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

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

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 Ovaries Adrenals GFRGFR Cortex:  aldosterone  Cortisol Androgens (+) ACTH Theca Cells  Androstenedione & Testosterone Granulosa Cells Estrone & Estradiol (+) FSH (+) LH

Sitokrom P450 scc 17 α OH ase Desmolase 17 β OH SDH Desmolase ? 5 α redüktase Asetat Kolesterol Pregnanolon Progesteron 17 OH Pregnanolon 17 OH Progesteron DHEA Androstenedion Androstenediol Testosteron DHT E2 E1 E3 3 β OH SDH 17 β OH SDH AROMATAZ

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

In women Major circulating androgens ( in descending order of serum concentration ) DHEA-S ( micg/dl) DHEA (1-10 ng/ml) Androstenedion ( 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 3alpa androstenediol glucuronide ( 3alpha-AG) is the peripheral metabolite of DHT and can be used as a marker of peripheral androgen metabolism. Low clinical utility…

%80 SHBG %19 Albumin %1 serbest T %69 SHBG %30 Albumin %1 serbest E2 %8 SHBG %85 Albumin %7 serbest Androstenedion %18 CBG %80 Albumin %2 serbest P4

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

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

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

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

Causes of Hirsutism (4)  Not-Hormonal 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)

Laboratory investigation Indication UltrasonographyIdentification of the adrenal/ovarian tumor to demonstrate PCO FSH-LH-EstradiolEvaluation of gonadal axis TestosteroneDemonstration of androgen excess (mostly indicate ovarian source) DHEASDemonstration of androgen excess (mostly indicate adrenal source) 17-OH PWhen NCAH considered ACTH testHormonal diagnosis of NCAH Suggested laboratory investigations in hirsute women 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>200ng/dL – May indicate ovarian neoplasm

Total Testosterone Normal Value (0.2 –0. 8 ng/ml ) - (2 0 – 80 ng/ dl ) > ng/dl

DHEAS ( micg/dl) >700 micg/dl

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

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

The management of hirsutism depends on; 1-Underlying cause, 2-Contraceptive needs, 3-Patient’s preference 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 GnRH 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 GnRH 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 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 and 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