Hormone replacement therapy (HRT) is a therapy used to relieve the various symptoms of menopause. Menopause is a period of time during which a woman’s ovaries no longer produce the hormones estrogen and progesterone, resulting in the cessation of menstrual periods. This usually occurs between the ages of 45 and 55 but can vary from person to person (Canadian Cancer Society 2026). These symptoms vary person to person; however, the most common ones include vasomotor symptoms such as hot flashes and genitourinary syndromes such as vaginal dryness (Valdes et al. 2026). Other experiences include mood swings, sleeping troubles, and elevated levels of anxiety. HRT has been proven to be effective at improving the quality of life for people experiencing menopause; however, studies show an increase in breast and ovarian cancer risk for those using HRT (Canadian Cancer Society 2026).
To understand the potential emergence of cancer, it is important to look at the molecular mechanism. The two main kinds of HRTs are estrogen therapy and combination therapy, which includes progesterone along with estrogen (Cleveland Clinic 2024). There are two kinds of estrogen therapies, systemic and local. Systemic estrogen therapy is administered through pills, patches, sprays, gels, or a vaginal ring (The Menopause Society 2026). It is absorbed into the bloodstream, impacting the entire body, and is more frequently linked to cases of cancer. Local therapy, also known as low-dose vaginal estrogen, has minimal absorption into the bloodstream (Breast Cancer.org 2026). This is because it is administered into the vagina and is effective for both moisturizing and rebuilding tissue (The Menopause Society 2026).
Estrogen is a steroid hormone that plays a critical role in the reproductive system, as it can be seen altering gene transcription in specific organs and tissues in the uterus through nuclear transcription factors. Nuclear transcription factors are proteins that bind to specific promoter or enhancer DNA sequences found within the nucleus (Ly et al. 2013). These genes are altered when estrogen binds and activates associated receptors, allowing nuclear transcription factors to bind to promoter regions in their targeted genes (Valdes et al. 2026). The transcription of these genes allows for the development and regulation of reproductive tissue; however, they can also promote cell growth and tissue proliferation when there is prolonged exposure to estrogen. Estrogen stimulates transcription of hormone-sensitive cells, particularly in tissues such as the breast and the endometrium (Cancer Research UK 2026). As a result, these tissues are repeatedly stimulated to grow, increasing the chances of errors during DNA replication, leading to cancer-causing mutations (Valdes et al. 2026). It is more common in estrogen-only HRTs as it particularly impacts the uterine lining, often causing endometrial hyperplasia that can become cancerous if it persists. This is why progesterone is often added in conjunction with estrogen to counteract its effects (Cancer Research UK 2026).
Overall, hormone replacement therapy can improve the quality of life for individuals during menopause, but it can also have detrimental side effects on cancer risk. Various factors, such as the type of therapy and method of administration, play a role in its impact. Estrogens’ molecular mechanisms explain why prolonged use or unopposed exposure may increase these risks for some individuals, highlighting the importance of altering the treatments based on each individual’s needs.
Refrences
Breast Cancer.org. 2026. “Hormone Replacement Therapy (HRT) and Breast Cancer Risk.” https://www.breastcancer.org/risk/risk-factors/using-hormone-replacement-therapy.
Canadian Cancer Society. 2026. “All about Hormone Replacement Therapy (HRT).” Canadian Cancer Society. https://cancer.ca/en/cancer-information/reduce-your-risk/understand-hormones/all-about-hormone-replacement-therapy-hrt.
Cancer Research UK. 2026. “Does HRT Increase Risk of Cancer? | Cancer Research UK.” https://cancerresearchuk.org/about-cancer/causes-of-cancer/hormones-and-cancer/does-hormone-replacement-therapy-increase-cancer-risk.
Cleveland Clinic. 2024. “Hormone Therapy for Menopause.” Cleveland Clinic. https://my.clevelandclinic.org/health/treatments/15245-hormone-therapy-for-menopause-symptoms.
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