16 Hirsutism

HirsutismDr Fida Al-Asali

Hirsutism Increase in terminal hair: face, chest,

back, lower abdomen, inner thighs of a woman◦Androgen excess◦ Increased DHT

Hypertrichosis: Generalised non-sexual vellus hair

growth◦hereditary◦medication◦malignancy

Male features: Deepening voice, frontal balding, incr.

Muscle mass, clitoromegaly, breast atrophy, male body habitus

◦ Androgen excess◦ Adult onset CAH “21-hydroxylase

deficiency”◦ XY females◦ Iatrogenic◦ Cushing’s syndrome and acromegaly

Virilization

Adult hair 2 types Hair growth is dynamic Anagen - growing phase active mitoses in basal matrix e.g. scalp hair, face Catagen – rapid involution phase Telogen –Resting phase

Physiology

Androgens initiate growth and increase rate of

mitoses in all but scalp hair Estrogens : slow rate & initiation of

growth Progestins : minimal direct effect Pregnancy : can increase the

synchrony of hair growth, periods of growth & shedding

Endocrine

Factors influence Hair Growth

Local skin temperature Blood flow Summer > Winter

Non hormonal factors

Dehydroepiandrosterone (DHEA)-a weak carbon-5 androgen secreted principally by the andrenal gland

DHEAS almost 100% by adrenal gland Androstendione (A) - a weak carbon-4 androgen

secreted in equal amounts by the adrenal glands and ovaries

Testosterone (T)- a potent carbon-4 androgen secreted by the adrenal glands and ovaries and produced in adipose tissue from the conversion of androstendione

Dihydrotestosterone (DHT)-even more potent than testosterone.The conversion from testosterone is the result of action of 5 -a reductase

Main androgens

Ovary T, A T Theca cell (LH, insulin/IGF-1) Granulosa cell E

Adrenal A, DHEA

T 5α reductase DHT

Production rate in the normal female is 0.2 to 0.3 mg/day

Normal total testosterone concentration in serum is below 0.8ng/ml

◦50% peripheral conversion◦25% ovary( midcycle)◦25% adrenal

Testosterone

Testosterone transported:

Normal women Hirsute women

80% SHBG 79% SHBG

19% Albumin 19% Albumin

1% Free 2% Free

Cutaneus manifestation of hyperandrogenism

Women have male-pattern hair growth In areas :

upper lip chinsideburn area upper neck chestupper armlower abdomenintergluteal regionperineumthigh

Hirsutism

Hirsutism rating scale by Ferriman Gallwey>8 points - hirsutism

Variable – ethnic Higher in Africans & Mediterranean 5-10% of reproductive age

Hirsutism: Incidence

NOT a diagnosis but

a manifestation

Hirsutism

PCOS 75% Idiopatic hirsutism 15%Adrenal hyperplasia 3%Cushing’s disease 1%Hyperprolactinemia 1%Tumor of the ovary 1%Tumor of the adrenal 0,1%After medications 1%

Causes of hyperandrogenism:

Non Neoplastic vs Neoplastic

oCushing’s Syndrome Glucocorticoid excess by excessive ACTH

secretion with concomitant rise in androgen intermediates. adenomas, paraneoplastic syndromes,

adrenal tumors. SX: hirsutism, acne, menstrual irreg, etc…..

oCAH 21-alpha-hydroxylase = no GC/aldo, salt

wasting and adrenal insuff at birth. Female infants – ambig genitalia Adult onset – mild virilization and menstrual irreg

Adrenal Disorders

◦3B-hydroxylase & 3B-HSD Precursors shunted to testosterone & androstenedione

Females = hirsutism/virilization/cortisol def. & varying degrees MC excess/deficiency with respective enzyme deficiencies

Adrenal Disordres Cont

Non-neoplasticPCOS

Cycle of excess androgenic stimulation of LH cystic ovarian changes, chronic anovulation/amenorrhea, virilization, hirsutism, obesity,

LH-FSH ration > 2:1

Theca Lutein CystsTheca internal cells normally Androstenedione & TCysts excess androgens during nl or molar pregnancyHirsuitisms & ocassional virilization

Stromal Hyperplasia & HyperthecosisHyperplastic stroma or foci increased activityHirsuitism & virilizatoin with increased ovarian size

Ovarian Disorders

Neoplastic Functional Ovarian Tumors• Produce variable amounts of androgen Sex-cord mesenchymal tumors, Sertoli-Leydig

tumors, granulosa-theca tumores, hilar cell tumors, luteomas…..

Non-functional Ovarian Tumors Do not secrete androgens themselves but may stimulate proliferation in adjacent ovarian stromaKrukenberg’s tumor, cystademona…

A variety of drugs decrease SHGB, resulting in increased levels of free T to interact at cellular level.

Androgens and corticosteroids also SHBG

Examples: anabolic steroids, minoxidil, phenytoin, diazoxide, cyclosporin, danazol.

Drugs & Exogenous Hormones

History-detailed• Onset-duration, severity• Other symptoms of virilization• Menstrual hx• Infertility• Hx suggestive of other medical

conditions- • Cushing’s syndrome or hypothyroid

Medications

Clinical assessment of hirsutism

Evaluate severity using Ferriman-Gallwey scoring system

Signs of virilization Acanthosis nigricans Pelvic exam

P/E

Ferriman–Gallwey scoring system

Used to quantify the amount of hair growth.

