European Journal of Neurology 2014, 21: 1168–1177
doi:10.1111/ene.12450
Reproductive factors and Parkinson’s disease risk in Danish women N. Greenea, C. F. Lassenb, K. Rugbjergb and B. Ritza a
Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA; and bDepartment of Epidemiology, Danish Cancer Society, Copenhagen, Denmark
Keywords:
case control studies, Parkinson’s disease, reproductive factors Received 26 November 2013 Accepted 17 March 2014
Background and purpose: Parkinson’s disease is more common in men than women by a ratio of about 1.5:1 and yet there is no consensus to date as to whether female reproductive factors including hormone use affect Parkinson’s disease risk. Our objective was to examine the relationship between Parkinson’s disease and female reproductive factors in the largest population-based Parkinson’s disease case control study to date. Methods: Seven hundred and forty-three female Parkinson’s disease cases diagnosed between 1996 and 2009 were selected from the Danish National Hospital Register, diagnoses confirmed by medical record review, and the cases were matched by birth year to 765 female controls randomly selected from the Danish Civil Registration System. Covariate information was collected in computer-assisted telephone interviews covering an extensive array of topics including reproductive and lifestyle factors. Results: After adjusting for smoking, caffeine and alcohol use, education, age, and family Parkinson’s disease history, inverse associations between Parkinson’s disease and early menarche (first period at ≤11 years), oral contraceptives, high parity (≥4 children) and bilateral oophorectomy were found; adjusted odds ratios and 95% confidence limits were respectively 0.68 (0.45–1.03) for early menarche, 0.87 (0.69– 1.10) for oral contraceptives, 0.79 (0.59–1.06) for high parity and 0.65 (0.45–0.94) for bilateral oophorectomy. Little support for associations between Parkinson’s disease and fertile life length, age at menopause or post-menopausal hormone treatment was found. Conclusions: Reproductive factors related to women’s early- to mid-reproductive lives appear to be predictive of subsequent Parkinson’s disease risk whereas factors occurring later in life seem less important.
Introduction Parkinson’s disease (PD) is a neurodegenerative disorder involving multiple systems that affects women less than men in terms of motor and nonmotor features [1,2]. Indeed, most epidemiological studies reported an approximate male to female ratio of 1.5:1 [3], raising the possibility that female hormones such as estrogens may play a protective role and yet, to date, there is no consensus as to whether or how female reproductive factors and hormone use may affect PD risk [4–14]. Some studies suggested that conditions resulting in reduced endogenous Correspondence: N. Greene, Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E. Young Drive, CHS 73-274A, Box 951772, Los Angeles, CA 90095-1772, USA (tel./fax: +310 825 0941; e-mail: [email protected]).
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estrogen levels increase risk whilst treatments with estrogen decrease risk of PD in women [6,7,9]. However, there are also reports to the contrary [8,11,12,14] and some studies found no association between post-menopausal hormone use and PD [5,14]. A recent study of the anti-estrogenic tamoxifen treatment for breast cancer suggested a five-fold increased rate of PD in participants shortly after receiving treatment [15], in contrast to an animal study which suggested that tamoxifen may be neuroprotective [16]. Results for early age at menopause [5,6,8,9,11], age at menarche [8,9,11], parity [5,8, 9,11,14] and type of menopause [4–6,8,9,11,14] have been inconsistent with regard to their influence on women’s PD risk. In view of these inconsistencies and to gain a better understanding of the role of female reproductive © 2014 The Author(s) European Journal of Neurology © 2014 EAN
Reproductive factors and Parkinson’s disease
factors and hormone status in association with PD, and possibly to help identify preventive strategies for vulnerable groups of women, the relationship between women’s reproductive histories and hormone use patterns and PD risk in one of the largest worldwide PD case control studies to date was examined in which only cases with medical-record-confirmed idiopathic PD were included.
