title: The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance.
abstract: Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS).
  
  
  
  The aim of this paper was to present an evidence base for the management of anovulatory PCOS.
  
  
  
  The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus.
  
  
  
  Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is ≥35 kg/m2and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good cumulative pregnancy rates and multiple pregnancy rates can be minimized with adherence to recommended protocols. CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be used as first-line therapy. Metformin alone has limited benefits in improving live birth rates. Gonadotropins and laparoscopic surgery can be used as second-line treatment. There is no clear evidence for efficacy of acupuncture or herbal mixtures in women with PCOS. For women with PCOS who fail lifestyle and ovulation induction therapy or have additional infertility factors, IVF can be used with the safer gonadotropin releasing hormone (GnRH) antagonist protocol. If a GnRH-agonist protocol is used, metformin as an adjunct may reduce the risk of ovarian hyperstimulation syndrome. Patients should be informed of the potential side effects of ovulation induction agents and of IVF on the foetus, and of the risks of multiple pregnancy. Increased risks for the mother during pregnancy and for the child, including the exacerbating impact of obesity on adverse outcomes, should also be discussed.
  
  
  
  This guidance generation and evidence-synthesis analysis has been conducted in a manner to be considered for global applicability for the safe administration of ovulation induction for anovulatory women with PCOS.
authors: Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals, Leeds LS14 6UH, UK a.balen@nhs.net.
authors: Adam H
authors: AH
authors: Balen
authors: Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals, Leeds LS14 6UH, UK.
authors: Lara C
authors: LC
authors: Morley
authors: Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Monash Medical Centre, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia.
authors: Marie
authors: M
authors: Misso
authors: Institute of Reproductive & Developmental Biology, Hammersmith Hospital, London, UK.
authors: Stephen
authors: S
authors: Franks
authors: Penn State College of Medicine, 500 University Drive, H103, Hershey, PA 17033, USA.
authors: Richard S
authors: RS
authors: Legro
authors: Faculty of Medicine, University of Colombo, PO Box 271, Kynsey Road, Colombo 008, Sri Lanka.
authors: Chandrika N
authors: CN
authors: Wijeyaratne
authors: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors: Elisabet
authors: E
authors: Stener-Victorin
authors: Department of Reproductive Medicine & Gynaecology, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors: Bart C J M
authors: BC
authors: Fauser
authors: The Robinson Institute, University of Adelaide, Norwich House, 55 King William Street, North Adelaide, SA 5005, Australia.
authors: Robert J
authors: RJ
authors: Norman
authors: Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Monash Medical Centre, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia.
authors: Helena
authors: H
authors: Teede
mesh_terms: D000858:Anovulation / Q000150:complications / Q000628:therapy*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D002996:Clomiphene / Q000627:therapeutic use; D032921:Consensus; D005260:Female; D005300:Fertility Agents, Female / Q000627:therapeutic use; D005307:Fertilization in Vitro / Q000009:adverse effects; D006062:Gonadotropins / Q000627:therapeutic use; D000070497:Healthy Lifestyle; D006801:Humans; D007247:Infertility, Female / Q000209:etiology / Q000628:therapy*; D000077289:Letrozole; D008687:Metformin / Q000627:therapeutic use; D009570:Nitriles / Q000627:therapeutic use; D009765:Obesity / Q000150:complications / Q000628:therapy; D016471:Ovarian Hyperstimulation Syndrome / Q000517:prevention & control; D010060:Ovulation; D010062:Ovulation Induction / Q000379:methods; D011085:Polycystic Ovary Syndrome / Q000150:complications / Q000175:diagnosis / Q000208:ethnology / Q000628:therapy*; D017410:Practice Guidelines as Topic; D011247:Pregnancy; D011967:Receptors, Gonadotropin / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D047072:Aromatase Inhibitors; D005300:Fertility Agents, Female; D006062:Gonadotropins; D009570:Nitriles; D011967:Receptors, Gonadotropin; D014230:Triazoles; D002996:Clomiphene; D000077289:Letrozole; D008687:Metformin
keywords: anovulatory infertility; aromatase inhibitors; clomiphene citrate; gonadotropin therapy; laparoscopic ovarian diathermy; lifestyle; metformin; ovulation induction; polycystic ovary syndrome (PCOS); weight management