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

Disclosures

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

Abstract and Introduction

Abstract

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.

Introduction

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.

1 2 3 4

Next Section

Table 1. Descriptive characteristics of the Swedish study population during 2005–2012
Characteristics	MHT ever-users N = 290 186 Number (%)	MHT non-users N = 870 165 Number (%)
All colon cancer	1106 (0.4)	5022 (0.6)
All rectal cancer	487 (0.2)	2204 (0.3)
Histological type and tumour location
Colon adenocarcinoma	1073 (0.4)	4841 (0.6)
Rectal adenocarcinoma	461 (0.2)	2126 (0.2)
Left-sided colorectal adenocarcinoma	882 (0.3)	4130 (0.5)
Right-sided colorectal adenocarcinoma	627 (0.2)	2675 (0.3)
Overlapping or unspecific sites	25 (0.02)	162 (0.02)
Age groups, years
<60 y	108 631 (37.4)	325 747 (37.4)
60–69 y	93 490 (32.2)	267 323 (30.7)
≥70 y	88 065 (30.4)	277 095 (31.8)
Menopausal hormone therapy
All MHT	290 186 (100.0)	-
Oestrogen only	117 996 (40.7)	-
Tibolone only	17 992 (6.2)	-
Oestrogens combined progestins	154 198 (53.1)	-
Route of administration
Oral	243 682 (84.0)	-
Cutaneous/transdermal	35 826 (12.4)	-
Both	10 678 (3.7)	-
Oestrogen-only users
Oestradiol only	53 339 (45.2)	-
Oestriol only	55 653 (47.2)	-
Conjugated oestrogens only	1161 (1.0)	-
Other, mixed	7843 (6.7)	-
Tibolone-only users	17 992 (100.0)	-
Oestrogen + progestin users
Progesterone-derived only	47 308 (30.7)	-
Testosterone-derived only	85 659 (55.6)	-
Other, mixed	21 231 (13.8)	-
Mode of EP-MHT administration
Only continuous combinations	92 381 (59.9)	-
Only sequential combinations	28 263 (18.3)	-
Other, mixed	33 554 (21.8)	-
EP-MHT preparations and regimens
Progesterone derived, continuous	30 123 (19.5)	-
Progesterone derived, sequential	3341 (2.2)	-
Testosterone derived, continuous	53 360 (34.6)	-
Testosterone derived, sequential	21 247 (13.8)	-
Other, mixed	46 127 (29.9)	-
Comorbidities
Ever parous (in-hospital delivery)	117 861 (40.6)	353 282 (40.6)
Thrombotic events	40 316 (13.9)	120 931 (13.9)
Hysterectomy	51 811 (17.9)	155 138 (17.8)
Diabetes mellitus	15 936 (5.5)	48 422 (5.6)
Obesity	5146 (1.8)	15 526 (1.8)
Alcohol-related disorders	7293 (2.5)	21 455 (2.5)
Smoking-related disorders	13 601 (4.7)	40 994 (4.7)
Osteoporosis	8256 (2.9)	22 764 (2.6)

