Hirsutism Virilization Assoc Prof Gazi YILDIRIM M D

Hirsutism & Virilization Assoc. Prof. Gazi YILDIRIM, M. D. Yeditepe University, Medical Faculty Dept of Ob&Gyn

Objectives • To define – Hirsutism • To learn – Androgen biosynthesis • To treat – Hirsutism

HIRSUTISM APPEARANCE OF EXCESSIVE COARSE (TERMINAL)HAIR IN A PATTERN NOT NORMAL IN THE FEMALE • Definition highlights the abnormal distribution of excess hair growth , such as facial , chest, or upper abdominal hair

HYPERTRICHOSIS GROWTH OF HAIR IN EXCESS OF THE NORMAL WHILE LIMITED TO A NORMAL PATTERN OF DISTRIBUTION • It is frequently associated with the use of medication such as antiepileptics

VIRILIZATION REFERS TO CONCURRENT PRESENTATION OF HIRSUTISM WITH A BROAD RANGE OF SIGNS SUGGESTIVE OF ANDROGEN EXCESS, SUCH AS • ACNE, • FRONTOTEMPORAL BALDING, • DEPPENING OF THE VOICE , • A DECREASE IN BREAT SIZE • CLITORAL HYPERTROPHY

Normal Androgen Synthesis Pituitary (+) AC Cortex: G TH F Adrenals (+) R aldosterone Cortisol Androgens LH Ovaries (+) FS Theca Cells Androstenedione & Testosterone H Granulosa Cells Estrone &

Asetat Kolesterol Sitokrom P 450 scc Progesteron Pregnanolon 17 OH Pregnanolon 17 -20 Desmolase DHEA 17 α OH ase 3 β OH SDH 17 α OH ase E 3 17 OH Progesteron 17 -20 Desmolase M O AR Androstenedion 17 β OH SDH ? Z A AT 17 β OH SDH E 1 17 β OH SDH AZ Androstenediol Testosteron O AR 5 α redüktase DHT T MA E 2

Adrenal Korteks %25 T %25 %50 %50 Androstenedion DHEA %30 DHEAS %20 %50 Over %100

In women Major circulating androgens (in descending order of serum concentration) • • • DHEA-S (100 -350 micg/dl) DHEA (1 -10 ng/ml) Androstenedion (0. 5 -2. 0 ng/ml) Testosterone (20 -80 ng/dl) DHT

EXCESS REPONSIVITY TO ANDROGEN TESTOSTERONE 5 -ALPHA -REDUCTASE DIHIDROTESTOSTERONE

DHT • Major nuclear androgen • Produced only in the periphery • Circulating level is low and do not reflect the 5 alpha reductase activity • 3 alpa androstenediol glucuronide (3 alpha-AG) is the peripheral metabolite of DHT and can be used as a marker of peripheral androgen metabolism. • Low clinical utility…

%1 serbest %19 Albumin %1 serbest %7 serbest %2 serbest %30 Albumin %85 Albumin %80 SHBG %69 SHBG %8 SHBG T E 2 Androstenedion %18 CBG P 4

Men %3 serbest %19 Albumin Normal Women %1 serbest %78 SHBG T (200 -800 ng/dl) Hirsute Women %2 serbest %19 Albumin %80 SHBG %79 SHBG T (20 -80 ng/dl)

Causes of Hirsutism (1) Adrenal Ø Congenital adrenal hyperplasia ü 21 -hydroxylase deficiency ü 11 -hydroxylase deficiency ü 3 -hydroxysteroid dehydrogenase deficiency Ø Cushing’s syndrome Ø Androgen-secreting adrenal tumors

Causes of Hirsutism (2) Ovarian Ø Androgen-secreting ovarian neoplasms ü Sertoli-leydig cell tumors ü Granulosa-theca cell tumors ü Hillus-cell tumors Ø Pregnancy-related ü Luteoma ü Hyperreactive leuteinalis Ø Hyperthecosis Ø Polycystic ovary syndrome

Causes of Hirsutism (3) Exogeneous medications Ø Hormonal ü Anabolic steroids ü Danazol ü Oral contraceptives containing androgenic progestins ü Glucocorticoids ü ACTH ü Metyrapone

Causes of Hirsutism (4) Ø Not-Hormonal ü ü ü Ø Ø Ø Diazoxide Phenytoin Psoralens Streptomycin Phenothiazine Minoxidil Severe insulin resistance syndromes Hyperprolactinemia SHBG defect (primary or secondary) Menopause Idiopathic hirsutism Idiopathic hyperandrogenism

Physical Exam • • • Hair pattern Balding Body habitus Female contours Atrophic breast changes Clitoromegaly Ovarian masses Cushingoid features Acanthosis nigricans (associated w/ PCOS)

