Diagnosis and management of infertility in patients with polycystic ovary syndrome (PCOS): guidelines from the Italian Society of Human Reproduction (SIRU) and the Italian Centers for the Study and Conservation of Eggs and Sperm (CECOS Italy)

Abstract

The polycystic ovary syndrome (PCOS) is a multifaced disease of the reproductive age associated with several comorbidities including infertility. Very few documents regarding the management of the infertility in women with PCOS, including guidelines, position papers and consensus conferences, are available in the literature. The Italian Law indicates that health professionals must comply with the recommendations set out in the guidelines developed by public and private bodies and institutions, as well as scientific societies and technical-scientific associations of the health professions, except for specific cases. Unfortunately, no guideline for the diagnosis and the management of infertility in women with PCOS is currently available in Italy. In 2024, the Italian Society of Human Reproduction (SIRU) and the Italian Centers for the Study and Conservation of Eggs and Sperm (CECOS Italy) pointed out the need to produce Italian guidelines on this topic and established a specific working group to develop those guidelines. The working group chose to adapt the guideline with highest quality to the Italian context rather than developing a de novo document. The International Evidence-Based Guideline for the Assessment and Management of PCOS guidelines were selected. All recommendations regarding the diagnosis and the management of women with PCOS and infertility extracted, adapted to the Italian context and improved incorporating new recommendations or practical comments and suggestions where needed.

Introduction

Polycystic ovary syndrome (PCOS) is a multifaced disease of the reproductive age associated with several comorbidities, including infertility [1]. Patients with PCOS frequently undergo diagnostic and therapeutic procedures for reproductive problems [2]. Ovulatory dysfunction, one of the criteria for PCOS diagnosis [3], is frequently associated with menstrual irregularities, especially oligo-amenorrhea, and is considered the main cause of infertility in women with PCOS [4]. However, several experimental and clinical findings underline that the fertility in women with PCOS may be also affected for abnormalities in endometrial [5] and oocyte [6] competence, irrespectively from ovulatory dysfunction.

Recent data seem to confirm that a correct therapeutic flow-chart, as suggested by available recommendations, can optimize the reproductive chances in women with PCOS allowing to reach a long-term fecundability like or slightly higher in comparison with women without the disease [7, 8].

In Italy, the Law n. 24 2017, indicates that health professionals must comply, except for specific cases, with the recommendations set out in the guidelines developed by public and private bodies and institutions as well as scientific societies and technical-scientific associations of the health professions. These guidelines must be developed following a scientific methodology [9] and approved by the National Center for the Clinical Excellence, Quality and Safety of the Care (CNEC, Centro Nazionale per l’Eccellenza Clinica, la Qualità e la Sicurezza delle Cure), an institutional organism directly referring to the Ministry of Health.

No specific guideline for the diagnosis and management of infertility in PCOS is currently available in Italy [10]. In 2015, an endocrinological and gynecological consensus statement of the Italian Society of Endocrinology was published [11]. That consensus statement reported in a narrative fashion few generic recommendations about the treatment of infertility in women with PCOS. In addition, the two main therapeutical innovations in the treatment of infertile women with PCOS, i.e. letrozole administration as ovulation inductor and GnRH antagonist use in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), were not contemplated [12].

Based on these considerations, the Italian Society of Human Reproduction (SIRU, Società Italiana di Riproduzione Umana) and the Italian Centers for the Study and Conservation of Eggs and Sperm (CECOS Italy, Centri Conservazione Ovociti e Spermatozoi - Italia) decided to produce an official document for the diagnosis and management of infertility in women with PCOS to be adopted in Italy. This report aims to detail the methodological process followed and the results obtained.

Methods

The methodology used agreed with the provisions of the National System Guidelines System (SNLG, Sistema Nazionale Linee-Guida) and all the steps were carried out in accordance with the specific Manual of CNEC (https://www.iss.it/documents/20126/7949265/Manuale+Metodologico+-+marzo+2023.pdf/01f4bc8e-f3e6-66ec-bbe1-e80186908c6c?t=1679921943422).

