Management of Polycystic Ovary Syndrome in India

Existing Guidelines:

Currently, no strategy for stratifying the risk of PCOS in the general population has been suggested by any major guidelines. The clinical practice guidelines from Endocrine society, USA,^[29] PCOS Australian alliance, Australia,^[30] The Royal College of Obstetricians and Gynecologists (RCOG), UK,^[31] and Society of Obstetricians and Gynecologists of Canada (SOGC), Canada^[32] have not proposed a system of risk classification in general population. However, in Indian clinical practice a preliminary assessment of risk in general population is likely to help in further referrals to higher medical centers for appropriate diagnosis and management. Such a risk classification is only to help in a preliminary assessment and not to posit an alternative scheme of diagnosis; in primary care settings such a risk classification is likely to help in proper channeling of patients to specialized centers for systematic diagnosis.

Recommendations on risk factors for assessment of PCOS

• It is recommended that Indian women showing at least one biochemical characteristic in conjunction with one clinical symptom should be considered for further evaluation for the likelihood of PCOS (Grade A, EL 3).

  1. Biochemical characteristics: high BMI for overweight/obesity >23 kg/m² for adults and > 97.5 ^th percentile for age in adolescents), insulin resistance (aconthosis nigricans as clinical marker of insulin resistance), family history of diabetes or PCOS, obesity and inadequate lifestyle, any marker of lipid metabolic dysregulation (elevated serum total cholesterol, triglyceride and LDL-C levels),

  2. Clinical symptoms: pubertal deviations (early or late), disturbances in periodicity/ timing of menstrual cycle, presence of PCO and clinical signs of hyperandrogenism such as early acne or hirsutism, persistent severe acne, frequent relapse in acne, acne in facial 'V' area, persistent acne and hirsutism for more than two years

• In women suspected to have PCOS, it is recommended to screen and appropriately document all clinical and biochemical risk factors in the case history (Grade A, EL 4).

• It is recommended that patients who currently show either a clinical symptom or fit into a biochemical characteristic may be referred for further diagnosis when feasible or should be regularly monitored for appearance of other presentations of PCOS (Grade A, EL 4)

• It is recommended that individual patients with two or more clinical risk factors be subjectively assessed by the gynecologist and referred to an appropriate healthcare provider for further diagnosis of PCOS (Grade B, EL 4).

Biochemical hyperandrogenism

Biochemical hyperandrogenism is a measure of androgen levels, determined by total, bioavailable, or free serum testosterone (T) levels.^[36] In addition, the free androgen index (FAI=100 x [total testosterone/ Sex hormone-binding globulin]) is also widely used.^[30] However, total serum T levels are considered more reliable and suitable for diagnosing androgens status.^[3,37] Given the methodological challenges, variability in T levels during pubertal development,^[38] and uncertainty in clinical practice^[39] defining absolute values using local assays that are diagnostic of PCOS and/or to exclude other causes of hyperandrogenism is preferable. Further, since the physiological T levels alter with pharmacological agents used for induction of periods, diagnosis of AE should not be carried in these subjects.

Clinical hyperandrogenism

Clinical hyperandrogenism includes hirsutism, acne, and androgenic/ central alopecia.^[30]

A. Hirsutism: Hirsutism is the excessive growth of thick, dark terminal hair in women where hair growth is normally absent.^[40] The modified Ferriman-Gallwey (mFG) score is used to grade hirsutism,^[41] which is also used in India.^{[37,42,43,44]} A score of 0 (none) to 4 (severe) in nine areas of the body is assigned with a maximum possible score of 36. Scores < 4 indicate mild hirsutism, 4-7 indicate moderate hirsutism, ≥ 8 indicate severe hirsutism.^[40,41] In addition, presentation of AN with or without obesity is suggested an additional diagnostic criteria in adults and adolescents [Figure 2].

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Figure 2

Treatment algorithm for acne, based on endocrine evaluation-Recommendation of Indian Acne Association

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B. Acne: Acne can be graded as mild, moderate, and severe forms of acne, based on the number and types of inflammatory lesions [Appendix Table 1]. The prevalence of acne varies in relation to age and ethnicity. In girls, acne starts between 12-14 years of age, and in boys between 14-16 years of age.^[45] A description of the location and type of acne lesions according to the age group, as described by the Indian Acne Association (IAA) is presented in Appendix Table 2.

Among the different variants of acne, the SAHA syndrome (seborrhea, acne, hirsutism, alopecia) denotes acne specific to endocrine abnormality of a subject. When diagnosing PCOS in adolescents, acne, a common and transient feature^[46] should not be interpreted in isolation, as is the case with androgenic alopecia.^[47]

C. Alopecia: Androgenic/central alopecia may also be presented as female pattern hair loss in some patients with PCOS. Ludwig score is used to grade androgenic alopecia.^[48]

Existing guidelines

The clinical practice guidelines from Endocrine society, USA,^[29] PCOS Australian alliance, Australia,^[30] The RCOG, UK,^[31] and SOGC, Canada^[32] endorse the Rotterdam criteria for the diagnosis of PCOS. However, all guidelines advocate that specific phenotypes leading to diagnosis of PCOS be documented in all research studies and clinical care.

