Metabolic Disorders and Weight Loss Treatment in Polycystic Ovary Syndrome: Clinical Diagnosis, Lifestyle and Adjunctive Interventions

I. Overview of Polycystic Ovary Syndrome (PCOS) Polycystic ovary syndrome (PCOS) is a significant cause of irregular menstruation and excessive androgens in women. When fully manifested, clinical manifestations include irregular menstrual cycles, hirsutism, acne, and often obesity. Most women with PCOS are overweight or obese, and they have a higher than average risk of diabetes and metabolic disorders. Pregnancy in women with PCOS usually requires fertility medication to induce ovulation. Although PCOS cannot be completely reversed, symptoms can be alleviated with treatment. Most women with PCOS lead normal lives without significant complications. The most conservative estimate of PCOS prevalence is around 6%, but the actual prevalence may be closer to 10%. The pathogenesis of PCOS involves abnormalities in the reproductive and metabolic systems. Women with PCOS have multiple small follicles (small follicles with a diameter of 29 mm) accumulating in their ovaries, hence the name polycystic ovary syndrome (PCOS). These small follicles fail to grow to the size required to trigger ovulation. As a result, the levels of estrogen, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) become unbalanced. Androgens are normally produced by the ovaries and adrenal glands, including testosterone, androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS). Normally, the ovaries produce very little testosterone, but production increases in PCOS, possibly due to high levels of luteinizing hormone (LH) and elevated insulin levels in the blood. Insulin stimulates theca cells to secrete androgens. Approximately half of PCOS cases involve insulin resistance and compensatory hyperinsulinemia. Insulin regulates blood glucose levels and is a hormone produced by specialized cells (B cells) in the pancreas. When blood glucose levels rise (e.g., after eating), pancreatic B cells produce insulin to help the body use glucose for energy. If glucose levels do not respond to normal insulin levels, the pancreas produces more insulin. This excessive production of insulin is called hyperinsulinemia. When increased insulin levels are needed to maintain normal glucose levels, it is called insulin resistance. However, if increased insulin levels cannot completely control blood glucose levels, the person develops impaired glucose tolerance (also known as prediabetes). Type 2 diabetes is defined as elevated blood sugar levels despite elevated insulin levels. Insulin resistance and hyperinsulinemia can occur in both normal-weight and overweight women with polycystic ovary syndrome (PCOS). Up to 35% of obese women with PCOS develop impaired glucose tolerance (prediabetes) by age 40, and up to 10% develop type 2 diabetes. Women with PCOS have a significantly higher risk of developing these conditions compared to women without PCOS. Regarding the diagnosis of PCOS, according to the 2011 Chinese diagnostic criteria for PCOS, the following diagnostic terms are used: ① Suspected PCOS: Oligomenorrhea, amenorrhea, or irregular uterine bleeding are essential diagnostic criteria. Additionally, one of the following two criteria must be met: clinical manifestations of hyperandrogenism or hyperandrogenemia; or polycystic ovaries on ultrasound. ② Confirmed PCOS: After meeting the above suspected PCOS diagnostic criteria, other diseases that may cause hyperandrogenism and ovulation abnormalities must be ruled out one by one to confirm the diagnosis of PCOS. According to the Rotterdam criteria, a diagnosis of PCOS requires meeting two of the following three criteria: ① Menstrual irregularities due to anovulation or irregular ovulation. ② Evidence of elevated androgen levels. Evidence can be based on physical signs (excessive hair growth, acne, or male pattern baldness) or blood tests (high androgen levels). ③ Pelvic ultrasound examination of polycystic ovaries. Furthermore, there cannot be other causes of elevated or irregular androgen levels (e.g., congenital adrenal hyperplasia, androgen-secreting tumors, or excessive prolactin). Generally, if PCOS is diagnosed, blood glucose and lipid tests are recommended. An oral glucose tolerance test is the best method for diagnosing prediabetes and/or diabetes. Many clinicians treating PCOS patients also recommend screening for sleep apnea through questionnaires or overnight sleep studies in a sleep laboratory. For women with moderate to severe hirsutism (excessive hair growth), blood tests for testosterone and DHEAS are recommended. All women diagnosed with PCOS should be followed up long-term by a healthcare professional. The risk of other health problems increases over time in untreated PCOS patients. II. Medical Weight Loss Treatment for Polycystic Ovary Syndrome (PCOS) PCOS management encompasses addressing all manifestations of the syndrome (hirsutism, oligomenorrhea, infertility, obesity, and glucose intolerance), depending on the patient's goals. Weight loss reduces metabolic risk, restores ovulatory menstrual cycles, and may increase live birth rates, making it a first-line intervention for most women with PCOS. Treatment for obese women with PCOS is similar to that for obese women without PCOS, including diet and exercise, weight-loss medications (although their use is limited), and bariatric surgery. 