Materials and methods Study subjects
This population-based case control study (PASIDA: Parkinson’s Disease in Denmark) was conceived to examine the interplay of occupational, lifestyle and genetic factors as these relate to the risk of idiopathic PD in Denmark. Figure 1 describes the case selection process in detail. In all, 2084 women, aged 35 years or older at diagnosis, with a PD diagnosis between 1996 and 2009 in the Danish National Hospital Register [17] were identified and our invitation to participate was restricted to those female cases from 10 of Denmark’s 15 neurological centers (the catchment area of the remaining five centers overlapped with
the included 10 centers). Inclusion criteria were having documented PD after medical record review, being alive and well enough to participate at the time of the scheduled interview (2008–2010) and speaking English or Danish. Women with research protection were excluded as were those without contact information and those with dementia or a cerebrovascular disease hospital diagnosis within the 3 years preceding the PD diagnosis. Of the 1078 invited to participate, 237 declined. In all, 743 medical-recordconfirmed female PD cases agreed to participate and were interviewed (participation rate 75% of medical-record-confirmed PD cases). Up to 10 potential controls per case were initially selected at random, matched on sex and birth year, from the Danish Central Population Register [18] and alive and free of PD at the time the case was identified in the Danish National Hospital Register. Potential controls were telephoned in random order until one agreed to participate. This resulted in 1651 potential female controls being invited and, of these, 765 agreed to be interviewed (46%). When the medical record review for a case revealed no idiopathic PD, the control already chosen and interviewed was then assigned to a different case with the same birth year. Thus, there
2084 females Aged ≥ 35 at primary dx of PD 1996–2009 in Hospital Register 583 excluded for dx outside of 10 centers 161 excluded as they had died by the time of recruitment 66 excluded for research protection 66 excluded for not being well enough to participate 39 excluded as unable to contact them 0 excluded for not speaking English or Danish 1169 cases 91 excluded for medical records arriving before invitations posted and showing no iPD 237 declined to participate 8 excluded for nomedical records 89 excluded for no iPD after medical record review 1 excluded for CVD before PD diagnosis 743 interviewed, medical record-confirmed iPD cases Figure 1 PASIDA female case selection flowchart.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
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were 743 female cases and 765 female controls with data for analysis. The study protocol was approved by the Danish Data Protection Agency and the UCLA Institutional Review Board. Reproductive history and covariate data
Detailed information on lifetime measures of reproductive factors and lifestyle and behaviors such as caffeine, alcohol consumption, smoking, exercise, as well as education, occupations and a family history of PD (defined as having a first degree relative with PD) was collected in structured telephone interviews. The degree of urbanization for each case and control was determined based on the population density of the home municipality as recorded in the Central Population Register 3 years before the date of the first hospital PD diagnosis of the respective case (this time was chosen because a review of Danish National Hospital Register data and Danish National Prescription Register [19] data showed that on average cases received their first medication 3 years before their hospital diagnosis). Statistical analysis
Descriptive, univariate and trend analyses were performed as well as unconditional logistic regression, adjusting for the matching factor, to examine how reproductive factors relate to PD. Use of conditional logistic regression analyses for matched pairs did not change our results; thus, to utilize all data collected, only results for unconditional models are reported below. Reproductive covariates were constructed to allow for comparison with previous research and to adequately investigate our hypotheses. In addition, guided by the existing PD literature, a model was constructed using directed acyclic graphs [20] to identify potential confounders and adjust for these. For the reproductive factors, age at menarche was treated as a continuous ordinal variable (9–11, 12–13, 14–15, ≥16) and dichotomous (≤11, >11 years) variable; use of high estrogen dose oral contraceptives (the variety available in the 1960s when our female subjects would have been initiating use) was coded as ever versus never as well as never versus 36 years (for comparison with other studies) and also ordinally (
doi:10.1111/ene.12450
Reproductive factors and Parkinson’s disease risk in Danish women N. Greenea, C. F. Lassenb, K. Rugbjergb and B. Ritza a
Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA; and bDepartment of Epidemiology, Danish Cancer Society, Copenhagen, Denmark
Keywords:
case control studies, Parkinson’s disease, reproductive factors Received 26 November 2013 Accepted 17 March 2014
Background and purpose: Parkinson’s disease is more common in men than women by a ratio of about 1.5:1 and yet there is no consensus to date as to whether female reproductive factors including hormone use affect Parkinson’s disease risk. Our objective was to examine the relationship between Parkinson’s disease and female reproductive factors in the largest population-based Parkinson’s disease case control study to date. Methods: Seven hundred and forty-three female Parkinson’s disease cases diagnosed between 1996 and 2009 were selected from the Danish National Hospital Register, diagnoses confirmed by medical record review, and the cases were matched by birth year to 765 female controls randomly selected from the Danish Civil Registration System. Covariate information was collected in computer-assisted telephone interviews covering an extensive array of topics including reproductive and lifestyle factors. Results: After adjusting for smoking, caffeine and alcohol use, education, age, and family Parkinson’s disease history, inverse associations between Parkinson’s disease and early menarche (first period at ≤11 years), oral contraceptives, high parity (≥4 children) and bilateral oophorectomy were found; adjusted odds ratios and 95% confidence limits were respectively 0.68 (0.45–1.03) for early menarche, 0.87 (0.69– 1.10) for oral contraceptives, 0.79 (0.59–1.06) for high parity and 0.65 (0.45–0.94) for bilateral oophorectomy. Little support for associations between Parkinson’s disease and fertile life length, age at menopause or post-menopausal hormone treatment was found. Conclusions: Reproductive factors related to women’s early- to mid-reproductive lives appear to be predictive of subsequent Parkinson’s disease risk whereas factors occurring later in life seem less important.
Introduction Parkinson’s disease (PD) is a neurodegenerative disorder involving multiple systems that affects women less than men in terms of motor and nonmotor features [1,2]. Indeed, most epidemiological studies reported an approximate male to female ratio of 1.5:1 [3], raising the possibility that female hormones such as estrogens may play a protective role and yet, to date, there is no consensus as to whether or how female reproductive factors and hormone use may affect PD risk [4–14]. Some studies suggested that conditions resulting in reduced endogenous Correspondence: N. Greene, Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E. Young Drive, CHS 73-274A, Box 951772, Los Angeles, CA 90095-1772, USA (tel./fax: +310 825 0941; e-mail: [email protected]).