Recommendations for the diagnosis of PCOS in adults and adolescents

• In women with PCOS, for the objective assessment of cutaneous manifestations such as hirsutism, acne and androgenic alopecia, Indian specific grading should be performed with appropriate scales and possibility of other etiologies should be excluded (Grade B, EL 3)

Current Evidence

Studies on PCOS from India reported a prevalence rate of 37.5%^[66] to 62.5%^[37] for obesity in patients with PCOS. A family history of obesity is also associated with PCOS phenotype.^[67] Obese women with PCOS have a higher incidence of characteristics of MS (hypertension, impaired glucose tolerance (IGT) and type 2 diabetes Mellitus (T2DM) as well as higher odds of irregular menstrual cycles and clinical hyperandrogenism than lean women with PCOS.^[66] Despite lack of large RCTs, the benefits of physical activity (at least 150 minutes of per week) in improving metabolic status and reducing the incidence of diabetes in high risk groups of general population have been demonstrated in small controlled studies.^[68,69]

In Indian adolescents with PCOS, compared to controlled (C) treatment with physical exercise, holistic yoga (Y) was found to significantly reduce the T levels (Y=-6.01, C=+2.61, p = 0.014), mFG score for hirsutism (Y=-1.14, C=+0.06, p = 0.002), and improved menstrual frequency (Y=0.89, C=0.49, p = 0.049).^[70]

Another RCT on adolescents with PCOS from India found significantly improved fasting insulin and glucose levels, HOMA-IR, and lipid values, independent of their anthropometric changes, with yoga practice compared to conventional physical exercise.^[71]

Existing guidelines

Clinical practice guidelines from Endocrine society^[29] and RCOG^[31] suggest exercise therapy in the management of weight and obesity in PCOS.

Recommendations on non-pharmacological management of PCOS- physical activity

• In adults and adolescents with PCOS, daily strict physical activity sessions for at least 30min/day or 150min/ week are recommended (Grade A, EL 4).

Current evidence

While the benefits of diet control on obesity and IR in PCOS have been widely reported, data from RCTs, especially in Indian women is limited. Women with PCOS have been reported to have higher prevalence of central obesity.^[72] In women with PCOS and obesity, weight loss through diet control has been shown to improve pregnancy rates, normalize hyperandrogenemia,^[64,73,74] improve insulin sensitivity, menstrual functions, and hirsutism.^[73,75]

However, no PCOS- specific diet has been reported. Therefore, it is essential to consult dietician for optimal weight management in women with PCOS. In patients with weight loss response after lifestyle modification + calorie-restricted diet as first-line therapy, weight neutral, insulin sensitizer drugs such as metformin can be used as second-line therapy.

Existing guidelines

The clinical practice guidelines from Endocrine society,^[29] RCOG^[31] and PCOS Australia alliance,^[30] suggest using low calorie diet as first-line therapy for the management of obesity in PCOS.

Recommendations on non-pharmacological management of PCOS- dietary

• For the management of obesity in adults (BMI > 23 kg/m²) and adolescents (BMI > 97.5 ^th percentile for age) with PCOS, it is recommended to follow lifestyle modifications in combination with healthy, balanced diet consisting of regular, calorie-restricted meals (Grade B, EL 4).

• In adult and adolescent women with PCOS, it is recommended to routinely screen for BMI and waist circumference as an index for increasing adiposity and development of hyperandrogenism (Grade A, EL 3).

• It is recommended to follow calorie restricted diet (low carbohydrate and fat, high protein) in consultation with dietician and lifestyle modification as first-line therapy for at least 6 months, then add metformin as second-line therapy (Grade B, EL 4).

Current evidence

In women with (MI), proliferation of endometrium can be inhibited using either cyclic progestin or combined oral contraceptives (COCs: estrogen + progestin). Low-dose COCs (< 50 mcg of estrogen in combination with a progestin) have been the mainstay of treatment for MI in patients with PCOS not willing to conceive. In order to reduce the risk of endometrial proliferative disorders, progesterone withdrawal bleeds are generally accepted as first-line therapy to ameliorate cycle regularity in women with PCOS. Three issues have to be considered while choosing a COC: type of progestin compound used, type of estrogen compound used (usually 30 mcg ethinyl estradiol [EE]), and dosage of progestin and estrogen compounds in combination.^[76]

