Evidence-based guideline: premature ovarian insufficiency.

Nick Panay, Richard A. Anderson, Bennie A, Cedars M, Melanie Davies, Carolyn Ee, Gravholt CH, Kalantaridou S, Kallen A, Kim KQ, Misrahi M, Aya Mousa, Rossella E. Nappi, Walter A. Rocca, Ruan X, Helena Teede, Nathalie Vermeulen, Vogt E, Amanda Vincent
Human reproduction open · 2024 · doi:10.1093/hropen/hoae065 · PMID:39660328 · PMC11631070
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This ESHRE guideline provides 145 evidence-based recommendations for the diagnosis and management of premature ovarian insufficiency, addressing updated criteria, sequelae, and treatment options.

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This evidence-based guideline provides comprehensive recommendations for the diagnosis and management of premature ovarian insufficiency, defined as loss of ovarian function before age 40. The document outlines diagnostic criteria involving menstrual irregularities and elevated FSH levels, while addressing multifaceted health consequences including fertility, bone density, cardiovascular risk, and psychological wellbeing. It emphasizes hormone therapy as a primary treatment to mitigate long-term health risks until the typical age of menopause. Relevance to endometriosis: listed as one indication for GnRH antagonists, though the paper's main focus is uterine fibroids.

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Abstract

Study questionHow should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature?Summary answerThe current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI.What is known alreadyPremature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI.Study design size durationThe guideline was developed according to the structured methodology for development of ESHRE guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and health care professionals. Literature searches and assessments were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials (RCTs) on POI included in the guideline.Participants/materials setting methodsBased on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly on those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee.Main results and the role of chanceNew data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help health care professionals to apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated FSH >25 IU is required for diagnosis of POI, and guidance that AMH testing, repeat FSH measurement, and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care.Limitations reasons for cautionThe guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI.Wider implications of the findingsThe guideline provides health care professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI.Study funding/competing interestsThe guideline was developed and funded by ESHRE, American Society for Reproductive Medicine (ASRM), Centre for Research Excellence in Women's Health in Reproduction Life (CRE-WHiRL), and International Menopause Society (IMS), covering expenses associated with the guideline meetings, literature searches, and dissemination of the guideline. The guideline group members did not receive payments. N.P. declared grants from Bayer Pharma (research and consultancy) and NIHR-research POISE; consulting fees from Abbott, Astellas, Bayer, Besins, Lawley, Mithra, Theramex, Viatris; honoraria from Astellas, Bayer, Besins, Gedeon Richter, Theramex, Viatris; support for attending meetings and/or travel from Astellas, Bayer, Theramex, Viatris; President, International Menopause Society, Medical Advisory Committee member, British Menopause Society, Patron Daisy Network. A.J.V. declared grants from Amgen Australia, Australian NHMRC, and Australian MRFF; consulting fees from IQ Fertility; honoraria from the Australasian Menopause Society; participation on a Data Safety Monitoring Board or Advisory Board of Astellas; Board Member of the International Menopause Society (2020 to current) and Past president of the Australasian Menopause Society (2017-2019); R.A.A. declared grants from Roche (Research support, to institution), and participation on a Data Safety Monitoring Board of Bayer. M.C. declared grants from NHI; payments or honoraria from Up-to-Date (as editor/reviewer); Board Member of American Society of Reproductive Medicine, and of American Gynecological and Obstetrical Society. M.D. declared (NIHR-HTA Reference Number: NIHR133461; NIHR-HTA Reference Number: NIHR128757; Action Medical Research and Borne: GN2818) consulting fees from a small personal medical practice, support for attending meetings and/or travel from ESHRE, Bayer and UCLH special Trustees; Participation on the Advisory Board of the British Menopause Society, UKSTORE project, the Progress Educational Trust, and the Turner Syndrome Support Society UK; Leadership or fiduciary roles in the British Fertility Society (Trustee), Elizabeth Garrett Anderson Hospital Charity (chair of Trustees), and the Essex Wynter charitable trust (Trustee). C.E. declared being Chair of a SIG from the Royal Australian College of General Practitioners Integrative Medicine Specific Interest Group and Program Lead for Next Practice Western Sydney Integrative Health. C.H.G. declared grants from Novo Nordisk Foundation (Nos. NNF15OC0016474 and NNF20OC0060610), sygesikringen danmark (No 2022-0189), and the Independent Research Fund Denmark (Nos. 0134-00406 and 0134-00130B); consulting fees from Novo Nordisk, Merck, and Astra Zeneca. S.K. declared grants from Roche diagnostics. A.K. declared grants from NIH R01 5R01HD101475; consulting fees as Medical Reviewer for Flo and for Healthline; honoraria as Medical Consultant for Summus; support for attending meetings from the Reproductive Scientist Development Program; Society for Reproductive Investigation Council Member and Society for Assisted Reproduction Registry/Validation Chair; R.E.N. declared consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, Theramex; honoraria from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck & Co, Novo Nordisk, Shionogi Limited, Theramex, Viatris; payment for expert testimony from Vichy Laboratories; Participation in Data Safety Monitoring Board of Advisory board from Astellas and Bayer Healthcare; President elect of the International Menopause Society (IMS). H.T. declared a grant from NHMRC Centre for Research Excellence for women's health in reproductive life. A.B. declared being chair of the Daisy Network Charity. The other authors have no conflicts of interest to declare.DisclaimerThis guideline represents the views of ESHRE, ASRM, CRE-WHiRL, and IMS, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. The collaborating societies make no warranty, expressed or implied, regarding the clinical practice guidelines and specifically exclude any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).
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Intro

