Abstract
Few studies have examined the associations of hypertension and antihypertensive medications with ovarian cancer. In particular, beta-blockers, one of the most commonly prescribed medications to treat hypertension, may reduce ovarian cancer risk by inhibiting beta-adrenergic signaling. We prospectively followed 90,384 women in the Nurses’ Health Study (NHS) between 1988–2012 and 113,121 NHSII participants between 1989–2011. Hypertension and use of antihypertensive medications were self-reported biennially. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We documented 948 ovarian cancer cases during follow-up. Similar results were observed in the two cohorts. While hypertension was not associated with ovarian cancer risk (Pooled HR=1.01; 95% CI=0.88, 1.16), current use of any antihypertensive medication was associated with slightly increased risk compared to never users (Pooled HR=1.18; 95% CI: 1.02, 1.37). This increased risk was primarily due to use of thiazide diuretics (Pooled HR=1.37; 95% CI: 1.13, 1.68). No associations were observed for beta-blockers or angiotensin-converting-enzyme inhibitors. Calcium channel blockers (CCBs) were associated with suggestively reduced risk (NHS HR=0.73; 95% CI: 0.53, 1.01), after adjusting for all antihypertensive medications. Associations were similar among hypertensive women and stronger for longer use of thiazide diuretics and CCBs. In conclusion, our results provided no evidence that beta-blockers were associated with reduced ovarian cancer risk. In contrast, we observed an increased risk for use of thiazide diuretics that should be confirmed in other studies.
Keywords: Ovarian cancer, Hypertension, Antihypertensive medications, Beta-blockers, Thiazide diuretics
Introduction
The longstanding debate over whether antihypertensive medication use contributes to cancer risk has led to numerous studies of clinical trial populations and in observational cohorts in the past several decades. These studies, however, have yielded inconsistent results.1–5 Most evaluated risk of total cancer, which could mask specific etiologic links only relevant for certain cancer sites. For example, a meta-analysis of 70 randomized controlled trials suggested an increased total cancer risk with combined angiotensin-converting-enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy,1 while there has been evidence for an inverse association of this regimen for colorectal cancer.6 Relatively little research is available for rarer cancers, as clinical trials had limited power for these tumor types, particularly gynecologic cancers. Due to the high prevalence of hypertension and widespread use of antihypertensive medication,7, 8 even a modest association could be important in understanding risk of rarer cancers.
Ovarian cancer is a relatively rare, but highly fatal, gynecological malignancy, which ranks as the fifth leading cause of cancer death among US women.9 To date, no prospective study has examined the association of antihypertensive medications with ovarian cancer risk. Particularly, laboratory data suggest that beta-blockers may antagonize the tumor-promoting actions of endogenous catecholamines signaling through beta2-adrenergic receptors expressed in ovarian cancer cells.10, 11 Improved survival associated with beta-blocker use in ovarian cancer patients has been observed in some,12, 13 but not all,14, 15 studies. Whether use of other types of antihypertensive medications was associated with ovarian cancer remain unknown. Further, only two studies have examined ovarian cancer risk in relation to hypertension and blood pressure, reporting no overall association.16, 17
Given the potential importance of the association but scarce epidemiologic data available, we examined the relationship between hypertension, antihypertensive medication use, and risk of epithelial ovarian cancer in the Nurses’ Health Study (NHS) and NHSII, which prospectively collected data on physician-diagnosed hypertension, use of different classes of antihypertensive medications and ovarian cancer diagnosis over 24 years of follow-up.
Methods
Study population
The NHS commenced in 1976, when 121,700 US female registered nurses aged 30–55 completed a baseline questionnaire regarding their medical history and lifestyle. The NHSII was established in 1989 among 116,430 nurses (age: 25–42). Every two years, participants were mailed a self-administered follow-up questionnaire to update their disease occurrence and lifestyle factors, including information on hypertension, blood pressure, and antihypertensive medication use (by type). For the present study, we excluded women who had a bilateral oophorectomy, menopause due to pelvic irradiation, or a prior diagnosis of cancer, other than non-melanoma skin cancer, before the return of their first assessment of antihypertensive use. This resulted in an analytical sample of 90,384 NHS participants between 1988–2012 and 113,121 NHSII participants between 1989–2011. The study protocol was approved by the institutional review board of the Brigham and Women’s Hospital.
