Polycystic ovary syndrome - Emerging treatments

Alpha-glucosidase inhibitors

Small studies have found that acarbose may reduce androgen levels, improve hirsutism, and ameliorate menstrual irregularity in women with polycystic ovary syndrome (PCOS), as well as improving markers of cardiovascular risk.[148] Its use is limited by gastrointesinal adverse effects.

Statins

Statins given in conjunction with oral contraceptive pills, have been shown to reduce circulating androgen levels further, improve the lipid profile, reduce hirsutism, and improve markers of inflammation in PCOS.[149]Studies have also suggested statins may be beneficial in conjunction with metformin.[150] While one Cochrane review found that atorvastatin reduced androgen levels (including total testosterone, free androgen index, androstenedione, and dehydroepiandrosterone) in women with PCOS, another Cochrane review concluded that it is uncertain whether statins improve hirsutism, acne, testosterone, or menstrual regularity due to limited evidence.[151][152] At least one study found that statins may reduce insulin sensitivity in PCOS, and a meta-analysis concluded atorvastatin therapy may reduce insulin resistance in PCOS.[153][154] In general, statins have been associated with a risk of new-onset diabetes, and women appear particularly susceptible.[155] While they are still experimental, further trials may establish a role for statins in PCOS. Although statin use is not recommended solely to treat hyper-androgenism in PCOS, treatment is acceptable in women who meet current cardiovascular risk-based criteria.[31][156]

Weight loss medicines

Weight loss agents such as orlistat and rimonabant have been given to women with PCOS in a few clinical trials. These agents appear to facilitate weight loss and result in beneficial metabolic and hormonal effects.[157][158] One meta-analysis found that orlistat significantly reduced BMI in women with PCOS compared with placebo, but the evidence was very-low certainty.[159] Another meta-analysis reported improved weight, hormonal, lipid, insulin, and fertility outcomes with orlistat plus oral contraceptive pills compared with oral contraceptive pills alone.[160]

Bariatric surgery

A few small trials have followed obese women with PCOS after bariatric surgery. Most women had restoration of regular menstrual cycles, accompanied by reduction in hyper-androgenic signs and symptoms, and some women were able to become pregnant.[157][161] One meta-analysis of six studies found that sleeve gastrectomy in women with PCOS resulted in reduced menstrual irregularity, lower testosterone levels, and increased sex hormone-binding globulin, along with improvement in BMI and glycemic and lipid parameters.[162] A meta-analysis found that the prevalence of PCOS dropped from 46% to 7% after bariatric surgery, with improvements in menstrual irregularity and hirsutism.[163] Some data suggest that bariatric surgery may be more effective for pregnancy outcomes than metformin in women with PCOS and BMI >40 kg/m².[164]

Pulsatile gonadotrophin-releasing hormone (GnRH)

Pulsatile GnRH can be given through automated intravenous or subcutaneous infusion pump to induce ovulation. This treatment has minimal risk and about a 50% ovulation rate. The main advantage is no risk of multiple gestation or ovarian hyperstimulation. However, effectiveness in live birth rate has not been adequately established.[165] Thus, this choice may be best for women at risk for ovarian hyperstimulation syndrome (OHSS) or who have experienced severe OHSS.

Gonadotrophins in vitro

A highly experimental measure to avoid ovarian hyperstimulation syndrome during in vitro fertilisation is to retrieve immature oocytes and treat these with gonadotrophins in vitro to mature them before fertilisation and implantation.[166] Very limited randomised trial evidence suggests that in vitro maturation may increase clinical pregnancy rate.[167] In the absence of sufficient randomised trials, a meta-analysis of current evidence suggested higher rates of clinical pregnancy and implantation with this technique but was inconclusive on whether the live birth rate was increased.[168]

Elective freezing of embryos

A multicentre trial randomised 1508 infertile women with PCOS who were undergoing their first cycle of in vitro fertilisation to receive either one or two fresh embryos or one or two embryos that had been previously frozen; the latter group experienced higher rates of live birth, lower pregnancy loss, and lower frequency of ovarian hyperstimulation syndrome; however, they had higher rates of pre-eclampsia.[169] In this trial, singleton pregnancies arising from frozen embryos were more likely to be large for gestational age while twin pregnancies had a higher risk of pre-eclampsia.[170] More studies are needed to establish the role of frozen embryo transfer in the management of infertile women with PCOS.

Acupuncture

A handful of studies have promoted acupuncture as a fertility treatment in PCOS; however, given inconclusive evidence of reproductive benefit in the limited number of randomised controlled trials (RCTs) that have been conducted to date, and the possibility of harm, this treatment must be considered experimental.[171] Meta-analysis of the few available RCTs in women undergoing assisted reproductive technology suggested improvement in pregnancy rates but no benefit on live birth rate with manual or electroacupuncture, although the included studies were deemed insufficiently robust to draw firm conclusions.[172][173] Subsequent to this meta-analysis, a multicentre trial randomised 1000 women with PCOS to active or sham acupuncture, with or without clomifene (250 in each group); while clomifene increased live births, active acupuncture did not.[174]

Thiazolidinediones

Insulin-sensitising thiazolidinediones (e.g., rosiglitazone, pioglitazone) have been studied in PCOS, but in far fewer studies than metformin. They are not commonly used in PCOS because they can lead to weight gain. In the US, from 2010 to 2013, rosiglitazone use was restricted due to a possible increased risk of myocardial infarction, and is no longer marketed in the European Union. Long-term pioglitazone use has been linked to a possible risk of bladder cancer. Animal studies suggest that thiazolidinediones may be associated with fetal growth restriction.[175] Thiazolidinediones appear to have similar effects to metformin regarding ovulation and pregnancy in PCOS.[176] One meta-analysis reported that thiazolidinediones alone and metformin plus a thiazolidinedione are more effective for improving lipid metabolism than metformin alone.[177]

Glucagon-like peptide-1 (GLP-1) receptor agonists

Meta-analyses have found that exenatide and liraglutide can improve weight and glucose levels in women with PCOS.[178][179] The most significant adverse effect was nausea.[180] One meta-analysis found that liraglutide plus metformin was more effective than metformin alone in terms of weight loss, waist circumference, fasting glucose, and fasting insulin, but the incidence of adverse reactions was high.[178] In a few studies, these agents modestly improved androgen levels and improved menstrual frequency, and some data suggests increased pregnancy and ovulation rates compared with metformin.[179][180][181] One small study found that treatment with semaglutide resulted in weight loss and normalisation of menstrual cycles in the majority of treated women with PCOS.[182] More studies are needed of newer GLP-1 receptor agonists in PCOS.