Women with premature ovarian insufficiency (POI) are exposed to a long period of estrogenic deficiency, which potentially brings higher health risks, especially regarding bone health. Recently Costa et al.  performed a systematic review of the literature to evaluate the effect of hormone therapy (HT) on bone mineral density (BMD) in women with POI. They performed a search in MEDLINE and EMBASE databases up to September 2021 and included studies that analyzed women with spontaneous idiopathic POI treated with HT, to whom BMD was evaluated. Analysis of risk of bias of the selected studies was also performed. The authors found 335 articles and selected 16 studies according to the inclusion criteria. Most of the studies revealed lower bone density in both the femoral neck and lumbar spine in women with POI compared with healthy women. Bone mass had the tendency to remain stable in women treated with estrogen + progestin therapy; however, in those already with bone mass loss, the therapy – in the doses most frequently used – was not able to revert the loss. Higher estrogenic doses seemed to have a positive impact on BMD, as did combined oral contraceptives used continuously. In addition, the interruption of HT for longer than one year was associated with significant bone loss. The authors conclude that although HT brings clear benefits, further studies are needed to establish its long-term effects, as well as doses and formulations with better protective effects on the bone mass of women with POI.
This is a useful systematic review  of the currently available data concerning POI and the impact of various HT regimens including menopause hormone therapy (MHT) and the combined oral contraceptive pill (COC) on BMD. Despite the stated limitations, it illustrates several issues which are important for clinical practice; these are:
- making the diagnosis of POI as early as possible is crucial in order to commence HT in a timely fashion to prevent bone loss, which may not be recoverable.
- ensuring adequate compliance with HT to optimize bone protection.
- avoiding the hormone free interval in COC users to maximize bone protection.
- prescribing a sufficiently high dose of HT to adequately protect, and ideally increase, BMD.
Unfortunately, long-term prediction of POI using biomarkers such as anti-mullerian hormone remains problematic [2,3]. We must therefore combine clinical acumen with public health information, for example, menstrual irregularities should be reported early to primary healthcare providers. Toolkits for primary care physicians can also be of assistance in the early diagnosis and efficient management of POI .
The focus of this paper was on BMD in women with POI. We must not lose sight of the fact that the gold standard outcome measure of bone health is fracture prevention, for which there are no good quality long term prospective randomized controlled data in women with POI. Even if bioequivalence of COC pill versus MHT is demonstrated regarding BMD, care must be taken in extrapolating this to fracture prevention; for instance, it is possible that the quality of preserved/formed bone with MHT is better than that with the COC pill. It also well recognized that the rationale for hormone replacement in POI is not only to prevent bone loss, but also to maintain the possibility of pregnancy, preserve quality of life, and protect against cardiometabolic and cognitive deterioration. For instance, some data indicate that MHT can achieve better cardiovascular benefits than the COC pill e.g. favorable blood pressure effects .
The meta-analysis  excluded studies of women with cancer, treatment with chemo or radiotherapy, surgical menopause, Turner syndrome and other genetic disorders. This was logical in terms of analyzing the “pure” effect of POI on BMD. However, these concerning populations of hypoestrogenic young women, also affected by the added impact of malignancy and/or iatrogenic interventions, or genetic disorders, should not be neglected, and are worthy of extensive research.
The principles of diagnosis and management of POI were comprehensively covered in the International Menopause Society (IMS) white paper published for World Menopause Day in 2020 . The paper illustrated the deficiency of large long-term prospective studies comparing the impact of MHT compared to COCs on bone health and other parameters. A large multicenter study funded by the National Institute of Health and Care Research in the UK (POISE) is currently recruiting women with POI of all causes and randomizing them to MHT versus COC. The primary outcome measure is the change in lumbar spine density at two years, but quality of life and cardiometabolic parameters will also be studied. Subjects will be randomized for five years with a possible observational extension after this.
The authors of the current commented meta-analysis  state that “further prospective studies, in different centers, with a randomized clinical trial design will, therefore be required to control for possible risks of bias regarding the different treatments, thus providing a better level of evidence.” Recommendations and guidelines are only as good as the data that are used for their formulation. The ESHRE guidelines on POI  are currently being updated in collaboration with Monash University, the American Society for Reproductive Medicine and the IMS. This should ideally remain a “live” document to facilitate regular updates as new data are published. In the absence of data from long term prospective randomized trials, large POI registries from the UK and China such as the https://poiregistry.net could usefully contribute data going forward. Preliminary registry data from the UK support the findings of the meta-analysis here commented  that in the absence of HT, BMD is reduced. The adage of “prevention is better than cure” has never been more apt than in young women with POI. Further POI registry data were also recently presented from Spain and Finland at the 2022 IMS World Congress in Lisbon, Portugal [9,10]. It is hoped that the totality of global data will be amalgamated from these and other registries in the future, to facilitate understanding and management of this distressing condition.
Professor of Practice, Imperial College London, UK
President, International Menopause Society
- Costa GPO, Ferreira-Filho ES, Simoes RDS, Soares-Junior JM, Baracat EC, Maciel GAR. Impact of hormone therapy on the bone density of women with premature ovarian insufficiency: A systematic review. 2023;167:105-112.
- Nelson SM, Davis SR, Kalantaridou S, Lumsden MA, Panay N, Anderson RA. Anti-Müllerian hormone for the diagnosis and prediction of menopause: a systematic review. Hum Reprod Update. 2023 Jan 18: dmac045.
- Rahman R, Panay N. Diagnosis and management of premature ovarian insufficiency. Best Pract Res Clin Endocrinol Metab. 2021;35(6):101600.
- Lambrinoudaki I, Paschou SA, Lumsden MA, et al. Premature ovarian insufficiency: a toolkit for the primary care physician. 2021;24(5):425-437.
- Stevenson JC, Collins P, Hamoda H, et al. Cardiometabolic health in premature ovarian insufficiency. 2021;24(5):474-480.
- Panay N, Anderson RA, Nappi RE, et al. Premature ovarian insufficiency: an International Menopause Society White Paper. 2020;23(5):426-446.
- Upton CE, Daniels JP, Davies MC. Premature ovarian insufficiency: the need for evidence on the effectiveness of hormonal therapy. 2021;24(5):453-458.
- European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI; Webber L, Davies M, Anderson R, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926-937.
- Muro-Blanc P, Ginot-Gasull M, Coma-Barbarà M, et al. The Premature Ovarian Insufficiency (POI) database in Spain. Basal and 2 years follow-up. Protocol code IIBSP health-IOP-2012-109. Clinical Trials.gov ID: NCT02068976. Abstract presented at the 18th IMS World Congress on Menopause, Lisbon, Portugal: 26-29 October 2022.
- Silvén H, Savukoski S, Pesonen P, et al. Association of genetic disorders with POI – a nationwide register-based study. Abstract presented at the 18th IMS World Congress on Menopause, Lisbon, Portugal: 26-29 October 2022.
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