The IA Consensus Evidence based Good Clinical Practice Recommendations ndian Story Of PCOD

1. The Indian Story
Of PCOD
Dr.Jyoti Agarwal

2. Delhi Gynaecologist Forum
CME on PCOD
Held on 5th May, Delhi
INVITED SPEAKER

3. The Indian Story Of
PCOD
A Consensus Evidence based
Good Clinical Practice Recommendations

4. ‘ Real knowledge is to know
the extent of one’s
ignorance ’

5. Why Indian PCOS Guidelines ?
Align the mind set of Indian clinicians
towards a common management of
PCOS
These recommendations have taken into account the
evidence from the West and also published and
unpublished good clinical practices from India

6. Recommendation
‘A suggestion or proposal as to the best course of
action, especially one put forward by an
authoritative body’
Guideline
‘A general rule, principle, or piece of advice’
Oxford Dictionary

7. Grading System for Recommendations
Strength of recommendation
A Strongly recommended
B Suggested
C Unresolved
Evidence Level (EL) based scientific liteature
1 At least one RCT or meta-analysis of RCTs
2 At least one non-randomized or non-controlled, prospective
epidemiological study
3 Cross-sectional study or surveillance or pilot study
4 Existing guideline or consensus expert opinion on extensive patient
experience or review
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science 2014;

8. Huge Impact On Reproductive , Metabolic , And
Cardiovascular Health Of Affected
Girls And Women

9. Epidemiology – Global Perspective
5-10 %
19.9 %
3.7- 22 %
11.9 %
Huge Disease Burden

10. The Indian Scenario…..
2 in every 5 adolescents 1 in every 5 adult women
Suffer from PCOS!!!
Malik et al. Management of Polycystic Ovary Syndrome in India.
Fertility Science & Research. Jan-Jun 2014

11. Drivers of the PCOS Epidemic
Earlier age of
onset of PCOS
Rise in childhood
obesity
(faulty lifestyle habits)
Genetic
Early onset of
Insulin resistance
Improved diagnostic
facilities & early
recognition
Improved patient
awareness

12. Dietary factors
Fast food culture
‘Dietary Westernization’
Carbohydrate , fat rich refined &
processed food with low dietary fibres
Mishra A & Vikram NK. Insulin Resistance Syndrome and Obesity in Asian Indians: Evidence and Implications. Nutrition. 2004

13. “Push button lifestyle”
Reduced Physical Activity:
South Asian women are particularly sedentary & are less physically
active when compared with other ethnic groups
Urbanization : Chronic stress
Hypothalamic-pituitary-adrenocortical and sympatho-adrenal
activations, precipitating insulin resistance in the long-term
Mishra A & Vikram NK. Insulin Resistance Syndrome (Metabolic Syndrome) & Obesity in Asian Indians:
Evidence and Implications. Nutrition. 2004

14. Other factors….
• Early-life adverse events:
• mostly malnutrition, results in adult-onset metabolic syndrome
• Asian Indian children born with a low birth weight showed
insulin resistance and dyslipidemia when they gained weight in
early childhood
• Role of sub-clinical inflammation as evidenced by raised C-
reactive proteins has also been postulated to trigger development of
PCOS later in life
Mishra A & Vikram NK. Insulin Resistance Syndrome (Metabolic Syndrome) & Obesity in Asian Indians: Evidence and
Implications. Nutrition. 2004

15. Role of Genetics
• No clear cut mode of inheritance
• Autosomal dominant
• Risk of developing PCOS is greater
40 % if sister is affected
10 % if mother is affected

