ISO 9001:2008

Management of Hyper-Androgenism: MADE EASY

Dr. Sharda JainSecretary-General

Delhi Gynaecologist Forum Dr. Jyoti Agarwal Dr. Jyoti Bhasker

ISO 14001:2004 (EMS) …..Caring hearts, healing hands

ISO 9001:2008

Chairman &Founder

Our Team

Our MISSION: To Distribute Knowledge to Gynaecologists

Hirsutism

Acne

Androgenic Alopecia

Virilization

Understanding Hyper-androgenism:

Diagnosis and Management

Dermatologists views Hyper-androgenism as SAHA

Seborrhea

Acne

Androgenic Alopecia

Hirsutism

Hirsutism• Excessive growth of thick terminal hair in a

male distribution in women (upper lip, chin, chest, back, lower abdomen, thigh, forearm)

• Most common presentation of endocrine disease.

• DD: Hypertrichosis, which is generalised excessive growth of vellus hair.

• The aetiology is androgen excess

VirilizationClinical features associated with a

high level of male hormones in women.

• Hirsuitism• Acne• Deepening of voice • Increased muscle mass• Breast atrophy

Observed in 70-80% of patients with Hyper-androgenism

86% women presented with acne repoted to have

excess androgen

80-90% of women with PCOS reported to have excess androgen

Hirsutsim

ACNE

PCOS

Hirsuitism: Causes• Idiopathic• POLYCYSTIC OVARIAN SYNDROME• Congenital adrenal hyperplasia• Exogenous androgen administration• Androgen-secreting TUMOUR of

ovary or adrenal cortex

PCOSSymptoms and their frequency Menstrual cycle disturbance – 70%- Oligomenorrhoea – 50%- Amenorrhoea – 20%

Hirsutism – 70%

Obesity – 50%- Overweight (BMI > 25 kg/m2) – 30%

- Obese (BMI > 27 kg/m2) – 20%

Acne – 30%

Androgenic alopecia – 10%

Acanthosis nigricans – 1 to 3%

Hirsuitism: PCOSMechanisms* ManifestationsPituitary dysfunction High serum LH

High serum prolactinAnovulatory menstrual cycles

OligomenorrhoeaSecondary amenorrhoeaCystic ovariesInfertility

Androgen excess HirsutismAcne

Obesity HyperglycaemiaElevated oestrogens

Insulin resistance DyslipidaemiaHypertension

Androgen/Productive site

Ovary(%)

Adrenal

(%)

Periphery

(%)

RelativeAndrogene

city

Testosterone 25 25 50 100Androstenedione 50 50 - 10DHEA 10 90 - -DHEAS - 100 - 5DHT - - - 300

Source of Androgen in Women

Normal Values of Serum Androgens

Testosterone (total) 20-80 ng/dlFree testosterone 0.6 – 6.8 pg/ml% free testosterone o.4-2.4%Androstene3dione 20 – 250 ng /dlDHEAS 100 – 350 µg/dl17 – hydroxprogesterone(follicular phase)

30 – 200 ng/dl

Insulin Resistance TEST (75gm glucose)

• 2 – HOURS GLUCOSE RESPONSE • NORMAL < 140 mg/dl• IMPAIRED 140 – 199 mg/dl• NIDDM ≥ 200mg/dl

Hirsuitism : Clinical Approach• The Severity of Hirsutism is Subjective• Important observations are –– Drugs and menstrual history

– Calculation of BMI

– Measurement of BP / metabolic syndrome – Examination for VIRILISATION (clitoromegaly,

deep voice, male-pattern balding, breast atrophy) – ACNE vulgaris– Cushing's syndrome

• When recent & with virilisation, suggestive of a rare androgen-secreting tumour

Androgens and Hirsuitism • Hirsutism can be caused by either an

increased level of androgens or an oversensitivity of hair follicles to androgens.

• Testosterone stimulates hair growth, (size, intensity of growth and pigmentation).

Therapeutic OptionsInhibition of androgen production from the ovaries

• ORAL CONTRACEPTIVES• Gonadotropin-releasing hormone analogs

Inhibition of androgen action

• Anti-androgens (cyproterone, flutamide, spironolactone)• 5α-reductase inhibitor (finasteride)

Insulin sensitizers

• Metformin• Thiozolidinediones

Progestogen Types in O.C.P.• First Generation – Norethisterone,

Norethisterone acetate, lynestrenol

• Second Generation – Levonorgestrel, Norgestrel

• Third Generatio –Desogestrel, Norgestimate, Gestodene

• Fourth Generation (Newer) –Drosperinone, (Anti- androgenic) Cyproterone acetate, ( Receptor -