The initial idea to develop the guidelines was spread and shared among the members of the Society during the VII National Congress of the SIRU (Bari, 11th-13th April 2024) and was approved. A formal proposal for sharing and participation was made to CECOS Italy that approved the collaboration. In consideration of the experience previously acquired [10], no specific funding was defined and the SIRU and the CECOS Italy themself participated to cover the expenditures.

SIRU and CECOS Italy steering committees defined an integrated Working Group on Italian Guideline for Infertility in PCOS. That working group was defined according to principles of professional and specialist representation and excluding components that declared any potential important conflict of interest. It included citizens' and patients' associations, different professions (including lawyer, biologist, doctor, and midwife), and medical specialties (including medical genetics, obstetrics and gynecology).

The complete methodological process of elaboration of the guideline followed the “GRADE-ADOLOPMENT approach” based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision (EtD) frameworks [13]. It was performed through meetings conducted in teleconferences for reducing the expenses/costs. Any disagreements were resolved by consensus methods.

According to the methodology already followed and previous experience [10], the Working Group chose to adapt, rather than to develop, available guideline of high methodological quality to the Italian context. Thus, the Working Group systematically searched recent available guidelines on the diagnosis and management of infertility in women with PCOS, assessed their quality, and selected the guidelines with the highest quality to use as reference. The search was conducted using key terms such as "polycystic ovary syndrome" or "PCOS" matched with "guideline", “consensus conference”, “position paper”, “position statement”, “scientific statement” or “recommendation” on main websites, including PubMed, Web of Science, Google Scholar, Cochrane Library. All articles that referred to guidelines for the diagnosis and management of infertility in women with PCOS were screened without language restriction reading the full text. The guidelines intercepted were then rated for quality using the Italian version [14] of the Appraisal of Guidelines for Research and Evaluation II (AGREE II) scoring system [15, 16], and the item with the highest AGREE II score was chosen as the reference document. That reference document was adapted (https://www.gimbe.org/pagine/569/it/agree-ii) deleting or changing recommendations considered not relevant, repetitive, debatable, or not/poorly applicable to the Italian context, and reporting the specific reason for each change (deletion or change). No specific attempt was planned and made to update the reference document.

The revised document was analyzed to identify new issues not assessed in the reference guideline, not previously addressed in the SIRU-guidelines for the diagnosis and management of infertility in Italy [10], and potentially relevant for the Italian context and from a clinical point of view. New clinical issues were defined using specific clinical questions and developed according to the Population, Intervention, Comparison and Outcomes (PICO) model [17]. Specifically, the “Population” comprised of infertile patients with PCOS, the “Intervention” encompassed each strategy, procedure, or treatment employed to diagnose or treat infertility in women with PCOS, the "Comparison" involved neither intervention (diagnostic and/or therapeutic) nor a placebo/sham arm or another potentially active intervention, and the “Outcomes” were ranked by importance in evaluating intervention effects case-by-case using three main categories, i.e. critical, important but not critical, and of limited importance.

Using the same websites mentioned above, a further extensive search of published studies was performed for each item using the hierarchy of evidence starting from systematic reviews and meta-analyses, randomized controlled trials (RCTs) up to experimental data or expert opinion, and the highest evidence was used. Each study was analyzed, and the certainty of evidence and the study quality was defined using specific tools. Data published up to August 19, 2024, were collected, analyzed, interpreted, and integrated into the referral guideline.

Each new item of the document was reported according to the GRADE system (https://gdt.gradepro.org/app/handbook/handbook.html) to rate the quality of evidence and the strength of recommendations using a direct and standardized language and graphical descriptions to improve simplicity and transparency. The methodology used was optimized after the selection of the available guideline to harmonize the document (Table 1).

Table 1 The grading of the quality of evidence and the strength of recommendations are here reported together with the graphical descriptions and the terminology used. This methodology was the same used in the referral guideline [3] to harmonize the final document with the regard of the new clinical items analyzed

The text including specific recommendations for infertile patients with PCOS was summarized integrating the different items in operative and integrated document for its largest diffusion and applicability.