1. Lifestyle Interventions for Weight Loss: Lifestyle interventions are the preferred foundational treatment for PCOS patients, especially those who are overweight or obese. These interventions include dietary control, exercise, and behavioral interventions. Lifestyle interventions can effectively improve health-related quality of life in overweight or obese PCOS patients. (1) Weight loss goals: Short-term studies have shown that for women with PCOS, even mild weight loss (a 5% reduction of 1000 kcal/day, or a 7% to 10% reduction of original body weight over 6-12 months) can reduce body weight and androgen levels compared to a high-protein/low-carbohydrate diet (30% protein, 40% carbohydrates, 30% fat, MHCD) and a low-protein/high-carbohydrate diet (15% protein, 55% carbohydrates, 30% fat, CHCD) on the basis of total energy restriction. MHCD significantly increases insulin sensitivity, reduces hyperinsulinemia, and thus reduces insulin resistance. Currently, low-carbohydrate diets are very popular among PCOS patients because they can reduce hyperinsulinemia and thus reduce insulin resistance. Ketogenic and low-carbohydrate diets can not only significantly improve body weight and insulin resistance in PCOS patients, but also have a significant effect on hyperandrogenemia associated with PCOS. In 2018, my country issued the "Chinese Expert Consensus on Ketogenic Diet Intervention for Polycystic Ovary Syndrome (2018 Edition)". Other studies have shown that low glycemic index diets can improve hirsutism and acne by lowering insulin and testosterone levels in PCOS patients (regardless of obesity); energy-restricted meal replacements can also reduce BMI, improve metabolic and hormonal indicators, and increase the probability of conception in obese PCOS patients. Currently, there is no strong evidence that one diet is better than another for women with PCOS. Regardless of the macronutrient ratio, weight loss and improved clinical outcomes can be achieved by restricting total energy intake. Diets need to be tailored to the dietary habits of PCOS patients, using flexible and personalized methods to reduce energy intake and avoid excessive restriction and nutritional imbalance. A balanced diet is recommended under the premise of total energy control, with carbohydrates accounting for 45%–60%, choosing low glycemic index foods; fat accounting for 20%–30%, mainly monounsaturated fatty acids, with saturated and polyunsaturated fatty acids both less than 10%; and protein accounting for 15%. This should be continued for 6 months, and for patients planning pregnancy, it is recommended to continue until pregnancy is confirmed. If weight loss is less than 5% of original body weight after 36 months of lifestyle intervention and metformin treatment, it is recommended to combine or switch to orlistat to reduce fat absorption. Another weight-loss-related medication is a glucagon-like peptide-1 (GLP-1) receptor agonist, which was recommended for use in women with PCOS in the 2014 European Endocrine Society position statement on PCOS. Currently, two GLP-1 receptor agonists (exenatide and liraglutide) approved and used both domestically and internationally have been studied in PCOS. Studies have shown that both exenatide and liraglutide, whether used alone or in combination with metformin, are effective in reducing body weight. The weight-loss effect of 3mg liraglutide even surpasses that of liraglutide combined with metformin. GLP-1 receptor agonists can reduce body mass index, waist circumference, and may moderately reduce androgen levels, thus improving ovarian function. 3. Surgical weight loss: For obese PCOS patients who have not achieved therapeutic goals through lifestyle interventions and medication, bariatric surgery can be a reasonable option. Bariatric surgery can effectively reduce body weight, improve menstrual cycles, alleviate insulin resistance, suppress hyperandrogenemia, improve PCOS, and enhance fertility. The expert consensus on perioperative management in bariatric and metabolic surgery (2019 edition) recommends a BMI ≥ 27.Patients with obesity and polycystic ovary syndrome (PCOS) weighing 5 kg/m² should undergo surgical treatment according to the "Guidelines for Surgical Treatment of Obesity and Type 2 Diabetes in China". For women with a waist circumference ≥85 cm, the surgical recommendation level may be increased as appropriate. Sleeve gastrectomy and gastric bypass are standard surgical procedures for weight loss. For PCOS patients desiring fertility after surgery, sleeve gastrectomy is the preferred option to avoid nutritional deficiencies during pregnancy due to malabsorption. It is recommended to wait more than 12 months after surgery before considering pregnancy, and contraception should be used during this period.