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Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Infertility is a prevalent presenting feature of PCOS, and approximately 75% of these women suffer infertility due to anovulation. Lifestyle modification is considered the first-line treatment and is associated with improved endocrine profile. Clomiphene citrate (CC) should be considered as the first line pharmacologic therapy for ovulation induction. In women who are CC resistant, second-line treatment should be considered, as adding metformin, laparoscopic ovarian drilling or treatment with gonadotropins. In CC treatment failure, Letrozole could be an alternative or treatment with gonadotropins. IVF is considered the third-line treatment; the ‘short’, antagonist-based protocol is the preferred option for PCOS patients, as it is associated with lower risk of developing ovarian hyperstimulation syndrome (specifically by using a gonadotropin-releasing hormone agonist as ovulation trigger), but with comparable outcomes as the long protocol.

Keywords

clomiphene citrate gonadotropins IVF laparoscopic ovarian drilling letrozole metformin polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies, affecting 5–10% of women at reproductive age [1]. PCOS is a heterogeneous disorder characterized by several clinical and metabolic abnormalities. The need to establish universally accepted diagnostic criteria led to the Rotterdam consensus meeting in 2003, concluding that diagnosis of PCOS should be based on at least two of three major criteria, including oligo/anovulation, clinical and/or biochemical signs of hyperandrogenism and polycystic ovaries as identified by ultrasonography, also excluding other androgen excess disorders [2].

The primary etiology of PCOS is still largely unknown; but it is believed to be a multifactorial disorder involving genetic and environmental factors [3,4]. There are a plethora of health implications that have been associated with the diagnosis of PCOS, many of these constituting lifelong complications such as cardiovascular disease and Type II diabetes [5]. Insulin resistance plays a central role in the pathophysiology of the syndrome, and can be found in 60–80% of all women with PCOS and in 95% of obese women with PCOS [6].

PCOS is the most common cause of anovulation. Out of all couples seeking treatment for infertility, 30% of cases are due to anovulation [7], and It is estimated that 90% of anovulation cases are actually caused by PCOS [8]. Infertile women with PCOS should undergo a thorough infertility workup to look for other causes of infertility. Where the only cause is anovulation, a number of infertility treatments have been proposed (Figure 1). The objective of this review is to provide an update of the best available evidence for PCOS related infertility treatment.

Figure 1.

General polycystic ovary syndrome treatment work flow.

Lifestyle modification

Approximately 50–70% of women affected with PCOS are overweight or obese [9]. Obesity is associated with insulin resistance and compensatory hyperinsulinemia [10]. Insulin acts through the insulin receptors on ovarian theca cells to stimulate both its proliferation and androgen secretion [11]. Insulin also decreases the secretion of sex hormone-binding globulins (SHBG) from the liver, which results in an increase in free androgen level [12]. High local androgen levels in the ovaries disrupt the estrogenic environment in the growing follicles and leads to follicular stasis and atresia [13]. Androgens are also aromatized in adipose tissue to estrone, which exerts a negative feedback on follicle-stimulating hormone (FSH) secretion from the pituitary gland.

The Androgen Excess and PCOS Society recommends that lifestyle modification should be the primary therapy for metabolic complications, and may improve ovulatory function and pregnancy in overweight and obese patients with PCOS [14]. Admittedly, there are very few good quality randomized controlled trials (RCTs) to show improvement in ovulation or pregnancy rate following lifestyle modification. A Cochrane systematic review published in 2011, comparing lifestyle intervention (diet, exercise or combination of these) versus minimal intervention, identified only six RCTs, of which none provided details about live birth rate, two studies reported on pregnancy data and three studies described ovulation data. Of the two RCTs reporting data on pregnancy, only two of 20 women in one arm (lifestyle modification) and zero of 51 women in the other arm (minimal intervention) were actively seeking pregnancy, rendering any comparison of pregnancy rates between the two interventions meaningless [15]. In the three RCTs reporting on ovulation, the definition of ovulation varied between trials from resumption of regular menstruation to laboratory evidence of ovulation.