Current evidences from India in the management of MI in women with PCOS are available on COCs with two progestin components- drospirenone and desogestrel. The effects of two COCs 3 mg drospirenone vs. 0.15 mcg desogestrel (in combination with 30 mcg EE) on MI in women with PCOS were compared for 6 month treatment period and 6 months post-treatment.^[42] Although patients from both groups achieved menstrual regularity during the treatment, higher proportion of patients from drospirenone group continued to have regular cycles (44.8%) than desogestrel group (17.2%) at 6 months post-treatment (p < 0.01). In another study, drospirenone group was effective in reducing the hirsutism score in patients with both MI and.^[42] Overall, drospirenone containing COCs are more efficient compared to desogestrel containing COCs because of its anti-androgenic effects on menstrual cycle regularity, lipid profile, Blood Pressure(BP), and hormonal profile.^[42] Besides drospirenone and desogestrel, other progestins commonly used in India for clinical practice, either as cyclic progestin or COCs, for the management of MI in women with PCOS include natural micronized progesterone, dienogest, nor-ethisterone and the levonorgestrel- intrauterine system (LNG-IUS).

Since there is limited evidence of use of COCs in adolescents with MI, physician discretion is needed to judge the long-term effects of estrogen component during normal pubertal development. With clinical experience on patients with PCOS pan-India, the expert panel has suggested use of only low-dose COCs for short-periods (up to7 days) to attain MI in 12-16 year old patients. In this age group, MI was defined as achievement of at least 4 cycles/ year. Similarly, in adolescents above 16 years of age, use of low-dose COCs is permissible for the management of MI.

The AE in women with PCOS is also linked to IR and consequent hyperinsulinemia,^[77] driving the use of insulin sensitizers such as metformin^[78] and thiazolidinediones^[79] in the management of PCOS. The effects of metformin on glucose homeostasis and improved cycle pattern are mainly attributed to increased insulin sensitivity.^[80] Metformin in combination with a low-dose anti-androgen (spironolactone) was more beneficial than either drug alone in improving MI in adult women with PCOS, presenting with oligo-/amenorrhea, hyperandrogenism and PCO morphology.^[81,82]

However, metformin monotherapy for six months resulted in regular menses within 4 months of treatment, but a consistent reversal towards pre-treatment conditions was observed within 3 months of metformin withdrawal.^[83] Adverse events such as vomiting, nausea, diarrhea, and hyperadrenergic symptoms were reported in patients taking metformin including drug withdrawal in subjects.^[81] Therefore the expert panel recommends against the use of metformin as first-line therapy for MI, but as second-line therapy with or without low-dose COCs, if COCs are not successful or tolerated.

The duration of metformin treatment for treatment of ovulatory dysfunctions in adolescents is not established due to very limited evidence from long-term studies and conflicting evidences from short-term studies. Therefore an extrapolation of evidence from studies conducted in adults may be required to recommend the use of metformin in adolescents. Use of spironolactone alone for the management of MI seems clinically inappropriate, since MI have been reported in 18% patients with low-dose spironolactone (50-100 mg daily) and in 70% patients with high-dose (200 mg daily).^[84,85] In an Indian study, polyuria (> 5%), abdominal pain, MI (> 10%), and dryness of mouth were reported in patients with PCOS taking spironolactone, and caused drug withdrawal in four subjects.^[81]

Existing guidelines

The ACOG recommends low-dose COCs as primary treatment option for improved MI and other menstrual disorders in women with PCOS.^[86] The clinical practice guidelines from Endocrine society,^[29] RCOG^[31] and PCOS Australia alliance,^[30] also recommend use of hormonal contraceptives as first-line therapy for menstrual abnormalities of PCOS. The guidelines from Endocrine society^[29] further recommend screening contraindications to COC use via established criteria set by 'Centers for disease control and prevention (CDC)- US medical eligibility criteria for contraceptive use'.

Recommendations on management of menstrual irregularity in PCOS [Figure 2]

Current evidence

Hirsutism, acne and androgenic alopecia are the clinical symptoms of hyperandrogenism observed in women with PCOS. The AE in women with PCOS is manifested as excessive terminal hair growth and acne.^[87] A prevalence of 44.16% for hirsutism and AN and 20% for acne were observed in PCOS women from India.^[37] Features of clinical hyperandrogenism- hirsutism (33.6% vs. 28%) as well as acne and oily skin (40.6% vs. 22.6%) were found to be significantly higher in obese women with PCOS than lean PCOS women.^[66]

Lifestyle modifications

A recent review comparing minimal or no treatment with lifestyle modifications (diet, exercise, behavioral or combined treatments) in patients with PCOS, reported improved body composition, hyperandrogenism and IR in women with PCOS.^[18] Further, metformin + weight reduction therapy are reported to reduce IR and T levels in women with PCOS.^[88]

Pharmacological therapy

As with menstrual cycles, COCs are first-line agents for pharmacologic treatment of hirsutism in women not willing to conceive.^[76] COCs with anti-androgenic progestins such as cyproterone acetate (CPA), drospirenone, desogestrel are generally used for the management of hirsutism in women with PCOS. Parallel administration of direct (mechanical) hair removal methods ameliorates the condition and reduces the time required.

