Hirsutism

1. HIRSUTISM
PRESENTED BY DR. CYRIL THOMAS
MODERATOR – DR. NEETIKA

2. INTRODUCTION
• IN A FEMALE, HIRSUTISM IS DEFINED AS COARSE, DARK, TERMINAL HAIRS
DISTRIBUTED IN MALE PATTERN
• A PCOS ACCOUNTS OR 70 TO 80 PERCENT CASES OF HIRSUTISM,
WHICH TYPICALLY BEGINS IN LATE ADOLESCENCE OR THE EARLY
TWENTIES.
• IDIOPATHIC HIRSUTISM IS THE SECOND MOST RECRRUENT CAUSE (AZZIZ,
2003).
• ADDITIONALLY, VARIOUS DRUGS MAY ALSO LEAD TO HIRSUTISM, AND
THEIR USE SHOULD BE INVESTIGATED

3. SOME COMMON TERM
• VIRILISM
PRESENCE OF ANY ONE OR MORE OF THE FOLLOWING FEATURE
• DEEPENING OF VOICE
• TEMPORAL BALDING
• AMENORRHEA
• ENLARGEMENT OF CLITORIS(CLITOROMEGALY)
• BREAST ATROPHY
• HYPERANDRANDROGENISM
STATE OF INCREASED SERUM ANDROGEN LEVEL WITH OR WITHOUT ANY BIOLOGICAL EFFECT OF HYPERANDROGENEMIA
• HYPERTRICHOSIS
EXCESSIVE HAIR GROWTH LIMITED TO A NORMAL PATTERN OF DISTRIBUTION

4. ANDROGEN IN FEMALE
• DEHYDROEPIANDROSTERONE SULPHATE(DHEA-S)
• DEHYDROEPIANDROSTERONE (DHEA)
• ANDROSTENEDIONE
• TESTOSTERONE(T)
• DIHYDROTESTOSTERONE(DHT)

5. SOURCE OF ANDROGEN IN FEMALE

6. • MOST IF TESTOSTERONE(80%) IN CIRCULATION IS BOUND TO SHBG AND IS BIOLOGICALLY INACTIVE
• ABOUT 19% IS BOUND LOOSELY WITH ALBUMIN
• 1% OF TESTOSTERONE REMAINS FREE WHICH IS BIOLOGICALLY ACTIVE
• BIOLOGICAL EFFECT OF TESTOSTERONE IS METABOLICALLY CONVERTED IN TISSUE TO
DIHYDROTESTOSTERONE(DHT) BY ENZYME 5Ἀ-REDUCTASE
• 3 Ἀ-ANDROSTANEDIOL GLUCURONIDE (3 Ἀ-AG) IS TISSUE METABOLITE OF DHT
• 3 Ἀ-AG REFLECTS ACTIVITY OD ENZYME 5 Ἀ REDUCTASE AT TISSUE LEVEL

7. • BIOCHEMICAL MARKER FOR ANDROGEN COMPARTMENT
• TESTESTORONE FOR OVERIES
• DHEA-S FOR ADRENAL GLAND
• 3 Ἀ-AG FOR PERIPHERY

8. BIOLOGY OF HAIR GROWTH
• HAIR GROWS (AT 8-10 WEEKS OF GESTATION) FROM A INDIVIDUAL HAIR FOLLICLE THAT ARE
PART OF A PILOSEBACEOUS GLAND APPARATUS
• MAIN DIFFERENCE BETWEEN SEXES IS THE DEGREE OF DIFFERENTIATION OF THE HAIR
• HUMAN HAIR GROWTH IS CONTINUOUS
• HAIR GROWS IN A MOSAIC PATTERN (IN A GIVEN AREA ,HAIR ARE IN DIFFERENT STAGES OF
DEVELOPMENT)

9. GROWTH CYCLE OF THE HAIR: ACT
• ANAGEN : GROWTH PHASE,85- 90 %
OF THE LIFE CYCLE
• CATAGEN : RAPID INVOLUTION PHASE
• TELOGEN : QUIESCENT PHASE
THE GROWTH PHASE OR THE ANAGEN PHASE IS PRIMARILY INFLUENCED BY DISORDERS THAT STIMULATE
HAIR GROWTH AS WELL AS THERAPEUTIC MODALITIES