16. Association between PCOS &
Genetic mutations
Insulin secretion & action Insulin receptor (INSR) region
Insulin variable-number-tandem repeats (VNTR)
Insulin receptor substrate 1 (IRS-1)
Insulin receptor substrate 2 (IRS-2)
Calpain 10 (CAPN10)
Peroxisome proliferator-activated receptor ᵞ (PPAR-γ)
Protein phosphatase 1 regulatory subunit (PP1R3)
Gonadotropin secretion
& action
Follistatin (FST)
Androgen biosynthesis,
secretion, transport &
metabolism
Androgen Receptor (AR)
Sex-Hormone Binding Globulin (SHBG)
Cytochrome p450c17 (CYP17), Cytochrome p45011a (CYP11a)
11β-Hydroxysteroid dehydrogenase (11β-HSD)
1. Balen A. The pathophysiology of polycystic ovary syndrome: trying to understand PCOS and its endocrinology. Best Pract Res Clin Obstet Gynaecol. 2004
2. Goodarzi MO et al. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011 Apr;7(4):219-31
3. Jones MR et al. Polymorphism of the follistatin gene in polycystic ovary syndrome. Mol Hum Reprod. 2007 Apr;13(4):237-41
Follistatin gene
Strongest
association with
PCOS

17. Pathophysiology of PCOS
Jayasena CN, Franks S. The management of patients with polycystic ovary syndrome. Nat Rev Endocrinol. 2014 Oct; 10(10): 624-36
Goodarzi MO et al. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011 Apr;7(4):219-31

18. PCOS: Clinical Features
Hirsutism: 44 %
Acne: 20 %
Glucose intolerance 16.3 %
Obesity: 37.5 – 62.5 %
Amongst Indian women
with PCOS
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science 2014

19. Associated Co-morbidities
Associated
Co-
morbidities
Depression
Cardio-
vascular
Risk
Type 2
Diabetes
Mellitus
Endometri
al Cancer
Pregnancy
Compli-
cations
Obstructiv
e Sleep
Apnoea
NASH &
NAFLD
• Depression: 54 %
• Type 2 DM: 5 – 10 fold
higher risk
• Cardiovascular disease:
Relative risk of 1.53 as
compared to normal
subjects
• Pregnancy complications:
risk of gestational DM,
pre-term births
• NASH – 67%
Malik et al. Fertility Science & Research. Jan-Jun 2014
Add To The Burden Of PCOS

20. PCOS: Approach to
Diagnosis
L.IN.MA.WH.02.2016.0745 .

21. Gold Standard Diagnostic Criteria
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research. Jan-Jun 2014
In adult women, it is recommended that diagnosis of PCOS be made using the Rotterdam criteria,
meeting two of the following three conditions:
Androgen excess, Ovulatory dysfunction, Polycystic ovaries (Grade A, EL 4)

22. Biochemical
Characteristics
High BMI > 23 kg/m2 for
adults
> 97.5th percentile for age in
adolescents
High waist : hip ratio (> 0.85)
Acanthosis nigricans as clinical
marker of insulin resistance
Family h/o diabetes or PCOS,
Obesity and improper lifestyle,
Deranged lipid profile
Clinical symptoms
Pubertal deviations
(early or late),
Menstrual irregularity
Presence of polycystic ovaries and clinical
signs of hyperandrogenism such as:
Early acne or hirsutism,
Persistent severe acne,
Frequent relapse in acne,
Acne in facial ‘V’ area,
Persistent hirsutism , acne for > 2 yrs
Indian women showing at least one biochemical
characteristic in conjunction with one clinical symptom
should be considered for further evaluation (Grade A, EL 3)
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research. Jan-Jun 2014

23. Additional Recommendations
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research. Jan-Jun 2014
In adults ,
adolescents:
Presence of
ACANTHOSIS
NIGRICANS
with/ without
obesity is an
additional
diagnostic
criterion (Grade B,
EL 4)
Determination
of anti-mullerian
hormone levels
not
recommended
for diagnosis
(Grade A, EL 4)
In adolescents,
presence of
oligomenorrhea or
amenorrhea
beyond 2 years of
menarche – early
sign of PCOS
(Grade B, EL 4)

