Hirsutism2013

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Information about Hirsutism2013
Health & Medicine

Published on February 24, 2014

Author: elnashar

Source: slideshare.net

Hirsutism Aboubakr Elnashar Benha University Hospital, Egypt Email:elnashar53@hotmail.com

Outline • • • • • • • Introduction Definition Causes Clinical evaluation Investigations Treatment Guidelines

Introduction

Gynecological, Endocrinological, Cosmetic & Psychogenic: {great anxiety, nature of the disease, social acceptance}

Incidence Not known Mediterranean> Asian American females: 10% European: 5%

Cycle growth of hair Several months 2 weeks 3 months

Types of hair Lanugo Fetal hair Vellus Short, fine, Unpigmented Before puberty Terminal Long, coarse, pigmented arises from vellus hair Clinically, terminal hairs can be distinguished from vellus hairs primarily by their length (i.e.`0.5 cm) and the fact that they are usually pigmented.

Sites of hair Non sexual Sites Ambi-sexual Male sexual 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, Depend on Growth hormone Androgen in low concentration from from pituitary the adrenals & ovaries in females & adrenals in male upper pubic triangle, back. Androgen in high concentration

Androgen production Androstenedione 50% 50% Testosterone 25% 25% Adrenal 100% 50% DHEA 90% 10% DHEAS Ovary

Androgen in the blood Free Albumin SHBG Male Normal female Hirsute female 3% 1% 2% 19% 19% 19% 78% 80% 79%

Androgen at target cell (hair follicle) Testosterone (T) 5œ-reductase. Dihydrtestosterone (DHT) Androstanediol Glucuronide 3 alpha androstanediol glucuronide(3 alpha AG)

Definitions

Virilization: Defiminization: Atrophy of the breast & vagina Musculinization: Hirsutism, deepening of voice temporal balding. Increase: size of the clitoris, muscular mass & libido

 Main Causes of Virilization 1-CAH 2- Iatrogenic 3- Ovarian tumour 4- Cushing's syndrome.

Hirsutism: Latin hirsutus = shaggy, hairy Excessive growth of terminal hair in male sexual sites. Excessive: Socially unacceptable to the patient F& G score >8

Hypertrichosis Excessive growth of (Lanugo, vellus or terminal) hair in non-sexual sites (James et al, 2005) •Cong Acquired Drug-induced hypertrichosis •Localized Generalized Congenital hypertrichosis lanuginosa

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}.

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.

Causes

A. Ovarian: 1. PCOS: 90% 2. Tumors: 0.5% Virilizing ovarian tumors Luteoma of pregnancy 3. Dysgenesis B. Adrenal:5% 1.Cong adrenal hyperplasia 2.Tumors 3.Cushing syndrome C. Peripheral 1. Idiopathic: Regular ovulation & normal androgen levels 2. Insulin resistance – HAIRAN syndrome: HyperAndrogenic Insulin-Resistant Acanthosis Nigricans – 5H syndrome

A. Ovarian: 1. PCOS: 90%

 Rotterdam Criteria Of PCOS, 2003 2 out of 3 features are present: 1. Oligomenorrhoea and or Anovulation 2. Clinical Hyperandrogenism and/or hyperandrogenemia. 3. Polycystic ovaries (U/S). After exclusion of other etiologies.

 Clinical Hyperandrogenism 1. Hirsutism: The primary clinical indicator of androgen excess . 2. Acne : Potential marker 3. Androgenic alopecia: Poor marker unless with Oligomenorrhoea.  Hyperandrogenemia • FT) or FTI) are the more sensitive methods • Routine measurement of Androstenedione: are not recommended. • DHEAS is raised in small fraction of patient with PCOS .