• DHT) Dienogest

Mala – D, Mala – NLow androgenic

Lowest – Androgenic

Activity

WHICHCombined Oral Pills

Two primary purposes: 1. Treatment of acne and hirsutism 2. For contraception during treatment with isotretinoin

2nd GENERATION

3rd GENERATION

DROSPIRENONE CYPROTERONE

The lowandrogenic activity (compared to 1st gen)

More selective for progesterone receptor than for the androgen receptor and thus, have the lowest androgenic activity

Spironolactone derivative, has anti-androgenic and anti-mineralocorticoid activity. Thus, may improve signs of HA and estrogen-related fluid retention

Inhibits the binding of dihydrotestosterone (DHT) at its receptor and reduces the activity of 5 -reductase that αcatalyzes the transformation of testosterone in dihydrotestosterone

Indication for Hormonal Treatment in

Women with acne flare-ups before

menstruation

When oral contraception is

desirable

For contraception during treatment with

isotretinoin

In women, as an alternative when

repeated courses of isotretinoin are

needed

Women whose acne is not responding to

conventional therapy

Polycystic ovary syndrome

Women with clinical signs of

hyperandrogenism, such as androgenic

alopecia, SAHA syndrome

Women with late-onset acne (acne

tarda)

Proven ovarian hyperandrogenism

Proven adrenal hyperadrogenism

Katsambas AD et al. Clinics in Dermatology 2010; 28: 17–23

ACNE

Acne Indian GuidelinesGroup I Group II

• SAHA symptoms + • Late onset of acne/

persistence of acne +• Irregular Menses +• Obesity+

• Resistance to conventional therapy.• Early relapse/ moderate to severe

relapse after oral isotretinoin therapy.

Group I

Group II

Women with acne, depending on the symptoms are divided into

Endocrine Evaluation• LH:FSH Ratio• DHEAS• Total Testosterones + Free• 17 (OH) Progestrone, Prolactin

The treatment with hormones --- rule out ovarian and adrenal tumor and

the hormonal therapy should be acceptable to the patient

ACNE

in India: Management GuidelinesACNE HIRSUTISM

DHEAS

17(OH) Progestrone

Management of HYPER-ANDROGENISM :

Role of Combined Oral Pills

Cyproterone Pillis the MAGIC pill - most effective

Progestogen Types in O.C.P.• First Generation – Norethisterone,

Norethisterone acetate, lynestrenol

• Second Generation – Levonorgestrel, Norgestrel

• Third Generatio –Desogestrel, Norgestimate, Gestodene

• Fourth Generation (Newer) –Drosperinone, (Anti- androgenic) Cyproterone acetate, ( Receptor -

• DHT) Dienogest

Mala – D, Mala – NLow androgenic

Lowest – Androgenic

Activity

Biological activities of natural progesterone and synthetic progestins

Receptor Activity Progesterone LNG GTD DRSP CPA

Progestogenic + + + + +Anti-gonadotropic + + + + +Anti-estrogenic + + + + +Estrogenic - - - - -

Androgenic - + + - -Anti-androgenic + - - + ++

(+) effective; (±) weakly effective; (−) not effectiveLNG: levonorgestrel; GTD: Gestodene; DRSP: Drospirenon; CPA: Cyproterone

CPA v/s LNG combined with ethinyl estradiol in the

treatment of• A multi-centric study involving collaboration of

dermatologists and gynecologists in 8 centers

• 133 women were allocated to receive the drugs as mentioned in the below three groups for 6 cycles:– Cyproterone actetate (CPA) 2 mg + ethinyl estradiol 50 mcg*

(Group I, n=48)– Cyproterone acetate (CPA) 2 mg +ethinyl estradiol 35 mcg

(Group II, n=48)– Levonorgestrel (LNG) 150 mcg + ethinyl estradiol 30 mcg

(Group III, n=37)*Cyproterone actetate 2 mg + ethinyl estradiol 50 mcg combination is not available in India

ACNE

CPA v/s LG combined with ethinyl estradiol in the treatment of

Group nReduction

Mean SD+

Group I 46 -51 52

Group II 45 -61 31

Group III

37 -27 52

Using the Wilcoxon Rank Sum test, CPA combinations were found to be significantly

more efficient in reducing the number of acne lesions than LNG combination (p < 0.05).

Group nReduction

Mean SD+

Group I 45 -70 36

Group II 44 -72 27

Group III

36 -35 60

Using the Wilcoxon Rank Sum test, CPA combinations were found to be significantly more

efficient in reducing the number of acne lesions than LNG combination (p < 0.0001).