Ascertainment of ovarian cancer
Incident cases of ovarian cancer were reported on each biennial questionnaire. After obtaining permission from participants, a gynecologic pathologist blinded to exposure status reviewed pathology reports and related medical records to confirm the diagnosis. Tumor characteristics, including morphology, stage, histology, and invasiveness, were abstracted from these reports. Deaths of cohort members and the related cause of death were identified by family members, the US Postal Service, or the National Death Index. In a subset of 215 ovarian cancer cases, concordance between reviews of pathology records and surgical pathology slides was 98% for invasiveness and 83% for histologic type.18
Assessment of hypertension and blood pressure
Physician-diagnosed hypertension was self-reported biennially by participants from baseline (NHS: 1976, NHSII: 1989). Women were considered to have a history of hypertension if they had ever reported physician-diagnosed hypertension on the current or previous questionnaires. The validity of self-reported hypertension was assessed in 1982 in NHS and 2005 in NHSII. Among 51 NHS participants reporting hypertension whose medical records were obtained, all were confirmed to have blood pressure ≥140/90 mmHg;19 94% of 147 NHSII participants who self-reported physician-diagnosed hypertension were confirmed by medical records.20 In 1986, 1988, 1990 and every 4 years thereafter, NHS participants were asked to report their current usual systolic (SBP) and diastolic blood pressures (DBP), if checked within the past two years, in categories as described previously.21 NHSII participants reported their SBP/DBP in 1989, 1999, 2005 and 2009. Because we did not ask about antihypertensive medication use until 1988 in NHS (see below), we started the follow-up for the analyses of hypertension and ovarian cancer risk in 1988 to include the same study population in all analyses.
Use of antihypertensive medications
In NHS, participants were asked to report regular use of antihypertensive medications in the past two years by drug class, including beta-blockers, thiazide diuretics, calcium channel blockers (CCBs), ACEIs, and other antihypertensive drugs. These questions were first queried in 1988, and updated in 1994 and every two years thereafter (except ACEIs which were updated biennially from 1996). Because ARBs and Lasix (furosemide) were only asked in later follow-up periods, we did not have adequate power for individual evaluation of these drug classes and therefore combined them with other antihypertensive drugs. In NHSII, regular use of thiazide diuretics and any other antihypertensive medications were assessed biennially since 1989 (except in 1991). Beta-blocker use was assessed in 1989, 2001 and every two years thereafter. Other specific medication types were not asked until after 2001, therefore were combined with other antihypertensive drugs.
Statistical analysis
Person-years of follow-up accrued for each individual from the return date of the first questionnaire on antihypertensive medication use until the date of death, any cancer diagnosis including ovarian cancer (except non-melanoma skin cancer), bilateral oophorectomy, pelvic irradiation, or the end of the follow-up (NHS: June 2012; NHSII: June 2011), whichever occurred first. Women only contributed person-time for follow-up periods in which they completed the hypertension/antihypertensive medication questions (proportion of all person-years lost due to non-response: 15.6% for NHS and 11.6% for NHSII). Within each cohort, we used Cox proportional hazards models, stratified jointly by age and calendar time, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer according to history (yes, no) and duration (<5, 5–10, ≥10 years) of hypertension, SBP (<115, 115–134, 135–154, ≥155 mmHg), and DBP (<85, 85–94, ≥95 mmHg). We also evaluated the associations with use of any antihypertensive medications, beta-blockers and thiazide diuretics, as these have been assessed since baseline in both cohorts. Medication use was categorized into current (reported use on current questionnaire) and past (reported use on any previous questionnaires), with never use of any antihypertensive medication as the reference. Multivariable HRs were adjusted for hormonal and reproductive risk factors for ovarian cancer (most updated biennially), including menopausal status (premenopausal, postmenopausal), parity (nulliparous, 1, 2, 3, >3 children), duration of oral contraceptive use (never, <1, 1–5, >5 years), duration of postmenopausal hormone use by type (never, <5, 5–10, >10 years for estrogen only and estrogen plus progesterone separately), history of tubal ligation (yes, no), history of hysterectomy (yes, no), family history of breast cancer or ovarian cancer (yes, no) and duration of breastfeeding (months, continuous). Analyses were conducted in individual cohort first, and then pooled as one large dataset with additional stratification by cohort. Competing risks Cox models22 were used in the pooled analysis to examine whether the associations with hypertension, blood pressure and antihypertensive medications differed by ovarian tumor histologic subtypes (serous/poorly differentiated, endometrioid, other subtypes) and aggressiveness (rapidly fatal within 3 years of diagnosis or not23).