The document was subsequently subjected to a public consultation with the aim of collecting feedback on the preliminary version of the recommendations, as well as to evaluate their applicability and feasibility. Specifically, the document was announced by email to SIRU and CECOS Italy members and potential stakeholders. Then, it was published for two weeks on the SIRU’s website (https://www.pmaumanizzata.com) to receive further comments and additional suggestions. The participants to public consultation included bioethicists, biologists, endocrinologists, gynecologists, oncologists, immunologists, midwives, psychologists, citizens and patient representatives, and pharmaceutical and biomedical industry representatives. It was asked to provide personal, professional, and contact data, and to list any changes suggested to the clinical recommendations, indicating the related reasons, including possible obstacles to their application, and any useful reference. The Working Group analyzed the suggested changes and integrated those deemed appropriate in the final document.

After the public consultation, the document was submitted to an external review to improve the quality of the document and to collect feedback on the draft version of the recommendations. Two well-recognized international experts were identified, contacted and asked to revise the final document. The Working Group assessed the suggestions and comments received and included those considered relevant in the final version of the document.

The SIRU decided to update the guidelines every two years to integrate new scientific evidence to support modifying pre-existing recommendations or to draft novel recommendations, and to submit the final document to Reproductive Biology and Endocrinology for the normal process of international peer reviewing.

Results

The Fig. 1 details the entire methodological process followed to produce an official document for the diagnosis and management of infertility in women with PCOS in Italy.

Fig. 1

Guideline development process. PICO model: Population, Intervention, Comparison and Outcomes model; GDG: Guideline Development Group; GRADE frameworks: Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision frameworks; RCTs: randomized controlled trials

After online search and evaluation of the available guidelines, the Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of PCOS [3] resulted to have the highest AGREE II score and were selected as the guiding reference for this project. The full details on the methodological aspects, the technical evidence and administrative reports of those recommendations are available online on the following website: www.monash.edu/medicine/mchri/pcos.

These recommendations [3] are international guidelines involving all aspects of the PCOS, organized in sections, and covering five specific areas of interest, including screening, diagnostic and risk assessment and life stage; psychological features and models of care; lifestyle management; management of nonfertility features; and assessment and management of infertility.

Initially, the Working Group extrapolated section number five titled “Assessment and management of infertility”. This section was used as the initial document. Other recommendations originally reported in the other sections [3] were selected if considered relevant for making more complete the new document. The total items initially included in the analysis were 116. Specifically, 60 and 56 items for Sect. 5 and for all other sections, respectively, were extracted.

All original recommendations extracted were analyzed for relevance and applicability to the Italian context, contextualized to adult infertile women and accordingly modified. Redundant/repetitive items were also deleted. After the revision process, a total of 93 items remains in the document (Supplementary Table 1). These items resulted modified from the original version in 24 (40%, 24/60) and 34 (61%, 34/56) cases for Sect. 5 and for all other sections, respectively. The quality of evidence and the strength of recommendations did not change for the revised/adapted items in comparison with the original one.

Secondly, the Working Group identifies new issues not assessed in the reference guideline [3] and considered potentially relevant from a clinical point of view. Table 2 reports these new critical topics as questions and their answers. As already mentioned in the Methods section, a similar methodology used in the original paper [3] and following to the GRADE system (https://gdt.gradepro.org/app/handbook/handbook.html) was applied for these new areas of clinical interest to harmonize the document with special regard for the terminology, the quality of evidence and the strength of recommendations (Table 1).

Table 2 New issues not specifically assessed in the reference guideline [3] and considered potentially relevant from a clinical point of view. These new topics are presented as clinical questions

The public consultation of the SIRU-CECOS Italy guideline was attended by external reviewers, including biologists, medical doctors (endocrinologists and gynecologists), midwives, psychologists, representatives of citizens, patients, and pharmaceutical and biomedical industries. During this phase, the items previously defined have been subject to minor revisions; however, their total number and content were unchanged.