Each area of the body is scored for the amount of hair.

6–8 :mild 8–15: serious > 15: overt

T, androstenedione, DHEAS ◦ adrenal source◦ Abdominal CT & medical tests r/o CAH or Cushings

DEAHS normal or minimally elevated◦ Ovarian source◦ Pelvice U/S r/o tumor

Elevated LH-FSH ratio◦ Ratio>3 suggests PCOS

Rapid Onset Virilization w/ T>200ng/dL◦ May indicate ovarian neoplasm

Investigations

Baseline 17-OH progesterone Dexamethasone suppression test Pelvic imaging

If androgen excess NOT readily evident: MRI, venous blood draws, Free T, 5-alpha reductase activity to check for peripheral T conversion

Diagnosis & Evaluation

Women with greater activity of 5 -a reductasein in the skin

Normal ovulationRegular menstrual cycleNormal hormone concentrations

Constitutional hirsutism

Mechanical removal of hair

◦ Shaving, plucking, bleaching, depilation◦ Electrolysis achieves permanent hair

removal. If done poorly, it maybe associated with scarring.

◦ Laser depilation is most effective in women with pale skin and dark hair.

Treatment

Adrenal nonneoplastic: pharmacological androgen suppression◦ Prednisone 5mg qhs◦ Antiandrogens such as spirinolactone

Ovarian nonneoplastic:◦ OCPs suppress LH/FSH and SHBG◦ Progesterone alone suppresses LH and T

catabolism◦ Gonadotropin releasing hormone agonists

suppress LH/FSH but requires estrogen replacement

Treatment

Suppression of LH and therefore suppression of androgen production by the ovarian theca cells

Increases production of SHBG, which in turn decreases free circulating androgens

Decreases androgen secretion by the adrenal gland

Progestogens can possess androgen activity in laboratory studies, but clinically there is no

difference in the clinical suppression of androgenic symptoms.

The best hormonal contraceptive is the one that is best tolerated by the individual.

COCP for hirsutism

The combination of drospirenone 3 mg and ethinyl oestradiol 30 mg (Yasmin) given cyclically is also effective for the treatment of hirsutism and acne associated with PCOS

Yasmin

2nd line monotherapy or in combination with OCP in severe cases

Work to suppress hirsutism by competitive inhibition at the level of the testosterone receptor.

All are equally effective. Should be combined with effective

contraceptive to avoid feminization of a male fetus. Cyproterone acetate SpironolactoneFlutamide Finasteride

Antiandrogens

The combination of an anti-androgen, cyproterone acetate (CPA, 2 mg/day) and ethinyl oestradiol (35 µg/day) (Diane) is very effective treatment when given cyclically.

The addition of CPA 10–100 mg/day on the first 10 days of the combined medication has proved effective for more severe cases.

Mechanism of action:1. suppression of LH release by the anterior

pituitary2. Blocks androgen receptors3. as a progestogen in suppressing the action

of 5a reductase4. in combination with ethinyl oestradiol, it

increases SHBG concentrations.

Cyproterone acetate

Blocks androgen receptors Inhibits 5α reductaseDose 50-200mg/day between days 4

and 22 of cycle ; 50-75mg/day- mild to moderate hirsutism; 100-200mg/day severe hirsutism

Effect is dose-dependentS.E diuresis Postural hyptension Menstrual irregularities Hyperkalemia

Spironolactone(aldosteron antagonist)

used in prostate cancer ,It inhibits the binding of 5a-DHT to androgen receptor)

Potent androgen receptor antagonistDose 250 mg or 500 mg/day. S.E hepatotoxicity, which may be

severe and the incidence seems to increase with higher doses.....liver function!.

Flutamide

Inhibitor of 5α reductaseDose :1–5 mg/dayS.E : mild GI disturbances, dry skin,

decreased libidoTeratogenic Consider effective contraception

Finasteride

Tpical antiprotozoal Acts locally to inhibit hair follicle

ornithine decarboxylase enzyme Improvement within few weeks Regrowth of hair when stopped S.E obstruction of sebaceous glands

and hence worsening of acne Enhances effect of laser treatment

Eflornithine(Vaniqa®)

Insulin sensitizing agents Metformin- Studies controversial weight loss GnRH agonists Surgical

•Polycystic ovarian syndrome is one of the most common causes of hirsutism.

•Weight loss in obese patients may improve hirsutism.

•Virilism usually indicates significant pathology.

•The oral contraceptive pill is the most commonly used single therapy for hirsutism.

KEY POINTS

Thank you

Dehydroepiandrosterone sulfate >800 = adrenal tumor 500-800 congenital adrenal hyperplasia adult onset , we

can do basline 17-OH hydroxelase Lesser elevations we should think of PCOS so we must do -FSH/LH ratio , TSH , PRL -free androgen index -FSH and estradiol level for primary ovarian faliure -testosterone studies= radioimmuno assay,

equilibrium dialysis,total T -lipid profile , fasting blood sugar -ovarian ultrasound

Laboratory test

Free cortizol ,,, dexamethasone suppression test

Abdominal imaging … CT scan If pituitary causes are suspected…imaging Think about constitutional hirsutism -MRI , 5-alpha-reducatse activity , free T,

venous blood draws