Given the more consistent assessment of individual drug classes since baseline in NHS, additional analyses were performed in this cohort. First, we evaluated the associations with additional drug classes including CCBs, ACEIs and other antihypertensive drugs. Second, we assessed the potential for residual confounding by further considering major lifestyle factors for hypertension, including smoking (never, past, current), physical activity (MET-hours/week, in quintiles), body mass index (<20, 20–24.9, 25–29.9, ≥30 kg/m2), alcohol consumption (none, 1–4.9, 5–14.9, 15–29.9, ≥30 g/day), current aspirin use (yes, no), and intake of sodium, potassium, magnesium and caffeine (mg/d, in quintiles). Third, we simultaneously adjusted for all antihypertensive medications in a separate model to assess the independent effect associated with each drug class. We also examined whether these independent associations differed by BMI <25, ≥25 kg/m2), physical activity (below median, above median) or family history of breast or ovarian cancer (yes, no). Fourth, to address potential reverse causation that certain preclinical symptoms of ovarian cancer may lead to prescription of antihypertensive medications (e.g., diuretics may be prescribed to treat excess abdominal fluid), we conducted several lagged analyses to evaluate medication use at different time windows (e.g., 2–4 years prior to cancer diagnosis, 4–6 years prior to cancer diagnosis, and baseline) in relation to ovarian cancer. We also examined the associations according to duration of use (<5, ≥5 years). Fifth, since use of multiple antihypertensive drugs has become increasingly common in practice,8 we compared current monotherapy and polytherapy in relation to ovarian cancer risk. Finally, we repeated all analyses restricted to women who reported a diagnosis of hypertension to evaluate potential confounding by indication. Analyses were conducted in SAS 9.3 (SAS Institute Inc., Cary, NC), and all p-values were two-sided.
Results
In 2000, the midpoint of follow-up, 36% of the NHS participants (mean age: 65 yrs) were taking some form of antihypertensive medication. Eighty-nine percent of women who reported current use of antihypertensive medication had a history of hypertension, compared to 75% in past users and 27% in never users. The prevalence of use for each drug class among current users was 38% for beta-blockers, 23% for CCBs, 30% for thiazide diuretics, 29% for ACEIs and 24% for other blood pressure drugs. Compared to never users, current or past medication users tended to be older and have longer duration of estrogen-only PMH use, shorter duration of breastfeeding, greater prevalence of tubal ligation and hysterectomy, higher BMI, lower physical activity, and lower caffeine and higher sodium intake (Table 1). More than half of current antihypertensive users were concurrently using aspirin regularly. In the younger NHSII cohort (mean age: 46 yrs), use of any antihypertensive medication was less common (12%). The covariate distributions by medication use and the antihypertensive drug use patterns were similar to the NHS.
Table 1.
Age-standardized characteristics of the study population at the midpoint of follow-up
| Nurses’ Health Study (2000)
|
Nurses’ Health Study II (2001)
|
|||||
|---|---|---|---|---|---|---|
| Use of any antihypertensive medications | Use of any antihypertensive medications | |||||
| Never | Past | Current | Never | Past | Current | |
| Participants (n) | 33,566 | 6,252 | 22,069 | 83080 | 5348 | 11641 |
| Age, years | 64.8 (6.9) | 67.5 (7.0) | 67.6 (7.3) | 46.0 (4.6) | 48.0 (4.5) | 48.2 (4.4) |
| History of hypertension, % | 27 | 75 | 84 | 11 | 55 | 76 |
| Ever OC use, % | 48 | 50 | 50 | 75 | 74 | 85 |
| Duration of OC use2, months | 50.9 (46.7) | 49.7 (45.7) | 49.9 (45.7) | 67.2 (59.5) | 65.3 (59.0) | 66.2 (58.9) |
| Postmenopausal, % | 98 | 97 | 97 | 14 | 13 | 15 |
| Ever Estrogen PMH use3, % | 18 | 23 | 22 | 4 | 4 | 4 |
| Duration of estrogen-only PMH use2,3, months | 86.1 (76.0) | 92.2 (78.9) | 96.4 (82.2) | 1.9 (1.8) | 3.0 (2.9) | 2.9 (3.1) |
| Ever Estrogen-progestin PMH use3, % | 36 | 36 | 37 | 52 | 56 | 58 |