Nybacka et al. randomized 43 obese PCOS women to a diet therapy, exercise therapy or combination of both. After 4 months of treatment there was a significant decrease in BMI (5–6%) in all groups, a decrease in free testosterone and elevation in the SHBG levels. Thirty of the 43 women (69%) exhibited resumption of regular menstruation [16]. In a recent meta-analysis that included nine trials enrolling 583 PCOS obese women, it was shown that combination of diet and exercise resulted in a decrease in BMI, fasting blood glucose and insulin levels. However, due to short duration of follow-up, none of these trials reported on fertility outcome [17]. In an RCT of 20 overweight women with PCOS, comparing diet plus exercise with no lifestyle intervention, the mean number of ovulations per woman was 6 versus 2.8 respectively, over a treatment duration of 48 weeks, which did not reach statistical significance [18]. In another RCT, 22 obese women were divided to diet plus exercise therapy compared with office advice alone over a 24-week period and reported 60 versus 50% ovulatory cycles between the treatment and control group [19].

Significant methodological difficulties are the culprit in conducting prospective trials to assess long-term effect of lifestyle changes on pregnancy and delivery in women with PCOS. These long-term trials are associated with significant dropout rate of about 50% [20]. Thus it is difficult to extrapolate the results to a larger population of women with PCOS, because only a fraction will elect to take part, or will participate long enough to develop meaningful effects. Overall, lifestyle therapy does show some benefit with changes in body composition, improvements in insulin sensitivity and improvement in hyperandrogenism. Despite the absence of trials that show improved pregnancy and live birth rates, these metabolic changes may improve the efficacy of fertility treatments, and decrease obstetrical complications.

Clomiphene citrate

Clomiphene citrate (CC) has been the drug of choice for treating anovulation since its initial use in the early 1960s [21]. CC is a selective estrogen receptor modulator, having both estrogen agonist and antagonist properties [22]. However, in clinical use, clomiphene acts purely as an estrogen antagonist. CC competitively binds to the estrogen receptors primarily in the hypothalamus. The prolonged binding of CC to estrogen receptors interrupts the negative feedback at the hypothalamic level, which leads to increase in gonadotropin-releasing hormone (GnRH) secretion, and subsequently to increase in the production and secretion of pituitary FSH, which stimulates follicular growth and maturation [23]. When administered to PCOS patients, CC mainly increases GnRH pulse amplitude, but not frequency, which is already elevated in these patients [24].

The usual starting dose of CC is 50 mg/day, starting on day 2–5 of the cycle for 5 days. Ovulation usually occurs 5 to 10 days after treatment ends. If ovulation is not achieved, the dose can be gradually increased to 150 mg/day. If ovulation still does not occur, the patient is considered CC resistant. Overall, CC induces ovulation in 75–80% of patients [25]. After six to nine cycles of treatment, the cumulative pregnancy rate reaches 50–60%, thereafter cycle fecundability falls substantially [26]. Life table analysis of the most reliable studies indicated a conception rate up to 22% per cycle in women ovulating on CC [27]. In a systematic review and meta-analysis, including three RCTs which compared CC to placebo, it was found that CC improves ovulation rate (OR: 7.5; 95% CI: 3.24–7.23; p < 0.001) and pregnancy rate (OR: 5.8; 95% CI: 1.55–21.48; p < 0.009), but no trial reported on the live birth rate [28]. Adding human chorionic gonadotropin (hCG) as ovulatory trigger to CC does not improve reproductive outcomes; in a recent meta-analysis that included 305 patients in two RCTs, the ovulation rate and clinical pregnancy rate did not improve and the miscarriage rate did not decrease, following the addition of hCG [29].

The rates of twin and triplet pregnancy are 5–7% and 0.3%, respectively. The incidence of ovarian hyperstimulation syndrome (OHSS) is less than 1%, therefore there is no need for cycle monitoring during treatment. CC has a high safety profile and the rate of genetic and structural anomalies (3.9%) is comparable to natural conceptions [30].

Due to its efficacy and safety, CC is recommended as the first pharmacologic treatment choice for ovulation induction [27]. Duration of treatment should be limited to six cycles in responsive women. If pregnancy is not achieved, other factors of infertility should be excluded and second-line treatments should be considered.

Approximately 15% of PCOS patients do not respond to treatment and are considered CC resistant. Risk factors for CC resistance include obesity, insulin resistance, elevated serum androgen level and older age [31]. Recently, it was shown that serum level of anti-mullerian hormone (AMH) can predict ovarian response to CC; using a cut-off level of 3.4 ng/ml, women with higher AMH levels had significantly lower ovulation and pregnancy rates compared with women with lower AMH levels (48 vs 97%; p < 0.001 and 19 vs 46%; p = 0.034, respectively) [32]. Elevated AMH level can signify the increased amount of follicles arrested in the pre-antral and antral stages that fail to ovulate.