Treatment with two mg CPA was shown to significantly reduce mean FG scores from (14.3 to 5.7) after 12 weeks of therapy in women with PCOS.^[89] In another study, two mg CPA + 35 mcg EE (for 48 consecutive cycles) demonstrated significant reduction of mFG score (mean FG score 10.4) in 73% subjects.^[90] No significant side effects or patient withdrawal were reported during 48 cycles of therapy, probably due to considerable effects on hirsutism, complete remission of acne, excellent cycle regularity and endometrial control observed with EE/CPA.^[90]

Evidence from India comparing COCs: CPA, desogestrel (deso), and drospirenone (dros) in women with PCOS reporting MI+hirsutism, found that CPA showed the strongest anti-androgen activities with significant decrease in mFG score (treatment difference: CPA -5.29, dros -2.12, deso -1.69) after 12 months of treatment.^[91] In this study, very few patients reported adverse events: desogestrel group- bloatedness and sensation of weight gain, nausea and headache, rise of BP; CPA group- breast tenderness and absence of withdrawal bleeding in the pill-free week; drospirenone group- one patient with nausea, vomiting, and vertigo, another with altered liver function test. Studies on drospirenone (3 mg + 30 mcg EE)^[92] and desogestrel (150 mcg +30 mcg EE)^[91] also demonstrated significant improvement in mFG score (4.6 vs. 6.4) compared to baseline.

In another evidence from India, compared to metformin, spironolactone demonstrated better improvement in hirsutism score (12.5 ± 4.9 and 12.9 ± 3.2 at baseline to 10.0 ± 3.3 and 8.7±1.9, respectively) after 6 months therapy in women with PCOS reporting MI, hirsutism.^[93] Whereas finasteride (5 mg/day), a 5α-reductase inhibitor, in comparison with CPA (25 mg/day on days 5-14) + EE (20 mcg/day on days 5-25) was equally effective in reducing mFG scores after 9 months of treatment.^[94] However, due to the risk of teratogenicity (feminization of male infant) with their use,^[95,96] the expert panel has recommended to cease the use at least 6 months before planned pregnancy. Therefore, spironolactone and finasteride can be used as second-line treatment for the management of hirsutism in patients with PCOS.

Insulin sensitizers

In addition to hormonal therapy, administration of insulin sensitizers can improve the hyperinsulinemic as well as hyperandrogenic state in women with PCOS. However, due to limited evidence on use of metformin in adolescents without established glucose intolerance, the expert panel recommends against its use in adolescents with PCOS. Further, lifestyle modification is better than metformin in improving hyperandrogenism, obesity and signs of IR. Therefore the expert panel recommends lifestyle modification as first-line therapy followed by metformin in adolescents and children. Metformin should be initiated in children only after a wait-period of two years post-menarche.

By virtue of the nature of hyperandrogenism, the source of androgen cannot be eliminated permanently, and evidence suggests that hyperandrogenism requires long-term therapy. Therefore, ideal time to stop the hormonal therapy for hyperandrogenism cannot be established.

Risk of venous thromboembolism

Use of different COCs with varying risks of venous thromboembolism (VTE) is reported in general population.^[97] However evidence in women with PCOS is inconsistent. A recent meta-analysis of trials using either COCs with anti-androgens, or metformin in women with PCOS found that thromboembolic episodes were not reported in any study.^[98] A cross-sectional analysis on a database (2003-2008, US women) observed that PCOS women were more likely to have thromboembolism than those without and reported a protective association (OR 0.8; 95% CI: 0.73-0.98) with use of COCs.^[99] Since there is lack of consistent data on diagnosis and management of VTE specific to PCOS, the expert panel has suggested ways to minimize the risks and maximize the benefits of COC use. It is essential to regularly monitor the risk and provide three months of pause after one year of COC regimen. Investigations used to monitor VTE risk in general population (such as using duplex ultrasonography for deep vein thrombosis and chest X-ray/ ventilation-perfusion scan/ CT pulmonary angiography for pulmonary embolism) can also be adopted in women with PCOS.^[100]

Mechanical hair removal methods

Apart from the pharmacological approaches to deal with hirsutism, temporary and permanent methods of hair removal/ reduction should also be used as first-line therapy for management of hirsutism in women with PCOS. Permanent methods of hair reduction therapy include electrolysis and photo epilation devices such as laser and intense pulsed light. In patients seeking permanent hair reduction therapy, it is essential to initiate pharmacologic therapy to minimize hair regrowth. Temporary hair removal methods such as depilation, epilation, and bleaching are effective in reducing facial hair growth in women with PCOS. In addition, topical treatment with eflornithine, an ornithine decarboxylase inhibitor approved by United states of food and drug administration (US-FDA), is also effective.^[76,86,101]

Topical applications

Based on the clinical presentation of acne in individual patient, specific topical medication for mild and moderate acne, and maintenance therapy should be prescribed in consultation with dermatologist. Benzoyl peroxide, topical retinoids, and topical antibiotics are used as first-line treatment for acne management.

