HIRSUTISM

📌Definition - Excess terminal hair in a woman that occurs in a male pattern

📌Sites - beard, moustache, chest

📌May occur with or without a detectable increase in androgens

EPIDEMIOLOGY

📌Incidence-5–10% women

📌Age-Usually after the onset of puberty

📌If ectopic androgens - can occur at any age

📌Ethnicity-More common in whites

Pathogenesis

📌The major androgens in females:-

*Dehydroepiandrosterone sulfate (DHEA-S)

*Dehydroepiandrosterone (DHEA)

*Androstenedione

*Testosterone

*DHT

DHEA-S, DHEA, and androstenedione - proandrogens

📌These hormones exert their androgenic effects only after conversion to testosterone

📌Sebaceous glands contain enzymes that help in testosterone synthesis:

3β-hydroxysteroid dehydrogenase

17β-hydroxysteroid dehydrogenase

📌Testosterone is converted in the hair follicle to 5-dihydrotestosterone by the enzyme 5-α reductase

CAUSES OF HIRSUTISM

1) Hyperandrogenic hirsutism

*Polycystic ovarian syndrome (72–82%)

*Androgen secreting tumours (0.2%)

*Nonclassical congenital adrenal hyperplasia (2–4%)

*Idiopathic hyperandrogenemia (6–15%)

2) Non-hyperandrogenic hirsutism

*Medications

*Cushing’s syndrome

*Hyper/hypothyroidism

*Hyperprolactinemia

*Acromegaly

*Pregnancy

*Postmenopausal

3) Idiopathic hirsutism (4–7%)

POLYCYSTIC OVARIAN SYNDROME (PCOS)

📌Most common cause of hirsutism

📌72–82% of hirsutism

📌In India, prevalence - 6% to 9.13%

📌Increased LH levels

📌LH : FSH ratio > 2.17

📌High LH levels

📌Stimulation of the ovarian theca cells to produce androgens

📌Causing hyperandrogenism and hirsutism,hyperinsulinemia and insulin resistance

📌Increased conversion of progesterone to androstenedione in ovaries happens which ultimately gets converted to testosterone

📌Hyperinsulinemia - directly stimulate the ovarian androgen production by binding to IGF-I

📌2003 Rotterdam consensus criteria:

1)Clinical (acne or hirsutism) and/ or biochemical hyperandrogenaemia (measured elevated androgen levels).

2)Menstrual irregularity.

3)Polycystic ovarian morphology on USG.

2/3 🡪 PCOS

ANDROGEN  SECRETING  TUMORS

📌Rare cause of hirsutism

📌Ovarian or adrenal tumors can cause hirsuitism

📌Characterized by very high androgen levels (serum testosterone >200 ng/ml)

📌Rapid onset of hirsutism,Virilization with a palpable mass per abdomen

📌Features of virilization

• Deepening of voice

• Clitoromegaly

• Increased muscle mass

• Reduced breast size

• Amenorrhea

• Male pattern baldness

• Acne

• Hirsutism

• Increased libido

📌Adrenal tumors can also present with  rapid onset of Cushing’s syndrome

NON CLASSICAL CONGENITAL  ADRENAL  HYPERPLASIA    (CAH)

📌Late form of CAH

📌Due to the deficiency of 21-hydroxylase - causing increased levels of 17-hydroxyprogesterone and androstenedione

📌Other features: –

*Menstrual dysfunction

*Infertility

*Oligo-anovulation

IDIOPATHIC  HYPERANDROGENISM

📌Characterized by normal ovarian morphology and regular menstrual cycles with hyperandrogenism

