Benha University Hospital, Egypt

Email:elnashar53@hotmail.com

Hirsutism

Outline

• Introduction

• Definition

• Causes

• Clinical evaluation

• Investigations

• Treatment

• Conclusion

Introduction

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

social acceptance}

IncidenceNot knownMediterranean> AsianAmerican females: 10%European: 5%

Cycle growth of hair

Several months 2 weeks 3 months

Types of hairLanugo

Fetal hair

VellusShort,fine, UnpigmentedBefore puberty

TerminalLong, coarse, pigmented arises from vellus hair

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

Androgen production Androstenedione

Testosterone

Adrenal DHEA Ovary

DHEAS

50% 50%50%

25% 25%

90% 10%

100%

Androgen in the blood

Male Normal female Hirsute female

Free 3% 1% 2%

Albumin 19% 19% 19%

SHBG 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 & vaginaMusculinization: Hirsutism, deepening of voice, temporal balding. Increase size of the clitoris, muscular mass & libido

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 ofLanugo, vellus or terminal hair in non-sexual sites (James et al, 2005)•CongAcquired•LocalizedGeneralized

Congenital hypertrichosis lanuginosa Drug-induced hypertrichosis

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:.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 syndrome

B. Adrenal:•Cong adrenal hyperplasia•Tumors•Cushing syndrome

Congenital adrenal hyperplasia

C. PERIPHERAL•Idiopathic: Regular ovulation & normal androgen levels•Insulin resistance– HAIRAN syndrome: HyperAndrogenicInsulin-Resistant Acanthosis Nigricans– 5H syndrome

acanthosis nigricans.

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

Hirsutism

Anabolic steroids

Danazol

Metoclopramide

Methyldopa

Phenothiazines

Progestins

Reserpine

Testosterone

Hypertrichosis

Cyclosporine

Diazoxide

Hydrocortisone

Minoxidil

Penicillamine

Phenytoin

Psoralens

StreptomycinHunter, 2003

D. Drugs

Clinical evaluation

Primary objective: Confirm diagnosis Determine degreeExclude 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 systemsa. Ferriman & Gallwey(1961): 9 areas upper lip, chin, chestupper abdomen, lower abdomen, upper arm, thighs, upper back,lower back/buttocks

minimal=1, mild=2, moderate=3, severe=4

>8 = hirsutism

Degree of hair growth (Ferriman & Gallwey,1961)

b. Macnight (1964): divided the body into 7 areas: FaceNeckShouldersChestAbdomenback

Investigations

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 productionNot 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.

Testosterone (ng/dl)

>200 <200

U/S of the ovary Anovulation

(PRL, endom biopsy)

Adenxal mass Nothing

Laparotomy CT of the adrenala & ovaries

Laparotomy

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

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%

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 breastHypertensionShort stature

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 hyperplasia

Screening for Cushing syndrome•Rare•Indications: Centripetal obesity, buffalo humpMoon face, VirilizationPigmented stria, Hypertension

Dexamethazone suppression test( 1 mg orally at bed time)

Free cortisol (ug/dl

> 6 < 6

long term dexamethazone test Normal

 PCOS  TLH/FSH

usually inc2/1

 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

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 therapyMechanism: P: suppress ov steroidogenesis E: inc SHBG: dec FT

Best type:Avoid OCs containing norethisterone or levonorgestrel less androgenic, high estrogenDiane (cyproterone acetate), Gynera (gestodene), Marvelon (desogestrel), Cilest (norgestimate).Effect: 1. Dec T after 1-3 mo. 2. Additional benefits

2. ProgestinsIndication: If pills is contraindicated or unwanted Mechanism: inhibit ov steroidogenesis, inc clearance of androgen, inhibit 5 alpha reductasedec SHBG:inc FTDose: DMPA: 150 mg IM / 3 mo. MPA: 30 mg PO / dEffect: comparable to OCPs

3. Gn Rh analogue Indications: Failure of usual managementOverweight with severe hirsutismDose: 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 deficiencyUse with OCPs: {avoid problems associated with E deficiency & add benefits}Effects: highly effective & better than OCP alone

II. Adrenal suppression: GlucocorticoidsIndication: 1.High not moderate elevation of DHEAS (Sperof,2005)

2. CAHMechanism: 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 mgAdrenal hyperplasia: higher dosesEffects: 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 mg100-200 mg/d from D1-D21Mechanism : on receptor ovary & adrenalsLiver 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 remissionMechanism: on receptors Progestational effectWeak 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 OCPsEffects: 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

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

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).

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

•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)

III. LocalSuppress 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•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 regrowthS 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 regrowthfolliculitis, 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.

A modest & sustained improvement in 25% (Amer et al, 2002).

Guidelines for management1. 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.

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.

Conclusion

2Tests: T & 17 Oh P

Drugs: COCs & Spironolactone

Years Treatment

Benha University Hospital, Egypt

Email: elnashar53@hotmail.com