Menopausal Hormone Therapies and Risk of Colorectal Cancer

A Swedish Matched-cohort Study

Qing Liu; Johanna Simin; Justine Debelius; Katja Fall; Omid Sadr-Azodi; Lars Engstrand; Cecilia Williams; Nele Brusselaers


Aliment Pharmacol Ther. 2021;53(11):1216-1225. 

In This Article

Abstract and Introduction


Background: Menopausal hormone therapy (MHT) has been associated with various malignancies.

Aims: To investigate the association of various MHT regimens with the risk of colorectal cancer (CRC).

Methods: All MHT ever-users (n = 290 186) were included through the Swedish Prescribed Drug Registry, with a 1:3 group-level matching to non-users. Ever-users were defined as women who received ≥1 dispensed prescription of systemic MHT during 2005–2012 in Sweden. All CRC cases after drug initiation were extracted from the Swedish Cancer Registry. The association was assessed by multivariable conditional logistic and Cox regression models, presented as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) considering different regimens, duration and age at treatment initiation.

Results: Compared with non-users, MHT users had an overall reduced odds for colon (OR = 0.67, 95% CI 0.63–0.72) and rectal adenocarcinoma (OR = 0.66, 95% CI 0.60–0.73), especially among women aged 40–60 years. Current users of oestrogen-only preparations (E-MHT) showed a reduced odds (colon OR = 0.73, 95% CI 0.65–0.82; rectal OR = 0.76, 95% CI 0.64–0.90) compared to non-users, particularly with oestradiol and oestriol. Past E-MHT use showed stronger odds reductions (colon OR = 0.49, 95% CI 0.43–0.56; rectal OR = 0.36, 95% CI 0.28–0.45). Current use of oestrogen combined progestin therapy (EP-MHT) indicated a less prominent odds reduction (colon adenocarcinoma OR 0.62, 95% CI 0.54–0.72; rectal adenocarcinoma OR = 0.60, 95% CI 0.49–0.74) than past users. Tibolone showed an increased risk of left-sided colorectal adenocarcinoma. Oral and cutaneous MHT usage showed similar patterns.

Conclusions: MHT use may decrease colorectal adenocarcinoma risk, for both E-MHT and EP-MHT, and especially in past users.


Colorectal cancer (CRC) is the second-most diagnosed cancer in women and the third in men, remaining still a leading cause of cancer death.[1,2] This common and lethal cancer shows age and gender disparities during its long progress from a precancerous lesion to carcinoma.[3] Although CRC survival is approximately 25% better for women than men, this changes after menopause with a poorer prognosis for women over 65 years old compared to age-matched men.[3,4] In postmenopausal women, oestrogen and progesterone levels decline gradually with ageing while testosterone production from adrenal glands continues,[5] indicating the potential preventive role of particular female sex hormones in CRC promotion and progression. Low endogenous and exogenous oestrogens could be risk factors of CRC, besides previously identified risk factors including increasing age, hereditary factors, Westernised diet, low physical activity and smoking.[2,6] A potential mechanism could be oestrogen receptor beta (ERβ/ESR2) expressed in the colorectal continuum and sex hormone interaction mediating gut polyp formation, which has been shown in rodent models for CRC.[7]

In pre-clinical studies, menopausal hormone therapy (MHT) has been associated with some sex-hormone–related cancers.[8,9] The increased risk of breast cancer was observed especially in current and sequential use of MHT, and the typical oestrogen-only preparations seemed to be less harmful.[10] However, data on population level have remained sparse on CRC risk, particularly for its relationship with different preparations and regimens of MHT.

To fill these important knowledge gaps, we conducted this nationwide population-based study enrolling all contemporary Swedish MHT users during 2005–2012, to evaluate the association of different MHT treatment options on the risk of colorectal adenocarcinoma. Because colorectal adenocarcinoma (>95% in histopathologic diagnoses of CRC) initiated in left-sided and right-sided colorectal continuum showed clinically diversity,[11,12] we also categorised our first outcome as left- and right-sided CRC, along with the histologic classification of the colon and rectal cancer.