There are still no large trials assessing adjuvant treatments to improve response in CC-resistant women. In a large meta-analysis it was shown that in the subgroup of women who previously developed clomiphene resistance, adding metformin improved ovulation and clinical pregnancy rates [33]. In another meta-analysis that included four trials, it was shown that adding metformin to CC, in CC-resistant women, leads to increase in ovulation rate compared with CC alone (74.4 vs 26.3%; p < 0.001) [34]. This treatment should be considered before proceeding to more aggressive and expensive options.

Metformin

Metformin is a biguanide oral insulin-sensitizing agent, and currently is the most widely used drug for the treatment of Type 2 diabetes mellitus. Metformin decreases hepatic glucose production, decreases intestinal glucose uptake and increases peripheral glucose uptake by muscle and liver, which results in reduced insulin levels. The recognition of the central role of insulin resistance in PCOS pathogenesis which is present in 50–70% of patients, led to interest in using insulin-sensitizing agents to attempt to reverse the metabolic and the ovulatory dysfunction associated with this syndrome.

The first published report on the use of metformin as a treatment for PCOS was in 1994 [35]. Early studies, examining the reproductive system effects of metformin showed promising results, but most of these studies were observational in design and had small sample sizes. Indeed, two systematic reviews, published in 2003, showed that the majority of the published studies had a sample size of less than 30 women [36,37].

Two large RCTs examined the effectiveness of metformin, CC or placebo on live birth rate in women with PCOS. In the largest study to date, Legro et al. randomly assigned 626 infertile women with PCOS to receive CC, metformin or combination of both for up to 6 months. The live birth rate was 22.5% in the CC group, 7.2% in the metformin group and 26.8% in the combination therapy group (p < 0.001 for metformin vs both CC and combination therapy and p = 0.31 for CC vs combination therapy). The major drawback of this study was that it included mainly morbidly obese women with a mean BMI >35 kg/m² and therefore its results cannot be generalized to all patients with PCOS [38]. Moll et al. included 228 women with PCOS and investigated the effectiveness of CC plus metformin or CC plus placebo. They found that the ovulation rate was 64% in the metformin group compared with 72% in the placebo group (not significant), and no significant differences in either ongoing pregnancy, or spontaneous miscarriage rate [39]. Based mainly on these two randomized trials, The European Society of Human Reproduction and Embryology (ESHRE) and American Society of Reproduction Medicine (ASRM), in a joint meeting held in Thessaloniki in 2007, issued guidelines on ovulation induction in PCOS patients, in which they recommend CC as the drug of choice for ovulation induction in PCOS patients and that metformin should be added as an adjunctive to patients with impaired glucose tolerance [27].

In a recent Cochrane review, that included 3495 infertile PCOS women, and assessed the benefits of using metformin, it was shown that the clinical pregnancy rates were improved for metformin versus placebo (OR: 2.31; 95% CI: 1.52–3.51) and for metformin and CC versus CC alone (OR: 1.51; 95% CI: 1.17–1.96). This improvement in clinical pregnancy rate did not translate into improved live birth rate. When comparing metformin to CC, it seems that the clinical outcome depends on patients’ BMI. In non-obese patients (BMI <30 kg/m²), metformin reduced serum testosterone and fasting insulin levels more profoundly than in obese patients. In terms of reproductive outcome, nonobese women who took metformin achieved a higher clinical pregnancy rate compared with those who took CC (OR: 1.94; 95% CI: 1.19–3.16), while the opposite effect was observed in the obese group (OR: 0.34; 95% CI: 0.21–0.55). In obese patients, CC was associated with better live birth rate than metformin alone, but this effect could not be analyzed in the nonobese group due to high heterogeneity of the studies [33]. Whether the improved clinical pregnancy rate in the non-obese patient treated with metformin results from improved endocrine profile and/or reduced abortion rate, remains to be elucidated.

In the PCOSMIC study, 171 PCOS infertile women were categorized according to BMI. Overall, live birth rate for the standard care (CC + lifestyle modification) was not significantly different from standard care plus metformin (22 vs 30%; p = 0.28). However, in women with BMI <32 kg/m², metformin treatment alone was as equally effective as CC (29 vs 36%; p = 0.46) [40].

