com
  60. 60. 3. Flutamide (Eulexin) Indication: under tertiary center supervision Severe cases Failure of spironolactone & OCPs Dose: 250 - 500 mg/d Mechanism: antiandrogen. www.freelivedoctor.com
  61. 61. Side effects: dryness of the skin, increase appetite hepatotoxicity, expensive. It is unsuitable for treatment of hirsuitism (Speroff, 2005) Use with OCPs: 1. Add benefit 2. Avoid block androgen receptors in male fetus. Effects: Similar or better than Spironolactone www.freelivedoctor.com
  62. 62. IV. 5 alpha reductase inhibitors Finasteride (Proscar) Indication: under tertiary center supervision. Severe cases Mode of action: Inhibit 5 alpha reductase activity: blocking conversion of T to DHT. Dose: 2.5 - 5 mg /d www.freelivedoctor.com
  63. 63. Side effects: very minimal. Teratogenic Use with OCPs: To avoid risk on male fetus & added benefits. Effects: Flutamide or Spironolactone is more effective www.freelivedoctor.com
  64. 64. V. Insulin sensitizer: Metformin •PCOS IH: {insulin resistance} (Unluhizarci et al, 2004). •1500 mg/d •Dec serum insulin & T. Dec F&G score (Kazerooni et al, 2003 ; Kelly & Gordon, 2003) www.freelivedoctor.com
  65. 65. • Metformin Vs Dianette (EE2: 35 ug + cyproterone acetate: 2 mg) Dianette was more effective (Harborne et al, 2003). www.freelivedoctor.com
  66. 66. •Cyprotrone acetate was compared to (spironolactone, flutamide, finastride, GnRHa, Ketconazole): No differences in clinical outcomes (Cochrane library, 2003) www.freelivedoctor.com
  67. 67. •Spironolactone 100 mg/d is superior to finastride 5 mg/d & low dose cypr acetate 12.5 mg/d (first 10 days of the cycle) up to 12 months after the end of the treatment(Cochrane library, 2003) www.freelivedoctor.com
  68. 68. III. Local Suppress hair growth: Eflornithine Hydochloride (Vaniqa) Remove hair pigment: Bleaching Temporary depilation: shaving, chemical depilators Temporary epilation: plucking, waxing Permanent removal: Electrolysis, Laser & intense pulsed light www.freelivedoctor.com
  69. 69. 1. Suppress hair growth: Eflornithine 13.9% (Vaniqa) cream •inhibits ornithine decarboxylase (an enzyme in hair dermal papilla that is essential for hair growth). •Face, neck •Minimal s effects, can be used with other tt e.g. lasers, intense pulsed light, regrowth can take 2 ms •Must be continued indefinitely to prevent regrowth S effects: stinging, burning, tingling www.freelivedoctor.com
  70. 70. 2. Bleaching (remove hair pigment) •Hydrogen peroxide, often combined with amonia. •Face, arms •Hair lightens & softens, inexpensive •Hair discoloration, skin irritation, Lack of effectiveness www.freelivedoctor.com
  71. 71. 3. Temporary depilation (remove part of hair) a. Shaving: •All areas •Inexpensive, effective & does not cause change in hair quality, quantity or texture. •Daily need, skin irritation, quick regrowth folliculitis, time consuming, beard stubble www.freelivedoctor.com
  72. 72. b. Chemical depilators: •Break down & dissolve hair by hydrolysing disulhide bonds. •Extremities, groin, face •Quick, inexpensive, effective •Regrowth in days, skin irritation www.freelivedoctor.com
  73. 73. 4. Temporary epilation (remove the entire hair) a. Plucking: •Face, eyebrows, nipples, bikini area •Effective for small amount, inexpensive, regrowth can take weeks • Pain, skin irritation, postinflam pigmentation, folliculitis, slow, ingrown hairs, scarring www.freelivedoctor.com
  74. 74. b. Waxing: group plucking •Face, eyebrows, groin, trunk, extremities •Regrowth can take 6 weeks •Pain, postinflam pigmentation, scarring, slow, expense, irritation, folliculitis www.freelivedoctor.com
  75. 75. 5. Permanent removal (destruction of the dermal papilla) a. Electrolysis: •Needle is inserted into the hair follicle & a current is used to destroy the dermal papilla. •All areas, usually the face •May give permanent removal •Pain, scarring, painful, repeat treatments needed, time consuming, expensive, pigmentation www.freelivedoctor.com
  76. 76. b. Laser & intense pulsed light •Selective phototricholysis. A light source sufficient to penetrate to the follicular bulge & the papillae is directed at the hair by probe. •All areas •May give permanent hair reduction, efficient, painless •Dark hair required, expensive, scarring, skin pigmentation, repeated treatments usually necessary www.freelivedoctor.com
  77. 77. IV. Surgery •Tumor •LOD Discrepant & variable response. A modest & sustained improvement in 25% (Amer et al, 2002). www.freelivedoctor.com
  78. 78. Guidelines for management 1. The most desirable & effective tt is combination of OCP & antiandrogen. 2. Response is relatively slow, & at least 6 mo are required to demonstrate an improvement. 3. TT should be continued for at least 1- 2 yr. www.freelivedoctor.com
  79. 79. 4 There is no evidence that one agent is better than another & choices should be governed by cost & side effects. 5. The addition of GnRHa should be reserved for patients resistant to initial therapy. 7. Local methods should be used but reserved until hormonal therapy has reduced the rate of hair growth i.e. after 6 mo. www.freelivedoctor.com
  80. 80. Conclusion 2 Tests: T & 17 Oh P Drugs: COCs & Spironolactone Years Treatment www.freelivedoctor.com