Diet

Dietary changes provide the lynchpin for effective weight loss—but there is no clear evidence for the superiority of one particular dietary strategy over others. Therefore, a variety of dietary interventions may be planned, with care taken to individualize these interventions to food preferences and simultaneously avoid unduly restrictive or nutritionally unbalanced diets . To achieve weight loss, an energy deficit of 30% or 500–750 kcal/day (which equates to a daily intake of 1200–1500 kcal/day) could be advised, taking into account individual circumstances such as energy requirements, body weight, and physical activity . Wherever possible the support of a suitably qualified nutritionist will not only enable individualization of the strategy but also important ongoing support.

Exercise

Exercise is recommended for all women with PCOS, irrespective of their weight. PCOS is a risk factor for future weight gain and therefore women with normal weight should be advised a minimum of 150 min of moderate-intensity or 75 min of vigorous-intensity exercise per week aiming to achieve at least 30 min daily on most days .

Women who are overweight or obese should be advised a minimum of 250 min of moderate-intensity or 150 min of vigorous-intensity exercise per week .

Behavioral strategies

Cognitive behavioral interventions could be considered to support women with lifestyle interventions along with the setting of SMART (Specific, Measurable, Achievable, Relevant, and Time-Limited) Goals to help meet physical activity recommendations. In addition, self-monitoring devices such as fitness trackers could serve as a useful adjunct to support an active lifestyle .

Bariatric surgery

Bariatric surgery can be considered when PCOS is associated with morbid obesity, and where lifestyle changes have not been beneficial with weight loss, and where obesity makes planning fertility treatment inappropriate due to the heightened risks with pregnancy. Both gastric banding and bypass may be achieved with minimal access surgery. Undertaking bariatric surgery should be after thorough counseling. Pregnancy should be avoided for atleast 6–9 months after surgery until metabolic and nutritional stability has been achieved and the expertise of a nutritionist is of paramount importance.

When appropriately undertaken, there is evidence that bariatric surgery, in addition to its proven efficacy in improving life expectancy and reducing comorbidities such as diabetes mellitus and obstructive sleep apnoea, does improve the chances of natural conception and any loss of weight would logically improve the ovarian sensitivity to ovulation induction.

Oral ovulation induction agents

Clomiphene citrate (CC) has been established as an oral ovulation induction agent for the management of PCOS for many decades and so there is a substantial volume of data on its efficacy, safety, and side-effect profile. Significant interindividual variation in ovarian response to clomiphene mandates ultrasound monitoring of atleast the first cycle of ovulation induction. Both overresponse and underresponse to CC can cause therapeutic difficulties, with the risk of multiple pregnancy and anovulation respectively. A few months of varying doses of clomiphene can be required to identify the dose appropriate for a particular person, and there have been attempts to create algorithms to estimate the predicted success rates of clomiphene using age, body mass index (BMI), and androgen profiles . However, this algorithm did not prove to be clinically useful when evaluated in a different center, perhaps indicating the need for center-specific strategies tailored to the local population . The antiestrogenic effects of CC may impact both the endometrium and the HPO (hypothalamic-pituitary-ovarian) axis, leading to implantation failure and multiple ovulations respectively. The lowest effective dose should be used and there is little evidence for benefit of doses greater than 100 mg.

The aromatase inhibitor letrozole is now considered the first-line ovulation induction agent as randomized trial data indicates a superior live birth rate to CC with the added benefit of a higher likelihood of unifollicular ovulation, although this does not appear to translate to a reduced risk of multiple pregnancies when compared with CC . To our knowledge, there are no predictive algorithms designed to estimate the success of ovulation induction with letrozole, but there do appear studies indicating that letrozole is significantly superior to CC for women who have a higher BMI .

Once ovulation has been stimulated it is reasonable to continue therapy for atleast 6 months, depending upon the age of the woman and other factors that may affect the expected cumulative chance of conception. If pregnancy has not occurred, then IVF (in vitro fertilization) may be indicated. If ovulation is not achieved, then second-line therapies are required.

