Commissioning Brief - Background Information Letrozole for improving fertility in women with polycystic ovary syndrome HTA no 17/116 This background document provides further information to support applicants for this call. It is intended to summarize what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. Searches and information provided were up to date as of September 2017. Background information Source of topic This topic was identified during literature searches by the Women and Children s Health secretariat, sparked by a related Cochrane review. Patient group Polycystic ovary syndrome (PCOS) is a common condition that affects how a woman s ovaries work. It is the most common female hormone condition and is one of the leading causes of fertility problems in women (verity-pcos.org.uk). The exact cause of PCOS is unknown but there is thought to be a genetic element. The three main features of PCOS are: o irregular periods which means the ovaries don't regularly release eggs (ovulation) o excess androgen high levels of "male hormones" in your body, which may cause physical signs such as excess facial or body hair o polycystic ovaries ovaries become enlarged and contain many fluid-filled sacs (follicles) which surround the eggs It is unknown exactly how many women have PCOS, but it s thought to be very common affecting about 20% of women in the UK (nhs.uk). Many women have no symptoms but the presence of PCOS may become apparent when they experience difficulty in getting pregnant as a result of irregular ovulation or failure to ovulate at all. In such cases women are offered medication as a first-line treatment to induce ovulation to improve chances of conceiving naturally. NICE and other guidance NICE Clinical guideline CG156 (last updated August 2016) Fertility problems: assessment and treatment Page 1 of 7
NICE makes no mention of letrozole in its guidance. The use of letrozole for women with PCOS was reviewed as part of the evidence update in 2016. In the evidence update document, NICE cites the Cochrane review by Franik (2014 1 ) and the conclusion drawn from this is that This evidence suggests that in women with polycystic ovary syndrome, letrozole appears to be associated with a higher live birth rate, lower rates of multiple pregnancy and lower incidence of OHSS than clomiphene citrate. However, because of the low quality of the evidence base, no impact on NICE CG156 is expected. Current Guidance states: Offer women with WHO Group II anovulatory infertility one of the following treatments, taking into account potential adverse effects, ease and mode of use, the woman's BMI, and monitoring needed: o clomiphene citrate or o metformin or o a combination of the above. For women with WHO Group II ovulation disorders who are known to be resistant to clomiphene citrate, consider one of the following second-line treatments, depending on clinical circumstances and the woman's preference: o laparoscopic ovarian drilling or o combined treatment with clomiphene citrate and metformin[8] if not already offered as first-line treatment or o gonadotrophins. International guidelines/consensus documents There are differences between international guidelines on first line treatment for ovulation induction, (table below copied from Wang 2017 2 ). There remains no agreement, however, on which is the most effective first-line treatment between clomiphene and letrozole. In addition, there is a lack of clarity of effectiveness of the combined treatments of clomiphene with metformin and letrozole with metformin. Guidelines/consensus WHO guideline, 2016 Australian National Health and Medical Research Council (NHMRC) guideline, 2015 updated American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State Clinical Review, 2015 Italian Society of Endocrinology consensus, 2015 European Society of Endocrinology position statement, 2014 Endocrine Society, 2013 National Institute for Health and Care Excellence guideline, 2013 updated 2016 Society of Obstetricians and Gynaecologists of Canada guideline, 2010 European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine. (ESHRE/ASRM) consensus, 2008 First line ovulation induction or letrozole or letrozole or letrozole or letrozole Clomiphene, metformin, or clomiphene & metformin combined Current practice and proposed intervention Diagnosis of PCOS is made in the presence of two of the three diagnostic criteria 3 : Polycystic ovaries (either 12 or more peripheral follicles or increased ovarian volume (greater than 10 cm 3 ). Oligo-ovulation or anovulation. Page 2 of 7
Clinical and/or biochemical signs of hyperandrogenism. There is no cure for the condition so medical management is targeted at individual symptoms in association with lifestyle changes (patient.info). Current practice For women with PCOS wishing to conceive and presenting with infertility, the first-line treatment in the UK is clomiphene citrate, which may be used together with metformin. Clomiphene citrate (also known as clomifene or Clomid) is an oestrogen receptor modulator that increases ovarian stimulation, and has been used for this indication for decades 4. Treatment is taken for five days from day 2 of the cycle for up to 6 cycles (6 months). An overview of outcomes from Clomiphene citrate therapy indicates an overall ovulation rate of 73%, pregnancy rate of 36% and live birth rate of 29% over 6 months 5. However, the drug has a relatively high multiple-pregnancy rate (3 to 8%) as compared to the rate associated with unassisted conception (<1%) and an undesirable sideeffect profile including mood changes and hot flushes 4. Metformin is a widely used insulin sensitising drug linked to improvements in PCOS symptoms but can have gastrointestinal side effects. Metformin isn t licensed for treating PCOS in the UK, but because many women with PCOS have insulin resistance, it can