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Abstract

Polycystic ovary syndrome (PCOS) has been managed surgically since the development of wedge resection in the 1930s. Second-line surgical interventions for anovulation associated with PCOS include laparoscopic ovarian diathermy, which is as effective as medical induction of ovulation with gonadotropins, with a much reduced risk of multiple pregnancy. Bariatric surgery may be considered for morbidly obese patients with PCOS, although further research assessing such surgery specifically in PCOS patients is needed. Assisted reproduction, in the form of IVF with or without intracytoplasmic sperm injection, is usually indicated as third-line medical treatment or in the presence of other infertility factors. There is an ongoing debate concerning the relative merits of IVF and ovulation induction in PCOS, comparing the higher multiple pregnancy rate of ovulation induction with the greater cost and psychological stress of IVF.

Keywords

assisted reproduction infertility IVF polycystic ovary syndrome surgery

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Release date: 1 May 2012; Expiration date: 1 May 2013

Learning objectives

Upon completion of this activity, participants should be able to:

Compare laparoscopic ovarian drilling with metformin in the treatment of infertility among women with PCOS

Compare laparoscopic ovarian drilling with gonadotropin ovulation induction in the treatment of infertility among women with PCOS

Evaluate the role of bariatric surgery in the treatment of infertility among women with PCOS

Analyze the use of assisted reproductive technology in the treatment of infertility among women with PCOS

Surgical treatment in the form of ovarian wedge resection by laparotomy was first proposed for the treatment of infertility in women with polycystic ovary syndrome (PCOS) by Stein and Leventhal in 1935 [1]. However, this procedure was later largely abandoned, despite promising outcomes of initial series, owing to the risk of post operative adhesions and substantial loss of ovarian tissue, and was supplanted by the use of medical ovulation induction agents such as clomifene citrate and gonadotropins [2]. However, surgical approaches to ovulation induction have continued to play a part in the management of infertility associated with PCOS both in the form of laparoscopic ovarian diathermy, essentially a less traumatic modern version of ovarian wedge resection, and bariatric surgery. Surgical approaches to infertility are largely restricted to cases of anovulation, usually associated with PCOS, and include laparoscopic ovarian drilling/diathermy (LOD) and bariatric surgery for morbid obesity and infertility. Assisted reproduction is normally used as a third-line treatment for those suffering from infertility associated with anovulation and is also more widely used for couples with other causes of infertility including male infertility, tubal damage or unexplained infertility.

When assessing response to treatment for infertility it is important to differentiate between the various outcome measures. This review will provide information concerning live-birth rate, pregnancy rate and ovulation rate when this information is available. The preferred outcome method is the live-birth rate per cycle started when considering IVF treatment, but this is not available in many of the publications in this area. Results are frequently reported as ongoing pregnancy rate or other outcomes that are less relevant to clinicians and patients who are trying to select their optimum treatment.

LOD

LOD, a less invasive modification of ovarian wedge resection, was first described in women with PCOS by Gjønæss in 1984 who reported ovulation and pregnancy rates as 92 and 58%, respectively [3]. Since this time, LOD using both electrocautery (diathermy) and laser vaporization has been performed to create multiple (four to ten) puncture holes in the ovarian cortex and stroma; the mechanism of action is poorly understood but is believed to be similar to that of ovarian wedge resection with destruction of ovarian androgen-producing thecal cells, leading to local (conversion of androgenic intrafollicular environment to an estrogenic one) and systemic (reduction in serum levels of androgens and lutenizing hormone together with an increase in follicle-stimulating hormone levels) endocrine changes that are thought to promote follicular recruitment, maturation and subsequent ovulation [4]. In a narrative review reporting on the efficacy of LOD based predominately on observational studies, the spontaneous ovulation and pregnancy rates ranged from 54 to 76% and 28 to 56% at 6 months, and 33 to 88% and 54 to 70% at 12 months, respectively (Box 1) [2].

The most current systematic review and meta-analysis of randomized controlled trials (RCTs) examining all RCTs of infertile clomiphene citrate-resistant (CCR) women with PCOS undergoing LOD did not identify any RCTs comparing LOD with placebo/no treatment. However, there were five RCTs (338 CCR randomized patients) comparing LOD (6–12 months of follow-up) versus gonadotropin ovulation induction (three to six treatment cycles), and meta-analysis showed no difference in live-birth rate per patient, ongoing pregnancy rate per patient, ovulation rate per patient, miscarriage rate per pregnancy or quality of life between the two interventions, but there was a reduction in multiple pregnancy rate per ongoing pregnancy (1 vs 17%, respectively; odds ratio [OR]: 0.13; 95% CI: 0.03–0.59) with LOD in CCR PCOS patients. There were also less direct costs with LOD compared with gonadotropins [4].

