Dr. SK Wangnoo and Dr. D Sahu, as part of an exclusive Endocrinology series, expatiate on Polycystic Ovary Syndrome (PCOS) and share their expert commentary on the long-term management of the condition.

Polycystic ovary syndrome (PCOS) was first described by Stein and Leventhal in 1935 as a gynaecological disorder. It is however, a complex endocrinopathy in women of reproductive age group owing to its association with multiple metabolic comorbidities. It is usually characterised by a gamut of conditions i.e., hyperandrogenism, anovulation, menstrual irregularities, insulin resistance and/or the presence of multiple ovarian cysts. High incidence (42-73%) of spontaneous abortions in PCOS women has also been reported. These multiple endocrinopathies associated with PCOS, not only impose a financial burden on the individual patient but also drains the public health resources, more so in India which has a higher population of young women.

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Diagnosis of PCOS- Current practices

Although, there is no solitary criterion for the diagnosis of this syndrome, it is diagnosed based on a combination of the results of clinical, laboratory, and ovarian morphology in ultrasound. The clinicians have enumerated various criteria for diagnosis including NIH (1990), Rotterdam (2003) and AE-PCOS criteria; the Rotterdam criteria however, has been found to be more inclusive and is generally preferred.

Worldwide, prevalence rates of PCOS have ranged from 2.2% to 22.5%. Prevalence rates of PCOS vary widely among Asian communities with prevalence of 2.2% in Chinese, 5.29% in Thai, 15.2% in Iranian, and 6.3% in Sri Lankan. In comparison to western communities and other Asian communities, Indian women have been reported to have a higher prevalence of PCOS. The prevalence rate of PCOS in Indian women ranges between 3.7 to 36%.

The clinical manifestations of PCOS include oligomenorrhoea, hirsutism, excessive acne, and hair loss. In adolescence, it also causes significant psychiatric disturbances such as anxiety and depression.

PCOS is the leading cause of anovulatory infertility in women. The metabolic consequences include impaired glucose tolerance, type 2 diabetes, obesity and increased risk of cardiovascular diseases. Metabolic complications and increased cardiovascular morbidity were found to be more in the classic PCOS compared to other phenotypes, even after adjustment for obesity. Hyperandrogenic phenotypes of PCOS were found to be more prone to metabolic complications as compared to the phenotypes with normal androgen levels.

Clinicians now have three sets of criteria to choose from, though the Rotterdam criteria are found to be preferred.

According to the Rotterdam criteria, a diagnosis of PCOS can be made in the presence of at least two out of the following three abnormalities: hyperandrogenaemia/hyperandrogenism, oligo-anovulation, and PCO morphology on ultrasound.

• Hyperandrogenemia is the presence of elevated levels of serum testosterone and clinical hyperandrogenism is suggested by the presence of hirsutism, acne, and/or androgenic alopecia.
• An objective assessment of hirsutism can be done using modified Ferriman-Gallway score by grading of hair growth in nine specified body areas- a score of eight or more suggests significant hirsutism.
• Polycystic ovaries are defined by the presence of 12 or more follicles of 2 to 9 mm diameter and/or ovarian volume of >10 ml in at least one or both ovaries.

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Shortcomings of the PCOS diagnostic criteria

1. First, the criteria have not been validated in adolescents. While oligomenorrhoea and acne are more common in adolescents for several months after menarche, there is also lack of well-defined cut-off for androgen levels during pubertal maturation. However, owing to the long term metabolic and reproductive complications, early diagnosis and initiation of therapy is paramount and outweighs the harms and burden of a misdiagnosis.
2. Second, obesity, insulin resistance, and hyperinsulinaemia are common findings in adolescents with hyperandrogenism. Hence, these features should not be used to diagnose PCOS among adolescent girls.

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PCOS is a disease with a complex multipronged pathogenesis which is still under investigation

The various pathogenetic mechanisms of PCOS include abnormal gonadotropin-releasing hormone (GnRH) regulation leading to increased luteinising hormone (LH) and decreased follicle stimulating hormone (FSH); decreased response of ovarian follicles to FSH; increased anti-Mullerian hormone (AMH); follicular arrest and increased secretion of testosterone, estradiol and dehydroepiandrosterone (DHEA). Obesity, especially abdominal fat deposition, is the major predisposing factor for the expression of IR and metabolic phenotype in PCOS.

