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

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

G

F

R

Cortex:

aldosterone Cortisol

Androgens

(+) ACTH

Theca Cells Androstenedione & Testosterone

Granulosa CellsEstrone & Estradiol

(+) FSH

(+) LH

Sitokrom P450 scc

17 α OH ase 17 α OH ase

17-20 Desmolase

17 β OH SDH 17 β OH SDH

17-20 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

SD

H

17 β OH SDH

AROMATAZ

AROMATAZ

T Androstenedion DHEA

Adrenal Korteks

Over

%25

%25

%50

%50

%50

%50

%20

%100

%30 DHEAS

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

• 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 (200-800 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)AdrenalCongenital adrenal hyperplasia

21-hydroxylase deficiency11 -hydroxylase deficiency3 -hydroxysteroid dehydrogenase deficiency

Cushing’s syndromeAndrogen-secreting adrenal tumors

Causes of Hirsutism (2)Ovarian Androgen-secreting ovarian neoplasms

Sertoli-leydig cell tumorsGranulosa-theca cell tumorsHillus-cell tumors

Pregnancy-relatedLuteomaHyperreactive leuteinalis

Hyperthecosis Polycystic ovary syndrome

Causes of Hirsutism (3)Exogeneous medications Hormonal

Anabolic steroidsDanazolOral contraceptives containing androgenic progestinsGlucocorticoidsACTHMetyrapone

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

Ultrasonography Identification of the adrenal/ovarian tumorto 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

Suggested laboratory investigations in hirsute women

Unluhizarci K, Yilmaz S, Kelestimur F. Women’s Health, 2005

Lab.Evaluation of Hirsutism

Three basic hormonal evaluation1. Total testosterone2. DHEAS3. 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 TestosteroneNormal 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 >800 ng/dl

<1000 ng/dl >1000 ng/dl

TreatmentTreatment1-1-General principlesGeneral principles

--Detection and treatment of the underlying diseaseDetection and treatment of the underlying disease

--Multidisciplinary interventionsMultidisciplinary interventions

--Obesity treatmentObesity treatment

2-2-Drug therapyDrug therapy

--Adrenal suppressionAdrenal suppression

--Ovarian suppressionOvarian suppression

--Anti-androgen therapyAnti-androgen therapy

--ThTherapy for insulin resistanceerapy for insulin resistance

3-3-Cosmetic therapyCosmetic therapy

4-4-Education and psychotherapyEducation and psychotherapy

5-5-Combination therapy methodsCombination 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 OPTIONSGENERAL MEASURES :• Eliminating causative factors• Optimizing weight• Manage hairBleachingCutting or shavingElectrolysisLaser epilation

THERAPEUTIC OPTIONSManagement 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 OPTIONSChoice of OC• EE + Norgestimarte approved in USA• Cyproterone acetate used as progesterone

component in OcsOVARIAN 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 nigicansCommonly used agent is : Metformin andTroglitazone,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 OPTIONSManagement 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 treatmentMechanisms of anti-androgen treatment

1)1) Gonadotropin suppression Gonadotropin suppression

2)2) Stimulation of SHBG synthesis Stimulation of SHBG synthesis

3)3) Inhibition of 5- Inhibition of 5- reductase enzyme reductase enzyme

4)4) Binding to androgen receptor Binding to androgen receptor

5)5) Effects to steroid biosynthesis 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 - - - - + -

SpironolactoneSpironolactone

**Synthetic steroidSynthetic steroid

**Aldosterone and androgen antagonistAldosterone and androgen antagonist

**Competition with DHT for binding to receptorsCompetition with DHT for binding to receptors

**Inhibition of androgen synthesisInhibition of androgen synthesis

Cyproterone acetateCyproterone acetate

**A steroidic anti-androgen derivated from 17-A steroidic anti-androgen derivated from 17-

hydroxyprogesteronehydroxyprogesterone

**Inhibitory effect to testosterone and Inhibitory effect to testosterone and

dihydrotestosterone by binding to dihydrotestosterone by binding to

intracellular receptorsintracellular receptors

**Decreased ovarian testosterone production Decreased ovarian testosterone production

due to inhibition of LH secretiondue to inhibition of LH secretion

**There is a low glucocorticoid effectThere is a low glucocorticoid effect

Cyproterone AcetateCyproterone Acetate

Side effectsSide effects

Weight gainEdemaDecreased libidoHeadacheVomitingHepatotoxicityFatigueEnlarged mammary glandsMood changes

FinasterideFinasteride

**5 5 -reductase inhibitor-reductase inhibitor

**Inhibits conversion of testosterone to DHTInhibits conversion of testosterone to DHT

**It does not bind to androgen receptorsIt does not bind to androgen receptors

**There is no effect in testosterone secretionThere is no effect in testosterone secretion

FlutamideFlutamide

**Non-steroid, periferic androgen antagonistNon-steroid, periferic androgen antagonist

**Inhibitory effect in steroid biosynthesis (adrenal)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