Hirsutism Hirsutism

Hirsutism

Hirsutism Acne

PCOS with hirsutism

varian orgin. Lateral mammary hirsutism, score 1

mild but obvious female pattern hair loss Female androgenic alopecia Frontal and temporal hair loss Grading scale for female pattern hair loss

 Rotterdam U/S Criteria of PCOS At least one of the following: • 12 or more follicles measuring 2–9 mm in diameter • increased ovarian volume (>10 cm3).  The distribution of follicles and a description of the stroma are not required for diagnosis.  The presence of a single PCO is sufficient to provide the diagnosis.

hirsutism in a young woman with polycystic ovary syndrome. Note the acne lesions and excessive hair on her face and neck.

PCOS with hirsutism (Ferriman and Gallwey score 4) on the abdomen

Examples of hirsutism affecting the back, chest, and abdomen

2. Ovarian Tumors:0.5% 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} 3. Ovarian dysgenesis

Luteoma Uterus and adnexa during caesarian section—both ovaries were enlarged (mean diameter 8 cm).

B. Adrenal:5% 1.Cong adrenal hyperplasia 2.Tumors 3.Cushing syndrome Congenital adrenal hyperplasia Centipetal obesity in Cushing's syndrome Androgen secreting tumor

Adrenal SAHA. Central hirsutism, score 2 Adrenal SAHA. Severe papulo-pustular acne and central hirsutism

Cushing's Syndrome

Clinical manifestations % Centripetal obesity 79-97 Facial plethora 50-94 Glucose intolerance 39-90 Weakness, proximal myopathy 29-90 Hypertension 74-87 Psychological changes 31-86 Easy bruisability 23-84 Hirsutism 64-81 Oligomenorrhea or amenorrhea Acne, oily skin 55-80 26-80 Abdominal striae 51-71 Ankle edema 28-60 Backache, vertebral collapse, fracture rare

Cushing’s Syndrome One should be aware of the possibility of Cushing’s syndrome in women with stigmata of the : PCOS & Obesity as it is a disease of insidious onset and dire consequences

30-year-old woman with Cushing's disease showing round, plethoric "moon" face, facial hirsutism, and increased supraclavicular fat pads Forearm of a women man with Cushing's disease showing multiple ecchymoses due to minimal trauma.

C. PERIPHERAL 1.Idiopathic: Regular ovulation & normal androgen levels 2.Insulin resistance – HAIRAN syndrome: HyperAndrogenic Insulin-Resistant Acanthosis Nigricans – 5H syndrome acanthosis nigricans.

3. Aromatase deficiency 4. Glucocorticoid resistance 5. Hyperprolactinema can cause an increase in DHEAS. TT with bromocriptin: dec PRL & DHEAS

D. Drugs Hirsutism Anabolic steroids Danazol Metoclopramide Methyldopa Phenothiazines Progestins Reserpine Testosterone Hypertrichosis Cyclosporine Diazoxide Hydrocortisone Minoxidil Penicillamine Phenytoin Psoralens Streptomycin Hunter, 2003

Clinical evaluation

Primary objective: 1.Confirm diagnosis 2.Determine degree 3.Exclude life threatening diseases

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

Examination .General: Thyroid disease, Cushing syndrome, Signs of virilization, Signs of insulin resistance e.g. acanthosis nigricans.

.Breast: Galactorrhea {Hyperprolactinaemia can be accompanied by increase in adrenal androgen} .Pelvic: mass

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, >8 = hirsutism 15 = organic cause severe=4

Degree of hair growth (Ferriman & Gallwey,1961)

b. Macnight (1964): divided the body into 7 areas: Face Neck Shoulders Chest Abdomen back

Investigations

Total testosterone: measures the ovarian & adrenal activity. When testing for elevated androgen levels: measure an early morning plasma total testosterone level as the initial test.