Gonadotropin therapy

Gonadotropins can be utilized as a second-line therapy for ovulation induction when oral agents fail to elicit ovulation . However, they require much more intensive monitoring than oral ovulation induction and therefore usually fall under the remit of tertiary level infertility clinics, which have the appropriate expertise. Gonadotropin therapy carries a higher risk of overresponse leading to higher-order multiple pregnancies and ovarian hyperstimulation syndrome. However, when utilized appropriately by the skilled practitioner with low dose protocols and strict cancellation criteria, they achieve equivalent success rates with a good safety profile.

The low-dose step-up regimen employs a starting daily dose of 37.550 IU/day, which is only increased after 14 days if there is no response and then only by half an ampoule every 7 days . Treatment cycles using this approach can be quite long upto 28–35 days—but the risk of multiple follicular growths is lower than with conventional step-up regimens. The initiation of follicular growth requires a 10%—30% increment in the dose of exogenous (follicle stimulating hormone) and the threshold changes with follicular growth, due to an increased number of FSH receptors, so that the concentration of FSH is required to maintain growth is less than that required to initiate it. In ovulation induction protocols stimulation with gonadotropins does not require a background of pituitary desensitization. There is no difference in efficacy between the different gonadotropin preparations.

It can be very challenging to stimulate the development of a single dominant follicle in women with PCOS. Whilst attempts have been made to predict a multi follicular response by determining mid follicular endocrine profiles and numbers of small follicles, it is harder to do so before commencing ovarian stimulation and hence determine the required starting dose of gonadotropin. To prevent multiple pregnancies strict criteria are required before the administration of hCG (human chorionic gonadotropin) with no more than two follicles ≥ 14 mm, with the largest > 17 mm. This requires appropriate training, skill, and audit of outcomes, as ovulation induction therapy requires an understanding of the variability of ovarian response and more sensitivity than when “superovulation induction” is used for IVF regimens.

The fact that gonadotropin ovulation induction is successful for CC-resistant patients leads to its assessment in treatment-naïve patients and indeed, it was found that the cumulative clinical pregnancy rate was greater in those who received gonadotropins compared with CC . In this study 252 women were randomized to receive 3 cycles of either CC, starting dose 50 mg rising to 150 mg if no ovulation, or recombinant FSH (rFSH), in a low-dose protocol starting with 50 IU with weekly increments of 25 IU when necessary. Clinical pregnancy rates were 16.1% per cycle with CC and 26.1% with FSH ( P = .006). The chance of conceiving in the first cycle with rFSH was twice that with CC and the cumulative live birth rate after 3 cycles was 62% with rFSH compared with 42% with CC. However, differences in cost and convenience may of course limit the choice of FSH as first-line treatment.

Laparoscopic ovarian surgery

Laparoscopic ovarian surgery (LOS) commonly known as ovarian diathermy or drilling (LOD) is now the only surgical method of ovulation induction being a refinement of the classical technique of ovarian wedge resection. LOD is useful in two settings: first, opportunistically when laparoscopy has to be performed for other reasons such as assessment of the patency of fallopian tubes, and second, where gonadotropin ovulation induction is inappropriate due to reasons of expense, or logistical difficulties with ovulation monitoring. Of course, it is always important to thoroughly discuss the pros and cons of the alternatives with the patient so that she can make an informed decision.

Ovarian drilling, in contrast to medical ovulation induction, carries the benefit of sustained response, thus providing ongoing treatment for PCOS-related infertility for several months. In addition, even where resumption of menstrual cycles may not spontaneously occur after ovarian drilling, quite frequently there is resumed sensitivity to CC in women who had been clomiphene-resistant .

The mechanism of action is unclear. There is no doubt that minimal damage is required to stimulate ovulation. Furthermore, in our first paper to look at unilateral diathermy , we showed that the ovary that ovulated first after the procedure was often the ovary that had not been treated with diathermy. We hypothesized that tissue damage causes the release of growth factors that might then sensitize the ovary to endogenous FSH and thereby initiate follicular recruitment. With increasing knowledge about the nonhormonal factors that contribute to follicular development in the months before the follicle develops sensitivity to FSH it may also be that LOD influences these very early pathways. Suffice to say that minimal damage is required and the aim of surgery should not be to significantly reduce the ovarian volume or cause extensive damage to the ovary.