Therefore, LOD has been recommended by an expert international consensus group as second-line therapy in CCR PCOS [5]. A subsequent RCT, also supporting this recommendation, has demonstrated no difference between LOD and up to six cycles of clomifene citrate in terms of live birth, pregnancy, ovulation and miscarriage rates in therapy-naive women with PCOS [6].

Two RCTs with conflicting results have compared metformin to LOD in CCR PCOS [7,8]. The first of the RCTs to be published compared metformin to LOD in 120 overweight (BMI 25–30 kg/m²) CCR women with PCOS with follow-up over 6 months and found no difference in ovulation rate per cycle (55 vs 53%; p > 0.05) or clinical pregnancy rate per patient (72 vs 56%; relative risk [RR]: 1.28 with 95% CI: 0.99–1.70 favoring metformin) but a reduced miscarriage rate per pregnancy (15.4 vs 29%; p < 0.05), higher live-birth rate per patient (59 vs 36%; RR: 1.63 with 95% CI: 1.08–2.46) and lower costs (50 vs €1050; p < 0.05) with metformin [8,9].

The later RCT to be published compared metformin with LOD in 110 CCR PCOS patients with a mean BMI of 36 kg/m² who were also insulin resistant, with follow-up over 6 months or 30 weeks (whichever occurred first). In this study, metformin was less efficacious than LOD with a reduced ovulation rate per cycle (33 vs 51%; RR: 2.05 with 95% CI: 1.4–2.9; p = 0.001), pregnancy rate per cycle (4 vs 8%; RR: 2.19 with 95% CI: 1.03–4.63; p = 0.03), and cumulative pregnancy rate per patient (20 vs 38%; RR: 2.47 with 95% CI: 1.05–5.81; p = 0.03) in conjunction with a higher proportion of patients who never ovulated (33 vs 14%; RR: 2.85 with 95% CI: 1.11–7.29; p = 0.02) but no difference in first trimester miscarriage rate per pregnancy (18 vs 19%; RR: 1.05 with 95% CI: 0.16–6.9; p = 0.09) [7].

Box 1.

Laparoscopic ovarian drilling.

Background

Surgical ovarian wedge resection by open laparotomy was one of the first treatments for anovulation due to PCOS

First report

LOD procedure was first described by Gjønæss in 1984

Techniques

Four to six punctures per ovary using either electrocautery (diathermy) or laser vaporization

Mechanism of action

Poorly understood but believed to be via destruction of ovarian androgen-producing thecal cells leading to local and systemic reduction in androgen levels thus promoting follicular growth and ovulation

Indications

Anovulatory PCOS women with CCR, particularly when there are other indications for laparoscopy

Results at 6 months

Spontaneous ovulation rate: 54–76%

Pregnancy rate: 28–56%

Results at 12 months

Spontaneous ovulation rate: 33–88%

Pregnancy rate: 54–70%

Predictors of poor success

Morbid obesity (BMI >35)

Marked biochemical hyperandrogenism (serum T ≥4.5 nmol/l)

Duration of infertility >3 years

LH/FSH ratio <2.0 (i.e., low basal LH levels)

Advantages

No requirement for monitoring as no increased risk of multiple pregnancy

Disadvantages

Possible short-term effect

Surgical risks of laparoscopy, general anesthesia and ovarian damage including (rarely) ovarian atrophy, failure and adhesion formation

CCR: Clomiphene citrate resistance; FSH: Follicle-stimulating hormone; LH: Lutenizing hormone;

LOD: Laparoscopic ovarian drilling/diathermy; PCOS: Polycystic ovary syndrome.

Data taken from [1 –3].

The same group of researchers who published the first of the RCTs comparing metformin with LOD subsequently conducted a RCT comparing metformin combined with clomifene citrate with LOD, and reported a higher ovulation rate per cycle (72 vs 56%, respectively; p = 0.023) and lower cost of treatment (119.6 vs US$316.8, respectively; p < 0.001) but no difference in cumulative pregnancy rate (61 vs 62%, respectively; p = 1.0), miscarriage rate per pregnancy (17 vs 13%, respectively; p = 1.0) or cumulative live-birth rate (52 vs 54%, respectively; p = 1.0) in 55 randomized CCR PCOS patients with a mean BMI of 30 kg/m² (all had a BMI <35 kg/m²) over 6 months follow-up [10].