Table 2. Ever, current and past use of menopausal hormone therapy (MHT) and risk of colon and rectal adenocarcinoma, in Swedish women during 2005–2012, adjusted for age and MHT preparations
	Number (%) of cases MHT users	Number (%) of cases Non-users	OR (95% CI)				P for interaction by age
	Number (%) of cases MHT users	Number (%) of cases Non-users	All women	<60 y	60–69 y	≥70 y	P for interaction by age
Colon adenocarcinoma
All MHT ever-users
All MHT	1073 (0.4)	4841 (0.6)	0.67 (0.63–0.72)	0.45 (0.36–0.55)	0.73 (0.65–0.83)	0.70 (0.64–0.76)	<0.001
Oestrogen only	580 (0.5)		0.62 (0.57–0.68)	0.36 (0.17–0.40)	0.52 (0.41–0.65)	0.68 (0.62–0.75)	<0.001
Tibolone only	62 (0.3)		0.83 (0.64–1.06)	0.96 (0.53–1.75)	0.85 (0.60–1.21)	0.65 (0.41–1.02)	<0.001
Oestrogen + progestin	431 (0.3)		0.77 (0.69–0.84)	0.52 (0.41–0.67)	0.87 (0.74–1.01)	0.78 (0.67–0.91)	<0.001
Current MHT users
All MHT	585 (0.5)		0.82 (0.75–0.89)	0.49 (0.37–0.65)	1.10 (0.93–1.30)	0.89 (0.80–0.99)	<0.001
Oestrogen only	342 (0.6)		0.73 (0.65–0.82)	0.33 (0.19–0.57)	0.74 (0.54–1.01)	0.85 (0.75–0.96)	<0.001
Tibolone only	24 (0.4)		1.04 (0.69–1.55)	1.40 (0.62–3.13)	1.05 (0.59–1.85)	0.66 (0.30–1.48)	<0.001
Oestrogen + progestin	219 (0.3)		1.02 (0.89–1.17)	0.53 (0.37–0.75)	1.40 (1.14–1.71)	1.14 (0.92–1.43)	<0.001
Past MHT users
All MHT	488 (0.3)		0.55 (0.50–0.61)	0.41 (0.41–0.55)	0.54 (0.45–0.64)	0.55 (0.49–0.62)	<0.001
Oestrogen only	238 (0.4)		0.49 (0.43–0.56)	0.20 (0.10–0.39)	0.39 (0.28–0.54)	0.53 (0.46–0.61)	<0.001
Tibolone only	38 (0.3)		0.79 (0.57–1.09)	0.70 (0.29–1.69)	0.76 (0.49–1.19)	0.64 (0.37–1.11)	<0.001
Oestrogen + progestin	212 (0.2)		0.62 (0.54–0.72)	0.51 (0.36–0.72)	0.60 (0.49–0.75)	0.59 (0.48–0.74)	<0.001
Rectal adenocarcinoma
All MHT ever-users
All MHT	461 (0.2)	2126 (0.2)	0.66 (0.60–0.73)	0.61 (0.48–0.78)	0.76 (0.64–0.91)	0.61 (0.53–0.71)	<0.001
Oestrogen only	219 (0.2)		0.60 (0.49–0.64)	0.34 (0.20–0.58)	0.55 (0.40–0.75)	0.60 (0.51–0.71)	<0.001
Tibolone only	33 (0.2)		0.98 (0.69–1.38)	0.90 (0.40–2.02)	0.98 (0.62–1.55)	0.70 (0.35–1.41)	<0.001
Oestrogen + progestin	209 (0.1)		0.79 (0.68–0.91)	0.72 (0.54–0.96)	0.89 (0.71–1.10)	0.65 (0.49–0.85)	<0.001
Current MHT users
All MHT	276 (0.2)		0.89 (0.79–1.01)	0.83 (0.61–1.12)	1.09 (0.86–1.37)	0.93 (0.78–1.11)	<0.001
Oestrogen only	145 (0.3)		0.76 (0.64–0.90)	0.55 (0.30–1.02)	0.81 (0.54–1.21)	0.87 (0.71–1.06)	<0.001
Tibolone only	18 (0.3)		1.62 (1.02–2.59)	0.81 (0.20–3.24)	1.51 (0.78–2.92)	1.98 (0.94–4.18)	<0.001
Oestrogen + progestin	113 (0.2)		1.09 (0.90–1.32)	0.97 (0.68–1.37)	1.24 (0.92–1.68)	1.12 (0.79–1.60)	<0.001
Past MHT users
All MHT	185 (0.1)		0.47 (0.41–0.55)	0.42 (0.29–0.62)	0.59 (0.47–0.75)	0.37 (0.29–0.46)	<0.001
Oestrogen only	74 (0.1)		0.36 (0.28–0.45)	0.14 (0.04–0.44)	0.39 (0.25–0.62)	0.37 (0.28–0.49)	<0.001
Tibolone only	15 (0.1)		0.66 (0.40–1.10)	0.96 (0.36–2.57)	0.74 (0.40–1.39)	0.13 (0.02–0.90)	<0.001
Oestrogen + progestin	96 (0.1)		0.60 (0.49–0.74)	0.51 (0.33–0.79)	0.70 (0.53–0.94)	0.41 (0.27–0.62)	<0.001