A recent meta-analysis that included 285 non obese PCOS patients showed that there are no significant differences in the efficacy of metformin and CC in clinical pregnancy rate and live birth rate, making metformin a reasonable choice for these patients [41].

Understanding the post receptor signaling of insulin has led to the emergence of novel treatments to overcome insulin resistance. Inositol (INS) is a member of the vitamin B complex and is incorporated in cell membrane as phosphatidyl-myoinositol, the precursor of Inositol triphosphate, which acts as a second messenger regulating the activity of several hormones including FSH, TSH and Insulin [42]. The two main isomers of Inositol are myoinositol (MI) and d-Chiro-Inositol (DCI). MI and DCI supplementation has shown to improve features of the metabolic syndrome including insulin sensitivity, lipid levels and blood pressure [43]. PCOS patients show increased DCI urinary clearance and consistent DCI urinary loss, presumably leading to a tissue depletion of DCI-phosphoglycans, which disrupts insulin signaling pathway [44]. In a recent meta-analysis of 6 studies that included 300 PCOS patients, it was shown that MI supplementation reduced plasma insulin, luteinizing hormone (LH)/FSH ratio and testosterone levels, and was able to induce normal menstrual cycles and improve oocyte quality [45]. The positive systemic effect on PCOS patients is achieved by both MI and DCI, however, supplementation of DCI in high doses can have disappointing effect on ovarian function and oocyte quality [46]. It seems that the most appropriate supplemental dose should be based on the plasma MI/DCI physiologic range which is normally 40:1 [47]. Further large RCTs and better understanding of INS function are warranted to provide a well-grounded rationale for INS supplementation in PCOS patients.

Aromatase inhibitors

Aromatase inhibitors (AIs) have been proposed as an alternative to CC treatment for ovulation induction. CC has some clinical and pharmacologic disadvantages; the discrepancy observed between ovulation and pregnancy rates has been attributed to CC antiestrogenic effect on the endometrium and cervical mucus [48], and its prolonged half-life results in the depletion of estrogen receptors, and disruption of the intact feedback mechanism in the hypothalamus-pituitary axis. This disruption results in increased and prolonged elevation in FSH level which can cause multifollicular growth and ovulation and increase the risk of multiple pregnancies. AIs blocks the conversion of androgens to estrogens in the ovarian follicles, peripheral tissues and the brain. The decrease in estrogenic activity releases the hypothalamus-pituitary from negative feedback, allowing for an increase in FSH secretion. Since AIs are short-acting (half-life of 48 h) and do not have effect on estrogen receptors, the central feedback mechanism remains intact and as the dominant follicle grows and estrogen levels rise, normal negative feedback occurs centrally [49]. This results in suppression of FSH and the smaller growing follicles undergo atresia, leading to a single dominant follicle growth and ovulation.

Letrozole, the most commonly used AI for ovulation induction, is administered in doses between 2.5–7.5 mg/day for 5 days starting on day 3–7 of the menstrual cycle. The first pilot study to test Letrozole for ovulation induction was published in 2001 [50]. Despite the potential advantages, the use of Letrozole was discouraged in 2005 following a report, which was never published in a peer-reviewed journal, suggesting a significant increase in congenital cardiac and bone malformations in newborns associated with Letrozole use [51]. This report prompted the manufacturer to issue a statement against the use of Letrozole in reproductive age women. Of note, later publications did not find any association between Letrozole use and fetal anomalies [30].

Over the last decade several studies were published on the use of Letrozole for ovulation induction in PCOS women. In a systematic review and meta-analysis published in 2012, it was shown that Letrozole is as effective as CC in ovulation rate, pregnancy rate, live birth rate and multiple pregnancy rates. It was evident from this review that most studies were small, there were few high-quality trials and the study population included both CC-naive and -resistant patients. The authors conclusion was that Letrozole should not be recommended as first-line pharmacological therapy for ovulation induction in PCOS patients [52].

In 2014, Legro et al. reported the results of the largest RCT to date comparing Letrozole and CC in PCOS patients; the study included 750 treatment-naive women that were equally randomized to receive either Letrozole (up to 7.5 mg/day for 5 days) or CC (up to 150 mg/day for 5 days) for up to five cycles. Women who received Letrozole had significantly higher ovulation rate (61.7 vs 48.35%; p < 0.001) and higher cumulative live birth rate (27.5 vs 19.1%; p = 0.007) compared with women who received CC. The multiple pregnancy rate did not differ between the groups (3.4% in the Letrozole group versus 7.4% in the CC group). The Mean BMI of the study groups was 35 kg/m². In the subgroup of women with BMI <30 kg/m², both treatments were equally effective in term of live birth rate [53].