Suggested laboratory investigations in hirsute women Laboratory investigation Indication Ultrasonography Identification of the adrenal/ovarian tumor to demonstrate PCO FSH-LH-Estradiol Evaluation of gonadal axis Testosterone Demonstration of androgen excess (mostly indicate ovarian source) DHEAS Demonstration of androgen excess (mostly indicate adrenal source) 17 -OH P When NCAH considered ACTH test Hormonal diagnosis of NCAH Unluhizarci K, Yilmaz S, Kelestimur F. Women’s Health, 2005

Lab. Evaluation of Hirsutism Three basic hormonal evaluation 1. Total testosterone 2. DHEAS 3. AM 17 -hydroxyprogesterone

Diagnosis & Evaluatoin • 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>200 ng/d. L – May indicate ovarian neoplasm

Total Testosterone Normal Value (0. 2 – 0. 8 ng/ml) - (20 – 80 ng/dl) >150 -200 ng/dl

DHEAS (100 -350 micg/dl) >700 micg/dl

17 –hydroxyprogesterone (<0. 2) ng/ml ) - (<200) ng/dl ) <200 ng/dl 200 -800 ng/dl <1000 ng/dl >800 ng/dl

Treatment 1 -General principles -Detection and treatment of the underlying disease -Multidisciplinary interventions -Obesity treatment 2 -Drug therapy -Adrenal suppression -Ovarian suppression -Anti-androgen therapy -Therapy for insulin resistance 3 -Cosmetic therapy 4 -Education and psychotherapy 5 -Combination therapy methods

ü The management of hirsutism depends on; 1 -Underlying cause, 2 -Contraceptive needs, 3 -Patient’s preference ü At least 6 -9 months of treatment is necessary for clinical response

THERAPEUTIC OPTIONS GENERAL MEASURES : • Eliminating causative factors • Optimizing weight • Manage hair Bleaching Cutting or shaving Electrolysis Laser epilation

THERAPEUTIC OPTIONS Management of excess ovarian androgen production : Standard therapy is : combined E+P, most commonly OCs • It reduces ovarian androgen production • It increases SHBG • It induces competition at the cellular level for binding to the androgen receptor

THERAPEUTIC OPTIONS Choice of OC • EE + Norgestimarte approved in USA • Cyproterone acetate used as progesterone component in Ocs OVARIAN SUPPRESSION BY LONG ACTING Gn. RH ANALOGUE • Can be used for functional ovarian androgen overproduction and even for malignant condition • But to be used for long with back-up

THERAPEUTIC OPTIONS • Long acting Gn. RH analogues used • But there is doubt that this therapy will be beneficial over Ocs • INSULIN SENSITIZING AGENTS: For PCO with acanthosis nigicans Commonly used agent is : Metformin and Troglitazone, Pioglitazone, Rosiglitazone

THERAPEUTIC OPTIONS • MANAGEMENT OF EXCESS ADRENAL ANDROGEN PRODUCTION • Metabolic correction of the disorder, usually with exogenous steroids • Dexamethasone, mostly used, But LIMITED ROLE

THERAPEUTIC OPTIONS Management directed to the target organ and cells • Competition with Androgen receptors: – Spironolactone, – Flutamide, – Ketoconazole, – Cyproterone acetate • 5 -alpha reductase Inhibitors : – Finasteride

Mechanisms of anti-androgen treatment 1) Gonadotropin suppression 2) Stimulation of SHBG synthesis 3) Inhibition of 5 - reductase enzyme 4) Binding to androgen receptor 5) Effects to steroid biosynthesis

Mechanisms of actions of the commonly used anti-androgens Androgen receptor blockade Clearence of androgens Effect on LH secretion Glucocorticoid activity 5 -a reductase activity Progestogen like activity Cyproterone acetate + + - + Spironolactone + + - - - + Drospirenone + + + - - - Flutamide + - - - Finasteride - - + -

Spironolactone *Synthetic steroid *Aldosterone androgen antagonist *Competition with DHT for binding to receptors *Inhibition of androgen synthesis

Cyproterone acetate *A steroidic anti-androgen derivated from 17 hydroxyprogesterone *Inhibitory effect to testosterone and dihydrotestosterone by binding to intracellular receptors *Decreased ovarian testosterone production due to inhibition of LH secretion *There is a low glucocorticoid effect

Cyproterone Acetate Side effects Weight gain Edema Decreased libido Headache Vomiting Hepatotoxicity Fatigue Enlarged mammary glands Mood changes

Finasteride *5 -reductase inhibitor *Inhibits conversion of testosterone to DHT *It does not bind to androgen receptors *There is no effect in testosterone secretion

Flutamide *Non-steroid, periferic androgen antagonist *Inhibitory effect in steroid biosynthesis (adrenal)

Eflornithine hydrochloride 13. 9% • Eflornithine 13. 9% cream is a topical treatment that does not remove the hairs, but acts to reduce the rate of growth and appears to be effective for unwanted facial hair on the mustache and chin area. • It can be used in combination with other treatments to give the patient the best chance for successful hair removal. • Eflornithine acts as an inhibitor of L-ornithine decarboxylase which may be important in controlling hair growth and proliferation