This guideline on premature ovarian insufficiency (POI) offers best practice advice on the care of women with POI. POI is a clinical condition characterized by loss of ovarian function, indicated by irregular menstrual cycles together with biochemical confirmation of ovarian insufficiency before the age of 40. POI is to be differentiated from the usual-age of menopause, as women with POI have unique needs and management options. They may not only suffer from symptoms associated with estrogen deficiency, but can also experience other issues, with a significant impact on their quality of life and later health outcomes. POI affects fertility, bone health, cardiovascular health, sexual function, psychological health, and neurological function, making it a challenge for patients and health care professionals (HCPs) ( Webber et al. , 2016 ). This guideline on POI describes the impact of POI on these different domains and discusses treatment options for each of them and monitoring needs where relevant. The information on treatment indications is included in a chapter on hormone therapy (HT), which also covers further topics related to risks and options for HT in general and in women with POI, and comorbidities where data exist. In other chapters, non-hormonal and complementary treatments in POI are also discussed, as well as lifestyle and puberty induction. Furthermore, the clinical guideline provides recommendations on the diagnosis of POI and the recommended assessment of causation, with some elaborated guidance on care for women at the time of diagnosis and implications for their relatives. This paper summarizes the recommendations as they are included in the Evidence-based Guideline on POI. For further information and details, the reader is referred to the full guideline published on the societies’ websites. This guideline is limited to POI and does not apply to women with low ovarian reserve. Reference to early menopause is included where evidence is available but was not the focus of the key questions.