24. Minimal workup of PCOS in
Adolescents should include 5 tests
(Grade A ,EL 4 )
• Serum total testosterone (cut off 60 ng / dl )
• OGTT ( zero, two hrs after 75 gm glucose load)
• Serum 17 - hydroxy progesterone (done at 8 am)
• Serum TSH
• Serum prolactin levels
PCOS is a Diagnosis of Exclusion

25. Management

26. Lifestyle modification forms the
first step

27. Lifestyle modifications: Diet control
• Eat healthy, balanced diet consisting of calorie-
restricted meals (reduced by 500 Kcal/day) (Grade
B, EL 2)
Diet
• Do not STARVE … No CRASH DIET
• Foods with low glycemic index
• Eat small quantities at regular intervals
• Routinely screen for BMI and waist
circumference as an index for increasing adiposity
and development of hyperandrogenism (Grade A,
EL 3)
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research. Jan-Jun 2014;

28. Lifestyle Modifications:
Aim to spend 1,000 - 2,000 kcal/week
EXERCISE
• Daily strict physical activity (either exercise or
yoga) for at least 30min/day or 150min/
week (to reduce at least 5% of initial body weight
(Grade A, EL 4)
ROLE OF
YOGA
• Yoga is recommended as a part of lifestyle
management work up (Grade B, EL 3)
Malik et al. Good Clinical Practice Recommendations on Management of Infertility in Patients with Polycystic Ovary Syndrome
from India. Fertility Science & Research. Article in Press.

29. Pharmaco
-therapy
• PCOS patients with subfertility who are
morbidly obese (BMI >35 kg/m2),
pharmacological methods of ovulation
induction should be avoided before
weight reduction (Grade B, EL 4)
• Treatment with orlistat is recommended
under medical supervision in an event of
unsuccessful weight reduction , diet and
exercise alone for 2-3 months in
morbidly obese patients (Grade B, EL 1)
Malik et al. Good Clinical Practice Recommendations on Management of Infertility in Patients with Polycystic Ovary Syndrome
from India. Fertility Science & Research. Article in Press.
Lifestyle Modifications:
Recommendations

30. Bariatric
Surgery
• Bariatric surgery is recommended as second-
line treatment in morbidly obese (BMI >35
kg/m2) subfertile PCOS patients who are
unsuccessful in achieving weight reduction by
lifestyle modifications (Grade B, EL 4)
• In PCOS patients with BMI >50 kg/m2,
bariatric surgery is suggested as first-line
therapy for weight reduction (Grade B, EL 4)
• It is recommended to avoid conception for at least 12
months after bariatric surgery (Grade B, EL4)
Malik et al. Good Clinical Practice Recommendations on Management of Infertility in Patients with
Polycystic Ovary Syndrome from India. Fertility Science & Research. Article in Press.
Lifestyle Modifications:

31. SUCCESS RATE
Lifestyle (LS) - 3-5%
LS + Pharmacotherapy - 5-15%
LS + Surgery – 50 – 65%
Years

32. Recommendations For
Management Of
Pcos-related
Menstrual Irregularity

33. In Adults with Menstrual Irregularity
• Recommended to include
progesterone withdrawal
bleeds as first line therapy till
menopause to avoid the risk
of endometrial proliferative
disorders (grade A,EL 4)
• COC containing drospirenone
and desogestral are preferred
(Grade A, EL 1)
• Drospirenone is more
beneficial than desogestrel in
Indian conditions
• Metformin is not
recommended as first line
therapy (Grade A, EL 4)
• Spironolactone is not
recommended for menstrual
irregularity

34. In Adolescents with Menstrual Irregularity
• Use low dose COC,s
with or without anti –
androgenic progestins -
drospirenone &
desogestrel
• Between 12 – 16 yrs
Progesterone only pills
to be used for a short
period (upto 7 days)
• After 16 yrs low dose
COC,s to be used
(Grade A ,EL 4)