After revisions following the public consultation, the document underwent further revision by two international experts. Specifically, dr. Raoul Orvieto (Sheba Institute of Tel Aviv, Israel) and dr. Didier Dewailly (University of Lille, France) were invited to revise the recommendations/suggestions adapted from reference document (Supplementary Table 1) and the new recommendations/suggestions (Table 2). The Working Group prepared a comprehensive response to the Reviewers’ comments. The Reviewers’ suggestions were included when considered relevant. Specifically, a total of 38 suggested revisions were addressed, of which 24 were accepted and 14 rejected. After international experts’ revisions, 5 and 3 items were modified and deleted, respectively, from the adapted items of the referral document [3], while 3 further new items were included and extrapolated from the same publication [3]. Eleven and 2 items were modified and deleted, respectively, from new recommendations included by the Working Group.

Following the revisions, a total of 93 recommendations were adapted from the PCOS International Guidelines [3]. A total of 14 new topics were analyzed, leading to the definition of 21 new clinically relevant recommendations (Table 2).

Finally, the Working Group sub-grouped all recommendations (integrating the new items to the main document) in specific sections (Table 3): 1. PCOS diagnosis, 2. preconception risk factors in PCOS (including the screening/diagnosis of PCOS-related comorbidities), 3. interventions for improving general and reproductive health in infertile women with PCOS, 4. general principles of infertility management in women with PCOS (including infertility assessment, drugs administration, complementary interventions/drugs), 5. treatment of PCOS-related anovulatory infertility (first-, second-, and third-line treatments), and 6. IVF in women with PCOS. An algorithm (Algorithm 1) for the management and treatment of infertile patients with PCOS has been implemented (Fig. 2).

Table 3 Final document from the SIRU and the CECOS Italy on the diagnosis and management of infertility in patients with PCOS in Italy including published/adapted and new recommendations after integration of the comments/suggestions from public consultation and international experts

Fig. 2

(Algorithm 1). Strategy for the management and treatment of infertile patients with PCOS according to SIRU and CECOS Italy guidelines. AMH: anti-Mullerian hormone, CC: clomiphene citrate, IVF: in vitro fertilization, PCOM: polycystic ovarian morphology, PCOS: polycystic ovary syndrome, US: ultrasound

The final document and Algorithm 1 are reported in Italian to prevent potential inaccuracies in translation, respectively in Supplementary Table 2 and Supplementary Fig. 1.

Discussion

Clinical guidelines are considered a valuable tool for enhancing the quality of care provided to patients. By consolidating evidence on specific topics, these guidelines facilitate clinicians in making timely, evidence-based decisions for their patients. They support the adoption of effective interventions while discouraging those that are ineffective or potentially harmful. Moreover, guidelines can enhance patient empowerment, shape public policy, standardize care practices, and inform the creation of performance measures and evaluations for diseases [18]. Additionally, clinical guidelines contribute to reducing healthcare costs by streamlining decision-making processes, minimizing unnecessary interventions, and promoting the efficient use of resources while maintaining high standards of care [18]. Evidence-based guidelines are indispensable for assisting physicians, policymakers, and patients across all medical fields, with particular significance in reproductive medicine. These general concepts on the need of clinical guidelines are particularly important for PCOS. In fact, PCOS is a condition with a considerable economic impact, in relation to the therapies needed to promote fertility in these patients [19]. Indeed, in about 50% of cases, PCOS patients do not achieve a pregnancy requiring to be scheduled for IVF programs [7, 12].

Despite these premises, few specific documents have been produced about the management of PCOS-related infertility [11, 12, 20], whereas many others focused on PCOS management included only brief sections on ovulation induction in this clinical contest [21,22,23,24]. In 2019, the International PCOS Network produced a specific document of evidence-based recommendations regarding the assessment and treatment of infertility in patients with PCOS [25]. More recently, an updated document on all clinical aspects of PCOS was published [3]. A specific section was dedicated to the management of infertility in women with PCOS [3]. The critical analysis of these documents suggests that, over the last few years, evidence-based medicine has driven new approaches for treating infertility in patients with PCOS, changing rapidly and deeply the clinical practice [12].