Despite a risk of postoperative adhesions following LOD [5], a single RCT has shown that a second-look laparoscopic adhesiolyis performed 3 months following LOD in CCR women with PCOS has no benefit in terms of pregnancy or miscarriage rates per patient over 6 months follow-up [11].

In summary, LOD is recommended as a second-line therapy in CCR PCOS patients and is an alternative to gonadotropin therapy with equal efficacy but lower risk of multiple pregnancy and cost. There is conflicting evidence as to whether metformin alone or LOD is more beneficial in terms of reproductive outcome. Based on a single small RCT with a primary end point of live-birth rate and sample size defined arbitrarily [10], there was no evidence of a difference in pregnancy or live-birth rate between 6-months treatment with either clomifene citrate combined with metformin or LOD.

Bariatric surgery

Bariatric or weight-loss surgery in the general population results in approximately 15–30% weight loss that is sustained in the long term [12]. A Cochrane review of bariatric surgery in the general population found that such surgery resulted in greater weight loss than conventional treatment in obesity (BMI >30 kg/m²) and a reduction in comorbidities such as diabetes and hypertension based on three RCTs and three prospective cohort studies [13]. However, this review did not assess fertility outcomes.

Another systematic review of bariatric surgery in the general population assessed reproductive outcomes and reported that case–control and cohort studies show improved fertility and a reduction in obstetrical complications such as gestational diabetes, macrosomia and hypertensive disorders of pregnancy, but the incidence of intra-uterine growth restriction appears to be increased. No conclusions could be drawn regarding the risk of preterm labor and miscarriage [14].

We are not aware of any published RCTs assessing the effectiveness of bariatric surgery specifically in PCOS women. A recent review on the treatment of obesity in PCOS published by an expert international panel of PCOS researchers appointed by the Androgen Excess and PCOS Society identified two uncontrolled observational studies in morbidly obese and overweight PCOS women that reported improvement in menstrual cyclicity, ovulation and natural conception [15]. This same review also reported that while bariatric surgery is a potential future treatment option for obese PCOS women, the criteria for performing such bariatric surgery are still largely debatable and more scientific research is required. However, a consensus was reached in the British Fertility Society guidelines that fertility treatment should be deferred in the general population of women who are morbidily obese, until they have lost weight to below a BMI of 35 kg/m² [16]. The results of pregnancies achieved after bariatric surgery have recently been reviewed [17]. The review supports the conclusion that the risk of adverse maternal and neonatal outcome could be reduced in women who are morbidly obese with PCOS by bariatric surgery before pregnancy. However, the review also identifies the lack of high-quality information. Further studies are recommended.

Assisted reproductive technologies in the patient with PCOS

Stimulated intrauterine insemination

The first published report on intrauterine insemination (IUI) was in 1962 [17,18]. IUI has since become a widely used fertility treatment, with the rationale for its use being to increase the conception rate in infertile couples by increasing the chance that the maximum number of healthy sperm reaches the site of fertilization in the fallopian tube [18,19].

Based on a lack of RCTs comparing the pregnancy rates of IUI versus timed intercourse during ovulation induction in women with PCOS, a consensus by a group of international experts concluded that combining IUI with ovulation induction may be considered in anovulatory women with PCOS where there is associated male factor infertility or failure to conceive despite successful induction of ovulation. The efficacy of such treatment ranges from 11 to 20% clinical pregnancy rate per cycle with a multiple pregnancy rate ranging from 11 to 36% based on a limited number of studies on women with PCOS [5].

Since this consensus report, a RCT comparing three consecutive cycles of clomifene citrate ovulation induction with either IUI or timed intercourse as first-line treatment for anovulatory infertility in 188 therapy-naive women with PCOS (525 cycles) with a BMI <30 kg/m², patent fallopian tubes and a male partner with normal semen analysis has been published. This study showed comparable outcomes between the two treatment groups with no difference in clinical pregnancy rate per cycle (8.5 vs 7.9%; p = 0.26) or per woman (23.6 vs 22.1%; p = 0.33), miscarriage rate per pregnancy (18.1 vs 19.0%; p = 0.31) and live-birth rate per woman (19.3 vs 17.9%; p = 0.33), respectively [20].

Therefore, the addition of IUI to the first three cycles of clomifene citrate ovulation induction does not improve reproductive outcomes for the PCOS woman where anovulation is the sole cause for infertility.

