Abstract
Background
Several studies have identified a possible interaction between age and hormone replacement therapy on colon neoplasm risk. We re-evaluated this interaction and determined if this interaction may be explained by the longer duration of estrogen use in older, rather than younger, women.
Methods
Included in the case-control study were 755 women (169 cases and 586 controls.) who were recruited from patients with no prior history of colorectal neoplasm and undergoing an elective colonoscopy examination.
Results
There was a significant interaction between age and hormone replacement therapy use (p = 0.03) with current estrogen users who were over 56 years of age having a reduced odds of colon adenoma (OR = 0.40, 95% CI 0.16-0.98) when compared to never users. Both older women who had used hormone replacement therapy for 3 or less years (OR = 0.07, 95% CI 0.006-0.81) and those reporting greater than 10 years of use (OR = 0.27, 95% CI 0.09-0.80) had a reduced adjusted odds for adenomas when compared to nonusers. No apparent association with estrogen replacement therapy was found among younger women (< 56 years).
Conclusions
Duration of use is not likely to explain the stronger association of hormone replacement therapy use with colon neoplasm in older women. Additional work is needed to better characterize the underlying mechanisms associated with this interaction.
Keywords: colon cancer, polyps, hormone replacement therapy, chemoprevention
Introduction
Case-control and cohort studies have suggested a protective effect for hormone replacement therapy (HRT) on colorectal neoplasm. (1-5) An intriguing observation has been a possible interaction between age and HRT use in colorectal neoplasm. Several studies have demonstrated that older women appear to derive a greater protective effect from HRT than younger women. (5-11) One possible explanation for this interaction is that age may represents a proxy for duration of HRT use. (12) Most studies, however, have been inconsistent regarding the association of colorectal neoplasm risk with the duration of HRT use (1). The purpose of this study was to evaluate the association of colorectal adenomas with HRT use, in particular, the interaction of HRT use and age in the risk of colorectal adenomas.
Materials and methods
Study participants were identified from consecutive patients undergoing elective colonoscopy at the Vanderbilt University Medical Center or the Tennessee Valley Healthcare System, Department of Veterans Affairs Hospital between February 2003 and December 2005. Eligible patients were invited to participate in the study prior to their scheduled colonoscopy. The results of patient colonoscopies were recorded using standardized data entry forms and information on the number, location, and size of any identified colonic polyp was collected. Cases included subjects diagnosed with one or more histologically confirmed adenomatous polyps. Controls were patients with normal polyp-free colons on complete colonoscopy. Exclusion criteria included patients with a known or suspected inherited colorectal cancer syndrome, a prior history of cancer, a history of inflammatory bowel disease, a prior adenoma diagnosis, and aged less than 40 years or greater than 75 years.
From a total of 4508 potentially eligible subjects, 3085 (68.4%) consented to participate and telephone interviews were completed on 2679 (87%). For the current analysis we included only postmenopausal females resulting in 172 cases and 630 controls. We also excluded one subject who indicated she had never had a menstrual period and 46 subjects with missing data on hormone replacement therapy resulting in an analytic sample consisted of 169 cases and 586 controls.
A telephone survey was conducted for each consenting patient to collect information on demographic, family history and lifestyle factors, such as reproductive history and use of exogenous estrogen. Self-reported height and weight were collected and used to calculate body mass index (BMI), which was then categorized using the Centers for Disease Control classification scheme for BMI (normal < 25.0, overweight 25 – 30, obese > 30).
Differences between cases and controls were compared using the Student's t test for continuous variables or the χ2 test for categorical variables. Unconditional logistic regression models were used to estimate the risk of colorectal adenomas associated with exogenous hormone use. Stratified analyses were used to evaluate effect modification by age and duration of use. Using the postmenopausal control distribution, age was dichotomized using the median value and duration of use was categorized into tertiles. All models were adjusted for age, race, family history of colorectal cancer or adenomatous polyps, body mass index, smoking status, alcohol use, educational attainment, physical activity level, and use of non-steroidal anti-inflammatory drugs. To test for an interaction between age and HRT use, an interaction term was created using age as a continuous variable. Results were also stratifying by the age of initiation of HRT (in tertiles), timing of initiation of HRT (>1 year prior to menopause, 1 year before or after menopause, > 1 year after menopause) and type of menopause (natural, surgical). All statistical calculations were performed using SAS version 9 (SAS Institute, Cary, NC).