Results

The scope of the guideline on POI is to provide guidance on the management of POI. In line with research on the topic, terminology, and discussion, the guideline is focused on women. The guideline group recognizes that there are individuals living with POI who are transgender or who do not identify with the terms used in the literature. Throughout, the term ‘women with POI’ is used, but this is not intended to isolate, exclude, or diminish any individual’s experience nor to discriminate against any group. Key Question: What should this condition be called? Key Question: How should POI be defined? Premature ovarian insufficiency (POI) is a condition defined by loss of ovarian activity before the age of 40 years. POI is characterized by amenorrhea or irregular menstrual cycles with elevated gonadotropins and low estradiol. In this guideline, cessation of ovarian function in women aged from 40 and <45 (age 40–44 years) will be termed early menopause. Early menopause is outside the scope of the current guideline, but the evidence and recommendations may be relevant to women with early menopause. Key Question: What is the prevalence of POI in the general population? PICO Question: What are the risk factors for POI? gynaecological surgical practice lifestyle factors such as smoking treatment regimens for malignant and chronic diseases. Diagnosis of POI ( Fig. 2 ) Summary of the recommendations on diagnosis of premature ovarian insufficiency (POI), as well as the recommended further testing to establish a cause for POI . *Fragile X premutation testing is indicated in all women diagnosed with POI. This needs to be performed as a specific test as multigene panels and NGS are not useful in detecting FMR1 premutation. 21OH-Abs, 21-hydroxylase autoantibodies; BSO, bilateral salpingo-oophorectomy; NGS, next-generation sequencing; TSH, thyroid-stimulating hormone. PICO Question: What are the symptoms of POI? PICO Question: What investigations should be performed for diagnosis of POI? STRONG ⊕⊕◯◯ The guideline group recommends the following diagnostic criteria: disordered menstrual cycles (spontaneous amenorrhea or irregular menstrual cycles) for at least 4 months and an elevated FSH concentration > 25 IU/l. FSH assessment should be repeated after 4–6 weeks if there is diagnostic uncertainty. FSH testing for the diagnosis of POI does not have to be timed to a specific day of the menstrual cycle. Pregnancy should be excluded in women presenting with amenorrhea. Use of hormonal therapy (including oral, injectable, or long-acting contraceptives) may conceal or cause amenorrhea or irregular menstrual cycles, and potentially lower FSH concentrations. Some hormonal therapy (e.g. combined oral contraceptive) may need to be ceased before a diagnosis of POI can be confirmed. Women who had bilateral salpingo-oophorectomy (BSO) before age 40 have a diagnosis of POI, and additional diagnostic testing is unnecessary. PICO Question: What is the role of anti-Müllerian hormone to predict/diagnose POI? STRONG ⊕◯◯◯ PICO Question: What are the known causes of non-iatrogenic POI and how should they be investigated? STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ CONDITIONAL ⊕⊕◯◯ STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ PICO Question: how often should tests for autoantibodies be repeated? STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ Care for women with POI at diagnosis Key Question: What are the possible implications for relatives of women with POI? STRONG ⊕⊕◯◯ PICO Question: What are the consequences of POI for life expectancy? STRONG ⊕⊕◯◯ STRONG ⊕◯◯◯ PICO Question: What are the consequences of POI for fertility? STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ PICO Question: What fertility interventions are effective? STRONG ⊕⊕⊕◯ STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ PICO Question: What therapies are effective for fertility preservation and/or prevention of POI? CONDITIONAL ⊕⊕◯◯ PICO Question: What are the obstetric risks associated with POI? STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ PICO Question: How should fitness for pregnancy be assessed in women with POI? STRONG ⊕⊕◯◯ STRONG ⊕◯◯◯ STRONG ⊕⊕◯◯ STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ PICO Question: What are the consequences of POI for skeletal health? STRONG ⊕⊕◯◯ CONDITIONAL ⊕◯◯◯ PICO Question: What are the treatment options for bone protection and improvement? STRONG ⊕◯◯◯ CONDITIONAL ⊕⊕◯◯ STRONG ⊕⊕◯◯ CONDITIONAL ⊕◯◯◯ STRONG ⊕◯◯◯ STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ PICO Question: How should skeletal health be monitored in women with POI? STRONG ⊕⊕◯◯ STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ PICO Question: What are the consequences of POI for muscle health? CONDITIONAL ⊕⊕◯◯ PICO Question: What are the treatment options for muscle protection and improvement? CONDITIONAL ⊕◯◯◯ CONDITIONAL ⊕◯◯◯ STRONG ⊕◯◯◯ PICO Question: How should muscle health be monitored in women with POI? PICO Question: What are the consequences of POI for the cardiovascular system? STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ PICO Question: Is estrogen therapy cardio-protective? HCPs and women should be aware that estrogen therapy has beneficial cardiometabolic effects, which can influence cardiovascular disease risk. Non-use of HT is associated with an increased risk of cardiovascular events and mortality, and HT is therefore recommended until the usual age of menopause. STRONG ⊕⊕◯◯ PICO Question: Should cardiovascular risk factors be monitored? The guideline group recommends that all women with POI should have a lipid profile and diabetes screening at diagnosis. Thereafter, frequency of measurement should be based on the presence of hyperlipidaemia, hyperglycaemia, and additional risk factors or global cardiovascular risk. PICO Question: What are the consequences of POI on psychological wellbeing and quality of life? STRONG ⊕◯◯◯ PICO Question: What are the management options for reduced quality of life associated with POI? STRONG ⊕◯◯◯ PICO Question: What are the consequences of POI for sexuality? STRONG ⊕⊕◯◯ PICO Question: What are the management options for the effects of POI on sexuality? CONDITIONAL ⊕⊕◯◯ STRONG ⊕◯◯◯ PICO Question: What treatments are available for genitourinary symptoms in POI? STRONG ⊕◯◯◯ CONDITIONAL ⊕◯◯◯ CONDITIONAL ⊕◯◯◯ PICO Question: What are the consequences of POI on cognition/neurological function? STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ PICO Question: What are the management options for the effect of POI on cognition/neurological function? STRONG ⊕⊕◯◯ CONDITIONAL ⊕⊕◯◯ POI treatment ( Fig. 3 ) Management algorithm for premature ovarian insufficiency (POI), summarizing the recommendations on evaluation and screening, treatment options, and monitoring. Hormone therapy (HT) in POI: Principles and indications STRONG ⊕◯◯◯ STRONG ⊕⊕◯◯ PICO Question: What are the risks of HT? CONDITIONAL ⊕⊕◯◯ STRONG ⊕⊕⊕◯ STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ STRONG ⊕◯◯◯ PICO Question: What are the options for HT? STRONG ⊕⊕◯◯ STRONG ⊕⊕◯◯ Monitoring HT PICO Question: What is the role of testosterone therapy in POI? STRONG ⊕⊕◯◯ CONDITIONAL ⊕⊕◯◯ STRONG ⊕⊕◯◯ PICO Question: What are the specific considerations for HT in iatrogenic POI? STRONG ⊕⊕⊕◯ STRONG ⊕⊕◯◯ CONDITIONAL ⊕⊕◯◯ CONDITIONAL ⊕⊕⊕◯ CONDITIONAL ⊕◯◯◯ STRONG ⊕⊕⊕◯ STRONG ⊕◯◯◯ STRONG ⊕⊕◯◯ PICO Question: What non-hormonal therapies are available for POI? CONDITIONAL ⊕◯◯◯ PICO Question: What complementary treatments are effective for managing the sequelae of POI? STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ STRONG ⊕◯◯◯ PICO Question: What are the lifestyle management options for POI? STRONG ⊕⊕◯◯ PICO Question: How should puberty be induced? STRONG ⊕⊕◯◯ CONDITIONAL ⊕◯◯◯ Evidence for the optimum mode of administration (oral or transdermal) is inconclusive. HCPs may prefer transdermal estradiol as it results in more physiological estrogen concentrations. CONDITIONAL ⊕◯◯◯ STRONG ⊕◯◯◯