The need to translate and adapt international guidelines to each regional context has already been expressed by the authors themselves, to close the knowledge-practice gap, guide future research and enhance positive impact on the health of women with PCOS [26]. However, this wish has not always been fulfilled and national scientific societies have simply adopted these guidelines by providing a summary of them from a local perspective [27, 28]. Considering the absence of guidelines adapted to the Italian context for infertility in PCOS [10], SIRU and CECOS Italy decided to produce an official document for the diagnosis and management of infertility in women with PCOS following a methodology already adopted for the realization of the “2024 SIRU NICE-adapted guidelines” [10]. Simply providing a lay summary or referring to the original guideline is in our opinion a lost opportunity. A formal adaptation of the guidelines to the local context is a stronger and wiser approach.

Current paper provides a detailed account of the process involved in adapting to the Italian context the recommendations included in the "2023 International Evidence-based Guideline for the Assessment and Management of PCOS" related to infertility diagnosis and management (section number five of the original document [3]), which resulted to have the highest AGREE II score after our research and evaluation. A methodological process clinically important to produce the Italian Guidelines was to define other recommendations not reported in the section dedicated to the clinical management of infertile patients with PCOS if considered relevant for making complete the new document. After the first phase of adaptation of international recommendations and drafting of new ones, they were subjected to another two phases of revision. The first regarded the inclusion of new recommendations considered clinically useful and lacking in the main referral document. The latter regarded external revisions using public consultation and international Referees. A public consultation was performed by external reviewers, including biologists, medical doctors (endocrinologists and gynecologists), midwives, psychologists, representatives of citizens, patients, and pharmaceutical and biomedical industries. On the other hand, two international Referees, experts in female infertility and in PCOS, revised all recommendations by making several suggestions and revisions, which were discussed by the SIRU-CECOS Working Group and integrated when considered relevant. After the revision process, the final document integrated adapted recommendations from the PCOS International Guidelines [3] and 21 new clinically relevant recommendations, sub-grouped in specific sections (Table 3).

These guidelines present recommendations adapted from the 2023 International Guidelines for PCOS but differ in several key aspects. Firstly, the new recommendations are structured to be more practical, offering clinicians direct and tailored guidance based on specific patient conditions and clinical scenarios. This approach is particularly aligned with the characteristics of the Italian healthcare system. Secondly, they address gaps in the International Guidelines for PCOS, which left several clinical questions unresolved, by integrating insights from the latest Infertility Guidelines to provide more comprehensive recommendations [10]. Third, several specific aspects differentiate our document from the original referral document. For example, the approach to PCOS diagnosis. Here, we suggest evaluating all diagnostic criteria for PCOS in infertile patients, either because they are a negative prognostic factor for fertility, or to improve the counselling of the patient during pre-conceptional phase and pregnancy. We emphasize the importance of assessing anti-Müllerian hormone (AMH) levels in infertile patients with PCOS not as diagnostic criteria but to identify patients at high risk of ovarian hyperstimulation syndrome (OHSS), treatment failure or multiple pregnancy. This assessment is particularly crucial prior to initiating a cycle of ovarian stimulation.

The assessment of OHSS risk is critical in determining the appropriate therapeutic strategy [12]. Emerging evidence suggests, for instance, that the use of follitropin delta may offer advantages for patients with elevated AMH levels, who are more likely to be high responders [29, 30]. However, the clinical trials conducted in this area primarily involved highly selected populations with favorable prognoses and high ovarian responses, limiting the generalizability of the findings to broader, unselected infertile populations [31]. Consequently, the Working Group did not reach a consensus to deviate from the recommendations of the International Guidelines [3]. Instead, it opted to maintain the guidance of not endorsing a specific gonadotropin for infertile patients with PCOS, leaving the decision to the clinician’s discretion.