10. TYPES OF HAIR
• LANUGO : BODY HAIR SEEN IN THE FETUS AND NEWBORN
• VELLUS : FINE (DOWNY UNPIGMENTED) HAIR COVERING THE BODY
• TERMINAL HAIR : THICK PIGMENTED HAIR OF SCALP AND PUBIC AREA
THICKNESS OF THE TERMINAL HAIR VARIES FORM ONE INDIVIDUAL TO OTHER DEPENDING UPON
GENETIC, AND POSSIBLY NUTRITIONAL

11. ANDROGEN AND PILOSEBACEOUS UNIT
• PILOSEBACEOUS UNIT CONSISTS SEBACEOUS GLAND AND HAIR FOLLICLE
• BOTH ARE SENSITIVE TO ANDROGEN
• SEBACEOUS GLANDS ARE MORE SENSITIVE TO ANDROGEN THAN HAIR FOLLICLE
• HYPERSTIMULATION OF SEBACEOUS GLAND LEAD FIRST TO OILY SKIN AND SUBSEQUENT
INFECTION RESULT IN ACNE
• SKIN AND HAIR FOLLICLE ALSO PLAY ROLE IN SERVING AS TARGET ORGANS OF ANDROGEN
AND ALSO IN PRODUCING ANDROGEN FROM CIRCULATORY PROPHORMONES

12. MECHANISM OF EXCESSIVE HAIR GROWTH
• STIMULUS FOR EXCESSIVE HAIR GROWTH IS TESTESTRONE
• TESTESTRONE BINDS TO ANDROGEN RECEPTOR IN HAIR FOLLICLE  ACTIVATION OF 5Ἀ-
REDUCTASE CONVERT TESTOSTERONE TO DIHYDROTESTESTRONE AND ANDROSTENEDIOL
• THIS LEAD TO STIMULATION OF PROLIFERATION AND GROWTH OF TERMINAL HAIR(ANAGEN
PHASE)
• ONCE BLACE TERMINAL HAIR IS PRODUCED, CHANGES PERSISTS IN ABSENCE OF CONTINUING
ANDROGEN EXCESS

13. • INCREASED HAIR FOLLICLE STIMULATION AND INCREASED 5Ἀ-REDUCTASE ACTIVITY ENABLE
PROHORMONE DHEA AND ANDROSTENEDIONE TO BE METABOLIZED DIRECTLY TO DHT

14. CAUSES OF HIRSUTISM
• 1. OVARIAN CAUSES
• POLYCYSTIC (PCOS) OVARIAN (MOST SIGNIFICANT CAUSE)
• OVARIAN HYPERTHECOSIS: ANDROGEN SECRETING THECA INTERSTITIAL CELLS ARE
PRESENT IN WHOLE OVARIAN STROMA.
• OVARIAN NEOPLASM -
• SERTOLI-LEYDIG CELL TUMOR (ARRHENOBLASTOMA)
• HILUS CELL TUMOR
• LIPOID CELL TUMOR
• ANDROBLASTOMA
• GYNANDROBLASTOMA
• GONADOBLASTOMA

15. CAUSES OF HIRSUTISM
• 2. ADRENAL CAUSES
• CONGENITAL ADRENAL HYPERPLASIA(LATE ONSET)
• CUSHING'S SYNDROME
• ADRENAL TUMORS - (A) ADENOMA (B) ADRENAL CARCINOMA

16. CAUSES OF HIRSUTISM
• 3. DRUGS
• ANDROGENS
• ANDROGENIC PROGESTOGENS (17 NONSTEROIDS)
• ANABOLIC STEROIDS
• TESTOSTERONE
• GLUCOCORTICOIDS
• DANAZOL
• MINOXIDIL
• PHENYTOIN
• L-THYROXINE