📌No other explainable causes

📌Hormonal profile - similar to PCOS

📌Main source of androgens - ovaries

📌Accounts for 6–15% cases

MEDICATIONS CAUSING HIRSUTISM

📌Systemic steroids

📌Danazole

📌Minoxidil

📌Cyclosporine

📌Testosterone

📌Progestin only OCPs

📌Tamoxifene

📌Clomiphene

📌Phenytoin

ENDOCRINOPATHIES

1. Cushing’s syndrome

📌Disorder of adrenocorticotrophic hormone (ACTH) secretion

📌Results in increased cortisol secretion presenting with hypertension, Moon face, Abdominal stria, Irregular menses and Weight gain

2. Hyperthyroidism/hypothyroidism

📌Because androgen biosynthesis is regulated by thyroid hormones

3. Hyperprolactinemia

📌Rare cause of hirsutism

📌Other features –Amenorrhea, Infertility, Galactorrhea

4. Acromegaly

📌Mechanism of hirsuitism - poorly understood

📌GH 🡪 reduces SHBG levels – which in turn causes increased free testosterone levels

📌GH along with the high IGF-1 levels, hyperinsulinemia, and insulin resistance

📌Increases ovarian androgen production 🡪 hirsutism

PREGNANCY AND POST-MENOPAUSE

📌Pregnancy

*Characterized by biological hyperandrogenism

*High levels of testosterone are due to:-Adrenal sources, Decreased renal clearance and Stimulation by human chorionic gonadotropin

📌Post-menopause:Absence of ovarian estrogen production makes it  a relative state of hyperandrogenism

IDIOPATHIC  HIRSUTISM

📌Presence of hirsutism along with normal ovulatory function & normal circulating androgen levels

📌Not associated with virilization

📌10–20% cases

📌Exact pathogenesis - not fully understood

📌Increased sensitivity of the hair follicles to normal androgen levels

📌Higher 5-α reductase activity noted

📌Alteration in the androgen receptor function also is a proposed mechanism

HAIR-AN SYNDROME

📌HyperAndrogenic Insulin Resistant Acanthosis Nigricans

📌Inherited condition characterized by severe insulin resistance

📌Diagnostic criteria :

*Insulin levels - greater than 80 μu/ml basally and/or

*Greater than 500 μu/ml after an oral glucose challenge

📌Ovaries - enlarged and hyperthecotic -due to the effect of insulin on the theca cells

📌Symptoms-Acne, Obesity, Acanthosis nigricans, Hirsutism

SAHA   SYNDROME

📌Seborrhea, Acne, Hirsutism, and Androgenetic alopecia

📌Classified into four types according to their etiology:

(1) idiopathic

(2) adrenal

(3) ovarian

(4) hyperprolactinemic SAHA

EVALUATION OF A WOMAN WITH  HIRSUTISM

📌History and Clinical examination:-

The following should be specifically looked for:-

- features of hyperandrogenism

-Seborrhea, acne and androgenetic alopecia

-Cutaneous features of insulin resistance

-Acanthosis Nigricans

-Cutaneous features of Cushing’s syndrome

-Weight gain, striae, buffalo hump, moon face, redistribution of fat, proximal myopathy

-Signs of virilization such as clitoromegaly

-Record the waist circumference, blood pressure, and body mass index

-Systemic examination - palpation of the abdomen and pelvis - mass per abdomen

-Visual field defects - pituitary adenoma

-Prolactinoma - spontaneous or expressible galactorrhea

ASSESSMENT OF HIRSUTISM

📌Modalities of assessment- Objective and Subjective

*Objective modality of assessment-Vellus index

(Ratio of vellus hairs in a sample of around 100 shaved hairs)

*Subjective modalitiy is the Visual scoring of terminal hairs in specific body areas

Modified Ferriman Gallwey scoring system

<8 – Mild hirsutism

8 – 14 – Moderate hirsutism

≥15 – Severe hirsutism

INVESTIGATIONS

📌Aim:-

**Identify those with significantly high androgen levels

**To rule out underlying androgen secreting tumors

📌Hormonal assessment

📌Ovulatory assessment

📌Other blood tests-Fasting plasma insulin, FBS, LH, FSH, TSH, prolactin,DHEA-S, SHBG, Testosterone