be used "off-label" to encourage fertility and control the symptoms of PCOS (nhs.uk). Early studies of the use of metformin in the management of PCOS suggested an improvement in reproductive function, but more recent large prospective randomised studies have failed to demonstrate a significant benefit of this drug alone 5. The addition of metformin to clomiphene citrate, however, has been demonstrated to lead to significantly higher pregnancy rates than clomiphene alone 2 and hence this is included as the comparator in this proposed study. Given the potential benefits of metformin in fertility for women with PCOS, metformin is also proposed as an adjunctive treatment in the intervention arm of this study. Proposed intervention Letrozole is an aromatase inhibitor which acts to prevent oestrogen synthesis. Letrozole theoretically avoids the adverse effects of clomiphene as it does not affect oestrogen receptors and may reduce the risk of multiple follicle development 5, which can lead to an increased rate of multiple pregnancy. Letrozole has a better side-effect profile than clomiphene with fewer vasomotor and mood symptoms and has a more rapid clearance from the body 4. Letrozole is currently not recommended by NICE as a treatment for infertility in women with PCOS due to the low quality of evidence presented in a 2014 Cochrane review. However, in practice it is sometimes used to stimulate ovulation instead of clomiphene (nhs.uk). As with metformin, the use of letrozole for fertility treatment is off-label (nhs.uk). The potential for teratogenic effects with letrozole has been raised by one study published only in abstract form and never published in full. A number of publications have since indicated that letrozole is not associated with an increased risk of fetal anomalies 5. A recent network meta-analysis recommended letrozole as a first-line treatment for women with infertility as a result of PCOS due to its higher ovulation, pregnancy and live birth rate as well as lower multiple pregnancy rate relative to clomiphene 2. However, trials published since this review have not supported an increase in live birth rate with letrozole 6 7. Furthermore, there is a lack of evidence comparing letrozole and metformin to clomiphene combined with metformin which is the other recommended first-line treatment. In addition, there are few studies that have been adequately powered to report the key important outcome of live birth rate after treatment with letrozole, which is of greatest importance to patients and the NHS. A definitive randomised controlled trial is therefore proposed to determine the effectiveness and costeffectiveness of letrozole and metformin compared to clomiphene citrate and metformin on live birth rates. Page 3 of 7
Completed research Evidence Synthesis Wang (2017) Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis 2. Searched to April 2016 and included 57 trials reporting on 2,082 women. Findings: Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.58, 95% confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87; 1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to 0.92; respectively). Conclusion: Evidence on a head-to-head comparison between letrozole and the combination of clomiphene and metformin is lacking. Therefore, new trials comparing these two interventions are needed. Balen (2016) The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance 5. The aim of this paper was to present an evidence base for the management of anovulatory PCOS and provides a narrative review of the assessment and management of anovulatory infertility in PCOS. Searched to February 2014. The report strongly recommends: Clomiphene citrate or letrozole (when available and permissible) should be first-line pharmacological therapy to improve fertility outcomes in women with PCOS and anovulatory infertility, with no other infertility factors (high-quality evidence). The report suggests the weak recommendation that: Metformin could be combined with clomiphene citrate to improve fertility outcomes rather than persisting with further treatment with clomiphene alone in women with PCOS who are clomiphene resistant, anovulatory and infertile with no other infertility factors effective (highquality evidence). In summary the report concludes that: Clomiphene citrate is recommended as first-line pharmacotherapy and letrozole is an alternative. Metformin has limited benefits in improving live birth rates. Gonadotropins and laparoscopic ovarian diathermy (LOD) (drilling) can be used as second-line treatments. Cochrane review: Franik (2014) Aromatase inhibitors for subfertile women with polycystic ovary syndrome 1. Searched to September 2014. Included 26 RCTs (n=5,560 women), 6 of which compared letrozole to clomiphene citrate, one which compared letrozole to clomiphene citrate plus metformin and one which compared letrozole plus metformin to clomiphene plus metformin. Main results: When letrozole was compared with clomiphene (with or without adjuncts in both arms) followed by timed intercourse, the birth rate was higher in the letrozole group (OR 1.64, 95% CI 1.32-2.04; 9 RCTs n=1,738). However, the quality of studies was rated low for live birth and pregnancy outcomes and findings should be regarded with some caution. Page 4 of 7