Materials

The guideline was developed according to a well-documented methodology that is universal to ESHRE guidelines ( Vermeulen et al ., 2020 ). The guideline development group (GDG) was composed of past members of the guideline group from 2015 and additional experts, also representing the collaborating societies, constituting an international group of experts. The guideline group included two patient representatives/advocates. Key questions were formulated by the guideline group, based on the list of key questions from 2015, but extended following a scoping survey amongst patients and health professionals. The final guideline was built from a list of 40 key questions, of which four were answered with narrative reviews (hereafter referred to as ‘key questions’) and 36 with systematic reviews as PICO (Patient, Intervention, Comparison, Outcome) questions. For each PICO question, databases (PUBMED/MEDLINE) were searched from inception up to 30 January 2024, and limited to studies written in English. From the literature searches, studies were selected based on the PICO questions, assessed for quality, and summarized in evidence tables ( www.eshre.eu/guidelines ). For the narrative questions, a similar literature search was conducted. Collected data were summarized in a narrative summary and conclusions were formulated. An integrity review using the Research Integrity in Guidelines and evIDence synthesis (RIGID) methodology was performed on 32 randomized controlled trials (RCTs) of treatments in the POI-specific population ( Mousa et al. , 2024 ). GDG meetings were organized (primarily online), for presentation and discussion of the evidence and draft recommendations until consensus was reached. Each recommendation was labelled as strong or conditional, and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach was applied to indicate the strength of the supporting evidence (High ⊕⊕⊕⊕, Moderate ⊕⊕⊕◯, Low ⊕⊕◯◯, Very low ⊕◯◯◯). Good practice points (GPPs) based on clinical expertise were added where relevant to clarify the recommendations or to provide further practical guidance. Strong recommendations suggest that the recommended option applies in most circumstances, whereas conditional recommendations are dependent on specific factors, which need to be considered with benefits/risks weighed before applying a given option ( Fig. 1 ). Suggested interpretation of the strong and conditional recommendations included in the guideline by patients, health care professionals (HCPs) and health care policy makers. The guideline draft and an invitation to participate in the stakeholder review (i.e. public consultation) were published on the ESHRE website between 17 April and 27 May 2024. The invitation to contribute to the stakeholder review was circulated to all collaborating and partnering organizations. All comments were processed by the guideline group, either by adapting the content of the guideline and/or by replying to the reviewer. The review process was summarized in the review report, which is published on the ESHRE website ( www.eshre.eu/Guidelines ). Overall, 61.0% of the 374 comments to the content resulted in an adaptation or correction in the guideline text. This guideline will be considered for update 4 years after publication, with an intermediate assessment of the need for updating 2 years after publication.

