Introduction Menopause which is defined as a permanent physiological, or natural, cessation of menstrual cycle, plays an important role in the development of ocular surface dryness symptoms and there is an increased prevalence of dry eye in women, especially those aged over 50. Despite the high prevalence of dry eye in post-menopausal women (PMW), very few studies have been undertaken to understand dry eye disease in a group of PMW who are not on Hormone Replacement Therapy (HRT). Studies in the past on PMW have primarily focused on the relationship between HRT and dry eye. Hence, a series of studies were undertaken to understand the clinical aspects of dry eye and their relationship to a variety of tear film components, in a group of PMW with and without symptoms of dry eye. The specific aims of each chapter were as follows: • Chapter 4: To characterize symptoms of dry eye using questionnaires, namely Ocular Surface Disease Index Questionnaire© (OSDI) and the Indiana Dry Eye Questionnaire (DEQ). • Chapter 5: To characterize clinical signs and symptoms in participants who present with and without symptoms of dry eye. • Chapter 6: To compare tear osmolality and ferning patterns in participants with and without dry eye symptoms. • Chapter 7: To investigate the potential relationship between subjective symptoms and clinical signs with tear film lipocalin and lysozyme concentrations in participants with and without dry eye symptoms. • Chapter 8: To optimize a technique for the isolation of total RNA (ribo nucleic acid) and total protein derived from conjunctival epithelial cells collected via conjunctival impression cytology (CIC). • Chapter 9: To quantify the expression of MUC1 (mucin1) and MUC16 (mucin16) mRNA and protein and to investigate the potential relationship between mucin expression and tear film breakup time in a group of participants with and without dry eye symptoms. Methods • Chapter 4: Participants were categorized as being symptomatic or asymptomatic of dry eye based on their response to the OSDI questionnaire. These results were then compared to the DEQ, which has questions related to the frequency of ocular surface symptoms and their diurnal intensity. • Chapter 5: Non invasive tear breakup time (NITBUT) was evaluated using the ALCON Eyemap®. Tear volume was assessed using the Phenol Red Thread (PRT) test and bulbar conjunctival hyperemia was measured using objective (SpectraScan PR650© Spectrophotometer) and subjective (slit lamp) methods. • Chapter 6: Tears were collected via capillary tube. A freezing point depression osmometer was used to measure the osmolality of the tear film. The tear ferning test was performed and evaluated for the quality of ferning, based on the Rolando grading system. • Chapter 7: Tears were collected via capillary tube and an eye wash method. Tear lysozyme and lipocalin concentrations were determined via Western blotting. • Chapter 8: CIC was collected using either Millipore (MP) or Poly Ether Sulfone (PES) membranes. RNA and protein isolation was performed using two different RNA isolation techniques. Two methods of protein isolation from CIC discs were evaluated. RT-PCR of mRNA for MUC1 and western blotting of lipoxygenase type 2 protein (LOX2) was performed to confirm the collection of intact RNA and total protein respectively. • Chapter 9: Tears were collected via capillary tube and an eye wash method. CIC was collected using MP membrane. Expression of MUC1 and MUC16 mRNA was assessed via real time PCR. Expression of both membrane-bound and soluble MUC1 and MUC16 were quantified via Western blotting. Results • Chapter 4: The OSDI total score and sub scores for the Non Dry Eye (NDE) and Dry Eye (DE) groups were significantly different (NDE =7.43 ± 7.71 vs DE = 24.87 ± 13.89; p<0.001). The DEQ scores showed that the DE group exhibited a higher frequency and intensity of symptoms than the NDE group, which worsened as the day progressed (p<0.001). • Chapter 5: The DE group exhibited a significantly shorter NITBUT (5.3 ± 1.7 vs 7.0 ± 2.7 secs; p=0.0012). Tear volume was significantly lower for the DE group (19.3 ± 5.1mm vs. 16.3 ± 5.6mm; p=0.031). Bulbar hyperemia was significantly higher in the DE group for both objective (u’ = 0.285 ± 0.006 vs. 0.282 ± 0.006; p=0.005) and subjective techniques (48.4 ± 10.0 vs 40.6 ± 10.4; p=0.0011). • Chapter 6: Osmolality values in DE individuals were significantly higher than the NDE (328.1 ± 20.8 vs. 315.1 ± 11.3 mOsm/kg; p = 0.02). There was a significant difference between the DE and NDE participants for the ferning patterns (p = 0.019). No significant correlation between tear osmolality and tear ferning was noted (DE: r = 0.12; p > 0.05, NDE: r = -0.17; p > 0.05). • Chapter 7: No difference in tear lysozyme or lipocalin concentration was found between DE and NDE groups, irrespective of tear collection method. Method of collection significantly influenced absolute concentrations (p<0.008). • Chapter 8: There was no significant difference between the two procedures used to isolate RNA and protein from CIC membranes (p>0.05). Total RNA yield was greater with the MP membrane. The mean yield of protein extracted from MP membrane using the two protein isolation techniques also did not show a significant difference. • Chapter 9: No difference was found in the expression of either MUC1 or MUC16 protein or mRNA expression between symptomatic DE and NDE (p>0.05). Weak