| Duration of estrogen-progestin PMH use2,3, months | 64.9 (46.4) | 62.7 (45.0) | 65.6 (48.0) | 2.8 (2.3) | 2.7 (2.1) | 2.8 (2.4) |
| History of tubal ligation, % | 20 | 23 | 22 | 21 | 24 | 26 |
| History of hysterectomy, % | 20 | 26 | 25 | 8 | 14 | 13 |
| Family history of breast or ovarian cancer, % | 18 | 17 | 19 | 12 | 11 | 14 |
| Parous, % | 95 | 95 | 95 | 81 | 78 | 79 |
| Number of children in parous women | 3.2 (1.5) | 3.2 (1.5) | 3.2 (1.5) | 2.3 (1.0) | 2.2 (1.0) | 2.2 (0.9) |
| Duration of breastfeeding in parous women | 6.5 (10.4) | 5.9 (9.8) | 5.8 (9.8) | 15.1 (13.8) | 11.9 (11.9) | 12.4 (13.0) |
| Current smokers, % | 11 | 11 | 9 | 8 | 10 | 9 |
| Body mass index, kg/m2 | 25.7 (4.8) | 28.0 (6.0) | 28.2 (5.9) | 26.1 (5.7) | 29.3 (7.4) | 30.7 (7.9) |
| Physical activity, MET-hours/week | 19.0 (18.6) | 16.0 (16.5) | 15.8 (14.8) | 22.2 (24.9) | 20.9 (25.1) | 18.1 (19.2) |
| Current regular aspirin use, % | 33 | 30 | 53 | 8 | 9 | 17 |
| Alcohol use, g/day | 5.4 (8.3) | 5.0 (8.7) | 5.2 (8.8) | 3.5 (5.8) | 3.3 (6.6) | 3.1 (6.1) |
| Caffeine intake, mg/day | 265 (197) | 236 (193) | 234 (178) | 242 (199) | 241 (202) | 228 (191) |
| Potassium intake, mg/day | 2981 (498) | 2978 (529) | 2989 (505) | 3056 (533) | 3027 (574) | 3025 (533) |
| Sodium intake, mg/day | 1954 (396) | 1969 (427) | 1976 (379) | 2105 (340) | 2121 (364) | 2127 (342) |
| Magnesium intake, mg/day | 321 (68) | 318 (69) | 319 (65) | 332 (74) | 326 (76) | 326 (71) |
Mean (SD) for all such values
Duration among ever users
Among postmenopausal women
The associations of hypertension, blood pressure and antihypertensive medication use with risk of ovarian cancer were similar in NHS and NHSII (Pheterogeneity >0.07; Table 2). In pooled analyses of the two cohorts adjusted for reproductive and hormonal factors, we did not observe an increased risk for ovarian cancer for women with versus without a history of hypertension (HR=1.01; 95% CI: 0.88, 1.16) or with longer duration of hypertension (HR for ≥10 yrs versus normotensive=1.11; 95% CI: 0.94, 1.31). Neither SBP (HR for ≥155 versus <115 mmHg=0.91; 95% CI: 0.61, 1.38) nor DBP (HR for ≥95 versus <85 mmHg=1.04; 95% CI: 0.79, 1.37) was significantly associated with ovarian cancer risk. Compared to never use of any antihypertensive medications, a slight increase in risk was noted for current use (HR=1.18, 95% CI: 1.02, 1.37), which appeared to be driven by thiazide diuretics (HR=1.37; 95% CI: 1.13, 1.68). Beta-blockers were not associated with risk (HR=1.19; 95% CI: 0.97, 1.46).
Table 2.
Risk of ovarian cancer according to hypertension, blood pressure and antihypertensive medication use in the Nurses’ Health Study and the Nurses’ Health Study II
| Nurses’ Health Study
|
Nurses’ Health Study II
|
Pooled multivariable HR (95% CI) | |||||
|---|---|---|---|---|---|---|---|
| Case/P-T | Age-adjusted1 | Multivariable2 | Case/P-T | Age-adjusted1 | Multivariable2 | ||
|
|
|||||||
| Hypertension | |||||||
| History of hypertension | |||||||
| No | 323/771,673 | 1.00 (ref) | 1.00 (ref) | 198/1,811,826 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| Yes | 364/708,184 | 1.02 (0.87, 1.19) | 1.01 (0.86, 1.19) | 63/398,653 | 1.04 (0.78, 1.40) | 1.02 (0.76, 1.37) | 1.01 (0.88, 1.16) |
| Duration of hypertension | |||||||
| 0 yr | 323/771,673 | 1.00 (ref) | 1.00 (ref) | 198/1,811,826 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| <5 yrs | 57/145,084 | 0.81 (0.61, 1.08) | 0.81 (0.61, 1.08) | 33/199,503 | 1.14 (0.78, 1.65) | 1.11 (0.76, 1.62) | 0.90 (0.72, 1.13) |
| 5–10 yrs | 62/145,635 | 0.87 (0.66, 1.15) | 0.86 (0.66, 1.14) | 16/88,053 | 1.10 (0.65, 1.85) | 1.09 (0.65, 1.84) | 0.91 (0.71, 1.16) |
| ≥10 yrs | 245/417,466 | 1.14 (0.95, 1.36) | 1.14 (0.96, 1.36) | 14/111,096 | 0.82 (0.47, 1.43) | 0.80 (0.46, 1.38) | 1.11 (0.94, 1.31) |
| Systolic blood pressure3 | |||||||
| <115 mmHg | 114/244,818 | 1.00 (ref) | 1.00 (ref) | 90/961,184 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| 115–134 mmHg | 338/724,807 | 0.85 (0.69, 1.06) | 0.86 (0.69, 1.06) | 122/818,060 | 1.30 (0.98, 1.73) | 1.28 (0.96, 1.69) | 0.99 (0.83, 1.18) |
| 135–154 mmHg | 185/361,011 | 0.84 (0.66, 1.07) | 0.84 (0.66, 1.07) | 16/121,024 | 0.91 (0.53, 1.57) | 0.89 (0.51, 1.53) | 0.92 (0.74, 1.14) |