Hormone therapy

Hormone therapy is suggested as first-line therapy for androgenic acne in women with PCOS, SAHA syndrome, HAIRAN syndrome (hyperandrogenism, IR, AN), or cutaneous hyperandrogenism. The IAA consensus guideline further justifies hormonal therapy in refractory/difficult acne and in nodulocystic acne where isotretinoin is either contraindicated or inadequate.^[45] However, due to the multiple causes of acne vulgaris, evaluation of hormonal status is a prerequisite before initiating hormone therapy.^[45]

Treatment with two mg CPA (+35 mcg EE) for 12 cycles significantly reduced acne score in all 41% cases (at baseline), with improved facial acne by the end of third cycle and improved thorax and back acne by end of 6th cycle.^[89] Treatment with CPA/EE combination for 48 cycles demonstrated a complete recovery of various types of acne lesions (moderate 67%, severe 33% cases at baseline) in all subjects (100%) within 24 cycles of treatment.^[90] In a study conducted in Indian women with PCOS, CPA demonstrated numerically higher reduction in acne score (CPA -1.52, drospirenone -1.42, desogestrel -1.41) compared to other pills.^[91] CPA has been well studied as an androgen receptor blocking agent, effective in acne management in females.^[103,104] Higher doses of CPA have been reported to be more effective than lower dose to treat acne.^[102]

In another study, drospirenone (3 mg + 30 mcg EE) containing COC showed significant improvement in acne at six cycles (54.9% vs. 31.4%, p < 0.05) compared to baseline.^[43] Although EE/drospirenone^[43] was administered only for 6 months, the beneficial effects in reducing hyperandrogenic features of hirsutism and acne were maintained up to 12 months after treatment. No adverse effects were reported. Similarly, desogestrel (150 mcg)+ EE 30 mcg) also showed significant improvement in the incidence of acne (54.1% vs. 23.4%) in women with PCOS from India after 6 cycles of treatment.^[44] No adverse effects were reported up to one year with EE/desogestrel also.^[44]

The guidelines issued by IAA recommend hormonal therapy in patients presenting acne with symptoms of SAHA syndrome (with or without irregular cycles) or resistance to conventional therapy/ relapse after isotretinoin therapy along with altered endocrine function. Based on the consensus developed by IAA, hormone therapy with low-dose EE/CPA or high-dose CPA or spironolactone are specifically suggested.^[45]

In adolescents with PCOS, improvement in acne was observed with the use of oral contraceptives with anti-androgen activity. In a latest randomized cross-over trial, therapy with medroxyprogesterone acetate and CPA for four months each,^[105] CPA significantly improved acne score and LH/FSH ratio.^[105] Due to the limited evidence on long-term use of COCs for hyperandrogenic features in adolescents, the expert panel suggested using COCs in adolescents based on the clinical presentation of acne, in consultation with a dermatologist.

A summary of studies conducted in India with COCs containing anti-androgen in progestins (cyproterone acetate, drospirenone, and desogestrel) for the management of hyperandrogenism features is presented in Appendix Table 3.

Existing guidelines

The clinical practice guidelines from Endocrine society,^[29] recommend use of hormonal contraceptives as first-line therapy for management of clinical features of hyperandrogenism such as hirsutism/acne in women with PCOS. The consensus guideline from IAA recommends the use of hormone therapy with low-dose EE/CPA or higher doses of CPA or spironolactone.^[45]

Recommendations for management of Hyperandrogenism in PCOS

Current evidence

Increased rate of depressive symptoms compared to non-BMI matched controls^[112,113] with prevalence ranging from 28 to 64% (for depression) and 34 to 57% (for anxiety) have been reported in women with PCOS.^[114,115] Also, a lower health related QoL^[116] and increased risk of mental depression are reported in women with PCOS.^[113] In Indian women a 54% prevalence of depression (GHQ28 score ≥ 8) was reported, of whom 72% were obese, 70% had hirsutism, 61% had acne and 56% were infertile indicating a considerable effect on QoL of these women.^[117] The Patient Health Questionnaire 9 (PHQ-9) can be used to measure the severity of depression [Appendix Table 4],^[118] whereas the generic Short Form-36 (SF-36)^[119] and disease-specific polycystic ovary syndrome questionnaire (PCOSQ)^[120] are used to assess the health related QoL in women with PCOS [Appendix Table 5].

Existing guidelines

The clinical practice guidelines from Endocrine society^[29] and PCOS Australian alliance, Australia^[30] suggest screening all women with PCOS for depression and anxiety by history and, if identified, provide appropriate referral and/or treatment.