IVF

The first successful human birth from IVF treatment was that of Louise Brown who was born in the UK on 25 July 1978 [21]. Since this time, IVF treatment has been developed to include injections of gonadotropins to achieve multi follicular ovarian development for subsequent egg retrieval, fertilization of eggs and the generation of embryos for transfer into the uterus. The success rates of IVF treatment has improved over time and, in 2005, 34% of cycles resulted in a clinical pregnancy and 28% of cycles a live birth, although success rates depend on the patient's age, with the highest pregnancy rates observed in women under 35 years of age where pregnancy and live-birth rates approach 43 and 37%, respectively. Risks involved with IVF treatment include multiple pregnancy, when multiple embryos are transferred, and a significant risk of ovarian hyperstimulation syndrome (OHSS). However, the risk of multiple pregnancy is more easily controlled with IVF than ovulation induction with gonadotropins, because with IVF the number of embryos transferred into the patient's uterus can be restricted to one or two, with cryopreservation of other good quality embryos for future use, whereas with ovulation induction it is not possible to completely avoid ovulation of more than one oocyte from smaller follicles [22].

Anovulation alone, in principle, is not an indication for IVF/intracytoplasmic sperm injection (ICSI) and therefore IVF/ICSI treatment in women with PCOS is recommended either as a third-line treatment (after failed first- or second-line therapies including clomifene citrate, gonadotropin or LOD ovulation induction) or in the presence of other infertility factors such as tubal damage, severe endometriosis or male factor infertility [5].

IVF/ICSI treatment in women with PCOS poses a number of clinical challenges, in particular that of moderate-to-severe OHSS, with a risk of approximately 10% compared with a risk of 0.5–4.0% observed in the general IVF population [23]. A meta-analysis has reported an OR of 6.8 (95% CI: 4.9–9.6) for the development of OHSS in ultrasound-determined PCOS patients compared with those with normal-appearing ovaries on baseline ultrasound [24].

Women with PCOS achieve pregnancy and live-birth rates similar to those of non-PCOS patients during conventional IVF cycles, as evidenced by a large systematic review and meta-analysis of nine observational studies comparing 458 women with PCOS (793 cycles) with 694 matched controls (1116 cycles). However, women with PCOS have a higher cycle cancellation rate prior to egg collection (13 vs 4%; OR: 0.5 with 95% CI: 0.2–1.0) due to absent/limited ovarian response or increased risk of OHSS. Women with PCOS also have a higher number of eggs collected (random effects weighted mean difference: +3.4 eggs with 95% CI: 1.7–5.1) and a lower fertilization rate resulting in no difference in the number of fertilized eggs compared with non-PCOS patients. The miscarriage rate per pregnancy was similar between PCOS and non-PCOS patients. In most of the studies, the incidence of OHSS was not clearly reported and therefore data regarding this risk were difficult to pool [25].

In 2011, a systematic review and meta-analysis of eight RCTs compared the gonadotropin-releasing hormone antagonist protocol with the long gonadotropin-releasing hormone agonist protocol in 783 randomized women with PCOS undergoing IVF/ICSI treatment [26,27]. This review found no difference in ongoing pregnancy rates (OR: 0.91; 95% CI: 0.67–1.22) or clinical pregnancy rates (OR: 0.87; 95% CI: 0.64–1.19) per woman, respectively, but there was a 10% lower risk of OHSS per woman with the antagonist protocol (risk difference: −0.10; 95% CI: −0.14 to −0.07). Therefore in the IVF/ICSI treatment of women with PCOS, the antagonist protocol would seem to be preferred to the long agonist protocol owing to the lower risk of OHSS, with no difference in reproductive outcomes. Overall success rates for IVF can be derived from the large UK Human Fertilization and Embryology Authority database. The success rates of IVF treatment have improved over time. The database showed a live-birth rate for IVF of 24.1% per cycle starting in 2008, an increase of 0.4% over the 2007 data. Data for 2006–2008 are shown in Table 1 [101]. A recent publication from the USA has identified final assisted reproductive technology success rates using cumulative pregnancy and live-birth rates, showing that cumulative live-birth rates in excess of 50% can be achieved for patients under 40 years of age after cumulative transfer of six embryos [28].

Table 1.

UK uptake of IVF and success rates (2006–2008).

	2006	2007	2008	Change 2007–2008 (%)
Number of cycles	44,275	46,829	50,687	+8.2
Number of patients	34,855	36,861	39,879	+8.2
Number of babies born through IVF	10,242 successful births giving rise to 12,596 babies	11,091 successful births giving rise to 13,672 babies	12,211 successful births giving rise to 15,082 babies	Births up +10.1, babies +10.3
IVF live-birth rate per cycle started	23.1%	23.7%	24.1%	+0.4
Multiple birth rate following IVF	22.7%	23.0%	23.2%	+0.2

Data taken from [101].

