Hormones, HRT, and cancer risk

Exogenous hormones, including menopausal hormone therapy (also called HRT for hormone replacement therapy) and combined oral contraceptives, have complex and bidirectional relationships with cancer risk. HRT and oral contraceptives are associated with modestly increased risk for certain hormone-sensitive cancers, particularly breast and (with combined oestrogen-progestogen HRT) endometrial cancer, while also offering protective effects against ovarian and colorectal cancer. The nature and magnitude of risk depend substantially on the type of hormone, formulation, duration of use, route of administration, and individual health context.

Oestrogen and progesterone, and their synthetic analogues in HRT and contraceptives, act on hormone receptors in breast, endometrial, ovarian, and other tissues. Prolonged oestrogen stimulation, particularly without opposing progestogen in women with an intact uterus, promotes endometrial cell proliferation and increases the risk of endometrial hyperplasia and carcinoma. In breast tissue, oestrogen and some progestogens stimulate cell division, increasing the probability of replication errors accumulating in cells already prone to malignant transformation. Oestrogen is also metabolised to catechol oestrogens that can form direct DNA adducts. Oral contraceptives suppress ovulation, which is protective against ovarian cancer by reducing cyclical rupture and repair of the ovarian epithelium. Progestin-containing regimens, including some injectable contraceptives and high-dose oral progestins, have been associated with meningioma risk in some cohort studies, likely through progesterone receptor stimulation in this receptor-positive tumour type.

A large Danish nationwide cohort study of 969,424 women found that systemic menopausal hormone therapy was not associated with increased all-cause mortality, providing partial reassurance about overall health outcomes, though cancer-specific risk at individual sites requires separate consideration. A narrative review found that earlier large trials, particularly the Women's Health Initiative, raised concerns that have since been nuanced: oestrogen-only HRT in post-hysterectomy women carries a lower breast cancer risk than combined oestrogen-progestogen therapy, and the type and dose of progestogen may substantially influence breast cancer risk. A retrospective cohort study found combined oral contraceptive use was associated with meningioma incidence, with the effect modified by race, obesity, and polycystic ovary syndrome status. A meta-analysis of reproductive factors and breast cancer found that hormonal exposures, including exogenous hormones, were associated with breast cancer risk across ethnic groups, with the protective effect of parity stronger in Asian than in Western populations, suggesting gene-environment interactions. A GBD analysis of global breast cancer burden identified exogenous hormone use among the contributing risk factors alongside other reproductive and lifestyle factors.

Women with a personal or family history of hormone-sensitive cancer, particularly breast cancer, or those carrying BRCA1 or BRCA2 pathogenic variants, face a more complex risk-benefit calculation regarding HRT. Among BRCA-mutated women who undergo risk-reducing bilateral salpingo-oophorectomy (BSO) before natural menopause, short-term HRT to manage surgical menopause symptoms is generally considered acceptable, as current evidence suggests it does not eliminate the cancer-preventive benefit of the procedure. Women on high-dose progestogen-containing regimens face elevated meningioma risk. Post-menopausal women with intact uteruses who take oestrogen-only HRT face elevated endometrial cancer risk without progestogen opposition.

The evidence base includes large randomised controlled trials (including the Women's Health Initiative), multiple large prospective cohort studies, and extensive meta-analyses spanning decades. The overall picture is one of modestly increased breast cancer risk with combined oestrogen-progestogen HRT, particularly with longer duration of use, alongside reduced ovarian and colorectal cancer risk. There is active scientific debate about which progestogen types and routes of administration carry the most favourable risk profiles. Oral contraceptives appear to reduce ovarian cancer risk substantially but may modestly increase breast cancer risk with prolonged use.

The relationship between exogenous hormones and cancer is one of the most extensively studied in oncology. Evidence indicates both increased and decreased cancer risks depending on the specific hormone, formulation, duration of use, and individual context. For women considering HRT, the evidence suggests modest increased breast cancer risk with combined therapy, offset by symptom relief and potential reductions in ovarian and colorectal cancer risk. The balance of these effects varies considerably by individual health history, making this an area where the evidence base is rich but individual application requires consideration of personal factors.