35. In Both Adults &
Adolescents
• If no impovement with COC,s or if COC,s are not
tolerated it is recommended to use insulin
sensitizers such as metformin with or without
progestins but not thiazolidnediones (Grade A ,EL 2 )
• Duration of metformin for ovulatory dysfuntions in
adolescents has not been established

36. Evidence-based Management
of Hyperandrogenism
in PCOS

37. Management Biochemical & Clinical
Hyperandrogenism requires long term
& multidimensional treatment
• Management of Acne
• Management of Hirsutism
• Management of Alopecia

38. Recommendations for management Acne
Oral COCs with anti androgen progestins as first
line therapy for all types of acne, in consultation
with a dermatologist (Grade A, EL 1)
Cyproterone acetate is more beneficial than other
progestins in Indian conditions
Topical medications can be used along with
pharmacological therapy (Grade A, EL 4)
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research 2014;
Anti-androgen Progestins: Cyproterone acetate, Drospirenone, Desogestrel

39. Acne Management
Clinical Evidence
Significant reduction in Acne scores with Cyproterone acetate at the end of 4 months
No significant change was found in the Medroxyprogesterone acetate arm
Chung et al. A Randomized crossover study of Medroxyprogesterone acetate and Diane-35 in adolescent girls with Pcos J Pediatr Adolesc
Gynecol. 2014

40. Treatment Algorithm:Acne
Acne
• Topical retinoids: comedones alone
• Topical antibiotic + retinoids: mild to moderate severe
inflammatory acne with papules and pustules
• Oral antibiotics: moderate to severe inflammatory acne
• Oral isotretinoin: papulonodular acne
Frequent relapse of acne/scarring/severe psychological disturbances
Oral isotretinoin
Treatment failure

41. Recommendations for Management
of PCOS related Hirsutism in adults
• Use of direct hair
removal methods along
with COCs with anti
androgen progestins are
recommended as first
line therapy
(Grade A, EL 1)
• Cyproterone acetate
is more beneficial in
Indian conditions
• No improvement or
intolerance to COCs
• Spironolactone or
Finasteride suggested
(Grade A, EL 2)
• Stop 6 months before
planning pregnancy
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research. Jan-Jun 2014

42. Adolescents With Hirsutism, Obesity
& Signs Of Insulin Resistance
• Lifestyle modification is first-line
• Metformin is second-line therapy with a wait
period of 2 years post-menarche
(Grade A, EL 4)
• If glucose intolerance is not established by OGTT
,metformin should not be given (Grade B, EL 4)
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research. Jan-Jun 2014

43. Hirsutism Management:
Comparison of different Progestins
0 1 2 3 4 5 6
Cyproterone acetate
Drospirenone
Desogestrel
5.29
2.12
1.69
Decrease FG Score
Cyproterone Acetate
shows the strongest anti-
androgenic activity after
12 cycles
Bhattacharya SM, Jha A. Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone
in patients with polycystic ovary syndrome. Fertil Steril. 2012 ;98(4):1053-9 a.
* FG Score: Ferrimen Gallway Score for Hirsutism
(n =58)
(n = 56)
(n =57)
171 pts

44. Hirsutism:
Role of Cyproterone acetate
0
20
40
60
80
100
Face Chest Abdomen Legs
100
62.5
81.2 81.2
45.4
9.1
40.9 40.9
%Patients
Baseline 12 cycles
2 mg cyproterone acetate + 35 mcg ethinyl estradiol
effectively reduce mean FG scores (14.3 to 5.7)
Golland IM, Elstein ME. Results of an open one-year study with Diane-35 in women with polycystic ovarian syndrome. Ann N Y Acad Sci. 1993 May 28;687:263-71.