Commonly employed methods for laparoscopic surgery include monopolar or bipolar electrocautery (diathermy) and laser Wedge resection of the ovaries resulted in significant adhesions—in 100% of cases in some published series. The risk of adhesion formation is far less after laparoscopic ovarian diathermy (10%–20% of cases) and the adhesions that do form are usually fine and of limited clinical significance. After laparoscopic ovarian surgery, with the restoration of ovarian activity, serum concentrations of LH and testosterone fall. Whether patients respond to LOD appears to depend on their pretreatment characteristics, with slim patients with high basal LH concentrations having a better clinical and endocrine response . There is no evidence that LOD improves menstrual regularity or androgenic symptoms of PCOS .

One of the best studies on LOD is the multicenter RCT (randomized controlled trial) performed in the Netherlands in which 168 patients, resistant to CC were randomized to either LOD ( n = 83) or ovulation induction with recombinant FSH (rFSH, n = 65) . The initial cumulative pregnancy rate after 6 months was 34% in the LOD arm versus 67% with rFSH. Those who did not ovulate in response to LOD were then given first CC and then rFSH so by 12 months the cumulative pregnancy rate was similar in each group at 67%. Thus, those treated with LOD took longer to conceive and 54% required additional medical ovulation induction therapy. Furthermore, the duration of effect may be limited to a few months. This study indicates the need both to take a pragmatic approach to the use of LOD, appreciate its limitations, and also the duration of effect.

The Cochrane review indicates no significant difference in live birth rates with LOD (with or without combining with other ovulation induction agents) when compared against medical methods of ovulation induction, such as clomiphene, letrozole, or gonadotropins (OR 0.77, 95% CI 0.59–1.01; 8 RCTs; n = 1034; moderate-quality evidence) . The risk of multiple pregnancies is significantly lower with LOD compared with ovulation induction with gonadotropins, and therefore does not need concomitant ultrasound monitoring. LOD could be used in preference to gonadotropins as a second-line ovulation induction agent in settings where ultrasound monitoring is unfeasible due to logistical or resource issues. This has to be balanced with the need for surgery and its associated risks and the longer time to pregnancy with LOD compared with gonadotropin therapy. The Cochrane review also noted that there are concerns regarding the long-term effect of LOD on ovarian function. Interestingly, there was no significant difference in live birth rates (OR 0.83, 95% CI 0.24–2.78; 1 RCT; n = 44; very low-quality evidence) between unilateral and bilateral ovarian drilling .

Two concerns with ovarian drilling are the risks of periovarian adhesions and iatrogenic damage to ovarian reserve, although these risks should be minimized if care is taken and limited damage caused to the ovaries. There is insufficient evidence of whether unilateral ovarian drilling performs equivalently to bilateral ovarian drilling . However, if further studies indicate equivalency of these two approaches, unilateral ovarian drilling could offer a solution to these aforementioned twin concerns of diminished ovarian reserve and periovarian adhesions.

Metformin

There is a clear association between insulin resistance and PCOS both in the pathophysiology and impact on fertility, and pregnancy complications, including anovulation, implantation failure, miscarriage, and preterm birth. Therefore, there has been much interest in exploring whether addressing the insulin resistance component of PCOS might help ameliorate its impact on fertility.

Trials to date indicate that metformin used on its own is a less effective ovulation induction agent than conventional ovulation induction agents such as CC . Metformin does appear to play a role in restoring sensitivity to clomiphene in women who are clomiphene resistant and some studies indicate that metformin has an effect on the endometrium which might help reduce complications during pregnancy such as miscarriage, but the findings from these studies do not meet the robustness required to advocate routine use of metformin for women with PCOS in pregnancy.

In contrast to other fertility medications, long-term use of metformin appears to improve anthropometric measures of women with PCOS . However, whether this translates to a lifetime reduced risk of chronic conditions such as hypertension or diabetes mellitus is still unknown.

Genetic variation has been suggested to be behind the significant clinical heterogeneity in the response to metformin in women with PCOS . Whilst there is evidence that genetic variations influence the glycemic response to metformin when prescribed as an oral hypoglycemic agent in diabetes mellitus , studies to date have been conflictive of the link between any particular genetic polymorphisms and clinical response in women with PCOS .