The prevalence of abnormal glucose tolerance detected by oral glucose tolerance test (OGTT) was found to be high (around 35%) in a large number of young Indian women with PCOS. Studies have consistently demonstrated the relationship between the well-known manifestation of hyperandrogenism among Indian PCOS women and the metabolic morbidities including insulin resistance (IR), glucose intolerance and cardiovascular risk in this population.

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Management of PCOS- As complex as the condition itself

The management and treatment of PCOS include a healthy diet, regular physical activity, and medications, which address the associated manifestations and co-morbidities. PCOS management strategies mainly aim at resolving the four major components of PCOS including regularity of menstrual cycle, control of hyperandrogenism (acne and hirsutism), management of infertility and insulin resistance (IR) along with its associated risk factors (type 2 diabetes mellitus, hyperlipidaemia, and obesity). Both non-pharmacological and pharmacological management strategies are important in the overall management of PCOS.

Exercise therapy alone or in combination with dietary interventions should be advised for the management of weight gain and obesity. It can also lead to improvement in cardiovascular risk factors. Thirty minutes per day of moderate to vigorous physical activity leads to reduction in the risk of diabetes and metabolic syndrome. Though randomised clinical trials for the effect of exercise in PCOS are lacking, sustained weight loss, as little as 5%, has been associated with improvement in hyperandrogenaemia and metabolic parameters in obese women with PCOS.

1. Hormonal contraceptives (HCs) are the mainstay in the treatment of menstrual irregularities and hirsutism in women with PCOS. They act by suppressing LH levels and therefore, ovarian androgen production as well as reducing bioavailable testosterone levels. In addition, some progestins have additional anti-androgenic activity, though studies have not demonstrated any significant difference in outcomes with various HCs.

In a randomised, single-blinded, dose-comparison study, Bhattacharya et al. [1] reported that OCP containing 20 μg ethinyl estradiol (EE) with drospirenone had similar effects on free androgen index in PCOS women as that containing 30 μg EE with drospirenone. However, it is important to screen women for the presence of any contraindications for therapy with HCs such as smoking, high blood pressure, or uncontrolled diabetes mellitus.

2. Metformin is also a widely-used therapy for PCOS. Endocrine societies recommend metformin in women with PCOS who have type 2 diabetes (T2DM) or impaired glucose tolerance (IGT) who fail lifestyle modifications and second-line treatment in women with PCOS having menstrual irregularities who cannot tolerate HCs. It has not been shown to have significant benefit in cutaneous manifestations of PCOS. Combinations of metformin and HCs have also been tried in women with PCOS.
   1. A six-month, open-label, randomised trial by Ganie et al [2], of low-dose spironolactone and metformin combination than either drug alone, showed the superiority of the former in terms of improved clinical parameters and compliance to treatment.
   2. A comparison of metformin and OCP (EE plus drospirenone) was done as a prospective observational study (n=46) over one year by Suvarna et al [3], and metformin alone was found to be equally effective in regularising menstrual cycles and treating hyperandrogenism in Indian women with PCOS.
   3. Use of non-hormonal options i.e., metformin and spironolactone, after a period of oral contraceptive use, was retrospectively studied by Kulshreshtha et al [4], in a small group of women with PCOS for regularisation of their menstrual cycles. They concluded that 75 per cent of women achieved regular cycles with non-hormonal treatment within one year of stopping OCPs.
3. Clomiphene citrate has been recommended as the first-line treatment for infertility in women with PCOS by the Endocrine Society. Metformin can also be used as an adjuvant to clomiphene for the prevention of ovarian hyperstimulation syndrome (OHSS) in women with PCOS though no improvement in live birth rates has been shown. Letrozole, an aromatase inhibitor has been shown to have superior live birth rates as compared to clomiphene that has been recommended by American College of Obstetricians and Gynecologists (ACOG) as first-line therapy for ovulation induction in women with PCOS.
4. Other drugs that have been tried but have shown to have limited or no benefit in include insulin sensitisers such as inositol and thiazolidinediones and statins.

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To conclude, the various metabolic, inflammatory, and autoimmune components including the obesity-related cytokines and oxidative stress markers in relation to the pathogenesis of PCOS highlight the multifaceted nature of the disorder and the need for further research into the subject to better delineate the contribution of each of these markers and mediators in the final expression of PCOS.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The authors of this article are practising Endocrinologists- Dr. Danendra Sahu, Consultant Endocrinologist, Apollo Centre for Obesity, Diabetes & Endocrinology (ACODE), New Delhi and Dr. Subhash Kumar Wangnoo, Senior Consultant Endocrinologist, Indraprastha Apollo Hospital, New Delhi.