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estrogen levels increase risk whilst treatments with estrogen decrease risk of PD in women [6,7,9]. However, there are also reports to the contrary [8,11,12,14] and some studies found no association between post-menopausal hormone use and PD [5,14]. A recent study of the anti-estrogenic tamoxifen treatment for breast cancer suggested a five-fold increased rate of PD in participants shortly after receiving treatment [15], in contrast to an animal study which suggested that tamoxifen may be neuroprotective [16]. Results for early age at menopause [5,6,8,9,11], age at menarche [8,9,11], parity [5,8, 9,11,14] and type of menopause [4–6,8,9,11,14] have been inconsistent with regard to their influence on women’s PD risk. In view of these inconsistencies and to gain a better understanding of the role of female reproductive © 2014 The Author(s) European Journal of Neurology © 2014 EAN
Reproductive factors and Parkinson’s disease
factors and hormone status in association with PD, and possibly to help identify preventive strategies for vulnerable groups of women, the relationship between women’s reproductive histories and hormone use patterns and PD risk in one of the largest worldwide PD case control studies to date was examined in which only cases with medical-record-confirmed idiopathic PD were included.
Materials and methods Study subjects
This population-based case control study (PASIDA: Parkinson’s Disease in Denmark) was conceived to examine the interplay of occupational, lifestyle and genetic factors as these relate to the risk of idiopathic PD in Denmark. Figure 1 describes the case selection process in detail. In all, 2084 women, aged 35 years or older at diagnosis, with a PD diagnosis between 1996 and 2009 in the Danish National Hospital Register [17] were identified and our invitation to participate was restricted to those female cases from 10 of Denmark’s 15 neurological centers (the catchment area of the remaining five centers overlapped with
the included 10 centers). Inclusion criteria were having documented PD after medical record review, being alive and well enough to participate at the time of the scheduled interview (2008–2010) and speaking English or Danish. Women with research protection were excluded as were those without contact information and those with dementia or a cerebrovascular disease hospital diagnosis within the 3 years preceding the PD diagnosis. Of the 1078 invited to participate, 237 declined. In all, 743 medical-recordconfirmed female PD cases agreed to participate and were interviewed (participation rate 75% of medical-record-confirmed PD cases). Up to 10 potential controls per case were initially selected at random, matched on sex and birth year, from the Danish Central Population Register [18] and alive and free of PD at the time the case was identified in the Danish National Hospital Register. Potential controls were telephoned in random order until one agreed to participate. This resulted in 1651 potential female controls being invited and, of these, 765 agreed to be interviewed (46%). When the medical record review for a case revealed no idiopathic PD, the control already chosen and interviewed was then assigned to a different case with the same birth year. Thus, there
2084 females Aged ≥ 35 at primary dx of PD 1996–2009 in Hospital Register 583 excluded for dx outside of 10 centers 161 excluded as they had died by the time of recruitment 66 excluded for research protection 66 excluded for not being well enough to participate 39 excluded as unable to contact them 0 excluded for not speaking English or Danish 1169 cases 91 excluded for medical records arriving before invitations posted and showing no iPD 237 declined to participate 8 excluded for nomedical records 89 excluded for no iPD after medical record review 1 excluded for CVD before PD diagnosis 743 interviewed, medical record-confirmed iPD cases Figure 1 PASIDA female case selection flowchart.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
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were 743 female cases and 765 female controls with data for analysis. The study protocol was approved by the Danish Data Protection Agency and the UCLA Institutional Review Board. Reproductive history and covariate data
Detailed information on lifetime measures of reproductive factors and lifestyle and behaviors such as caffeine, alcohol consumption, smoking, exercise, as well as education, occupations and a family history of PD (defined as having a first degree relative with PD) was collected in structured telephone interviews. The degree of urbanization for each case and control was determined based on the population density of the home municipality as recorded in the Central Population Register 3 years before the date of the first hospital PD diagnosis of the respective case (this time was chosen because a review of Danish National Hospital Register data and Danish National Prescription Register [19] data showed that on average cases received their first medication 3 years before their hospital diagnosis). Statistical analysis
Descriptive, univariate and trend analyses were performed as well as unconditional logistic regression, adjusting for the matching factor, to examine how reproductive factors relate to PD. Use of conditional logistic regression analyses for matched pairs did not change our results; thus, to utilize all data collected, only results for unconditional models are reported below. Reproductive covariates were constructed to allow for comparison with previous research and to adequately investigate our hypotheses. In addition, guided by the existing PD literature, a model was constructed using directed acyclic graphs [20] to identify potential confounders and adjust for these. For the reproductive factors, age at menarche was treated as a continuous ordinal variable (9–11, 12–13, 14–15, ≥16) and dichotomous (≤11, >11 years) variable; use of high estrogen dose oral contraceptives (the variety available in the 1960s when our female subjects would have been initiating use) was coded as ever versus never as well as never versus 36 years (for comparison with other studies) and also ordinally (