Free testosterone Good correlation with total production rate (= secretion rate + peripheral conversion rate) Good correlation with degree of virilization If the plasma total testosterone is normal in the presence of risk factors for hyperandrogenism or the presence of hirsutism that progresses despite therapy: measuring an early morning plasma total and free testosterone Free androgen index(FAI)= TX 100 / SHBG if > 4.5: PCOS •Not done routinely in presence of hirsutism

17 OHP: an intermediate metabolite in steroidogensis in the adrenals. In patients with a high likelihood of congenital adrenal hyperplasia [positive family history, member of a high-risk ethnic group such as Ashkenazi Jews (prevalence 1 in 27), Hispanics (1 in 40), and Slavics (1 in 50)], we recommend measurement of an early morning follicular phase level of 17-hydroxyprogesterone.  DHEAS: Good marker of Adrenal A production Not essential

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.

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%

Endocrine Society, 2008

Testosterone (ng/dl) >200 <200 U/S of the ovary Anovulation (PRL, endom biopsy) Adenxal mass Nothing Laparotomy CT of the adrenala & ovaries Laparotomy

Ovarian tumors should be suspected 1. Rapid onset of virilization 2. Unilateral adenxal mass 3. Testosterone >200 ng/dl. •TVS, CT or MRI.

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

17 oh P(ng/dl) morning < 200 > 200 Rules out adrenal hyperplasia 21-hydroxylase deficiency ACTH stimulation test (0.25 mg ACTH I.V.& 17 oh P at time zero & after 1 hour) Normal Rules out adrenal hyperplasia Abnormal Adrenal hyperplasia

Screening for Cushing syndrome •Rare •Indications: Centripetal obesity, buffalo hump Moon face, Virilization Pigmented stria, Hypertension

Dexamethazone suppression test ( 1 mg orally at bed time) Free cortisol (ug/dl >6 long term dexamethazone test <6 Normal

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

Treatment

Androgen Excess Society,2012

Lines of treatment I. General II. Specific III. Local IV. Surgery

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

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: Metformin

I. Ovarian suppression 1. Oral contraceptive pills The first line of therapy Mechanism: P: suppress ov steroidogenesis E: inc SHBG: dec FT

Best type: Avoid OCs containing norethisterone or levonorgestrel less androgenic or antiandrogenic high estrogen Diane (cyproterone acetate), Yasmin (Drospirenone) Clordion, Gestafortin, Lormin, NonOvlon, Normenon, Verton (Chlormadinone acetate) Gynera (gestodene), Marvelon (desogestrel), Cilest (norgestimate). Effect: 1. Dec T after 1-3 mo. 2. Additional benefits

We do not suggest one particular OCP over another for treating hirsutism (Endocrine Society, 20108) most androgenic progestin: Levonorgestrel, norethisterone low androgenicity: norgestimate and desogestrel progestins with antiandrogenic activity drospirenone and CPA One small trial did not demonstrate a difference in hirsutism efficacy between an OCP containing levonorgestrel and one containing desogestrel Levonorgestrel may adversely affect metabolic biomarkers when compared with other less androgenic progestins, but there are no data to suggest that these effects are associated with adverse clinical outcomes.

OCPs containing either 30–35 g ethinyl estradiol or the lower-dose 20-g preparations may be used for suppression of ovarian androgens. There are no clinical trials of 20-g OCPs for hirsutism, but these lower-dose preparations appear to be as effective as the 30- to 35-g preparations for acne.

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

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.

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

II. Adrenal suppression Glucocorticoids Indication: 1.High not moderate elevation of DHEAS (Sperof,2005) 2. CAH Mechanism: inhibit ACTH dependant androgen

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

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

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

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 effect

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

3. Flutamide (Eulexin) Indication: under tertiary center supervision Severe cases Failure of spironolactone & OCPs Dose: 250 - 500 mg/d Mechanism: antiandrogen.

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 We do not recommend one antiandrogen over another, except that we recommend against the use of flutamide.