Recommendations on management of depression in PCOS

• In adults and adolescents with PCOS, it is recommended to routinely screen for depression and anxiety with appropriate psychological instruments (Grade B, EL 3).

• In patients with PCOS evaluated with depression and/or anxiety, psychological counseling by an appropriate professional is suggested, based on severity of disease (Grade B, EL 4).

Current evidence

In patients with PCOS, negative self-image coupled with lower self-esteem owing to their physical appearance that significantly impacts the mood and QoL^[121] are observed. Similarly, significantly more patients with PCOS compared to community controls reported eating disorders (12% vs. 4%) and/or social phobia (27% vs. 2%)^[122], which may cause medical, psychological, social and occupational difficulties.^[123,124] Physical manifestations of PCOS such as hirsutism, obesity, MI and infertility can have a negative effect on the patients' sexual life.^[125]

Existing guidelines

The clinical practice guidelines from PCOS Australian alliance, Australia^[30] suggest the screening and assessment of patient's psychosocial dysfunctions and if identified, offer appropriate treatment.

6.1.2 Recommendations on management of other psychosocial dysfunctions in PCOS

• If a woman with PCOS is positive on screening for any psychosocial dysfunction, the practitioner should perform a more detailed clinical interview (Grade B EL 4).

• In those evaluated with any psychosocial dysfunction, appropriate treatment for improvement of quality of life is suggested (Grade B, EL 4).

Current evidence

Diagnosis of PCOS confers a 5- to 10- fold increased risk of developing T2DM.^{[126,127,128]} IR, resulting in hyperinsulinemia also plays a role in the pathogenesis of reproductive disorders in women with PCOS.^[126,129] The prevalence of glucose intolerance in Indian women with PCOS^[93] was reported as 16.3% (adults 19.1%, adolescents 9.7%).^[67]

Due to the risk of IGT, T2DM, and IR in PCOS, evaluation of abnormalities in glucose intolerance at periodic intervals is essential.^[9,31,82] ()A 75-gm (OGTT with 75 g- oral glucose load) has been recommended over measuring glycated hemoglobin (HbA1c) for the detection of T2DM^[130] and fasting glucose^[67] for assessment of IGT.^[2] An observational study from India reported '2-hour post-glucose insulin levels' as a better indicator of IR in women with PCOS than other techniques.^[131]

Lifestyle modification with exercise and diet are the first-line treatment for weight management and impaired IGT in women with PCOS. Due to the inherent IR in this condition, oral anti diabetics (OADs) particularly insulin sensitizers such as metformin are the most promising pharmacological option,^[132]. However, an early referral to specialist diabetological care is recommended for timely management of diabetes and its complications. Metformin alone or in combination with low-dose spironolactone/clomiphene has demonstrated significant alleviation of not only the MI but also glucose tolerance and insulin sensitivity in patients with PCOS.^[81,133]

Existing guidelines

The clinical practice guidelines from Endocrine society, USA recommend screening women with PCOS for IGT test and T2DM using OGTT or HbA1c and suggest rescreening based on development of clinical factors and/or symptoms of diabetes.^[29]

The RCOG suggests fasting blood glucose test or an OGTT for screening of diabetes in women with PCOS. The clinical practice guidelines from Endocrine society recommend use of metformin in women with PCOS with T2DM or IGT and fail lifestyle modification and suggest the same in adolescent stage if the goal is to treat IGT/MS.^[29]

Recommendations for the management of diabetes in PCOS

• In women with PCOS who develop symptoms and/or a risk factor of diabetes, screening at a clinically feasible periodicity is suggested (Grade B, EL 4).

• It is recommended to screen adult and adolescent women with PCOS for impaired glucose tolerance and T2DM using a 75 gm oral glucose tolerance test; an HbA1c test should be used only when an OGTT is not feasible (Grade A, EL 2).

• In women with PCOS who have impaired glucose tolerance or T2DM, it is recommended to use metformin alone, or in combination with oral contraceptives (Grade A, EL 1).

• Early referral to specialist diabetological care is recommended for timely management of diabetes and its complications (Grade A, EL 4)

Existing guidelines

The clinical practice guidelines from Endocrine society, USA,^[29] PCOS Australia alliance, Australia,^[30] RCOG,^[31] and AE-PCOS society^[136] recommend screening women with PCOS for CV risk factors. The clinical practice guidelines from Endocrine society^[29] suggest lifestyle modifications as first-line therapy for CVD and metformin as second line therapy in patients failing to achieve weight reduction with lifestyle modification.^[29] The RCOG guidelines^[31] suggest hypertension should be treated, but recommended against the use of routine lipid-lowering treatment in women with PCOS and risk of CVD. Consultation with specialists has been recommended by other guidelines for prescribing lipid lowering agents.