Results
Presented in Table 1 are major demographic characteristics and risk factors among cases and controls. Overall, current users of HRT had an adjusted odds ratio of 0.72 (95% CI 0.37 – 1.39) for colon adenomas when compared to never users. The interaction between age and current use of HRT was statistically significant (p = 0.03). Consistent with prior studies, the most pronounced effects for current users of HRT were in older women when compared to non-users. In neither older nor younger women was there a significant trend with respects to duration of HRT (Table 2). Older women who reported using HRT for 3 or less years or greater than 10 years both had a reduced odds for colon adenoma (OR = 0.07; 95% CI 0.006-0.81 and 0.27; 95% CI 0.09-0.80, respectively). Results stratified by age at initiation of HRT, timing of HRT with respects to menopause, and type of menopause are presented in Table 2. No consistent associations were found between age, HRT use, and adenoma risk when stratified by age at initiation of HRT as well as type of menopause. There was a significant trend (P = 0.01) suggesting a greater effect of HRT when initiated after menopause (OR = 0.15, 95% CI 0.02 – 1.01), as compared to peri-menopause (OR 0.33; 95% CI 0.11-1.00) or before menopause (OR = 0.67; 95% CI 0.19-2.29).
Table 1.
Selected characteristics among female cases and controls
| Characteristic | Cases (N = 169) | Controls (N = 586) | P-value |
|---|---|---|---|
| Age (mean yrs) | 59.5 | 57.3 | 0.0004 |
| Ethnicity, % white | 82.0 | 86.1 | 0.20 |
| Body mass index, | |||
| ≤ 24.9 kg/m2 | 39.1 | 39.3 | 0.96 |
| 25.0 – 29.9 kg/m2 | 30.8 | 29.7 | |
| ≥ 30.0 kg/m2 | 30.2 | 31.1 | |
| Family history, % | |||
| Colorectal cancer or adenomatous polyp | 21.7 | 17.4 | 0.21 |
| Education, % | |||
| ≤ High school | 24.9 | 23.1 | 0.61 |
| Some college | 30.8 | 28.9 | |
| College graduate | 23.7 | 22.2 | |
| > College | 20.7 | 25.8 | |
| Smoking status, % | |||
| Never | 51.5 | 62.5 | 0.0006 |
| Former | 27.8 | 27.6 | |
| Current | 20.7 | 9.9 | |
| Alcohol use, % | |||
| Never | 75.2 | 75.6 | 0.97 |
| Former | 11.2 | 10.6 | |
| Current | 13.6 | 13.9 | |
| Physical activity, % | |||
| Regularly exercise | 56.8 | 59.6 | 0.52 |
| Non-steroidal anti-inflammatory drugs, % | |||
| Current user | 43.0 | 41.5 | 0.79 |
Table 2.
Association of age and current hormone replacement therapy use with adenoma risk in postmenopausal women stratified by duration of use, age at beginning HRT, age at menopause, and timing of initiation of HRT
| Participant Age, yrs | ||||||
|---|---|---|---|---|---|---|
| < 56 | ≥ 56 | |||||
| Controls/Cases | OR1 | 95% CI | Controls/Cases | OR1 | 95% CI | |
| HRT Use | ||||||
| Never | 98/15 | 1.00 | 1.00 | 53/27 | 1.00 | 1.00 |
| Current | 123/27 | 1.38 | 0.47-4.02 | 141/31 | 0.40 | 0.16-0.98 |
| Test for interaction | P = 0.03 | |||||
| Duration of HRT Use | ||||||
| Never used | 98/15 | 1.00 | 53/27 | 1.00 | ||
| ≤ 3 yrs | 37/10 | 1.04 | 0.24–4.53 | 20/4 | 0.07 | 0.006-0.81 |
| 4 to 10 yrs | 37/5 | 0.51 | 0.09-2.90 | 23/9 | 1.24 | 0.31-4.91 |
| > 10 yrs | 23/9 | 8.41 | 1.37-51.58 | 66/15 | 0.27 | 0.09-0.80 |
| Test for trend | Ρ = 0.24 | P = 0.08 | ||||
| Age at initiation of HRT | ||||||
| Never used | 98/15 | 1.00 | 53/27 | 1.00 | 1.00 | |
| ≤ 43 yrs | 45/14 | 2.23 | 0.58-8.62 | 34/7 | 0.24 | 0.06-0.89 |
| 44 to 49 yrs | 32/5 | 0.77 | 0.16-3.62 | 31/9 | 0.24 | 0.05-1.13 |
| > 49 yrs | 20/5 | 1.27 | 0.20-8.02 | 44/12 | 0.57 | 0.57-1.75 |
| Test for trend | P = 0.81 | P = 0.36 | ||||
| Menopause status at HRT initiation | ||||||
| Never used | 98/15 | 1.00 | 53/27 | 1.00 | ||
| Pre- | 38/6 | 0.67 | 0.20-2.26 | 50/12 | 0.67 | 0.19-2.29 |
| Peri- | 77/19 | 1.63 | 0.51-5.19 | 69/13 | 0.33 | 0.11-1.00 |
| Post- | 8/2 | 4.25 | 0.31-59.25 | 22/6 | 0.15 | 0.02-1.01 |
| Test for trend | P = 0.24 | P = 0.01 | ||||
| Type of menopause in HRT users | ||||||
| Never used | 98/15 | 1.00 | 53/27 | 1.00 | ||
| Natural | 35/9 | 0.96 | 0.22-4.17 | 55/14 | 0.31 | 0.09-1.07 |
| Surgical/medical | 62/15 | 1.59 | 0.46-5.48 | 54/14 | 0.44 | 0.16-1.22 |
| Test for trend | P = 0.60 | P = 0.07 | ||||