17. CAUSES OF HIRSUTISM
• 4. GENETIC AND ETHNIC CAUSES
• 5. INCREASED SENSITIVITY OF PILOSEBACEOUS UNIT TO TESTOSTERONE.
• 6. HEPATIC DISEASES (DUE TO DECREASED SHBG LEVELS INCREASING FREE TESTOSTERONE
LEVELS.)
• 7. MISCELLANEOUS CAUSES: OBESITY, HYPOTHYROIDISM, HYPERPROLACTINEMIA
• 8. IDIOPATHIC 15%

18. Modified Ferriman-Galleway

19. Modified Ferriman-Galleway
•Modified Ferriman-Galleway Score: Used to diagnose hirsutism
•Score > 6: Indicates hirsutism (total score range 0-36)
•Scoring criteria:
•0: No terminal hair growth in assessed areas
•1: Minimal terminal hair growth
•2: Hair growth more than minimal but less than adult male
•3: Hair growth less than very hairy adult male
•4: Hair growth typical of well-virilized healthy males
•Severity Grades:
•Mild: Score up to 15
•Moderate: Score 16 to 25
•Severe: Score above 25

21. TREATMENT
• A PRIMARY GOAL IS LOWERING ANDROGEN LEVELS TO HALT URTHER CONVERSION OF VELLUS HAIRS
TO TERMINAL ONES.
• HOWEVER, MEDICAL THERAPIES WILL NOT ELIMINATE HAIR ALREADY PRESENT.
• MOREOVER, TREATMENTS MAY REQUIRE 6 TO 12 MONTHS BEFORE CLINICAL IMPROVEMENT IS APPARENT.
• FOR THIS REASON, CLINICIANS SHOULD BE FAMILIAR WITH TEMPORARY HAIR REMOVAL METHODS THAT
MAY BE USED IN THE INTERIM.
• PERMANENT COSMETIC THERAPIES CAN THEN BE IMPLEMENTED ONCE MEDICATIONS HAVE REACHED
MAXIMAL THERAPEUTIC EFFECT.

22. APPROACH
• THE FIRST STEP IN THE MANAGEMENT OF HIRSUTE WOMEN IS:
• TO REVIEW THEIR DIAGNOSIS (MOST COMMONLY POLYCYSTIC OVARY SYNDROME)
• THEIR GOALS AND EXPECTATIONS
• THE DEGREE OF DISTRESS CAUSED BY THE HIRSUTISM

23. TREATMENT OPTIONS
• PHARMACOLOGICAL THERAPY OR DIRECT HAIR REMOVAL METHODS
• THE CHOICE BETWEEN THESE OPTIONS DEPENDS ON
• (A) PATIENT PREFERENCES
• (B) THE EXTENT TO WHICH THE AREA OF HIRSUTISM THAT AFFECTS
• (C) ACCESS TO AND AFFORDABILITY

24. PHARMACOLOGICAL TREATMENT
• OVARIAN SUPRESSION
OCS
GNRH
• ANTIANDROGEN THERAPY
• INSULIN LOWERING DRUGS ( METFORMIN, TZDS)

25. OVARIAN SUPPRESSION
• THERE ARE TWO WAYS TO SUPPRESS OVARIAN ANDROGEN SECRETION
• GONADOTROPIN SUPPRESSION WITH A COMBINATION OF ESTROGEN AND PROGESTIN
• GONADOTROPIN SUPPRESSION USING A LONG-ACTING GNRH AGONIST

26. PHARMACOLOGICAL TREATMENTS
• MONOTHERAPY FOR OCS:
FOR THE MAJORITY OF WOMEN, OCPS WERE RECOMMEND
TO TREAT PATIENT-IMPORTANT HIRSUTISM
• BECAUSE OF ITS TERATOGENIC POTENTIAL,
RECOMMENDATION IS AGAINST ANTIANDROGEN
MONOTHERAPY UNLESS ADEQUATE CONTRACEPTION IS USED