In a recent Cochrane review it was shown that, compared to CC, Letrozole resulted in an increase in clinical pregnancy rates (OR: 1.4; 95% CI: 1.18–1.65; 15 trials including 2816 women) and increase in live birth rate (OR: 1.64; 95% CI: 1.32–2.04, nine trials including 1783 women).

The multiple pregnancy rate was lower with Letrozole treatment compared with CC (OR: 0.38; 95% CI: 0.17–0.84), there was no difference in the miscarriage rate, and both treatments were equally safe for the risk of ovarian hyperstimulation syndrome. In further analysis, it was shown that Letrozole did not have any advantages in women who were CC-resistant women in term of ovulation and clinical pregnancy rate [54].

In conclusion, Letrozole is at least as effective as CC, but in certain patients, such as those with obesity or CC failure, it may be a preferable alternative.

Laparoscopic ovarian drilling

Laparoscopic ovarian drilling (LOD) is the contemporary version of the ovarian wedge resection introduced in the 1930s by Stein and Leventhal to treat infertile PCOS women. Wedge resection was considered the gold standard treatment for ovulation induction, but it was largely abandoned due to the high rate of pelvic adhesion formation, approaching 100%, and the introduction of pharmacologic ovulation induction agents. The development of minimally invasive surgery, has led to a renewed interest in the surgical intervention for PCOS, and in 1984, LOD was first reported by Halvard Gjonnaess [55]. LOD is believed to achieve its effect by destruction of ovarian follicles and part of the ovarian stroma. This leads to local and systemic reduction of androgens and inhibin levels, followed by increased FSH levels, promoting follicular growth and ovulation [56]. LOD is most commonly performed using monopolar or bipolar electrocautery, or laser with comparable outcomes [57]. In the LOD procedure originally described, three to eight diathermy punctures are performed in each ovary, with each puncture having a diameter of 3 mm and depth of 3–4 mm [55]. Because of pelvic adhesion and reduction in ovarian reserve concerns, several modifications have been proposed [58]. Armar et al. described LOD with only four punctures per ovary using lower power, and reported ovulation and pregnancy rate of 86% [59]. This practice became widely adopted by many operators around the world. Another important modification to be considered is to perform unilateral instead of bilateral drilling. This technique was introduced in 1993 and was supported by subsequent RCTs [60,61]. In a recent review it was shown that unilateral and bilateral drilling were comparable in terms of ovulation rate (76 vs 72%; OR: 1.20; 95% CI: 00.59–2.46), pregnancy rate (51.7 vs 50.5%; OR: 1.00; 95%: CI 0.55–1.83) and live birth rate (36.4 vs 41%; OR: 0.83; 95% CI: 0.24–2.78) [62]. Following LOD, there is a decrease in serum LH and testosterone levels with no significant change in serum FSH level [56]. In addition, androstenedione, LH/FSH ratio and dehydroepiandrosterone sulfate are reduced, whereas SHBG is increased [55,63].

LOD is currently recommended as a second-line treatment for CC-resistant PCOS [27]. In a recent trial, Amer et al. compared LOD with CC as a first-line treatment in 72 women with PCOS; no significant difference was reported with respect to ovulation rate per woman and per cycle; 64 versus 76% and 70 versus 66% after LOD and CC treatment, respectively. Also, no significant difference was reported regarding pregnancy rate per woman and the cumulative pregnancy rate at 12 months follow-up: 27 versus 44% and 52 versus 63% after LOD and CC treatment, respectively. Live birth rate was comparable between both groups (46 vs 56% after LOD and CC treatment, respectively) [64]. In another recent trial, LOD was compared with continuation of CC for up to six further cycles in 176 infertile PCOS patients who failed to achieve pregnancy despite previous successful CC induced ovulation. The clinical pregnancy rate per patient and the cumulative pregnancy rate after six cycles were comparable in both groups (39 vs 33.7% and 47 vs 39.2%, respectively). Miscarriage and live birth rates were comparable in both groups [65]. It can be concluded from these trials that LOD has no advantages over CC as first-line treatment, or in CC failure. In CC-resistant PCOS, LOD can be a reasonable alternative. In a recent Cochrane review that evaluated nine trials and included 1210 women, there was no difference in live birth rate when LOD was compared with gonadotropins or to aromatase inhibitors [62]. There was significantly fewer live births following LOD compared with CC + metformin (OR: 0.44; 95% CI: 0.24–0.82; p = 0.01). The rate of multiple pregnancies was lower in the LOD group compared with trials using gonadotropins (OR: 0.13; 95% CI: 0.03–0.52; p = 0.004) [62].