OR adjusted for age (continuous), family history of colorectal tumor (yes, no), body mass index (≤ 24.9, 25.0 – 29.9, and ≥ 30.0 kg.m2), smoking status (never, current, former), alcohol use (never, current, former), ethnicity (white, non-white), education (≤ high school, > high school), physical activity (regular exercise, no regular exercise) and NSAID use (current user, not current user).
Discussion
We found that HRT use was associated with a reduced risk of colorectal adenoma only among older women and the interaction between age and HRT use was consistent in women using HRT for 3 or less years or those using HRT for greater than 10 years. Curiously, older women using HRT from 4 to 10 years had an increased odds, yet this was not statistically significant. Additionally, women under 56 years of age who noted greater than 10 years duration of HRT had an increased risk of colon adenomas. The confidence intervals however were quite large and this finding would need to be replicated in another sample. Age at initiation of HRT and type of menopause did not seem to impact the tendency towards greater protection in older women. There was a significant trend suggesting a stronger association of HRT with adenoma risk in older women who initiated HRT over 1 year after menopause compared to those who initiated HRT before menopause or at peri-menopause.
Our study does not support the hypothesis that older women benefit more from HRT therapy because they are likely to have used HRT for a greater duration when compared to younger women. As such, the beneficial effects of HRT may be more associated to when one begins estrogen replacement therapy rather than how long one is using HRT. It has been previously described that hypermethylation of the estrogen receptor (ER) is an age-related phenomena and that estrogen therapy reverses these changes with a subsequent increased in ER expression within colonic mucosa. (13, 14) As most colorectal tumors arise from cells that no longer express ER, it has been hypothesized that HRT may be protective by limiting ER methylation and subsequently limiting the number of cells which may progress to colorectal cancer. (14, 15) Thus HRT may offer the greatest benefit for women who have both lost ER expression due to hypermethylation while concomitantly lost their ability to reverse these changes through physiological estrogen withdrawal. Alternatively, estrogen therapy may also reverse age-related decreases in calcium absorption and directly impact serum 25(OH)D and 1,25(OH)2D levels.(16, 17) Several studies have suggested that calcium may reduce colorectal polyp risk. (18, 19) In our study the timing of initiation of HRT with respects to menopause (which could represent the duration of estrogen withdrawal) did appear to have an impact HRT protective effects, however the study sample was small and we had limited power to detect effects in these subgroups.
In conclusion, our study supports previous studies, which have found an interaction between age and HRT use and risk for colon neoplasm. Duration of estrogen use did not appear to modify this relationship. Future research is needed to better characterize the underlying mechanisms associated with this interaction.
Acknowledgments
The authors would like to thank the Tennessee Colorectal Polyp Study participants and staff. The authors would like to thank William Wu, Ming Li, and Heidi Chen for their assistance in data preparation. The authors would like to acknowledge the Department of Veterans Affairs, Tennessee Valley Healthcare System, GRECC for it administrative support in the preparation of the manuscript. This study was supported through the National Cancer Institute grant CA 95103 (Vanderbilt-Ingram Cancer Center SPORE in GI Cancer Grant), R01 CA97386 and the Tennessee Valley Healthcare System Veterans Affairs Clinical Research Center of Excellence.
Sources of support: This study was supported through the National Cancer Institute grant CA 95103 (Vanderbilt-Ingram Cancer Center SPORE in GI Cancer Grant), R01 CA97386 and the Tennessee Valley Healthcare System Veterans Affairs Clinical Research Center of Excellence.
Footnotes
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