Table 3. Ever and current use of menopausal hormone therapy (MHT) and colon and rectal adenocarcinoma risk in Swedish women during 2005–2012, by formulations and regimens
	Total number of women MHT users	Number of cancer cases in MHT users	OR (95% CI)
Colon adenocarcinoma
Oestrogen only, ever-users
Oestradiol only	53 339	157	0.51 (0.44–0.59)
Oestriol only	55 653	382	0.66 (0.59–0.73)
Conjugated oestrogens only	1161	9	0.99 (0.56–1.76)
Oestrogen only, current users
Oestradiol only	23 305	89	0.62 (0.52–0.75)
Oestriol only	26 634	232	0.76 (0.67–0.87)
Conjugated oestrogens only	38	1	2.78 (0.88–8.77)
EP-MHT regimens, ever-users
Continuous, progestin derived	30 123	88	0.78 (0.63–0.97)
Continuous, testosterone derived	53 360	215	0.94 (0.82–1.08)
Sequential, progestin derived	3341	4	0.40 (0.15–1.08)
Sequential, testosterone derived	21 247	1	0.43 (0.29–0.65)
EP-MHT regimens, current users
Continuous, progestin derived	10 956	40	1.06 (0.77–1.45)
Continuous, testosterone derived	18 664	107	1.41 (1.16–1.71)
Sequential, progestin derived	21 247	24	0.29 (0.04–2.05)
Sequential, testosterone derived	7875	10	0.53 (0.28–0.98)
Rectal adenocarcinoma
Oestrogen only, ever-users
Oestradiol only	53 339	83	0.60 (0.49–0.72)
Oestriol only	55 653	115	0.52 (0.43–0.63)
Conjugated oestrogens only	1161	1	0.36 (0.09–1.46)
Oestrogen only, current users
Oestradiol only	23 305	56	0.62 (0.52–0.75)
Oestriol only	26 634	75	0.76 (0.67–0.87)
Conjugated oestrogens only	38	0	NA
EP-MHT regimens, ever-users
Continuous, progestin derived	30 123	47	0.89 (0.67–1.19)
Continuous, testosterone derived	53 360	92	0.89 (0.72–1.09)
Sequential, progestin derived	3341	1	0.20 (0.03–1.45)
Sequential, testosterone derived	21 247	18	0.64 (0.40–1.02)
EP-MHT regimens, current users
Continuous, progestin derived	10 956	23	1.27 (0.84–1.92)
Continuous, testosterone derived	18 664	45	1.28 (0.95–1.72)
Sequential, progestin derived	1257	0	NA
Sequential, testosterone derived	7875	10	1.02 (0.54–1.90)

Table 4. Ever and current use of oral and cutaneous menopausal hormone therapy (MHT) and the risk of colon and rectal adenocarcinoma in Swedish women during 2005–2012, compared to MHT non-users
	Number of individuals (%) MHT ever-users	Number of cancers in MHT users	OR (95% CI)
Colon adenocarcinoma
All MHT use
Oral only	243 682 (84.0)	943	0.68 (0.64–0.73)
Cutaneous only	35 826 (12.3)	106	0.61 (0.51–0.75)
Oestrogen only
Oral only	91 202 (77.3)	499	0.62 (0.56–0.68)
Cutaneous only	22 019 (18.7)	71	0.58 (0.46–0.73)
Tibolone only
Oral only	17 992 (100.0)	62	0.87 (0.68–1.12)
Oestrogen + progestin
Oral only	134 488 (87.2)	382	0.79 (0.71–0.87)
Cutaneous only	13 807 (9.0)	35	0.72 (0.52–1.01)
Current MHT users
All MHT
Oral only	102 517 (82.5)	512	0.83 (0.76–0.91)
Cutaneous only	15 099 (12.1)	57	0.83 (0.64–1.08)
Oestrogen only
Oral only	42 149 (77.9)	291	0.72 (0.64–0.81)
Cutaneous only	9061 (16.7)	45	0.93 (0.69–1.25)
Tibolone only
Oral only	6104 (100.0)	24	1.04 (0.69–1.55)
Oestrogen + progestin
Oral only	54 264 (84.7)	197	1.07 (0.93–1.24)
Cutaneous only	6038 (9.4)	12	0.60 (0.34–1.06)
Rectal adenocarcinoma
All MHT use
Oral only	243 682 (84.0)	392	0.66 (0.59–0.73)
Cutaneous only	35 826 (12.3)	55	0.66 (0.50–0.86)
Oestrogen only
Oral only	91 202 (77.3)	169	0.52 (0.44–0.61)
Cutaneous only	22 019 (18.7)	41	0.69 (0.50–0.94)
Tibolone only
Oral only	17 992 (100.0)	33	0.98 (0.69–1.38)
Oestrogen + progestin
Oral only	134 488 (87.2)	190	0.82 (0.71–0.96)
Cutaneous only	13 807 (9.0)	14	0.60 (0.35–1.02)
Current MHT users
All MHT
Oral only	102 517 (82.5)	233	0.89 (0.78–1.02)
Cutaneous only	15 099 (12.1)	33	0.97 (0.69–1.37)
Oestrogen only
Oral only	42 149 (77.9)	113	0.70 (0.58–0.85)
Cutaneous only	9061 (16.7)	25	1.05 (0.70–1.56)
Tibolone only
Oral only	6104 (100.0)	18	1.62 (1.02–2.59)
Oestrogen + progestin
Oral only	54 264 (84.7)	102	1.16 (0.94–1.41)
Cutaneous only	6038 (9.4)	8	0.82 (0.41–1.64)