Approximately 30% of PCOS women fail to respond to LOD, identified as lack of menstruation and persistent anovulation 8 weeks after the procedure [56]. Identifying LOD success predictors is an important issue to improve outcome and avoid unnecessary surgery. In a recent review it was shown that obesity, long duration of infertility >3 years, low basal LH levels <10 IU/l, testosterone level >4.5 nmol/l and high basal AMH >7.7 ng/ml can be associated with poor response to LOD [66]. Considering the comparable efficacy of LOD to other induction agents, it may be an attractive option for PCOS women who need diagnostic laparoscopy during their fertility evaluation or in situations where cycle monitoring cannot be done with gonadotropin treatment.

Follicle stimulating hormone

For women with infertility due to PCOS, who are CC resistant or failure, second-line of treatment can be exogenous gonadotropins [27]. In PCOS, serum FSH is too low, hence exogenous gonadotropins are administered to increase its levels and stimulate follicular growth. Due to the presence of multiple follicles in PCOS, conventional doses of gonadotropins are associated with high rates OHSS and multiple pregnancies. However, low-dose gonadotropin therapy has been proven to be effective in inducing mono-follicular ovulation [27].

Initially, gonadotropins purified from postmenopausal women urine (HMG) contained both FSH and LH and were used effectively to induce pregnancy in the 1960s. Since then various modifications have been made to improve the specificity and purity of the gonadotropins. At present both HMG and recombinant preparations are used for PCOS (Table 1).

Table 1.

Gonadotropins for ovulation induction in polycystic ovary syndrome.

Gonadotropin	Source	Ingredients	Purity	Route of administration
HMG	Postmenopausal urine	FSH + LH	<5%	i.m.
uFSH	Postmenopausal urine	FSH	<5%	i.m.
uFSH-HP	Postmenopausal urine	FSH	>95%	i.m./s.c.
rFSH, Follitropin alpha, Follitropin beta	Genetically modified cells from Chinese hamster ovary	FSH	99%	i.m./s.c.

FSH: Follicle stimulating hormone; HMG: Human menopausal gonadotropin; HP: Highly purified; i.m.: Intramuscular; LH: Luteinizing hormone; rFSH: Recombinant FSH; s.c.: Subcutaneous; uFSH: Urinary FSH.

Although urinary-derived FSH preparations do not improve pregnancy rates when compared with traditional and less expensive HMG preparations, the use of urinary (u) FSH does result in a reduced risk of OHSS [67]. It might be expected that recombinant (r) FSH preparations with greater purity, would be superior to uFSH preparations. However, a systematic review of randomized controlled trials showed no difference in efficacy and safety between rFSH and uFSH [68].

The Thessaloniki ESHRE/ASRM-sponsored PCOS Consensus Workshop Group [27] mentioned above recommends one the following low-dose regimens:

Step-up protocol: dosing commences with 37.5–75 IU FSH for 7–13 days; if there is no follicle development on sonographic examination, dose is increased by weekly increments of 50% of initial dose; once follicle growth is detected, the same FSH dose is maintained until the follicle is fully developed. Once ovulation is determined, the couple can be guided for timed intercourse, or intrauterine insemination (IUI) can be performed. The workshop found the low-dose step-up protocol resulted in a monofollicular ovulation rate approaching 70%, a pregnancy rate of 20% per cycle. With respect to undesired effects, only 6% of patients had multiple pregnancies and OHSS occurred in approximately 1% of cases;

Step-down protocol: this method assumes that a high starting dose mimics the midcycle FSH surge [69]. With a starting dose of 150 IU FSH, the dose is reduced by 37.5 IU when a follicle of 10 mm is detected, and by the same amount every 3 days if follicular growth proceeds. Although both these regimens are comparable with respect to monofollicular development, the step-up protocol appears to be preferable in terms of safety and requires less experience and skill;

Sequential low-dose protocol, combining step-up and step-down regimens: the initial dose is 300 IU of rFSH on cycle day 3 and no treatment is given for the next 3 days (cycle days 4–6). FSH therapy is reinitiated on cycle day 7 (treatment day 5) by administering 75 IU/day after pertinent ultrasound scanning of the ovaries had been performed. This dose is maintained until cycle day 9 (i.e., 1 week after treatment was initiated) and then follows the low-dose step-up approach.