| ≥155 mmHg | 27/50,426 | 0.79 (0.51, 1.22) | 0.80 (0.52, 1.24) | 2/9,554 | 1.55 (0.38, 6.33) | 1.48 (0.36, 6.06) | 0.91 (0.61, 1.38) |
| Diastolic blood pressure3 | |||||||
| <85 mmHg | 251/482,315 | 1.00 (ref) | 1.00 (ref) | 150/1,329,888 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| 85–94 mmHg | 357/787,153 | 0.85 (0.72, 1.00) | 0.86 (0.73, 1.01) | 72/535,572 | 1.05 (0.79, 1.41) | 1.03 (0.77, 1.38) | 0.90 (0.78, 1.04) |
| ≥95 mmHg | 56/111,593 | 0.97 (0.72, 1.30) | 0.98 (0.73, 1.32) | 8/44,361 | 1.46 (0.71, 2.99) | 1.37 (0.67, 2.82) | 1.04 (0.79, 1.37) |
| Antihypertensive medication use | |||||||
| Never used any drug | 364/903,010 | 1.00 (ref) | 1.00 (ref) | 204/1,886,706 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| Past used any drug | 56/95,137 | 1.20 (0.89, 1.62) | 1.20 (0.89, 1.61) | 10/104,583 | 0.64 (0.33, 1.21) | 0.64 (0.34, 1.21) | 0.93 (0.51, 1.70) |
| Currently using any drug | 267/481,710 | 1.17 (0.99, 1.38) | 1.14 (0.96, 1.35) | 47/219,189 | 1.41 (1.01, 1.97) | 1.37 (0.98, 1.91) | 1.18 (1.02, 1.37) |
| Beta blockers4 | |||||||
| Past users | 44/85,494 | 1.02 (0.73, 1.42) | 1.00 (0.72, 1.39) | 3/33,320 | 0.56 (0.18, 1.77) | 0.58 (0.18, 1.82) | 0.95 (0.69, 1.31) |
| Current users | 110/185,575 | 1.25 (1.00, 1.56) | 1.22 (0.98, 1.53) | 11/77,787 | 0.92 (0.50, 1.71) | 0.88 (0.47, 1.64) | 1.19 (0.97, 1.46) |
| Thiazide diuretics4 | |||||||
| Past users | 69/111,778 | 1.21 (0.92, 1.60) | 1.18 (0.90, 1.56) | 10/65,188 | 0.95 (0.50, 1.82) | 0.94 (0.49, 1.79) | 1.15 (0.90, 1.48) |
| Current users | 112/173,765 | 1.38 (1.11, 1.72) | 1.35 (1.08, 1.68) | 17/77,948 | 1.42 (0.86, 2.36) | 1.37 (0.83, 2.28) | 1.37 (1.13, 1.68) |
P-T: person-time
Stratified by age and calendar time
Age-adjusted model plus adjusted for menopausal status, parity, duration of breastfeeding, duration of oral contraceptive use, duration of postmenopausal hormone use by type, history of tubal ligation, history of hysterectomy, and family history of breast cancer or ovarian cancer
Person-time and number of cases were different from hypertension analysis as blood pressure was asked less frequently than hypertension
For individual classes of antihypertensive drugs, there was another category not shown which included women who had ever used other antihypertensive drugs than the one under study
We evaluated the associations further in NHS. The results for hypertension, blood pressure (data not shown) and use of any antihypertensive medication, thiazide diuretics, and beta-blockers (Table 3) remained essentially unchanged after further accounting for lifestyle factors. When considering additional drug classes, no significant associations were observed with current use of CCBs, ACEIs or other antihypertensive drugs, but there was a positive association for past use of CCBs (HR=1.39; 95% CI: 1.00, 1.92) and other antihypertensive drugs (HR=1.43, 95% CI: 1.10, 1.87; Table 3). These associations appeared stronger when restricted to women with a history of hypertension. Comparable HRs (95% CIs) for current use among women with hypertension were 1.39 (1.01, 1.90) for beta-blockers, 1.55 (1.14, 2.10) for thiazide diuretics and 1.38 (0.97, 1.97) for ACEIs and, for past use, 1.57 (1.04, 2.36) for CCBs and 1.77 (1.25, 2.52) for other hypertensive drugs. However, mutual adjustment for antihypertensive medications substantially attenuated most of the associations. While current use of thiazide diuretics and past use of other antihypertensive drugs still had statistically significant positive associations with ovarian cancer risk, beta-blockers and ACEIs were not associated with risk. Further, there was a suggestively lower risk among current users of CCBs in the overall population (HR=0.73; 95% CI: 0.53, 1.01) and among hypertensive women (HR=0.75; 95% CI: 0.54, 1.06). These associations did not differ significantly by BMI, physical activity or family history (P-interaction≥0.39; data not shown), although the association with current use of thiazide diuretics was suggestively stronger for women with BMI ≥25 kg/m2 (HR=1.70; 95% CI: 1.21, 2.40).