The recommendations of the PCOS International Guidelines left some unresolved issues and gaps that we tried to fill. For example, current guidelines tried to make clearer is the opportunity to assess the seminal and tubal factor before starting the therapy to induce ovulation in PCOS. It is now explicitly recommended that the seminal factor should always be assessed. We also recommend executing a tubal patency testing on an individual basis when the tube patency is not clear (i.e. in absence of previous pregnancies). In the referral document [3], the flowchart on which was based the management of infertility in the PCOS patient included a central pathway following best practice evidence, but also side indications that left wide discretion to the clinician. In particular, International Guidelines lacked clear directives on the number of therapeutic cycles to perform before declaring pharmacological failure, as well as criteria for deciding when to repeat the same treatment or to start an IVF program. To address these shortcomings, the Working Group synthesized widely accepted notions from clinical practice and formally incorporated them into these updated guidelines. We have therefore clearly indicated the protocols for letrozole, clomiphene citrate (CC) and metformin administration and detailed the definitions of CC- and letrozole-resistance and CC- and letrozole-failure. At the same time, we have chosen to advise how long to continue a treatment before moving on to the next one, while leaving the clinician the freedom to adapt this choice to the individual clinical context. The most recent evidence suggests a repeat of CC administration in relation to the anti-estrogenic effects of CC itself [32]. Endometrial thickness > 7 mm after six cycles of CC may suggest a repetition of another six cycles, rather than the transition to gonadotropins [32]. On the contrary, there is no evidence in the literature about the opportunity to use letrozole in the long term. However, the absence of antiestrogenic effects on the endometrium would suggest the possibility of continuation up to 12 cycles in younger patients [12].

Another controversial issue raised during the formal reviewing process was the use of AMH for infertile women with PCOS. Although AMH is considered by international guidelines as a biomarker of PCOM in adults, no cut-off level or commercial kit is recommended or suggested [3]. In addition, serum AMH levels have a large variability closely dependent on the patient’s BMI and age [33]. Therefore, the decision to exclude AMH from the diagnostic criteria, as reflected in current guidelines, is a cautious approach due to the variability of AMH values, and lack of standardized values and kits. On the other hand, the evaluation of AMH levels may be crucial to personalize the treatment strategy of patients with PCOS in an infertility setting [34].

The strengths of these guidelines lie not only in the practical recommendations but also in the methodology employed. The adaptive framework of the International Guidelines enabled the development of updated, tailored, and high-quality recommendations without requiring substantial financial or human resource investments. The work was further enhanced by contributions from a specialized expert group on PCOS and fertility, supplemented by a transparent public consultation that engaged a diverse range of professionals and the input of two independent international experts. Nonetheless, we recognize certain limitations that remain. Overall, the quality of evidence in PCOS research is frequently low to moderate. Further studies are required to provide more definitive and clear guidance for the clinical management of infertile patients with PCOS, addressing the gaps currently left to clinician discretion. Secondly, the adaptability of these guidelines to the Italian healthcare context is constrained by significant regional disparities. Assisted reproductive technologies (ART) procedures are currently covered only in specific infertility centers within certain regions, limiting the uniform application of these guidelines across the country. While the SIRU-CECOS Italy guidelines may be relevant in regions that provide ART services, they may not be applicable in regions where such services are unavailable. Additionally, Italy has more private ART centers than public ones, and most of these facilities lack cryopreservation capabilities (https://w3.iss.it/site/RegistroPMA/PUB/Centri/CentriPma.aspx). However, the Italian government recently recognized ART as an essential healthcare service, mandating all regions to provide access to it for citizens starting January 1, 2024. This policy change will likely enhance the applicability of these guidelines. Nevertheless, a significant challenge that remains to be addressed at the politic level is the prolonged waiting times for accessing ART services through the national healthcare system.

In conclusion, the current document now represents for SIRU and CECOS Italy the formal Italian guidelines for diagnosis and treatment of infertility in women with PCOS, and it replaces the section about the ovulatory dysfunctions included in the NICE-adapted guidelines from the SIRU for the diagnosis and management of infertility in Italy [10].