Clinical issues and their management
Women with PCOS tend to have reproductive issues such as oligomenorrhoea and anovulation. Many will need assistance when they are unable to conceive spontaneously. In addition, they are likely to have endocrine problems such as hirsutism and metabolic issues such as obesity, insulin resistance, and dyslipidaemia.
The following sections aim to provide an approach to and management of the clinical problems that women with PCOS will face in their life course.Oligo/amenorrhoea
Up to 79% of women with PCOS will have irregular menstrual cycles (30); many of these women present to the gynaecologist to manage their menstrual periods. Irregular cycles are attributable to anovulation and usually result in a hyperoestrogenic state which may predispose to the risks of developing endometrial hyperplasia and carcinoma (40). Haoula and colleagues observed that women with PCOS have a 2.89-fold (95% confidence interval (CI) 1.52-5.48) increased risk for endometrial cancer (41) and in these women, when intervals between menstruation become longer than 3 months (i.e. fewer than four periods each year), this is associated with endometrial hyperplasia (42). A prospective study of 56 consecutive amenorrhoeic women with PCOS who underwent transvaginal ultrasound to assess the endometrial thickness concluded that the endometrial thickness was positively correlated with endometrial hyperplasia; no cases of endometrial hyperplasia were observed when the endometrial thickness was less than 7 mm (42).
Good clinical practice will involve the regular induction of a withdrawal bleed using cyclical progestogens for at least 12 days (43, 44), or oral contraceptive pills (various formulations with different generations of progesterone preparations), or the intrauterine system with local release of progestogens, commonly known as the Mirena system (Bayer Plc, Newbury, United Kingdom).
These interventions are advisable in oligomenorrhoeic women with PCOS (45), but the most effective regimen remains unclear and can be dependent on the patient's preference and risk profile; however, there remains a lack of randomized clinical trials examining this aspect (46).Another contributing factor to the irregular cycles and potentially other endocrine and metabolic disturbances noted in women with PCOS is the high body mass index (BMI) observed in these women. A modest but non-significant trend in the prevalence of PCOS with increasing BMI has been reported (47). Obesity and especially abdominal obesity can cause relative hyperandrogenaemia, characterized by reduced levels of SHBG and increased levels of bioavailable androgens delivered to target tissues (48, 49). In adult overweight and obese women with PCOS, menstrual abnormalities and chronic oligoanovulation are more frequent than in normal-weight women (49). In a small study looking at 12 morbidly obese women with PCOS, an average postoperative weight loss of 41 kg in the first year improved hyperandrogenism, insulin resistance, dyslipidaemia, and hypertension and reversed the PCOS diagnosis (50).
A Cochrane review concluded that lifestyle intervention (incorporating diet, exercise, and behavioural modifications) improves body composition, hyperandrogenism (high male hormones and clinical effects), and insulin resistance in women with PCOS. There was no evidence of effect for lifestyle intervention on improving glucose tolerance or lipid profiles and no literature assessing clinical reproductive outcomes, quality of life, and treatment satisfaction (51). Another clinical practice guideline by Legro and colleagues recommended the use of exercise therapy in the management of overweight and obesity in women with PCOS despite there being no large randomized trials of exercise in women with PCOS; exercise therapy, alone or in combination with dietary intervention, improves weight loss and reduces cardiovascular risk factors and diabetes risk in the general population.
They also mention that weight loss is likely beneficial for improvement of both reproductive and metabolic dysfunctions but weight loss is likely to be insufficient as a treatment for normal-weight women with PCOS (52).Subfertility
Women with PCOS are more likely to encounter anovulation—in a large series of women with PCOS, close to half of these women had primary infertility and a quarter of them reported secondary infertility (53). Anovulatory infertility which included PCOS is common and accounts for 25-40% of women with infertility in populationbased studies (53, 54). Moreover, PCOS is the most common cause of ovulatory dysfunction, accounting for 70-90% of ovulatory disorders (55) with prolonged periods of anovulation associated with increased infertility (56).
Thcrclorc, in women with PCOS, the first step to regain fertility is to ensure ovulation and this can be performed using various ovulation induction agents such as clomiphene citrate, letrozole, and gonadotropins. Metformin, an insulin sensitizer, has also been tried in women with PCOS not only to correct metabolic disturbances but also to correct hyperandrogenism and for ovulation induction.
Clomiphene citrate has been recommended by the Endocrine Society Clinical Practice Guideline as the first line of therapy for anovulatory infertility for women with PCOS (52). Many multicentre clinical trials had demonstrated the benefits of clomiphene citrate for anovulation (57-59) and that the results are similar to that of gonadotropins (60). Palomba and colleagues (61) also reviewed the literature on metformin usage in PCOS and suggested that in anovulatory infertile therapy-naive PCOS patients, the combined approach of metformin plus clomiphene citrate is not better than clomiphene citrate or metformin monotherapy. Using metformin as a second-line approach, the authors concluded that in women who received gonadotropins as treatment for anovulation, metformin addition reduces the duration of gonadotropins administration and the doses of gonadotropins required and increases the rate of monoovulations, reducing the risk of cancelled cycles.
