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Oestrogen changes at menopause: insights into obesity-associated breast risk and outcomes

Nature Reviews Endocrinology (2025)Cite this article

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Abstract

Many diseases, including breast cancer, increase in women after menopause and with obesity. This Review addresses novel insights that link obesity, oestrogens, inflammation and breast cancer. Adipose tissue is chronically inflamed in obesity owing to pre-adipocyte expansion and activation of nuclear factor-κB (NF-κB), which upregulate pro-inflammatory cytokines. Obesity also impairs immunosurveillance. Emerging data indicate that the major oestrogens before and after menopause have opposing effects on inflammation. In contrast to the anti-inflammatory properties of premenopausal 17β-oestradiol, the dominant postmenopausal oestrogen, oestrone, is pro-inflammatory. Oestrone is synthesized in adipocytes, therefore the expanded adipose tissue biomass in obesity increases oestrone levels in both men and women, promoting NF-κB-driven inflammation. These pro-inflammatory effects of oestrone are also oncogenic, promoting breast cancer progression in laboratory models. The dominance of oestrone and loss of 17β-oestradiol might underlie the increased prevalence of hormone-responsive breast cancer after menopause, particularly in the context of obesity. Although oestrogens account for much of the excess breast cancer risk with obesity, data on 17β-oestradiol and oestrone levels in the breast and circulation in postmenopausal women, whether or not obesity is present, are limited. Weight loss is associated with reduced breast cancer risk and improved outcomes. The opportunity to use potent weight loss drugs as adjuncts to cancer therapy is discussed.

Key points

  • Increased oestrogen levels in obesity account for much of the increased breast cancer risk and mortality associated with obesity.

  • Activation of NF-κB contributes to oestrone-driven inflammation in adipose tissue and breast cancer.

  • The dominant premenopausal oestrogen, 17β-oestradiol, opposes NF-κB-driven inflammation in obesity, whereas oestrone, which dominates after menopause, promotes it.

  • Oestrone stimulates breast cancer stem cells, tumour growth and metastasis.

  • Oestrone and oestradiol levels in blood and in normal and malignant breast tissue, and their increase with weight gain after menopause need to be better characterized as they inform cancer risk.

  • Preclinical data support implementation of weight loss programmes as an adjuvant therapy for hormone-driven breast cancer and have implications for other cancers that have an increased risk and mortality in obesity.

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Fig. 1: Crosstalk between an oestrone-bound ER and NF-κB in cancer and surrounding adipose tissue under conditions of obesity.

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Authors and Affiliations

  1. Georgetown University School of Medicine, Washington, DC, USA

    Maiko Sho

  2. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    Maiko Sho & Joyce Slingerland

  3. Department of Oncology, Georgetown University, Washington, DC, USA

    Maiko Sho & Joyce Slingerland

  4. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    Rehana Qureshi

  5. Department of Pathology, University of Miami, Miami, FL, USA

    Rehana Qureshi

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Sho, M., Qureshi, R. & Slingerland, J. Oestrogen changes at menopause: insights into obesity-associated breast risk and outcomes. Nat Rev Endocrinol (2025). https://doi.org/10.1038/s41574-025-01208-7

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