Adrenal malignancy – DHEA-S > 8000ng/mL

Ovarian malignancy – DHEA-S levels normal

📌USG to ruleout PCOS

📌CT/MRI to rule out ovarian or adrenal tumors

📌Cranial MRI to rule out prolactinemia

MANAGEMENT OF HIRSUTISM

📌Measures aimed at:-

Removing unwanted terminal hair

Reducing the androgen drive to vellus–terminal conversion

📌Addressing other issues:-

Menstrual disturbances

Infertility

Cardiac risk

Type 2 diabetes

Obesity

📌Life style modifications:-

Exercise

Behavioural therapy

Diet

📌PHARMACOLOGICAL THERAPY

OCPs

Anti-androgens

📌Other adjuvant therapies-

Insulin sensitizers

Glucocorticoids

GnRH analogs

📌ORAL CONTRACEPTIVE PILLS:-

*OCPs - estrogen (ethinyl estradiol 0.03–0.035 mg)-progestin

*Considered safe and cost effective

*Progestins with low androgenic activity-Norethindrone acetate, Ethynodiol diacetate, Desogestrel, Gestodene, Norgestimate

*Mechanism of action of OCPs in treatment of hirsutism:-

-Reducing the ovarian androgen production by suppressing LH and FSH

-Decreases adrenal androgen production

-Antagonizes 5-α reductase and androgen receptors

Estrogen in OCPs - increases SHBG, thus decreasing free testosterone

*Side effects of OCPs: –

Irregular vaginal bleeding

Breast tenderness

Mild fluid retention

Weight gain

Gastrointestinal upset

Risk of thromboembolism

Mood changes

Abnormal liver function tests

Loss of libido

📌ANTI-ANDROGENS TO TREAT HIRSUTISM

Spironolactone

Drospirenone

Cyproterone acetate

Finasteride

Flutamide

Bicalutamide

📌SPIRONOLACTONE:-

Androgen receptor antagonist

Dose-dependent and competitive androgen receptor inhibitor

Inhibits 5-α reductase activity

Dose varies from 50 to 200 mg/day

At the start of treatment, a dose of 50–100 mg/day

Increased by 25 mg/day once in 3 months

Takes 6 months for effective therapy

Side effects – Fatigue, Postural hypotension, Headache, Syncope

Absolute contraindications - Pregnancy, Hyperkalemia, Abnormal uterine bleeding, Renal insufficiency

Should not be used with-Other potassium sparing diuretics

Serum electrolytes and blood pressure-Measured every 4 weeks in the initial months

Contraception - required

📌CYPROPTERONE ACETATE:-

17-hydroxyprogesterone acetate derivative.

Progestogenic effects.

Competes with testosterone and DHT for binding to the androgen receptors.

Causes gonadotropin suppression.

Decreases the testosterone and androstenedione levels.

Doses of 50–100 mg/day combined with 30–35 μg of ethinyl estradiol.

Side effects: Loss of libido, Adrenal insufficiency

📌DROSPIRINONE

Unique progestin derived from spironolactone

Anti-androgenic and anti mineralocorticoid activities similar to progesterone

No estrogenic, androgenic, glucocorticoid, or anti-glucocorticoid activity

Binds to the androgen receptors 🡪 inhibits ovarian androgen synthesis.

Side effects – Migraine, Depression, Change in weight, Nausea

📌FINASTERIDE

Inhibits the type 2 isoenzyme of 5-α reductase

Reduces DHT levels

Dose 2.5 mg/day

Teratogenic - Contraception required

No other major adverse effects reported

📌FLUTAMIDE:-

Nonsteroidal androgen receptor antagonist

Used off-label

Dose varies from 250 to 750 mg/day

Serious side effect – liver toxicity

Other side effects: Nausea, Diarrhea, Appearance of greenish urine,Vomiting, Dry skin