Additionally, metformin administration in infertile women with PCOS scheduled for IVF cycles is useful to reduce the risk of ovarian hyperstimulation syndrome (61).Aromatase inhibitors have been proposed as another oral treatment option to treat anovulatory infertility in women with PCOS. A large National Institutes of Health-sponsored, multicentre, double-blind, randomized, clinical trial which included 750 subjects has been completed with a marked superiority in live birth rate of letrozole over clomiphene for the treatment of anovulatory infertility in women with PCOS together with a comparable safety and tolerance profile between the two drugs (62). Although concerns about the relative teratogenicity of letrozole compared to clomi- phene remain, the results of this trial and other publications have been reassuring (63).
Ovarian electrocautery can be considered for selected anovulatory patients with a normal BMI as an alternative to ovulation induction as anovulation associated with PCOS has long been known to be amenable to surgical treatment (64). A long-term cohort study has demonstrated persistence of ovulation as well as normalization of serum androgens and SHBG up to 20 years after laparoscopic ovarian electrocautery in over 60% of subjects, especially if they have a normal BMI (65).
Endocrine issues
Women with PCOS who have marked hyperandrogenism and anovulation are shown to have the highest incidence of metabolic disturbances (66). Insulin resistance is noted to be present in around 65-80% of women with PCOS independent of obesity (67) which is further exacerbated by excess weight (68). Earlier-onset hyperglycaemia and rapid progression to type 2 diabetes mellitus is also reported in women with PCOS (69) and PCOS is classified as a non-modifiable risk factor for type 2 diabetes mellitus (70). Type 2 diabetes mellitus and cardiovascular disease risk are worsened in women with PCOS known to be insulin resistant (71) regardless of their high BMI (72).
Lifestyle therapy has been shown to prevent or delay progression to type 2 diabetes, therefore it is important to perform early screening in women with PCOS. An oral glucose tolerance test is considered to be appropriate for screening women with PCOS for diabetes. However, it would be reasonable to carry out HbA1c measurements where women are unwilling to have oral glucose tolerance tests or where the resources are not readily available (64). Women, particularly of south Asian descent, who are more likely to be insulin resistant, should have an oral glucose tolerance test done regardless of their BMI (73). Rescreening is suggested every 3-5 years, or more frequently if clinical factors such as central adiposity, substantial weight gain, and/or symptoms of diabetes develop in any women with PCOS (52). New compounds such as decanoic acid have been demonstrated to be effective in reversing the endocrine and metabolic abnormalities of the letrozole-induced PCOS rat model, raising the possibility that diets including decanoic acid could be beneficial for the management of both hyperandrogenism and insulin resistance in PCOS (74).Obesity and the metabolic syndrome
Obesity and especially abdominal obesity can result in relative hyperandrogenaemia, characterized by reduced levels of SHBG and increased levels of bioavailable androgens delivered to target tissues (48, 49). Abdominal obesity is also associated with an increased testosterone production rate and a non-SHBG-bound androgen production rate of dehydroepiandrosterone and androstenedione (75). These mechanisms serve to explain the associations in women with PCOS and obesity. Women with PCOS, as compared with age- and BMI-matched women without the syndrome, appear to have a higher risk of insulin resistance, hyperinsulinaemia, glucose intolerance, dyslipidaemia, and an increased prothrombotic state, thereby resulting in a higher rate of type 2 diabetes mellitus, subclinical atherosclerosis, vascular dysfunction, and cardiovascular disease (76).
All women with PCOS should be assessed for cardiovascular disease risk by assessing individual cardiovascular disease risk factors, as stated earlier, at the time of initial diagnosis. The Royal College of Obstetricians and Gynaecologists in the United Kingdom has recommended that in daily clinical practice, hypertension should be treated and lipid-lowering treatment is not recommended routinely and should only be prescribed by a specialist (64). Although statins improve lipid profiles and reduce testosterone levels in women with PCOS, there is no evidence that statins improve resumption of menstrual regularity or spontaneous ovulation, nor is there any improvement of hirsutism or acne based on a Cochrane review (77). The first-line management is to initiate weight-loss strategies with calorie-restricted diets (with no evidence that one type of diet is superior) for adolescents and women with PCOS who are overweight or obese (52). Metformin can be offered as first-line therapy for obesity management and/or management of women with PCOS known to have type 2 diabetes mellitus or impaired glucose tolerance who failed lifestyle modifications. Bariatric surgery may be an option for morbidly obese women with PCOS (BMI of 40 kg/m2 or more or 35 kg/m2 or more with a high-risk obesity-related condition) if standard weight loss strategies have failed (64).Hirsutism and its management
PCOS represents the major cause of hirsutism in women (52) and is present in approximately 65-75% of patients with PCOS (although this figure is lower in Asian populations) (78, 79). Hirsutism may predict the metabolic sequelae of PCOS (80) or failure to conceive with infertility treatment (81), hence treatment of hirsutism is twofold—to correct the hyperandrogenism and metabolic disturbances and for cosmetic purposes. Based on a Cochrane review by van Zuuren and colleagues, treatments for hirsutism may need to incorporate pharmacological therapies, cosmetic procedures, and psychological support (82). For mild hirsutism, there is evidence of limited quality that oral combined contraceptive pills are effective. Flutamide 250 mg twice daily and spironolactone 100 mg daily appeared to be effective and safe, albeit the evidence was low to very low quality. No firm conclusions can be drawn on the use of finasteride 5 mg daily. As the side effects of antiandrogens and finasteride are well known, such drugs must be used with caution in managing women with hirsutism. There was low-quality evidence that metformin was ineffective for hirsutism (82). Therefore, medical treatments can be offered although laser and photoepilation therapies are useful adjuncts and may have to be utilized in conjunction with medical therapies.