45. Bhattacharya et al 2012
At the end of 12 months, CPA significantly decreased the
Free Androgen Index as compared to Desogestrel
0
2
4
6
8
10
12
CPA Drospirenone Desogestrel
FreeAndrogenIndex
Effect of drugs on Free Androgen Index
At start of therapy
After 12 months
Bhattacharya et al. Comparative study of therapeutic effects oral contraceptive pills containing desogestrel, cyproterone acetate and drospirenone in
patients with polycystic ovary syndrome. Fertil Steril. 2012
Current Indian Evidence

46. Recommendations
Management of Alopecia in PCOS
Alopecia
• In women with PCOS presenting with
alopecia, COCs and androgen
blockers are recommended as first line
therapy (Grade B, EL 3)

47. When to stop ???
The ideal time to stop hormonal therapy for
hyper androgenism cannot be established
with existing evidence (grade A, EL4 )
If Risk of thromboembolism , identify susceptible
patients , pause treatment for 3 months after
one year of treatment

48. Due to insufficient evidence alternative and
complimentary therapeutic options like
acupuncture , myoinositol ,omega 3 fatty acids
are not recommended (Grade B, EL4)
Alternative Therapy

49. PCOS-
related
Infertility

50. PCOS-related Infertility
ESHRE Recommendations ACOG Recommendations
1. Obesity adversely affects reproduction and is associated with
anovulation, pregnancy loss, and late-pregnancy complications.
• Weight loss before infertility treatment improves ovulation rates in
women with PCOS, but there are limited data that it improves
fecundity or lowers pregnancy complications.
• Treatment of adverse lifestyles, including obesity and physical
inactivity, should precede ovulation induction
• The best diet and exercise regimens are unknown, but caloric
restriction and increased physical activity are recommended
2. Clomiphene citrate remains the treatment of first choice for
induction of ovulation in most anovulatory women with PCOS
3. At present, use of metformin in PCOS should be restricted to those
patients with glucose intolerance
4. Low-dose FSH protocols are effective in achieving ovulation in
women with PCOS, but further refinement is needed to better
control the safety of these regimens
5. Laparoscopic ovarian surgery is an alternative to gonadotropin
therapy for CC-resistant anovulatory PCOS
1. An increase in exercise combined with dietary change
has consistently been shown to reduce diabetes risk
comparable to or better than medication (Level A)
2. Improving insulin sensitivity with insulin-sensitizing
agents is associated with a decrease in circulating
androgen levels, improved ovulation rate, and improved
glucose tolerance (Level A)
3. The recommended first-line treatment for ovulation
induction remains the antioestrogen clomiphene citrate
(Level A)
4. If clomiphene citrate use fails to result in pregnancy, the
recommended second-line intervention is either
exogenous gonadotropins or laparoscopic ovarian
surgery (Level B)
5. A low-dose regimen is recommended when using
gonadotropins in women with PCOS (Level C)

52. Infertility
Estrogen modulators
•Clomiphene citrate
•Letrozole
CC resistant/failure
•Low-dose gonadotropins
•Glucocorticoids
Insulin sensitizers
•Metformin + CC
• Metformin (if BMI ≥30 kg/m2 to
prevent OHSS
•Laparoscopic surgery +gonadotropins
•Bariatric surgery if BMI ≥35 kg/m2
First-line
Second-line
Third-line
No improvement
No improvement
PCOS-related Infertility: Management Algorithm

53. Metabolic Syndrome : PCOD
Important Public Health Problem

54. Management of NAFLD and NASH in PCOS
• Provide with sufficient
awareness on symptoms
and complications of
NAFLD & NASH
(Grade B, EL 4)
• Carry out screening in pts
with insulin resistance &
metabolic syndrome
(Grade B, EL 4)
• Rx with vitamin E is
preferred (GradeB,EL 1)
• Metformin is not
suggested for reduction
of metabolic syndrome
(GradeB, EL 1)
Liver Involvement Should Be Managed Aggressively
With A Multidisciplinary Approach(grade B, EL 1)

55. Metabolic Syndrome
• C e n t ra l
O b e s i t y
• H y p e r t e n s i o n
• D i a b e t e s
M e l l i t u s
• D y s l i p i d e m i a
HYPERURICEMIA
NASH
NAFLD