correlations were found between the NITBUT values compared with either soluble or membrane bound MUC1 and MUC16 expression. Conclusions • Chapter 4: Questionnaires are useful tools to symptomatically divide participants into dry eyed and non dry eyed candidates. However, the questionnaire used to categorise patients can impact on the outcome variables determined. • Chapter 5: Post-menopausal women with dry eye symptoms demonstrate shorter NITBUT, lower tear volume and increased bulbar conjunctival hyperemia than those who have no symptoms. • Chapter 6: Tear osmolality in DE is higher than in NDE. There is a tendency towards less ferning in persons over 50 years of age, regardless of their symptoms. • Chapter 7: Comparison of clinical data with lipocalin and lysozyme concentrations failed to reveal statistically significant correlations. The concentration of either protein was not associated with tear stability or secretion. • Chapter 8: The total RNA yield was greater with the MP membrane. RNeasy Mini (RN) (Qiagen) method is recommended due to enhanced speed as well as on-column isolation and DNase digestion capabilities. CIC with MP membranes followed by immediate freezing and then extraction and processing facilitates the collection of total protein from human conjunctival cells. • Chapter 9: No difference was found in the expression of either MUC1 or MUC16 protein or mRNA expression between symptomatic PMW and asymptomatic controls.

Introduction Menopause which is defined as a permanent physiological, or natural, cessation of menstrual cycle, plays an important role in the development of ocular surface dryness symptoms and there is an increased prevalence of dry eye in women, especially those aged over 50. Despite the high prevalence of dry eye in post-menopausal women (PMW), very few studies have been undertaken to understand dry eye disease in a group of PMW who are not on Hormone Replacement Therapy (HRT). Studies in the past on PMW have primarily focused on the relationship between HRT and dry eye. Hence, a series of studies were undertaken to understand the clinical aspects of dry eye and their relationship to a variety of tear film components, in a group of PMW with and without symptoms of dry eye. The specific aims of each chapter were as follows: • Chapter 4: To characterize symptoms of dry eye using questionnaires, namely Ocular Surface Disease Index Questionnaire© (OSDI) and the Indiana Dry Eye Questionnaire (DEQ). • Chapter 5: To characterize clinical signs and symptoms in participants who present with and without symptoms of dry eye. • Chapter 6: To compare tear osmolality and ferning patterns in participants with and without dry eye symptoms. • Chapter 7: To investigate the potential relationship between subjective symptoms and clinical signs with tear film lipocalin and lysozyme concentrations in participants with and without dry eye symptoms. • Chapter 8: To optimize a technique for the isolation of total RNA (ribo nucleic acid) and total protein derived from conjunctival epithelial cells collected via conjunctival impression cytology (CIC). • Chapter 9: To quantify the expression of MUC1 (mucin1) and MUC16 (mucin16) mRNA and protein and to investigate the potential relationship between mucin expression and tear film breakup time in a group of participants with and without dry eye symptoms. Methods • Chapter 4: Participants were categorized as being symptomatic or asymptomatic of dry eye based on their response to the OSDI questionnaire. These results were then compared to the DEQ, which has questions related to the frequency of ocular surface symptoms and their diurnal intensity. • Chapter 5: Non invasive tear breakup time (NITBUT) was evaluated using the ALCON Eyemap®. Tear volume was assessed using the Phenol Red Thread (PRT) test and bulbar conjunctival hyperemia was measured using objective (SpectraScan PR650© Spectrophotometer) and subjective (slit lamp) methods. • Chapter 6: Tears were collected via capillary tube. A freezing point depression osmometer was used to measure the osmolality of the tear film. The tear ferning test was performed and evaluated for the quality of ferning, based on the Rolando grading system. • Chapter 7: Tears were collected via capillary tube and an eye wash method. Tear lysozyme and lipocalin concentrations were determined via Western blotting. • Chapter 8: CIC was collected using either Millipore (MP) or Poly Ether Sulfone (PES) membranes. RNA and protein isolation was performed using two different RNA isolation techniques. Two methods of protein isolation from CIC discs were evaluated. RT-PCR of mRNA for MUC1 and western blotting of lipoxygenase type 2 protein (LOX2) was performed to confirm the collection of intact RNA and total protein respectively. • Chapter 9: Tears were collected via capillary tube and an eye wash method. CIC was collected using MP membrane. Expression of MUC1 and MUC16 mRNA was assessed via real time PCR. Expression of both membrane-bound and soluble MUC1 and MUC16 were quantified via Western blotting. Results • Chapter 4: The OSDI total score and sub scores for the Non Dry Eye (NDE) and Dry Eye (DE) groups were significantly different (NDE =7.43 ± 7.71 vs DE = 24.87 ± 13.89; p<0.001). The DEQ scores showed that the DE group exhibited a higher frequency and intensity of symptoms than the NDE group, which worsened as the day progressed (p<0.001). • Chapter 5: The DE group