Although the principal indication for gonadotropins use is for ovulation induction in women with PCOS, who exhibit CC resistance or failure, there are other cases where they may be used. Homburg and Howles recently conducted an RCT to compare the outcome of ovulation induction with CC versus low-dose gonadotropins (FSH). They found that both pregnancies and live births were achieved more effectively and rapidly following ovulation induction with low-dose FSH rather than with CC. Nevertheless, they conceded that these results would have to be balanced by convenience and cost, which would clearly be in favor of CC. However, they suggested that FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly in older patients [70].

Based on the available results from multistudy analysis, it appears that low-dose gonadotropins may be the most effective drugs when IUI is combined with ovarian stimulation [71]. This approach awaits further research.

IVF

IVF is considered the third line treatment for PCOS related infertility [27]. After the introduction of the GnRH antagonist two decades ago, there has been an ongoing debate on the preferred ovarian stimulation protocol in PCOS women. In a recent meta-analysis in the general IVF population, it was shown that the GnRH agonist ‘long protocol’ and the GnRH antagonist ‘short protocol’ are comparable in term of live birth rate and ongoing pregnancy rate, but with a significant reduction (50%) in the occurrence of OHSS in the GnRH antagonist protocol [72]. Safety of IVF treatment is of paramount importance, as the incidence of clinically important OHSS has been reported to be significantly higher in women with PCOS (15%) compared with those with normal ovaries (3%) [73]. In a recent meta-analysis that compared the long and short protocols, using hCG as ovulation trigger, it was shown that the short protocol was associated with significantly lower incidence of moderate and severe OHSS (relative risk 0.60; 95% CI: 0.48–0.76; p < 0.0001). In addition, stimulation duration and the total amount of gonadotropins were lower in the short protocol, with no significant difference in the number of cancelled cycles, or the clinical pregnancy rate [74]. These results were reproduced in other recent systematic reviews [75,76].

Another important advantage of the GnRH antagonist protocol is that it allows final oocyte maturation to be triggered with a bolus of GnRH agonist instead of hCG, a procedure which is known to significantly reduce or totally eliminate the risk of OHSS in high-risk patients. Of 2034 patients triggered with a GnRH agonist in published studies only one patient developed mild OHSS, whereas 83 of 1810 patients triggered with hCG (4.6%) developed OHSS [77].

Executive summary

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and the most common cause of anovulatory infertility.

The diagnosis of PCOS is based on the Rotterdam consensus criteria, and should include at least two of the following three criteria: oligo/anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries as identified by ultrasonography, also excluding other androgen excess disorders.

Lifestyle modification

Lifestyle modification is considered the first-line treatment for PCOS women and is recommended for both obese and lean PCOS women.

Lifestyle modification has been shown to be associated with improved endocrine profile such as increased insulin sensitivity, decreased androgen levels and increase in sex hormone binding globulin levels.

Although trials that show resumption of regular ovulation and improved pregnancy rate are scarce, lifestyle modification should be recommended as first-line treatment because it is associated with favorable response to pharmacologic induction of ovulation, and is associated with lower obstetric complications.

Clomiphene citrate

Clomiphene citrate (CC) should be used as the first-line pharmacologic treatment for ovulation induction in PCOS women.

CC induces ovulation in 75–80% of PCOS women, and after six to nine cycles of treatment, the cumulative pregnancy rate reaches 50–60%.

If ovulation cannot be achieved with CC, then the patient is considered to have CC resistance. If pregnancy cannot be achieved after six ovulatory cycles then the patient is considered to have CC failure.

Metformin

Metformin alone has been shown to improve ovulation and clinical pregnancy rate but not live birth rate.

In none-obese women (BMI <30 kg/m²) metformin is comparable to CC in term of ovulation rate, clinical pregnancy rate and live birth rate, while In obese women (BMI >30 kg/m²) CC has been shown to be superior to metformin.

Metformin combined with CC has a higher ovulation, pregnancy and live birth rate compared with CC in CC-resistant PCOS patients.

Letrozole

Letrozole is at least as effective as CC in term of ovulation induction, clinical and live pregnancy rate.