56. Metabolic Syndrome: Diabetes Mellitus
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research. Jan-Jun 2014; 1(1): 23-4
Screen for
impaired
glucose
tolerance &
T2DM using 75
gm OGTT
(Grade A, EL 2)
Women with
impaired glucose
tolerance or
T2DM
Metformin alone
or in combination
with oral
contraceptives
(Grade A, EL 1)
Early referral
to specialist
for timely
management
& prevention
of its
complications
(Grade A, EL 4)

57. Management of cardiovascular risk in PCOS
Risk Factors
• Obesity
• Smoking
• Hypertension
• Dyslipidemia
• IGT
• C- reactive protein
• Homocysteine
• Family h/o CVD
High Risk Factors
• Metabolic syndrome
• T2DM
• Overt vascular disease
• Overt renal disease
Screen for cardiovascular disease by assessing risk factors
(Grade A, EL 1)

58. Management of cardiovascular risk in PCOS
Repeat lipid profile &
OGTT at 6 months for
borderline risk & one
year for normal profile
patients
(Grade B , EL 4 )
Specialist care is
needed in all patients
with risk factors
irrespective of the
severity of symptoms
(Grade A, EL 4)

59. Guidelines for management of Endometrial Cancer
Women without abnormal bleeding: routine
screening using TVS not recommended
(Grade B, EL 1)
Women with unexpected bleeding/ spotting: TVS
assess endometrial thickening (Grade B, EL 4)
India: Endometrial thickness > 4 mm using TVS is
taken as cutoff
Regular oncologic referrals for screening
(Grade A, EL 4)
Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility Science & Research. Jan-Jun 2014; 1(1): 23-4

60. To reduce the risk of Endometrial Cancer
• Progestogens: Induce withdrawal bleed every 3 to 4 months
(Grade B, EL 3)
• Metformin: Reduce atypical endometrial hyperplasia
• Metformin + CPA: Showed normal epithelia with no evidence of
endometrial carcinoma
Progestogens or metformin reduce endometrial cancer risk
1. Chittenden et al. Reprod Biomed Online. 2009;19:398–
405.
2. Haoula et al. Hum Reprod. 2012;27:1327–1331.
3. Wild et al. Hum Fertil Camb. 2000;3:101-5
4. Roy et al. J Hum Reprod Sci. 2012; 5(1): 20–25
5. Saxena et al. J Endocrinol Metab. 2012;16:996–999.
6. Kar et al. J Hum Reprod Sci. 2012;5(3):262-5.
7. Cheung et al. Obstet gynaecol. 2001 ;98(2):325-31.
8. Session et al.Gynaecol Endocrinol 2003;17(5):405–7.
9. Shen et al. Obstet gynaecol 2008;112 (2 pt 2):465–7.
10. Legro et al. Am J Obstet gynaecol 2007; 196:402.
11. Li Xi et al. J Cancer. 2014 Jan 28;5(3):173-81.

61. Management of depression and
psychosocial dysfunction in PCOS
Depression
• Should be routinely
screened for depression and
anxiety with appropriate
psychological instruments
(Grade B, EL 3)
• Psychological Counseling by
appropriate professional
(Grade B, EL 4)
Other Psychosocial Dysfunction
• When positive for any
psychosocial dysfunction
more detailed counseling
(Grade B, EL 4)

62. Management of obstructive sleep
apnea
• Routinely screen for OSA and insomnolence
• Sleep Study if required
• Refer to appropriate institution for treatment
Loud Snoring , Day Time Sleepiness , Morning Headaches
Indicates OSA

63. Indian story ends …….
GCPRs put forth by IFS
is a path breaking
effort to streamline the
management of PCOS
which will go a long
way in handling the
uniqness of our Indian
pts

64. ADDRESS
11 Gagan Vihar, Near
Karkari Morh Flyover,
Delhi - 51
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