Table 3.
Hypertension, blood pressure and antihypertensive medication use in relation to risk of ovarian cancer in the Nurses’ Health Study
| Overall population
|
Among hypertensive women
|
|||||
|---|---|---|---|---|---|---|
| Case/P-T | Multivariable 11 | Multivariable 22 | Case/P-T | Multivariable 11 | Multivariable 22 | |
| Antihypertensive medication use | ||||||
| Never used any antihypertensive drug | 364/903,010 | 1.00 (ref) | 1.00 (ref) | 83/207,559 | 1.00 (ref) | 1.00 (ref) |
| Past used any antihypertensive drug | 56/95,137 | 1.19 (0.88, 1.61) | – | 38/73,288 | 1.22 (0.80, 1.85) | – |
| Currently using any antihypertensive drug | 267/481,710 | 1.13 (0.95, 1.35) | – | 243/427,338 | 1.30 (0.99, 1.71) | – |
| Beta blockers3 | ||||||
| Past users | 44/85,494 | 0.99 (0.71, 1.38) | 0.84 (0.57, 1.23) | 35/74,002 | 1.04 (0.68, 1.60) | 0.79 (0.48, 1.29) |
| Current users | 110/185627 | 1.22 (0.97, 1.53) | 1.04 (0.79, 1.37) | 96/158,657 | 1.39 (1.01, 1.90) | 1.08 (0.75, 1.57) |
| Calcium channel blockers3 | ||||||
| Past users | 47/64,226 | 1.39 (1.00, 1.92) | 1.19 (0.86, 1.65) | 41/57,649 | 1.57 (1.04, 2.36) | 1.18 (0.83, 1.68) |
| Current users | 48/110,384 | 0.85 (0.62, 1.17) | 0.73 (0.53, 1.01) | 45/99,663 | 0.98 (0.67, 1.45) | 0.75 (0.54, 1.06) |
| Thiazide diuretics3 | ||||||
| Past users | 69/111,778 | 1.18 (0.89, 1.56) | 1.15 (0.85, 1.54) | 60/101,448 | 1.30 (0.90, 1.88) | 1.15 (0.83, 1.59) |
| Current users | 112/173,765 | 1.35 (1.08, 1.69) | 1.35 (1.04, 1.74) | 107/159,179 | 1.55 (1.14, 2.10) | 1.41 (1.07, 1.86) |
| ACE inhibitors3 | ||||||
| Past users | 40/68,069 | 1.16 (0.81, 1.65) | 0.98 (0.68, 1.40) | 39/65,986 | 1.33 (0.87, 2.04) | 1.02 (0.70, 1.49) |
| Current users | 65/109,094 | 1.19 (0.90, 1.58) | 1.01 (0.75, 1.34) | 63/105,670 | 1.38 (0.97, 1.97) | 1.05 (0.78, 1.42) |
| Other hypertensive drugs3 | ||||||
| Past users | 81/107,690 | 1.43 (1.10, 1.87) | 1.37 (1.04, 1.82) | 79/102,381 | 1.77 (1.25, 2.52) | 1.56 (1.15, 2.11) |
| Current users | 71/129,042 | 1.15 (0.87, 1.51) | 1.10 (0.82, 1.47) | 68/121,758 | 1.35 (0.95, 1.93) | 1.20 (0.87, 1.64) |
P-T: person-time
Stratified by age and calendar time in months, and adjusted for menopausal status, parity, duration of breastfeeding, duration of oral contraceptive use, duration of postmenopausal hormone use by type, history of tubal ligation, history of hysterectomy, family history of breast cancer or ovarian cancer, body mass index, physical activity, smoking, alcohol consumption, aspirin use and intake of sodium, potassium, magnesium and caffeine
Multivariable 1 plus mutually adjusted for all other antihypertensive medications
For individual classes of antihypertensive drugs, there was another category not shown which included women who had ever used other antihypertensive drugs than the one under study
Use of any antihypertensive medications and specifically, thiazide diuretics and other antihypertensive medications, were consistently associated with increased risk of ovarian cancer regardless of the timing of their use, such as 2–4 years prior to cancer diagnosis, 4–6 years prior to cancer diagnosis or at baseline (Supplementary Table 1). Use of beta-blockers, calcium channel blockers or ACEIs during any of these time windows were not associated with ovarian cancer. Compared to never use of any antihypertensive medications, longer duration of any antihypertensive medication use (P-trend=0.006), particularly use of thiazide diuretics (P-trend=0.01), ACEIs (P-trend=0.07) and other antihypertensive drugs (P-trend=0.009), was associated with a higher risk of ovarian cancer; these associations appeared stronger among women with hypertension (Supplemental Table 2). After mutually adjusting for duration of use of all antihypertensive medications, only thiazide diuretics (P-trend=0.03) and other antihypertensive drugs (P-trend=0.07) had a positive duration-response association, whereas longer duration of CCB use had a suggestively reduced risk for ovarian cancer (HR for ≥5 years versus never use=0.72; 95% CI: 0.49, 1.04; P-trend=0.11).