Not recommended as first-line therapy

📌BICALUTAMIDE

Newly developed nonsteroidal pure antiandrogen drug

Idiopathic hirsutism and PCOS -low dose (25 mg/day)

Liver abnormalities may occur at a dose of 50 mg/day

📌INSULIN SENSITISERS - METFORMIN

Treatment of hirsutism associated with hyperinsulinemia and insulin resistance

Reduce levels of insulin

Increase insulin sensitivity

Normalization of menstruation

Result in weight loss

Improvement in lipid profiles

📌TOPICAL MEDICATIONS

Eflornithine

Finasteride

📌TOPICAL EFLORNITHINE

Topical eflornithine 13.9% cream - FDA approved

MOA - irreversibly inhibiting L-ornithine decarboxylase enzyme

Impedes cellular growth and differentiation in the hair follicle

Twice a day application for 8 weeks

Does not remove the hairs, but, Miniaturizes the hairs, Makes them fine

Side effects - redness, stinging, pruritus

Safety in pregnancy - not documented

Disadvantages - Regrowth of hair to the pretreatment levels within 8 weeks of discontinuation

Nonresponse - seen in 30% of patients

📌TOPICAL FINASTERIDE

5-α reductase inhibitor

Finasteride 0.25% cream

Twice a day for 6 months

Disadvantages – Cost

Requirement of concurrent contraception

📌PHYSICAL METHODS OF HAIR REMOVAL

Shaving and plucking - Most widely used.

Various means of plucking hairs - use of tweezers, waxing and threading

📌DEPILATORY CREAMS

Contain thioglycolates that dissolve sulphur bonds within the keratin molecules - making the hair gelatinous

📌ELECTROEPILATION(ELECTROLYSIS)

More permanent method

Fine wire is slid into the hair follicle - ablated by an electric current using galvanic electrolysis, thermolysis or a combination of the two (‘blend’)

A slow method most suited to relatively small areas of hirsutism

📌BROAD BAND IPL

Represents a relatively cheaper technology

Preferred in less pigmented hair.

Likely to achieve some of the benefits of laser therapy

📌LASER HAIR REMOVAL

📍Diode lasers work best

The gap between treatments allows those hairs initially in telogen to move into anagen

Selective delivery of energy to the hair follicle, specifically to the bulge region

Cause destruction to the follicle stem cells

Additional melanin targets – Follicular hair shaft, Outer root sheath of the infundibulum, Hair bulb matrix.

Melanin in the hair matrix - absorbs wavelengths between 600 to 1100 nm

📍Long‐pulse ruby (694 nm)

📍Long‐pulse alexandrite (755 nm)

📍Long‐pulse diode (808 nm)

📍Long‐pulse nd:yag (1064 nm)

📍Intense pulsed light (IPL, 590–1200 nm)

Energy is converted into heat - diffuses laterally beyond the actual follicle to the biological ‘target’

Thermal relaxation time of a hair follicle is 10–50 ms - pulse duration should be adjusted to match these parameters

Extension of the pulse duration beyond the thermal relaxation time – Delivery of thermal damage to the surrounding non‐pigmented stem cells

Likely to induce more consistent follicular destruction

Lighter skin phototypes (I–III) – 755 nm alexandrite, 808 nm diode laser

Darker skin phototypes (IV–VI)- 1064 nm Nd:YAG laser

Ideal patient for hair removal – individual with lighter skin (phototypes I–III) and dark brown to black hair

Fluence - titrated up if necessary

Typically, three to eight treatments spaced at 6–10‐week intervals

Expected acute phase response to treatment : A perifollicular reaction - erythema and focal oedema surrounding the follicle

CONCLUSION

📌Hirsutism requires in depth clinical evaluation & investigations.

📌Main pharmacological treatment – OCP.

📌Addition of antiandrogens if response is suboptimal.

📌Hair removing methods – shaving, waxing, plucking – effective but temporary.

📌Lasers, photoepilation & electrolysis – effective for long term hair removal but are expensive.