Oral hypoglycemic agents other than metformin

Given the data on metformin in ameliorating the clinical features of PCOS, other hypoglycemic and insulin sensitizing agents have been explored as alternative options. These include thiazolidinediones, Glucagon-like peptide (GLP)-1 analogues, and inositol.

Data to date indicates that metformin is superior to thiazolidinediones (such as rosiglitazone and pioglitazone) in reducing the long-term cardiovascular risks associated with PCOS .

GLP-1 analogues such as semaglutide are more expensive than metformin. The available data suggests that GLP-1 analogues might be more effective at improving insulin sensitivity and reducing weight as compared with metformin but at a cost of a higher incidence of side effects such as nausea and vomiting .

There are two isoforms of inositol; myo-inositol, and D-chiro-inositol, which do not appear to have much difference in their clinical impact in PCOS . Whilst the use of myo-inositol alone has not been found to enhance reproductive outcome , when combined with D-chiro-inositol, a small study has suggested an improved live birth rate with IVF/ICSI (intracytoplasmic sperm injection) . Overall the available data on inositol is rather limited and head-to-head comparisons with metformin have yet to show any significant difference, thus limiting its clinical utility .

Chinese herbal medicine

Berberine is a component of Chinese herbal medicine. A three-armed RCT comparing berberine, letrozole, and berberine with letrozole as ovulation induction agents for 644 women with PCOS noted cumulative live birth rates of 22%, 36%, and 34% respectively, indicating a lack of evidence to recommend its use either alone or as an adjunct to letrozole .

Acupuncture

A recent Cochrane review concluded that the available low-quality evidence does not show any improvement in clinical pregnancy rates or live birth rates with acupuncture when compared with sham acupuncture .

In vitro fertilization

IVF is considered as the third-line management for PCOS when first and second-line agents have not been successful in achieving a pregnancy or when there are additional causes of infertility such as pathology of the fallopian tubes or sperm abnormalities in the woman’s partner. The presence of polycystic ovaries is a major risk factor for developing OHSS (ovarian hyperstimulation syndrome) during IVF and GnRH antagonist protocols for pituitary suppression are associated with a reduced risk (OR 0.61, 95% CI 0.51—0.72; 36 RCTs; n = 7944; moderate-quality evidence) whilst not compromising the live birth rate (OR 1.02, 95% CI 0.85–1.23; 12 RCTs; n = 2303; moderate-quality evidence) .

The GnRH antagonist cycle also allows the use of GnRH agonist rather than human chorionic gonadotropin (hCG) as the preovulatory trigger further reducing the risk of OHSS (OR 0.15, 95% CI 0.05–0.47; 8 RCTs, 989 women; moderate-quality evidence) . The use of a GnRH agonist in this way is associated with a lower live birth rate due to a deficient luteal phase (OR 0.47, 95% CI 0.31–0.70; 5 RCTs, 532 women, moderate-quality evidence) . Two approaches have been suggested to overcome the luteal phase deficiency—supplementation with exogenous estrogen and progesterone in the luteal phase or rescuing the corpus luteum using low dose hCG given either alongside the buserelin trigger or on the day of the oocyte retrieval. Use of modified luteal phase support appears to lead to similar live birth rates with a GnRH agonist trigger as with hCG (OR 0.84, 95% CI 0.62–1.14; 5 RCTs; n = 857) . An alternative approach has been elective cryopreservation of embryos following oocyte retrieval that is then followed by a frozen embryo transfer cycle—the “segmentation” approach . A recent multicenter trial including 1508 women found that the “segmentation” approach led to a higher live birth rate (49.3% vs 42.0%; RR 1.17, 95% CI 1.05–1.31) with a lower risk of OHSS (1.3% vs 7.1%, RR 0.19, 95% CI, 0.10–0.37), but a higher risk of preeclampsia (4.4% vs 1.4%, RR 3.12, 95% CI, 1.26–7.73) .

Kisspeptin is a protein that can act on GnRH neurons in the hypothalamus to stimulate FSH and LH release from the pituitary. It was tested in phase two, open-label trial of 60 women at risk of OHSS with acceptable pregnancy rates with no moderate or severe OHSS noted . Trials are ongoing, although the preparations are currently prohibitively expensive.