Reply: Premature ovarian insufficiency and the risk of breast cancer

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Sir,

We read with interest the letter to the Editor ‘Premature Ovarian Insufficiency and the Risk of Breast Cancer’ by Coelingh Bennink et al. (2025) as well as the narrative review referred to (Coelingh Bennink et al., 2023). However, they do not accurately reflect how this important topic is addressed in the recently published premature ovarian insufficiency (POI) guideline (https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Premature-ovarian-insufficiency), and they propose a treatment approach that has significant safety concerns.

The authors raise the concern that the POI guideline ‘does not address the decreased risk of breast cancer in women with POI’. Although the summary guideline publications (Panay et al., 2024a, 2024b, 2025) do not address this issue in detail, the section of the full guideline ‘Risk of breast cancer in women with POI’ does address this complex topic, citing the same publications, which indicate a 30–40% lower risk of breast cancer in women with menopause before age 40 years (Collaborative Group on Hormonal Factors in Breast Cancer, 2012; Wu et al., 2014) and in those with POI secondary to risk-reducing bilateral oophorectomy for BRCA1/2 gene carriers (Rebbeck et al., 2009). However, a 2024 study of a cohort of 613 Polish women with POI, not cited by Coelingh Bennink et al. (2025) but included in the POI guideline, indicated a 2-fold increased risk of breast cancer with causal and candidate genes identified (Allen-Brady et al., 2024). Thus, our understanding of the risk of breast cancer in this population is incomplete, with potential interacting factors including underlying genetic make-up, other reproductive and lifestyle factors, and hormone therapy.

The guideline systematic search focused on women with POI and, thus, studies of women with early menopause (Monninkhof et al., 1999) or related to menstruation (Coelingh Bennink et al., 2023) may not have been captured.

The guideline acknowledges the ‘considerable debate on the effect of different progestogens on the risk of breast cancer’ (Stahlberg et al., 2004; Seeger and Mueck, 2008). In theory, progesterone has a less proliferative and a more apoptotic effect than androgenic progestogens. However, the evidence is largely observational and relates to women with usual age of menopause; as noted in the guideline, there are no data specific to POI (Schneider et al., 2009; Vinogradova et al., 2020).

We note that ‘these differing agonist and antagonist effects contribute to the variable adverse effects profile (for example, breast cancer or venous thromboembolism [VTE]) and this should be considered when deciding on the hormone therapy (HT) regimen’ (Stanczyk et al., 2013).

These points all support the conclusions that:

We strongly disagree with the authors’ recommendation, ‘we propose to avoid the use of progestogens and treat POI patients with estrogens only, […] monitor vaginal bleeding and endometrial growth regularly and only prescribe progestin withdrawal when needed’. The authors do not give sufficiently serious consideration to the long-established risk of endometrial hyperplasia and cancer with unopposed estrogen therapy in postmenopausal women. A Cochrane review and other publications report odds ratios ranging from 12 to 67 in studies using moderate- to high-dose unopposed estrogen compared to sequential combined hormone therapy over only 3 years duration (Furness et al., 2012; Sjögren et al., 2016). Of concern, endometrial hyperplasia was reported in 62% of women receiving unopposed moderate-dose estrogen therapy for 3 years compared with 1.7% of women receiving placebo therapy (Furness et al., 2012).

The guideline recommends hormone therapy for women with POI from diagnosis until the usual age of menopause, often resulting in decades of use. Monitoring of vaginal bleeding and endometrial thickness would not be a feasible or reliable strategy for all women with POI (Manley et al., 2024) on unopposed HT: this would, by design, increase interventions and result in patient and clinician anxiety.

Such a strategy might also be proposed for postmenopausal women taking HT, but nowhere has it been adopted or supported, and there is no evidence that it can adequately minimize the known risk of unopposed estrogen therapy (Manley et al., 2024).

Guideline methodology requires guideline development group consensus regarding recommendations. These are the relevant recommendations to this topic (Panay et al., 2024a, 2024b, 2025):

While feedback and opinion are part of the guideline process and actively requested during the stakeholder review, such feedback should be based on substantial evidence and devoid of commercial conflicts of interest. Whilst we welcome new studies that will increase the safety and efficacy of treatment for the diverse health concerns that women with POI face, our considered view is that there is no need for adaptation of the POI guideline or recommendations in the light of the arguments proposed by Coelingh Bennink et al. (2025).