Single-drug therapy for hypertension for each individual drug class, including monotherapy of thiazide diuretics, was not significantly associated with ovarian cancer risk in NHS, although the number of cases was small (HR=1.23; 95% CI: 0.88–1.72; Supplementary Table 3). Of note, women who used multiple antihypertensive medications contributed 37% of person-time among current antihypertensive users. Common dual therapies (including >3% of person-time among current users) were combinations involving thiazide diuretics, with HRs (95% CIs) 1.80 (1.12, 2.87) for use with beta-blockers and 1.61 (0.85, 3.08) for use with ACEIs in hypertensive women. Precision of the estimates for other combinations was limited as their use was less common.
In pooled analyses, associations with hypertension, blood pressure or antihypertensive medication use did not differ significantly by histologic subtype (Pheterogeneity≥0.19; data not shown). Although we did not observe significant differences in the association by tumor aggressiveness for hypertension or blood pressure (Pheterogeneity≥0.12), use of any antihypertensive medications had a stronger positive association with rapidly fatal tumors than less aggressive tumors (Pheterogeneity=0.03; for rapidly fatal tumors, HR=1.53; 95% CI: 1.04, 2.25 for past use; HR=1.30; 95% CI: 1.01, 1.66 for current use). Similar patterns were also observed for individual drug classes, but none of the differences reached statistical significance (Pheterogeneity≥0.17).
Conclusion
In this large prospective study, beta-blockers did not appear to be related to a reduced ovarian cancer risk, independent of other medications. Due to the common nature of polytherapy for hypertension, we also evaluated other specific medications and observed that current and long-term use of thiazide diuretics was associated with an increased risk of ovarian cancer, in contrast to a suggestion of an inverse association for CCB use. Our data also suggested that neither history nor duration of hypertension was associated with ovarian cancer risk.
Two previous studies reported similar findings on hypertension, blood pressure and ovarian cancer risk. A consortium of hospital-based case-control studies observed no association between hypertension and ovarian cancer.16 In the Metabolic Syndrome and Cancer project, there was an indication of a reduced ovarian cancer risk with increasing SBP, particularly among women ≥50 yrs (HR for highest versus lowest quintile of SBP=0.63; 95% CI: 0.35, 1.13),17 similar to our results in the older NHS cohort (HR for ≥155 versus <115 mmHg=0.80; 95% CI: 0.52, 1.24). This study also reported a positive association between blood pressure and endometrioid tumors, which was not observed in our subtype analysis. This association requires further clarification, as relatively few endometrioid cases were available in both studies (n<80).
Prescribing patterns of antihypertensive medications in our study, which followed the national trends,8 may be important to explain our results. Specifically, although multivariable analyses without mutual adjustment for other drug classes suggested a positive association for current and long-term use of beta-blockers and ACEIs, the risk estimates were substantially attenuated after accounting for other drugs, likely attributed to their common use in combination with thiazide diuretics.8 Adjusting for other medications also attenuated the positive association for past use of CCBs and resulted in a suggestively inverse association for current use. This attenuation of the association for past use likely reflects changes in prescribing practices over time to use of thiazide diuretics (e.g., 50% of past CCB users later used thiazide diuretics).8 Somewhat unexpectedly, we observed a significant positive association for thiazide diuretics, the most common and affordable antihypertensive medication. Although some early symptoms of ovarian cancer (e.g., retention of peritoneal fluid) may be indications for prescribing thiazide diuretics, such reverse causation is unlikely to entirely explain our results, as we observed the positive associations consistently in both cohorts, for use many years before diagnosis and when considering only women with hypertension.