Mean (%SD) reduction of the number of acne lesions after 4 months of treatment,

compared to pretreatment

Mean (%SD) reduction of the number of acne lesions after 6 months of treatment,

compared to pretreatment

Results:

ACNE

CPA v/s LG Combined with EE in the treatment of

Results:

Scoring: I =good, 2 = moderate, 3 =poor. Using the Wilcoxon/Kruskal- Wallis test the mean scores for CPA combinations were significantly better than those for LNG combination (p<O.OOl).

Average subjective assessments of the result of treatment in three groups at the end of the sixth treatment cycle

Group III

Group II

Group I

0 1 2 3

PatientDermatologistGynecologist

*

*

Carlborg L, CYPROTERONE ACETATE VERSUS LEVONORGESTREL COMBINED WITH ETHINYL ESTRADIOL IN THE TREATMENT OF ACNE, Acta Obstet Gynecol Scand 1986; 134:29-32

ACNE

Key Findings• After four cycles, patients treated with CPA combinations

had a similar reduction of acne, by 51 - 61 % compared with pretreatment, whereas those on LNG combination had an average reduction by 27%. (p < 0.05)

• At the end of the sixth cycle more than 60% of the patients in Group I or Group II had at least a 75% reduction of the number of acne lesions, whereas the corresponding figure for Group III was only 26%

• The reduction in the estrogen dose in Cyproterone acetate 2 mg +ethinyl estradiol 35 mcg not only produced an excellent bleeding pattern but also appeared to alleviate some of the side effects believed to be caused by estrogens.

CONCLUSIONA combination of Cyproterone acetate 2 mg +ethinyl estradiol 35 mcg with its low steroid content, few side effects and excellent effect on acne, seems to be the method of choice for women with acne accepting an oral contraceptive

Treatment of MILD HIRSUTISM

Hirsuitism: Treatment Cosmetic Measures

• Shaving, BLEACHING and waxing

• Electrolysis (Past) and LASER treatment : for small areas

• EFLORNITHINE CREAM : Inhibits ornithine decarboxylase in hair follicles & may reduce hair growth

Wt reduction in obese Hirsuite • High circulating levels of insulin are implicated

in women for the development of hirsutism. • Obese (insulin resistant hyperinsulinemic)

women are at high risk of becoming hirsute. • Treatments that lower insulin levels lead to

a reduction in hirsutism.• High concentration of insulin (directly and

through IGF I) is thought to stimulate theca cells in ovaries to produce androgens.

Hirsuitism: TreatmentIf these conservative measures have failed- • Anti-androgen therapy The life cycle of hair follicles is at least 3

months, so no improvement is likely before this. Only replacement hair growth is suppressed.

• Insulin-sensitising drugs Metphormin Have a role but unless the patient has lost

weight, the hirsutism will return once discontinued.

ANTI-ANDROGEN THERAPY• Androgen receptor antagonists–Cyproterone acetate–Spironolactone

• 5 -reductase inhibitors α (prevents conversion of testosterone to active form)- –Finasteride..??

• PCOD– Oestrogen (+ Cyproterone acetate)

• Suppress adrenal androgen production- –Glucocorticoids

CPA for Severe Hirsutism:results of a double-blind dose-ranging study

• Sixty hirsute women were allocated at random into three treatment groups: – 35 mcg ethinyl oestradiol and

2 mg CPA + placebo(Group I)– 35 mcg ethinyl oestradiol and

2 mg CPA with 20 mg CPA (Group II)

– 35 mcg ethinyl oestradiol and 2 mg CPA with 100 mg CPA (Group III)

Regimen n F-G Index Testosterone (nmol/l)

Group I 21 26(17-37)

2.5(1.6-4.8)

Group II 20 26 (18-44)

2.8(1.4-4.7)

Group III 19 28(17-39)

2.9(1.2-5.2)

• Individual dose regimens were blinded to both subjects and investigator

• F-G index, Ferriman and Gallwey Index for hirsutism• Data is expressed as the median (range).• There is no significant difference between any of the

variables between the groups.

Clinical Details of hirsute Women at baseline

Barth JH et al, Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study, Clinical Endocrinology 1991; 35: 5-10

CPA for Severe Hirsutism:results of a double-blind dose-ranging study• There was no difference between the three groups at the onset of therapy• The reduction by the lowest dose (Group I) was not significant until 6 months

whereas the reductions with the higher doses were significant after 3 months therapy

• There were no further significant reductions with any dose after the reduction achieved at 6 months therapy

Regimen 0 3 months 6 months 9 months 12 months

Group I 26(17-37)

25(19-33)

20(15-35)*

21(16-33) *†

19 (15-29) *†

Group II 26 (18-44)

23(15-32)*

20(13-30)*†

22(14-28) *†

16(12-32) *†

Group III 28(17-39)

25(15-34)*

21(13-29) *†

16(12-22) *†

18(11-30) *†

• Hair growth was subjectively measured using the Ferriman and Gallwey index• Reductions in hair growth compared *with time 0, † time 3 months are significant at P< 0.01 (Wilcoxon signed rank test)• This table includes data only on those women who completed at least 3 months therapy.