Conclusions: The main limitations in the evidence were poor reporting of study methods and possible publication bias. Moreover, there was a tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth, suggesting that results might be somewhat less favorable to letrozole if all studies reported live birth. Primary Research Liu (2017) Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial 7. In this trial conducted in China, 268 women with PCOS were randomised to clomiphene citrate (n=67), clomiphene and metformin (n=67), letrozole (n=67) or letrozole and metformin (n=67). Results: There was no significant difference in the live birth rate between LE (35.3%) and CC treatment (26.4%), p >0.05. There was no significant difference in live birth rate between the LE plus metformin group compared with LE treatment (36.8% vs. 33.9%). However, the combined therapy resulted in a higher abortion rate (21.1% vs. 12.9%). There was no significant difference in live birth rate between CC + MET and CC alone (31.0% versus 22.2%), p > 0.05). The addition of metformin to CC did not increase the abortion rate (13.8% versus 12.7%, p >.05). Note: The numbers of women in the individual groups was small which likely limits the power to detect a meaningful difference in the outcomes. Amer (2017) Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome 6. This UK trial enrolled 159 women with PCOS and subfertility to either clomiphene citrate (n=79) or letrozole (n=80) for up to 6 ovulatory cycles. Results: Pregnancy rate was significantly higher in the letrozole group (61%) than CC group (43%), p=0.022. Live birth rates were not significantly different between letrozole (49%) and CC (35%), p=0.089. Note: Doesn t include metformin in either group and the sample size was not powered to detect a difference in live birth rates. Ghahiri (2016) Letrozole as the first-line treatment of infertile women with poly cystic ovarian syndrome (PCOS) compared with clomiphene citrate: A clinical trial 8. This is a prospective randomized clinical trial comparing the efficacy of letrozole as the first-line management of the PCOS patients (n=50) in comparison to clomiphene citrate (n=50) in one private infertility clinic in Iran. Results: Pregnancy occurred in 29 of 50 patients in letrozole group (58%) and 24 of 51 patients in clomiphene group (47%). The difference was not statistically significant (P value = 0.23). Note: Doesn t include metformin in the control group and doesn t have live birth outcomes. Research in progress There are a number of ongoing studies in this area but none that have a primary or even secondary outcome of live birth rate. There were no studies identified taking place in the UK or which would provide data on cost-effectiveness. Page 5 of 7
Evidence Synthesis Helena Proni Fonseca, Augusto Canton Goncalves, Bruno Malteze Zuffo, Sergio Mazzola Poli de Figueiredo, Rodrigo Salmeron de Toledo Aguiar, Victor Minari Campos, Jose Mendes Aldrighi. Comparison of clomiphene citrate and letrozole for infertility treatment in polycystic ovary syndrome: a systematic review and meta-analysis. PROSPERO 2016:CRD42016039663. Note: unlikely to add anything new beyond the conclusions of already-published evidence syntheses. Also, does not mention adjunctive treatment with metformin. Rui Wang, Madelon van Wely, siladitya Bhattacharya, Robert Norman, Richard Legro, Ben Willem Mol. First-line treatment for women with WHO group II anovulation - an IPD meta-analysis. PROSPERO 2017:CRD42017059251. Review question(s): To estimate the relative effectiveness of the first-line ovulation induction with clomiphene citrate, metformin, letrozole, gonadotrophins, tamoxifen or a combination of clomiphene and metformin on pregnancy outcomes. Primary Research NCT01679574 Letrozole or Combined Clomiphene Citrate Metformin as a First Line Treatment in Women With Polycystic Ovarian Syndrome (PCO). Primary outcome: ovulation rate. Secondary outcomes: occurrence of pregnancy and miscarriage. N=200, completed 2012. Not yet published. Egypt. NCT02551367 Letrozole Versus Clomiphene Citrate for Ovulation Induction in Women With Poly Cystic Ovary Syndrome ( PCOS ) (LVCCFOROI). Primary outcome: ovulation rate. N=110, estimated completion July 2016. Not yet published. NCT02802865 Combined Letrozole and Clomid in Women With Infertility and PCOS. Primary outcome: ovulation. N=70, estimated completion June 2018. IRCT2016030926962N2 Comparing the efficacy of long-term and short-term doses of letrozole in ovulation induction among patients with polycystic ovary syndrome. Primary outcome: endometrial thickness. N=200, recruitment ongoing. Iran. IRCT2015100223621N4 Comparison of pregnancy rate with clomiphene citrate and letrozole and clomiphene alone in infertile patients with polycystic ovary syndrome. Primary outcome: endometrial thickness. N=450, recruitment ongoing. Iran. IRCT2015090323621N3 Comparison of induction and ovulation with Clomiphene plus Letrozole versus Clomiphene plus HMG in Clomiphene resistant polycystic ovary syndrome. Primary outcome: endometrial thickness. N=200, recruitment ongoing. Iran. NIHR Evaluation Trials and Studies (NETS) research There are currently no active studies relating to PCOS in the NIHR portfolio. References 1. Franik S, Kremer JA, Nelen WL, et al. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane database of systematic reviews (Online) 2014(2):Cd010287. Page 6 of 7
2. Wang R, Kim BV, van Wely M, et al. Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis. BMJ (Clinical research ed) 2017;356:j138. 3. Royal College of Obstetricians and Gynaecologists Green-top Guideline No.33. Long-term consequences of polycystic ovary syndrome, November 2014. 4. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. The New England journal of medicine 2014;371(2):119-29. 5. Balen AH, Morley LC, Misso M, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Human reproduction update 2016;22(6):687-708. 6. Amer SA, Smith J, Mahran A, et al. Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome. Human reproduction (Oxford, England) 2017;32(8):1631-38. 7. Liu C, Feng G, Huang W, et al. Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 2017:1-5. 8. Ghahiri A, Mogharehabed N, Mamourian M. Letrozole as the first-line treatment of infertile women with poly cystic ovarian syndrome (PCOS) compared with clomiphene citrate: A clinical trial. Advanced biomedical research 2016;5:6. Page 7 of 7