Letrozole should be considered as a second-line treatment in PCOS women with CC failure and has no advantage in clomiphene-resistant patients.

Laparoscopic ovarian drilling

Laparoscopic ovarian drilling (LOD) is an effective second-line treatment for clomiphene-resistant PCOS women but has no role in PCOS women with CC failure.

Unilateral ovarian drilling is as effective as bilateral drilling, and can be associated with lower risk of pelvis adhesions and decreased ovarian reserve.

Laparoscopic ovarian drilling should be considered in PCOS women who need diagnostic laparoscopy during their fertility evaluation or in situations where cycle monitoring cannot be done with gonadotropin treatment.

Follicle-stimulating hormone

Follicle-stimulating hormone is an effective second-line treatment in PCOS women with CC resistance or failure.

Recent randomized evidence suggests that gonadotropin therapy may be more effective than CC in therapy-naive PCOS women.

IVF

After the introduction of the gonadotropin-releasing hormone (GnRH) antagonist, the short protocol has become the preferred protocol for controlled ovarian stimulation, as it is associated with a lower risk for developing ovarian hyperstimulation syndrome compared with the GnRH agonist, long protocol.

Triggering final oocyte maturation with GnRH agonist in GnRH antagonist short protocol significantly reduces, or totally eliminates the, risk of ovarian hyperstimulation syndrome.

There is still disagreement between practitioners on the optimal way to trigger final oocyte maturation in the GnRH antagonist protocol. The results of the first RCT comparing GnRH agonist with hCG revealed an extremely high early pregnancy loss rate (80%) in the GnRH agonist trigger group, despite a standard luteal phase support [78]. The finding was interpreted as a luteal phase insufficiency caused by low circulating endogenous LH in the early and mid-luteal phase [79]. During the subsequent years, focus was directed toward rescuing the luteal phase; by an increase in the luteal LH activity with low-dose hCG, recombinant LH or GnRH agonist. Humaidan et al., in a proof of concept study, including 12 OHSS high-risk patients, rescued the luteal phase with a combination of a bolus of 1500 IU hCG on the day of oocyte retrieval and conventional luteal phase support consisting of vaginal progesterone and estradiol. This modified approach resulted in a live birth rate of 50%. One patient developed late OHSS and was treated on an outpatient basis [80]. Radesic et al. in a retrospective study, analyzed 71 consecutive OHSS high-risk patients (45% of them were PCOS patients). All patients were triggered with a GnRH agonist, followed by 1500 IU hCG administered after oocyte retrieval. This resulted in a clinical pregnancy rate of 52% per transfer and a miscarriage rate of 8%, one patient (out of 71) developed late onset severe OHSS that required hospital admission [81].

An alternative approach in patients at high risk of OHSS is to freeze all embryos after GnRH agonist triggering, and transfer subsequent freeze-thaw cycles. No incidence of OHSS was reported, and a high cumulative pregnancy rate was seen following this procedure [82].

Based on the results of the current clinical research, the GnRH antagonist protocol should be recommended instead of the long protocol when stimulating PCOS patients for IVF. If an extreme response is encountered, the clinician will always have the option of triggering final oocyte maturation with a GnRH agonist, followed by either modified luteal phase support, or a total freeze of embryos. Both approaches will ensure good reproductive and clinical outcomes, with very little risk of OHSS development.

Conclusion & future perspective

Apparently, the present PCOS diagnostic criteria (as described herein) include numerous disease entities that may share some common clinical details, but differ significantly as to their etiology. Conceivably, an obese PCOS patient, who resumes regular ovulation upon losing weight, represents a different entity that a lean PCOS patient. Given rapid development in our understanding of the human genome, future research will focus on identifying genetic and epigenetic PCOS etiologies, and may help fine-tune our clinical approach in an individualized manner. A growing research field is the study of fetal origin of adult disease. It is well established that an adverse in utero environment can affect fetal development and increase the risk for future adult morbidity (cardiovascular disease, obesity). In that line of reasoning, future research will focus on the precise implication of uterine environment on future PCOS development.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Treatment Strategies for the Infertile Polycystic Ovary Syndrome Patient

Abstract

Keywords

Lifestyle modification

Clomiphene citrate

Metformin

Aromatase inhibitors

Laparoscopic ovarian drilling

Follicle stimulating hormone

IVF

Conclusion & future perspective

Footnotes

References