Recommendations for the management of cardiovascular risk in PCOS

• It is recommended to screen for CV disease in adult women with PCOS by assessing risk factors: obesity (especially abdominal obesity), smoking, hypertension, dyslipidemia (increased LDL-C), vascular disease, IGT, high-sensitivity C-reactive protein, homocysteine, and family history of premature CVD (Grade A, EL 1).

• It is recommended to screen for CV disease in adult women with PCOS by assessing high risk factors: metabolic syndrome, T2DM, overt vascular or renal disease (Grade A, EL 1).

• It is suggested to assess obesity (by BMI and WC), lipid profile, oral glucose tolerance test, and BP in adult women at baseline, and repeat lipid profile and OGTT at 6 months for borderline risk and one year for normal profiles (Grade B, EL 4).

• Specialist CV monitoring and care is recommended in all patients showing CV risk factors, irrespective of the severity of their symptoms (Grade A, EL 4).

Current evidence

A population based cohort study among women with PCOS from Sweden observed that PCOS was strongly associated with pre-eclampsia (adjusted OR 1.45, 95% CI: 1.24-f1.69), preterm birth (2.21, 1.69 to 2.90), more than double risk of GDM (2.32, 1.88 to 2.88), and birth of large for gestational age infants (1.39, 1.19 to 1.62).^[142] The results are further confirmed in an independent meta-analysis by Kjerulff.^[143] Recurrent pregnancy loss (RPL) in women with PCOS is commonly associated with IR,^[144] hyperhomocystinemia (HHcy)^[145] and obesity.^[146] In a retrospective study on RPL, a significantly higher incidence of HHcy (70.63% vs. 57.26%, p < 0.04) and IR (56.34% vs. 6.83%, p < 0.0001) was observed in women with PCOS compared to controls. Further analysis revealed HHcy as a strong plausible factor for diagnosis of RPL than IR (probability percentage: HHcy=43.32%, IR=37.29%). Findings on association of PCOS and GDM are conflicting with respect to BMI. Recent systematic review and meta-analysis in women with PCOS observed a significantly higher risk for development of GDM in PCOS women than those without (OR: 2.89, 95% CI: 1.68-4.98), albeit with significant statistical heterogeneity due to sensitivity analysis (I (2) = 59.3%).^[147] An RCT in women with PCOS treated with metformin found no difference in the prevalence of pre-eclampsia (p = 0.18), preterm delivery (p = 0.12), or prevalence of GDM (p = 0.87) compared to controls during pregnancy.^[148]

A latest meta-analysis of RCTs (n=5) comparing the effects of metformin with insulin on glycaemic control, maternal and neonatal outcomes in GDM concluded that metformin is comparable with insulin and might be more suitable for women with mild GDM.^[149] An observational study from India reported significantly higher benefits of using metformin over insulin in the management of GDM and T2DM.^[150] Although metformin is reported to be comparable with or superior to insulin in terms of glycaemic control and neonatal outcomes, lack of strong evidence on use of metformin in Indian subjects restricts its clinical use.

Existing guidelines

The clinical practice guidelines from Endocrine society, USA^[29] recommend pre-conceptual assessment of BMI, BP and OGTT whereas RCOG guidelines recommend screening for GDM before 20 weeks of gestation, in PCOS women requiring ovulation.^[31] The clinical practice guidelines from Endocrine society^[29] and RCOG guidelines^[31] suggest against the use of metformin as first-line treatment for pregnancy complications in women with PCOS.

Recommendations for the management of pregnancy complications in PCOS

• In women with PCOS planning to have children, it is recommended to screen for markers of obesity, hypertension and IR to reduce the risk of pregnancy related complications (Grade A, EL 3).

• In women with PCOS who have experienced a miscarriage, it is suggested to assess serum homocysteine levels for identification and treatment of hyperhomocystenemia mediated repeated pregnancy losses (Grade B, EL 3).

• In women with PCOS, it is recommended not to use metformin therapy only during pregnancy until specific evidence on beneficial effects is demonstrated (Grade B, EL 3).

Current evidence

Long-term studies and meta-analyses have observed an increased risk of development of EC in women with PCOS.^{[151,152,153]} The symptoms, oligo-/amenorrhea, hirsutism, and infertility, as well as risk factors of PCOS, obesity and T2DM, are common to EC.^[154,155] Evidence for the applicability of transvaginal sonography (TVS) for predicting endometrial hyperplasia has been inconsistent in literature.^{[156,157,158]}

Indian studies on the measurement of endometrial thickness in women with PCOS have routinely used TVS at a cut-off of 4 mm.^{[159,160,161]} In the context of increased risk of EC in PCOS patients with prolonged amenorrhea, abnormal uterine bleeding, obesity and/or diabetes, it is essential to assess endometrial thickness and raise awareness about EC in these women. It has been established that inducing a withdrawal bleed every 3 to 4 months with progestogens can reduce the risk of EC in women with PCOS.^[156] However, since hyperinsulinemia is the primary cause of endometrial hyperplasia, use of insulin sensitizers can reduce the hyperplasia in these women. Overall, for timely detection and management of EC, it is appropriate to screen for development of cancer at regular intervals with reference to oncological specialist.

