Progress in understanding and management of premature ovarian insufficiency

The nomenclature, etiology, diagnosis, impact and management of premature ovarian insufficiency (POI) remain controversial and lacking in evidence. Whilst the International Menopause Society (IMS) 2020 White Paper on POI [1] provides a summary of the ‘state of the art’, this special issue is a more comprehensive review of each of the key topics, with emphasis on current and future research that will advance our knowledge of POI. In this special issue of Climacteric, we have invited key leaders in the field of POI to submit a series of papers which will bring the readers of Climacteric up to date with current understanding of this distressing condition.

If we are to effectively diagnose and manage this condition, it is vitally important that health-care professionals (HCPs), particularly in primary care, are equipped with the knowledge to do this. The aim of the POI Toolkit in this issue is to impart this information to as wide an audience as possible, hence the collaboration of key opinion leaders from IMS with those from the European Menopause Society which has resulted in co-publication in both Climacteric and Maturitas journals. It is our hope that this paper is used as a template by HCPs in both primary and secondary care to guide best practice in the care of women with POI.

The ability to predict POI well in advance of its occurrence would prevent a number of the potential sequelae. For instance, it would permit women to make choices about their family planning, which are not available to them once the diagnosis is confirmed. It would also prevent deterioration in quality of life and reduce the risk of long-term sequelae, as treatment could be instituted sufficiently early to prevent this. Unfortunately, there is still a long way to go to make this preventive strategy a reality. The authors of this paper emphasize that the heterogenous etiology and phenotypes of POI limit the generalizability of an individual test to accurately predict POI. However, sequential anti-Müllerian hormone estimation combined with modern genetic approaches may provide a useful predictive model in the future. Increasing awareness of the causes of menstrual abnormalities in HCPs and the general public would also help to make the diagnosis of this condition as early as possible.

The etiology of POI remains an enigma in many women; this is perhaps the area which requires the greatest scientific endeavor if we are to fully understand and prevent POI in the future [2]. Although the majority of cases are still regarded as being idiopathic, the discovery of novel candidate genes through mapping of the genomic landscape of POI is revealing that many of these cases are genetic in origin. The paper on the genetics of POI illustrates the considerable progress which has been made and identifies further areas of research which will surely render the term ‘idiopathic’ obsolete as far as the etiology of POI is concerned.

An area of controversy in the management of POI is what type of hormone replacement should be instituted? It is widely accepted that replacement should be recommended to women with POI unless there are genuine contraindications, and that it should be continued at least until the average age of menopause. However, there is still debate as to whether replacement should be with menopause hormone therapy (MHT) or the combined oral contraceptive pill (COCP). The small studies thus far suggest that bone and metabolic outcomes are better with MHT, but that it is more pragmatic for young women to be prescribed the COCP, especially if contraception is still required. As this question is still in equipoise, a large, long-term, randomized trial is required, and this is precisely what is planned with the POISE trial, as described in this issue. The trial will also give the opportunity to study long-term risks such as breast cancer, to confirm that women with POI on MHT do not have an excess risk compared to age-matched women with normally functioning ovaries.

The role of androgens in women remains a matter for debate, but there is little doubt that the profound decrease of testosterone production in women with spontaneous and iatrogenic POI contributes significantly to the loss of sexual desire, which can be distressing to the individual and couple. The paper on androgens addresses the available evidence for the physiological and pharmacological role of androgens not only in POI, but also in young, otherwise healthy, premenopausal women. The key question which remains unresolved is whether androgen replacement should be a routine part of MHT in women with POI; in this editor’s view, it should, at the very least, be part of the routine counselling process.

The impact of iatrogenic POI, particularly following bilateral salpingo-oophorectomy (BSO), is profound due to the immediate catastrophic premature loss of ovarian hormones. The authors of the paper on BSO behove us to very carefully consider the impact of surgical menopause given the significant loss of physical and psychological quality of life and long-term health which can follow [3]. Prophylactic removal of healthy ovaries should never be performed ‘routinely’, even in women who have been through natural menopause. It should also be widely recognized that women with the BRCA gene mutations undergoing prophylactic BSO can still be candidates for hormone replacement as this does not appear to attenuate the benefits of surgery.

It is well known that POI is associated with a significant increase in risk of osteoporosis, cardiovascular disease and neurological disorders such as dementia. There is now evidence of multimorbidity in women with POI which is well beyond the problems commonly recognized [4]. The paper on cardiovascular disease has been composed by a group of cardiologists, metabolic physicians and gynecologists to emphasize the importance of close collaboration in planning research and clinical strategies in women with POI. Not all studies show a positive cardiovascular outcome in women with POI using hormone therapy; this is possibly because of insufficient dosing, duration or due to metabolically unfavorable progestogens. There is more work to be done to understand how cardiometabolic outcomes can be optimally influenced through a combination of lifestyle measures, diet and modern hormone replacement regimens.

The assessment of bone health in young women with POI has been problematic due to the fact that maximal bone density is not achieved until their mid to late twenties. Prediction of a young woman’s peak bone strength according to her individual genetic potential is difficult. Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry has limitations. As stated by the author of the bone health paper, it does not distinguish cortical from trabecular bone, or provide information on bone quality, and the relationship between BMD and fracture risk is not well established in young cohorts. It is therefore important that new techniques such as high-resolution quantitative computed tomography are developed for the POI population. Review of the bone data in POI shows that most are from short-term trials and observational analyses; better quality data are required for both bone and muscle health. In the meantime, clinical management of women with POI should focus on maximizing bone health through dietary, lifestyle and hormonal interventions. The use of non-hormonal bone-sparing preparations such as bisphosphonates, denosumab and selective estrogen receptor modulators remains problematic due to the lack of data for efficacy and long-term safety in young women.

One of the most distressing effects of POI is the associated subfertility [5]. Whilst ovum donation in vitro fertilization remains an effective way to achieve a family in POI, this is not acceptable to a significant proportion of women for personal, ethical and cultural reasons. It is therefore imperative that research into novel approaches for fertility restoration continues in women with POI. The last paper addresses future interventions which might facilitate the use of remaining autologous oocytes and creation of new autologous oocytes. Primordial follicle stimulation and mesenchymal stem cell-based therapeutics appear to be the most promising of the novel techniques but are unlikely to yield routine clinical approaches for a number of years. The authors emphasize that clinical studies with appropriate controls are needed to substantiate preliminary claims of effectiveness of these novel approaches.

This special issue of Climacteric on POI has demonstrated that a considerable amount of research is being undertaken to overcome the burden of this condition. However, it will be a while before we have answers to many of the remaining diagnostic and management conundrums. Until that happens, it is this editor’s opinion that the following approaches should be adopted. First, evidence-based guidelines should be updated through systematic review and meta-analysis to clarify our contemporary knowledge on all aspects of POI. The comprehensive European Society of Human Reproduction and Embryology POI guidelines from 2015 are due to be revised through an ongoing collaborative effort [6]. Second, a global consensus statement should be formulated for the management of POI and future research strategies, using evidence from the systematic review. Third, the anonymized data of all women diagnosed with POI should continue to be prospectively uploaded into a global POI registry (such as https://poiregistry.net) to facilitate analysis of diagnostic and therapeutic approaches and their impact on clinical outcomes [7].

Potential conflict of interest

Dr Panay has lectured and/or acted in an advisory capacity for Abbott, Besins, Lawley, Kora, Mithra, Mylan, Novo Nordisk, Roche Diagnostics, SeCur, Shionogi, and Theramex.

Source of funding

No funding was received for the preparation of this article.