Although our study provided no evidence of lower ovarian cancer risk for beta-blockers, there may be an independent association for thiazide diuretics and CCBs. The biological mechanisms that may underlie our observations are unclear. The lack of an association between beta-blockers and ovarian cancer may reflect variations in beta-blocker specificity to beta2-adrenergic receptor,13, 24 which has been implicated in stress-mediated signaling pathway for ovarian carcinoma.11, 25 Notably, the most commonly prescribed beta-blockers are beta1-selective,26 and we did not have information regarding the type of beta-blockers. In light of the well-established pharmacological data that thiazide diuretics elevate circulating uric acid levels, while CCBs lower levels,27–30 it is possible that the opposite associations for thiazide diuretics and CCBs may be related to their regulation of uric acid excretion. Although the association between circulating uric acid and ovarian cancer has not been evaluated specifically, there is evidence for increased cancer incidence and mortality with higher serum uric acid.31–34 In addition, previous studies showed strong positive associations between uric acid and inflammatory markers,35, 36 such as C-reactive protein and interleukin-6, and inflammation has been implicated as an important carcinogenic pathway for ovarian cancer.37, 38 Interestingly, ‘other antihypertensive drugs’ displayed consistent duration-response positive associations with a magnitude similar to thiazide diuretics. This category may be largely made up of other types of diuretics, which can also induce hyperuricemia.30 Further, the combined use of thiazide diuretics and beta-blockers, the latter of which are also modestly hyperuricemic,39 was associated with an even greater risk than single use of thiazide diuretics. However, due to reduced statistical power we had limited ability to separately consider monotherapy and polytherapy, thus the possibility of chance findings cannot be excluded. The hypothesis that these medications may act through their effects on uric acid was not supported by the lack of association with hypertension, as renal excretion of uric acid is decreased among hypertensive people.40 Given the distinct pharmacological effects of different antihypertensive medications to lower blood pressure, other mechanisms should be explored. Additional prospective studies are required to confirm our findings and elucidate potential mechanisms.
Despite the major strengths of the study which include its large sample size, long follow-up, and regularly updated information on hypertension diagnosis, use of different classes of hypertensive medications and a variety of known ovarian cancer and hypertension risk factors, several limitations should be noted. First, the generalizability of the results may be limited, as the cohort included predominantly white registered nurses. Second, both hypertension and antihypertensive medications were self-reported, which may introduce non-differential misclassification and lead to biased risk estimates. However, the misclassification was likely small, because self-reported hypertension has previously been validated with excellent reliability in both cohorts, and health professionals were more knowledgeable in the types of medications they were taking thus reducing reporting errors.19, 20 Third, a concern in observational studies of medication use is the potential for confounding by indication. However, this is unlikely to explain the observed associations, as (1) hypertension was not associated with ovarian cancer risk, (2) the associations persisted when restricting to women with a history of hypertension, (3) thiazide diuretics and CCBs, despite the similar indication, had opposite associations with ovarian cancer, and (4) increasing duration of use was associated with stronger associations. Fourth, we did not have information on dose or frequency of drug use or the extent of hypertension severity/antihypertensive control. Also, we were not able to evaluate the associations with specific types of thiazide diuretics (e.g., chlortalidone, hydrochlorothiazide), other types of diuretics (e.g., loop-acting, potassium-sparing) or specific subclasses of beta-blockers (e.g., nonselective, beta1-selective) or CCBs (e.g., short-acting versus long-acting, or dihydropyridine versus non-dihydropyridine), which may provide important clues to the underlying mechanisms. Finally, the analyses of combination therapy and histologic subtype were both based on a small number of cases. Consortial efforts with larger size would be useful to clarify these associations.
In summary, our results do not support the hypothesis that beta-blockers may reduce ovarian cancer risk. While hypertension was not associated with ovarian cancer, there was an increased risk among those using thiazide diuretics. Further research is needed to confirm these associations and establish a potential mechanistic link.
Supplementary Material
What’s new?
In two large prospective US cohorts, we observed that, while hypertension and blood pressure were not associated with ovarian cancer risk, current and long-term use of thiazide diuretics was associated with significantly increased risk. No association was observed for beta-blockers, which were experimentally shown to inhibit ovarian tumor growth. Due to the common use of antihypertensive medications, these findings need to be confirmed in other studies, and may have important implications for ovarian cancer prevention.
Acknowledgments
Sources of financial support: This work was supported by the National Institutes of Health (grant number R01 CA163451, UM1 CA186107, P01 CA87969, UM1 CA176726).
We would like to thank the participants and staff of the Nurses’ Health Study and Nurses’ Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
Dr. Tianyi Huang is the recipient of the Harvey V. Fineberg Fellowship in Cancer Prevention at Harvard T.H. Chan School of Public Health.
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