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Treatment of WHO 2: Lifestyle Modifications
Introduction
Anovulation is the primary cause of subfertility in 15%–20% of women seeking fertility care. Normogonadotrophic, normoestrogenic anovulation (WHO 2) occurs commonly, and about 91% of women with WHO 2 anovulation fit the broader diagnostic criteria of polycystic ovary syndrome (PCOS) (1). PCOS occurs in up to 6%–18% of reproductive-age women, depending on the population studied. PCOS accounts for 70%–90% of all ovulatory disorders (2). Women are diagnosed as PCOS according to the Rotterdam consensus diagnostic criteria if two of the following criteria are identified: anovulation, clinical or biochemical hyperandrogenemia, or polycystic ovary morphology on ultrasound and after other endocrine causes of anovulation are excluded (2). The clinical manifestation of PCOS is variable due to the heterogeneity of PCOS being influenced by factors, including ethnicity, body weight, and body fat distribution. Women with PCOS may have a propensity to gain weight. Although the literature is variable, overweight and obesity are common in PCOS (pooled estimated prevalence of 61%, 95% CI 54–68), according to the WHO criteria.
Mechanisms of Anovulation
The pathophysiology of PCOS remains unclear but is most likely based on a multifactorial origin with a combination of genetic and environmental factors. Considerable evidence indicates that insulin resistance and the resulting hyperinsulinemia is the etiologic feature in 95% of obese and 75% of lean women with PCOS, and hyperandrogenemia can be detected in 60%–80% of women with PCOS (3).
Insulin resistance contributes to lower sex hormone binding globulin (SHBG) concentrations and, consequently, higher free androgen levels. High androgen levels directly influence intra-ovarian steroidogenesis, which leads to arrest of follicle growth and anovulation.
Obesity, in particular abdominal and visceral obesity, contributes to insulin resistance and a subsequent decrease in SHBG and increase in hyperandrogenemia. Excess weight therefore increases the risk of developing PCOS and overweight or obesity contributes to a more severe phenotype of PCOS with regards to the reproductive, psychological, and metabolic consequences.
Adipose tissue can store androgens, convert androgen precursors to active androgens, and secrete various peptides, collectively called adipocytokines. Increasing BMI can contribute to dysfunctional adipose tissue with increased secretion of pro-inflammatory adipocytokines and decreased secretion of adiponectin, an insulin-sensitizing adipocytokine. Altered regulation of adipocytokines, including leptin and adiponectin, may contribute to anovulation through effects on hypothalamic function, insulin resistance, or the ovary.
This chapter will aim to discuss lifestyle modification as a measure to achieve weight loss and resumption of ovulation in women with WHO 2 anovulation.
Lifestyle Modification
The optimal lifestyle modification program for achieving weight loss consists of dietary intervention and exercise in combination with behavior modification. The existing literature mainly addresses lifestyle modification in at-risk groups (including those at an elevated risk of developing DM2 or cardiovascular disease) of the general population and in anovulatory women with PCOS, but these findings can also be extrapolated to the group of non-PCOS women with WHO 2 anovulation.
Weight Loss and Prevention of Weight Gain (3)
In populations at risk for DM2, many randomized controlled trials (RCTs) report that lifestyle modification leads to weight loss, improvement in insulin sensitivity, decreased prevalence of DM2, and decreased risk factors for cardiovascular disease when compared to placebo or insulin-sensitizing drugs. Long-term weight loss and weight maintenance should be managed by long-term support in maintaining a healthy diet and increased exercise in combination with behavior modification. Lifestyle modification during pregnancy and limiting weight gain during pregnancy and modest preconception weight loss when women are overweight or obese can also contribute to improved fertility or a decrease in obesity-related pregnancy complications (LOE 1a) (4).
Many small and uncontrolled trials indicate that weight loss achieved through lifestyle modification in overweight/obese women with or without PCOS leads to loss of abdominal fat, improvement in insulin sensitivity, and decrease in hyperandrogenemia.
In overweight/obese women with PCOS, a modest weight loss of 5%–10% of total body weight leads to improvement of menstrual cyclicity and resumption of ovulation in up to 60% of these women. Small, uncontrolled trials have shown that loss of visceral fat and improvement in insulin resistance is required for resumption of ovulation in overweight/obese women with PCOS. One high-quality systematic review that assessed six RCTs showed that lifestyle modification in women with PCOS improves markers of insulin resistance and weight and central fat compared to minimal treatment or usual care (LOE 1a). There were minimal data available on clinical reproductive outcomes, such as resumption of ovulation or conception rates.
Based on general population data and emerging data in PCOS, lifestyle modification for weight loss in overweight/obese women with WHO 2 anovulation and prevention of weight gain in lean women should be recommended for improving general health, well-being, and reproductive outcomes (Table 20.2).
Diet and Macronutrient Composition (3)
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