Existing guidelines

The clinical practice guidelines from Endocrine society^[29] suggest against routine screening for endometrial thickness in women with PCOS. The RCOG guidelines suggest investigating oligomenorrheic women and absence of normal withdrawal bleeds using local protocols such as ultrasound scan, endometrial sampling and/or hysteroscopy^[31] and recommend treatment with progestogens to induce a withdrawal bleed at least every 3-4 months.

Recommendations for assessment and management of endometrial cancer in PCOS

• In women with PCOS without abnormal bleeding, routine screening using TVS is not recommended (Grade B, EL 1)

• In women with PCOS with unexpected bleeding and spotting, it is suggested to assess endometrial thickness using TVS and report the same to the physicians (Grade B, EL 4).

• In women with PCOS and risk of endometrial carcinoma, it is suggested to use progestogens every 3-4 months (Grade B, EL 3).

• Regular oncological referrals, for screening at a clinically feasible periodicity, are recommended for timely detection of endometrial cancer (Grade A, EL 4).

Current evidence

Studies have identified a higher incidence of obstructive sleep apnea (OSA) in women with PCOS compared to controls, even after controlling for BMI.^[162,163] Fasting plasma insulin levels and glucose-to-insulin ratios were strongest predictors for OSA. Therefore factors other than obesity may be involved in the high prevalence of OSA in women with PCOS. Interestingly, a decreased likelihood of OSA was reported in adult and post- menopausal women taking hormonal contraceptives.^[163,164] There is a lack of quality evidence on OSA in women with PCOS from India.

Existing guidelines

The clinical practice guidelines from Endocrine society^[29] suggest screening all overweight/ obese women with PCOS for symptoms suggestive of OSA and, if identified, diagnosed using polysomnography and referred for appropriate therapy. The RCOG guidelines suggest an enquiry of snoring and daytime fatigue /somnolence in all women with PCOS, and educate about the possible risks of OSA, and, if identified, offer diagnosis and appropriate therapy.^[31]

6.6 Recommendations for of obstructive sleep apnea in PCOS

In adult and adolescent women with PCOS, it is suggested to routinely screen for OSA and insomnolence, if symptoms are suggestive of OSA, investigate using polysomnography and refer to appropriate institution for further therapy (Grade B, EL 4).

Current evidence

Ethnicity, increasing age and characteristics of MS (obesity, hypertension, dyslipidemia and diabetes) are risk factors of non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis (NAFLD/NASH).^[165] A 15-60% prevalence of NAFLD is reported in women with PCOS.^{[166,167,168]} A cross-sectional, hospital-based study of women with PCOS from India reported a 67%, 31% and 35% prevalence of NASH, NAFLD and MS, respectively.^[169]

In the absence of other specific factors, serum markers for liver dysfunction (such as alanine amino transferase) may be used to screen PCOS women with co-existent IR and metabolic risk factors. However, because of low specificity and sensitivity of elevated levels of serum alanine amino transferase, diagnosing NAFLD in these women (PCOS with IR and/or MS) may require non-invasive quantification of fibrosis (ultrasound) and liver biopsy.^[170] In view of the potential complications of NAFLD and NASH in women with PCOS having IRand/or MS, early identification and management of NAFLD and MS is essential for overall reduction of effects of MS in PCOS women.

In non-diabetic non-cirrhotic NASH patients^[171] and pediatric NASH patients,^[172] treatment with vitamin E (800IU/day) for 96 weeks demonstrated significant improvement in serum aminotransferase levels, hepatic steatosis, and lobular inflammation (early stage features) but not portal inflammation and hepatic fibrosis (more advanced histologic features). However, based on a meta-analysis^[173] that showed that RCTs with vitamin E and other antioxidants were heterogeneous (with respect to type and dose of drug, treatment duration and follow-up, population [pediatric versus adult], and implementation of lifestyle intervention) a recent review noted a firm conclusion on the effect of vitamin E on NAFLD cannot be made.^[174]

Existing guidelines

The clinical practice guidelines from Endocrine society^[29] suggest against routine screening of NAFLD and NASH but provide awareness of their possibility in women with PCOS.

Recommendations for NAFLD and NASH in PCOS

• In adult and adolescent women with PCOS, it is suggested to provide sufficient awareness on symptoms and complications of NAFLD and NASH and carry out appropriate screening in those diagnosed with insulin resistance and/or metabolic syndrome (Grade B, EL 4).

• In patients with PCOS and NASH, treatment with vitamin E is preferred and metformin is not suggested for reduction of metabolic syndrome with specialist inputs from a multidisciplinary team (Grade B, EL 1).