27. MECHANISM OF ACTION
• OC THERAPY REDUCES HYPERANDROGENISM VIA A NUMBER OF
MECHANISMS INCLUDING:
• SUPPRESSION OF LH SECRETION AND OVARIAN ANDROGEN SECRETION
• STIMULATION OF HEPATIC PRODUCTION OF SHBG, REDUCING SERUM
FREE ANDROGEN CONCENTRATIONS
• A SLIGHT REDUCTION IN ADRENAL ANDROGEN SECRETION
• A SLIGHT BLOCKAGE IN THE BINDING OF ANDROGENS TO THEIR
RECEPTOR

28. DEFINITION
• PILLS CONTAINING LESS THAN 50 G OF EE ARE CALLED “LOW-DOSE”
Μ
OCS
• VIRTUALLY ALL LOW-DOSE OCS CONTAIN 35 G EE, AND THE DOSE
Μ
OF SYNTHETIC PROGESTIN RANGES BETWEEN 0.1 AND 3 MG
• EE HAS STRONGER EFFECTS THAN NATURAL ESTRADIOL ON HEPATIC
METABOLISM, INCLUDING SYNTHESIS OF SHBG, LIPOPROTEINS,
ANGIOTENSINOGEN, AND SOME ESTROGEN-DEPENDENT CLOTTING
FACTORS

29. SIDE EFFECTS
• KNOWN RISKS OF INCREASED DVT THROMBOSIS AND BREAST CANCER
• FOR THIS REASON, MANY CLINICIANS OPT FOR THE SAFER, BUT LESS EFFECTIVE, LOWER DOSE
CONTRACEPTIVE PILLS

30. ABSOLUTE AND RELATIVE CONTRAINDICATIONS TO
THE USE OF LOW-DOSE OCS ACCORDING TO THE
WHO GUIDELINE
1. 6 WEEKS POSTPARTUM IF BREASTFEEDING
2. SMOKER OVER THE AGE OF 35 Y (≥15 CIGARETTES PER DAY)
3. HYPERTENSION (SYSTOLIC ≥ 160 MM HG OR DIASTOLIC ≥ 100 MM HG)
4. HISTORY OF DEEP VENOUS THROMBOSIS/PULMONARY EMBOLISM
5. CURRENT DEEP VENOUS THROMBOSIS/PULMONARY EMBOLISM
6. MAJOR SURGERY WITH PROLONGED IMMOBILIZATION
7. KNOWN THROMBOGENIC MUTATIONS (EG, FACTOR V LEIDEN,
PROTHROMBIN MUTATION, PROTEIN S, PROTEIN C, AND ANTITHROMBIN
DEFICIENCIES)
8. A CURRENT CASE AND HISTORY OF ISCHEMIC HEART DISEASE
9. STROKE (HISTORY OF CEREBROVASCULAR ACCIDENT)

31. ABSOLUTE AND RELATIVE CONTRAINDICATIONS TO
THE USE OF LOW-DOSE OCS ACCORDING TO THE
WHO GUIDELINE
10. COMPLICATED VALVULAR HEART DISEASE
11. SYSTEMIC LUPUS ERYTHEMATOSUS WITH POSITIVE
ANTIPHOSPHOLIPID ANTIBODIES
12. MIGRAINE HEADACHE WITH FOCAL NEUROLOGICAL SYMPTOMS
13. CURRENT BREAST CANCER
14. DIABETES WITH NEPHROPATHY/RETINOPATHY/NEUROPATHY
15. OTHER VASCULAR DISEASE OR DIABETES OF> 20-Y DURATION
16. ACTIVE VIRAL HEPATITIS
17. SEVERE CIRRHOSIS
18. LIVER TUMORS

32. SELECTED RELATIVE CONTRAINDICATION
1. SMOKER OVER THE AGE OF 35 Y (<15 CIGARETTES PER DAY)
2. ADEQUATELY CONTROLLED HYPERTENSION
3. HYPERTENSION (SYSTOLIC 140–159 MM HG, DIASTOLIC 90–99 MM HG)
4. MIGRAINE HEADACHE OVER THE AGE OF 35
5. CURRENT GALLBLADDER DISEASE
6. PAST OC-RELATED HISTORY OF CHOLESTASIS
7. MILD CIRRHOSIS
8. USE OF DRUGS THAT AFFECT LIVER ENZYMES
9. ANTICONVULSANT THERAPY
10. ANTIRETROVIRAL THERAPY