Discussion

This paper provides an overview of recommendations for the management of POI, from prevalence, symptoms, diagnosis and causation, to sequelae, monitoring, and treatment. Overall, 145 recommendations have been formulated, 92 supported by research data and 53 good practice points (or statements) based primarily on clinical expertise. The guidelines are based on the best available evidence or, where data of sufficient quality were absent, on recommendations by the guideline group (good practice points). The current guideline and recommendations are an update of the ESHRE guideline: Management of women with POI, published in 2015/2016 ( Webber et al. , 2016 ). The key questions and topics covered in the guideline of 2015/2016 were updated based on the results of a scoping survey, and the evidence supporting the recommendations was updated based on data published between 2015 and 2024, where available. Of importance are new data indicating a higher prevalence of POI, 3.5–3.7%, than was previously thought ( Golezar et al. , 2019 ; Li et al. , 2023 ). This key finding emphasises that POI is not a rare disease, and quite common when the prevalence data for both POI and early menopause (12.2%) are combined, with significant individual and public health implications. Whilst most of the more recent studies confirm or clarify previous recommendations, almost all guideline questions contain recommendations in which significant changes in clinical practice are to be expected. One of the key differences relates to the diagnosis of POI, where the 2015/2016 guidance recommended FSH assessments on two occasions to diagnose POI. However, a single FSH assessment in combination with the characteristic clinical picture is now considered sufficient for POI diagnosis, and a second FSH assessment is only required in case of diagnostic uncertainty, such as where the initial FSH level is inconclusive or not in keeping with the clinical picture. This change in guidance should facilitate the rapid and efficient diagnosis of POI, which is particularly important in ensuring prompt commencement of treatment. Guidance regarding the role of AMH testing in the diagnosis and prediction of POI is also provided. While AMH should not be used as a primary diagnostic test, it may be of value in confirmation of the diagnosis where there is uncertainty, though we should be mindful that it is still not universally available, particularly in primary care. Recognition of advances in genetic testing is also included with a recommendation regarding next-generation sequencing where available. Although access to such testing currently varies between countries and regions, it is important that we strive to determine the aetiology of POI where possible as this may help to personalize individual and familial risks, particularly when linked to genes with specific implications for fertility and malignancy. A new recommendation was introduced regarding care for women at the time of diagnosis, emphasising the psychological impact that diagnosis can have and the importance of sensitively conveying the diagnosis and shared decision making. Emerging data indicate that changes in muscle parameters associated with POI occur, and thus a topic on muscle health was included. More research is urgently required in this area. A recommendation regarding the frequency of bone densitometry (DXA) (where available) to monitor osteopenia and osteoporosis in women with POI was also an important change from the previous version as this should facilitate the management of one of the most common and troublesome long-term problems associated with POI. However, the value of repeated DXA monitoring in women with normal bone density remains uncertain. The updated guideline again emphasises the importance of HT for symptom relief and prevention of chronic diseases in women with POI. However, it extends the 2015/2016 guideline by including recommendations regarding estrogen doses and regimens and continuous use of the combined oral contraceptive. Recommendations regarding testosterone therapy have also been updated, reflecting new evidence and a consensus statement regarding women at usual age of menopause, although further research in women with POI is still needed ( Davis et al. , 2019 ). Although data specific to POI populations are lacking, recommendations regarding the use of non-pharmacological therapies for menopausal symptoms, lifestyle management, and complementary therapies are included, mainly extrapolated from women at usual age of menopause. Non-hormonal pharmacological therapies recommended for menopausal women with vasomotor symptoms are likely to be effective in POI. Healthy lifestyle behaviours will benefit women with POI and should underpin all recommended interventions. Complementary therapies should not be used instead of HT because of limited evidence regarding efficacy, particularly for the long-term health sequelae of POI. Induction of puberty is now recommended from age 11 years with emphasis on the use of estradiol to optimize metabolic benefits, uterine, and breast development, rather than conjugated equine estrogens or ethinylestradiol. The literature searches not only resulted in recommendations being formulated but also highlighted a number of areas where the evidence was too scarce to formulate clear and strong recommendations. Of the evidence-based recommendations, almost 76% were formulated as strong recommendations (i.e. appropriate for most women with POI), even if the evidence base was limited to observational data (level very low or low), supporting a call for ongoing and future research. Hence, the guideline group concluded that there is still an urgent need for more research on the most appropriate diagnostic and treatment options, but also to further elaborate the impact of estrogen deficiency on the health and life expectancy of the women diagnosed with POI. This guideline provides 30 recommendations for research, intended to inspire researchers, and hopefully also to facilitate funding for studies in POI ( Supplementary File S1 ). In summary, the 2024 Guideline on POI is a comprehensive update of the existing evidence and should assist healthcare professionals in the care of women with POI. Active involvement and input by patient representatives at all stages was central to the success of this endeavour. The detailed guideline document can be accessed via the societies’ websites (e.g. www.eshre.eu/guidelines ). In order to maximize uptake of the guideline, plans for dissemination and translation to complement the guideline are currently being deployed.

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