Reduction in hair growth using the Ferriman and Gallwey index for women treated with three doses of cyproterone acetate

Efficacy of the combination ethinyl estradiol and cyproterone acetate on endocrine, clinical and

ultrasonographic profile in polycystic Ovarian Syndrome

• A total of 140 (age 24.1+ 4.9 years) premenopausal women with PCOS and acne, with or without hirsutism treated for 60 cycles with 0.035mg of ethinyl estradiol and 2mg cyproterone acetate

n=37

Effects of ethinyl estradiol/cyproterone acetate on mild hirsutism

n=38

Effects of ethinyl estradiol/cyproterone acetate on moderate hirsutism

0

20

40

60

80

100

0 0

44.8

100

84.2

ModerateMildRecoveries

Baseline (%)

12 cycles (%)

18 cycles (%)

24 cycles (%)

After 6 months

(%)

0102030405060708090

100

0

62.2

91.9100

83.8

MildRecoveries

After 6 months: 6 months of cessation of therapy

% %

Efficacy of the combination ethinyl estradiol and cyproterone acetate on endocrine, clinical and

ultrasonographic profile in polycystic ovarian syndrome

n=140

Effects of ethinyl estradiol/cyproterone acetate on treatment on acne

Baseline (%)

12 cycles (%)

18 cycles (%)

24 cycles (%)

After 6 months

(%)

0

10

20

30

40

50

60

70

80

90

100

0

55

79.3

100

78.6

SevereModerateMildRecoveries

Effects of ethinyl estradiol/cyproterone acetate on severe hirsutism

Baseline (%)

12 cycles (%)

36 cycles (%)

60 cycles (%)

After 6 months

(%)

0102030405060708090

100100

93.9

57.6

18.227.3

06.1

42.2 42.4

54.5

0 0 0

39.4

18.2

SevereModerateMild

n=33

• All Patients with mild and moderate hirsutism completely recovered, while severe hirsutism improved in mild-moderate form on 81.8% of cases and persisted as severe in 18.2%

• Regardless of its severity, acne disappeared within 12-24 treatment cycles • The Efficacy of the EE/CPA pill on acne and hirsutism was related to the duration and

continuity of the treatment and to the degree of hirsutism

% %

Cochrane Review

Hirsutism CPA + EE35 – Most effective

Combined oral contraceptive pills for treatment (Review)

• To determine the effectiveness of combined oral contraceptives (COCs) for the treatment of facial acne compared to placebo or other active therapies

• 31 trials with 12,579 participants– 10 studies used dummies – overall, 24 pairs of treatments or placebos were compared: 6

compared a birth control pill and a placebo, – 17 compared different types of birth control pills, and 1

compared a pill and an antibiotic.

Arowojolu AO, Gallo MF, Lopez LM, Grimes DA. Combined oral contraceptive pills for treatment of acne. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD004425. DOI: 10.1002/14651858.CD004425.pub6.

ACNE

• OCs that contained chlormadinone acetate or cyproterone acetate improved acne better than levonorgestrel. (CPA>> LNG)

• Drospirenone COC appeared to be more effective than norgestimate or nomegestrol acetate plus 17-estradiol but less effective than cyproterone acetate. (CPA > DRSP)

• COC with cyproterone acetate showed better acne outcomes than one with desogestrel, but the studies produced conflicting results

Arowojolu AO, Gallo MF, Lopez LM, Grimes DA. Combined oral contraceptive pills for treatment of acne. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD004425. DOI: 10.1002/14651858.CD004425.pub6.

Combined oral contraceptive pills for treatment (Review)

ACNE

PCOD

Metformin or OCPs

To USE or NOT to use?

Criteria to diagnose the polycystic ovary syndrome (PCOS) in adolescents

Palomba S et al. Gynecol Endocrinol, 2014; 30: 335–340

Decision tree for metformin or oral contraceptives (OCs) administration for treating

oligo-amenorrhea in adolescent with PCOSBMI, body mass

index; DM, diabetes mellitus; IGT,

impaired glucose tolerance; OGTT,

oral glucose tolerance test

Therapeutic Options of Hyper Antrogenism

Inhibition of androgen production from the ovaries

• Oral contraceptives - cyproterone pill √Inhibition of androgen action

• Anti-androgens - cyproterone pill √ - spironolactone √ - flutamide• 5α-reductase

Insulin sensitizers

• Metformin √• Thiozolidinediones

Acne / Hirsutism - cyproterone pill is the best

ISO 14001:2004 (EMS) …..Caring hearts, healing

hands

ISO 9001:2008

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