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

Side effects: very minimal. Teratogenic Use with OCPs: To avoid risk on male fetus & added benefits. Effects: Flutamide or Spironolactone is more effective Drugs in this class: Finasteride 5 mg (Proscar} Finasteride 1 mg (Propecia) Dutasteride (Avodart)

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) •Metformin Vs Dianette (EE2: 35 ug + cyproterone acetate: 2 mg) Dianette was more effective (Harborne et al, 2003).

Cochrane library (2003) •Cyprotrone acetate was compared to (spironolactone, flutamide, finastride, GnRHa, Ketconazole): No differences in clinical outcomes 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

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

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  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

2. Bleaching (remove hair pigment) •Hydrogen peroxide, often combined with amonia. •Face, arms Hair lightens & softens, inexpensive Hair discoloration, skin irritation, Lack of effectiveness

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

b. Chemical depilators: •Break down & dissolve hair by hydrolysing disulhide bonds. •Extremities, groin, face Quick, inexpensive, effective Regrowth in days, skin irritation

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

b. Waxing: group plucking •Face, eyebrows, groin, trunk, extremities Regrowth can take 6 weeks Pain, postinflam pigmentation, scarring, slow, expense, irritation, folliculitis

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

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

IV. Surgery •Tumor •LOD Discrepant & variable response. Modest & sustained improvement in 25% (Amer et al, 2002).

Guidelines Endocrine Society 2008 Diagnosis of hirsutism 1. We suggest against testing for elevated androgen levels in women with isolated mild hirsutism because the likelihood of identifying a medical disorder that would change management or outcome is low (2).

2. We suggest testing for elevated androgen levels in women with (2) • Moderate or severe hirsutism • Hirsutism of any degree when it is sudden in onset, rapidly progressive, or when associated with any of the following: – menstrual irregularity or infertility – central obesity – acanthosis nigricans – rapid progression – clitoromegaly

Treatment of hirsutism 1. For women with patient-important hirsutism despite cosmetic measures, we suggest either pharmacological therapy or direct hair removal methods (2). The choice between these options depends on (a)patient preferences, (b) The extent to which the area of hirsutism that affects wellbeing is amenable to direct hair removal, and (c) access to and affordability of these alternatives.

2.Pharmacological treatments a. Monotherapy For the majority of women, we suggest oral contraceptives to treat patient-important hirsutism (2) because of its teratogenic potential, we recommend against antiandrogen monotherapy unless adequate contraception is used (1| ). For women who cannot or choose not to conceive, we suggest the use of either oral contraceptive preparations (OCPs) or antiandrogens The choice between these options depends on patient preferences regarding efficacy, side effects, and costs.

We suggest against the use of flutamide therapy (2). We suggest against the use of topical antiandrogen therapy for hirsutism (2). We suggest against using insulin-lowering drugs as therapy for hirsutism (2).

For women with hirsutism who do not have classic or nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CYP21A2), we suggest against glucocorticoid therapy (2). We suggest glucocorticoids for women with hirsutism due to non classic congenital adrenal hyperplasia (NCCAH) who have a suboptimal response to OCPs and/or antiandrogens, cannot tolerate them, or are seeking ovulation induction (2).

We suggest against using GnRH agonists except in women with severe forms of hyperandrogenemia, such as ovarian hyperthecosis, who have a suboptimal response to OCPs and antiandrogens (2). For all pharmacologic therapies for hirsutism, we suggest a trial of at least 6 months before making changes in dose, changing medication, or adding medication (2).

b. Combination therapy If patient-important hirsutism remains despite 6 or more months of monotherapy with an oral contraceptive, we suggest adding an antiandrogen (2).

3. Direct hair removal methods For women who choose hair removal therapy, we suggest laser/photoepilation (2). For women undergoing photoepilation therapy who desire a more rapid initial response, we suggest adding eflornithine cream during treatment (2). For women with known hyperandrogenemia who choose hair removal therapy, we suggest pharmacologic therapy to minimize hair regrowth (2).

Benha University Hospital, Egypt Email: elnashar53@hotmail.com

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