33. SUBOPTIMAL RESPONSE
• ADD ANTIANDROGEN TO OC — IF THE PATIENT IS NOT SATISFIED WITH THE DEGREE OF
IMPROVEMENT IN HER HIRSUTISM AFTER SIX MONTHS OF MONOTHERAPY WITH AN OC, WE
SUGGEST ADDING AN ANTIANDROGEN

34. ANTIANDROGENS
• SPIRONOLACTONE
• CYPROTERONE ACETATE
• FINASTERIDE
• FLUTAMIDE

35. ANTIANDROGENS
• ANTIANDROGENS APPEAR TO BE AS EFFECTIVE AS OCS FOR HIRSUTISM.
• IT HAS BEEN SUGGESTED THAT NOT USING THEM AS MONOTHERAPY,
BECAUSE OF THE POTENTIAL ADVERSE EFFECTS ON A DEVELOPING MALE
FETUS IN UTERO.
• HEAD-TO-HEAD COMPARISONS OF INDIVIDUAL ANTIANDROGENS WERE
NOT AVAILABLE, ANTIANDROGENS ARE MORE EFFECTIVE THAN PLACEBO,
AND THERE DID NOT APPEAR TO BE IMPORTANT DIFFERENCES AMONG
THEM COMPARED WITH PLACEBO.

36. INSULIN-LOWERING DRUGS
• THE PLACE OF INSULIN REDUCTION THERAPIES IN TREATING HIRSUTISM,
PARTICULARLY IN THE ABSENCE OF THE MENSTRUAL OR METABOLIC
DISTURBANCES TYPICALLY SEEN IN CONJUNCTION WITH PCOS, IS
CONTROVERSIAL
• META-ANALYSIS OF 8 METFORMIN TRIALS FOUND NO SIGNIFICANT
REDUCTION IN FERRIMAN-GALLWEY SCORES WITH METFORMIN WHEN
COMPARED WITH PLACEBO
• J CLIN ENDOCRINOL METAB. 2008 APR;93(4):1135-42.

37. INSULIN LOWERING VS ANTIANDROGENS
• METAANALYSIS SHOWED THE ANTIANDROGEN GROUP HAD SIGNIFICANTLY
LOWER HIRSUTISM SCORES THAN THE METFORMIN GROUP (3.7; CI, 6.8 TO
0.6)
BUT WITH LARGE INCONSISTENCY ACROSS STUDIES (I=80%)
• FLUTAMIDE NNT = 2
• SPIRONOLACTONE TRIAL NNT = 5
• J CLIN ENDOCRINOL METAB. 2008 APR;93(4):1135-42

38. MONITORING
• WE SUGGEST A TRIAL OF AT LEAST 6 MO BEFORE
• MAKING ANY CHANGES IN DOSE
• ADDING A MEDICATION
• SWITCHING TO A NEW MEDICATION
• THE PATIENT'S ASSESSMENT OF HER RESPONSE TO THERAPY IS THE MOST IMPORTANT
OUTCOME
• AT EACH F/U VISIT, THE PATIENT SHOULD BE ASKED WHETHER SHE HAS NOTED ANY
DECREASED NEED FOR COSMETIC METHODS (SHAVING, PLUCKING, WAXING) TO MANAGE
HER HIRSUTISM
• IN ADDITION, WE DO TRY TO OBTAIN A FERRIMAN-GALLWEY SCORE AT BASELINE AND AT
EACH FOLLOW-UP VISIT ( HOWEVER, AS NOTED, THE SCORE IS UNRELIABLE IN WOMEN WHO
ROUTINELY USE COSMETIC HAIR REMOVAL METHODS)

39. CONT’D
• ROUTINE MONITORING OF SERUM ANDROGENS TO ASSESS THE RESPONSE TO DRUG
THERAPY IS NOT RECOMMENDED
• HOWEVER, IF THERE IS PROGRESSION OF HIRSUTISM DURING THERAPY, REPEAT BIOCHEMICAL
EVALUATION IS WARRANTED

40. TREATMENT