Future perspective

The best evidence to date on reproductive outcomes in women with PCOS supports LOD as second-line medical therapy in CCR women, and IVF/ICSI as third-line medical treatment or in the presence of other infertility factors.

Further RCTs are required to assess the effectiveness and safety of LOD and other second-line medical treatments such as metformin, with or without clomifene citrate, and gonadotropins in CCR women with PCOS. RCTs are also required to determine the efficacy and safety of bariatric surgery in the anovulatory PCOS woman with obesity.

Executive summary

Polycystic ovary syndrome

Surgical approaches to ovulation induction and IVF/intracytoplasmic sperm injection (ICSI) have continued to play an important part in the management of infertility associated with polycystic ovary syndrome (PCOS).

Laparoscopic ovarian drilling

Laparoscopic ovarian drilling (LOD) is a second-line therapy in clomifene citrate-resistant (CCR) women with PCOS that is equally effective as three to six treatment cycles of gonadotropin ovulation induction in terms of fertility outcome, but with a lower risk of multiple pregnancy and less direct costs.

There is conflicting randomized controlled trial (RCT) evidence as to whether metformin alone or LOD is more beneficial in terms of reproductive outcome.

Bariatric surgery

There is a lack of published RCTs on bariatric surgery in PCOS and further research, both observational studies and RCTs, are recommended.

Stimulated intrauterine insemination treatment

Where anovulation is the sole cause of infertility in PCOS, reproductive outcomes are not improved with the addition of intrauterine insemination to the first three cycles of clomifene citrate ovulation induction.

IVF/ICSI treatment

IVF/ICSI treatment in women with PCOS is recommended either as a third-line treatment (after failed first- or second-line therapies, including clomifene citrate, gonadotropin or LOD ovulation induction) or in the presence of other infertility factors such as tubal damage, severe endometriosis or male factor infertility.

Women with PCOS undergoing IVF treatment achieve similar pregnancy and live-birth rates to those of non-PCOS patients. However, women with PCOS experience a higher risk of ovarian hyperstimulation syndrome.

The gonadotropin-releasing hormone antagonist protocol may be preferable to the long gonadotropin-releasing hormone agonist protocol in women with PCOS undergoing IVF/ICSI treatment owing to the lower risk of ovarian hyperstimulation syndrome despite no difference in reproductive outcomes.

Future perspective

The best evidence to date on fertility outcomes in women with PCOS supports LOD as second-line medical therapy in CCR women, and IVF/ICSI as third-line medical treatment or in the presence of other infertility factors.

There remains a need for further high-quality research in the form of well-designed, adequately powered RCTs of sufficient long-term duration that assess the effectiveness and safety of infertility treatments for anovulatory women with PCOS, despite a large number of RCTs and systematic reviews of RCTs having been published.

Examples of such high-quality research required include comparing LOD with other second-line treatments in CCR PCOS women, such as metformin alone or metformin combined with clomifene citrate, and assessing bariatric surgery in obese women with PCOS.

There is a lack of high-quality evidence concerning bariatric surgery for anovulation. In our opinion, there is a window of opportunity to recruit such patients into adequately powered, high-quality RCTs on this topic, and all patients undergoing bariatric surgery for treatment of anovulation should be entered into an international registry to allow accumulation of further information on this developing topic.

Footnotes

Acknowledgements

The authors would like to thank and acknowledge N Peirce and C Leahy for their help in preparation of the references for this manuscript.

CME Author

Charles P Vega, Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA

Disclosure: Charles P Vega has disclosed no relevant financial relationships.

Authors and Disclosures

Michael F Costello, School of Women's & Children's Health, Division of Obstetrics & Gynaecology, University of New South Wales, Royal Hospital for Women, Sydney, NSW, Australia; Department of Reproductive Medicine & IVF Australia, Royal Hospital for Women, Sydney, NSW, Australia

Disclosure: Michael F Costello has disclosed no relevant financial relationships.

William L Ledger, School of Women's & Children's Health, Division of Obstetrics & Gynaecology, University of New South Wales, Royal Hospital for Women, Sydney, NSW, Australia; Department of Reproductive Medicine & IVF Australia, Royal Hospital for Women, Sydney, NSW, Australia

Disclosure: William L Ledger has disclosed no relevant financial relationships.

Editor

Elisa Manzotti, Publisher, Future Science Group

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

Evidence-based management of infertility in women with polycystic ovary syndrome using surgery or assisted reproductive technology

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