exhibited a significantly shorter NITBUT (5.3 ± 1.7 vs 7.0 ± 2.7 secs; p=0.0012). Tear volume was significantly lower for the DE group (19.3 ± 5.1mm vs. 16.3 ± 5.6mm; p=0.031). Bulbar hyperemia was significantly higher in the DE group for both objective (u’ = 0.285 ± 0.006 vs. 0.282 ± 0.006; p=0.005) and subjective techniques (48.4 ± 10.0 vs 40.6 ± 10.4; p=0.0011). • Chapter 6: Osmolality values in DE individuals were significantly higher than the NDE (328.1 ± 20.8 vs. 315.1 ± 11.3 mOsm/kg; p = 0.02). There was a significant difference between the DE and NDE participants for the ferning patterns (p = 0.019). No significant correlation between tear osmolality and tear ferning was noted (DE: r = 0.12; p > 0.05, NDE: r = -0.17; p > 0.05). • Chapter 7: No difference in tear lysozyme or lipocalin concentration was found between DE and NDE groups, irrespective of tear collection method. Method of collection significantly influenced absolute concentrations (p<0.008). • Chapter 8: There was no significant difference between the two procedures used to isolate RNA and protein from CIC membranes (p>0.05). Total RNA yield was greater with the MP membrane. The mean yield of protein extracted from MP membrane using the two protein isolation techniques also did not show a significant difference. • Chapter 9: No difference was found in the expression of either MUC1 or MUC16 protein or mRNA expression between symptomatic DE and NDE (p>0.05). Weak correlations were found between the NITBUT values compared with either soluble or membrane bound MUC1 and MUC16 expression. Conclusions • Chapter 4: Questionnaires are useful tools to symptomatically divide participants into dry eyed and non dry eyed candidates. However, the questionnaire used to categorise patients can impact on the outcome variables determined. • Chapter 5: Post-menopausal women with dry eye symptoms demonstrate shorter NITBUT, lower tear volume and increased bulbar conjunctival hyperemia than those who have no symptoms. • Chapter 6: Tear osmolality in DE is higher than in NDE. There is a tendency towards less ferning in persons over 50 years of age, regardless of their symptoms. • Chapter 7: Comparison of clinical data with lipocalin and lysozyme concentrations failed to reveal statistically significant correlations. The concentration of either protein was not associated with tear stability or secretion. • Chapter 8: The total RNA yield was greater with the MP membrane. RNeasy Mini (RN) (Qiagen) method is recommended due to enhanced speed as well as on-column isolation and DNase digestion capabilities. CIC with MP membranes followed by immediate freezing and then extraction and processing facilitates the collection of total protein from human conjunctival cells. • Chapter 9: No difference was found in the expression of either MUC1 or MUC16 protein or mRNA expression between symptomatic PMW and asymptomatic controls.

Endometrial cancer is the most common female reproductive cancer in the United States. Most known risk factors for endometrial cancer are either genetic or related to exposure to estrogens; less is known about risk due to environmental exposures. While several studies have examined the relationship between perineal powder use and ovarian cancer risk, only one study has addressed the relationship with endometrial cancer risk. The Women's Health Initiative Observational Study, a prospective cohort study of 93,676 United States postmenopausal women from 1993-2005, measured perineal powder use at baseline via self-report. Cases of endometrial cancer were self-reported and confirmed by both local and central physician adjudicators. Cox proportional hazards regression was used to examine the association between perineal powder use and endometrial cancer, adjusting for known risk factors. Of the 48,912 women in our analysis, 25,181 (52%) reported ever use of perineal powders. There were 452 incident cases of endometrial cancer diagnosed during 366,872 person-years of follow-up. Ever use of perineal powder was not significantly associated with increased risk of endometrial cancer (hazard ratio 1.05, 95% confidence interval 0.87-1.27). However, use of any perineal powder for 20 or more years was associated with a 30% increase in risk (hazard ratio 1.30, 95% CI 1.01-1.67) compared to never users. Use of powder on both a diaphragm and the perineal area was associated with a 39% increase in risk (hazard ratio 1.39, 95% CI 1.00-1.93). Cessation of perineal powder use, particularly on a diaphragm, may help reduce risk of endometrial cancer.

Striking differences exist between countries in the incidence of breast cancer, with rates higher in the West than in Asian countries. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The objective of this thesis was to compare established breast cancer risk factors, physical activity, and diet in three groups of postmenopausal women at substantially different risks of developing breast cancer – Caucasians (N = 413), Chinese born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants, 99% of whom coming from urban China (N = 421). In this cross-sectional study, information on risk factors and diet were collected by telephone, and physical activity and anthropometric data were obtained at a home visit. Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, and less often had a family history of breast cancer or a benign breast biopsy. Estimating 5-year absolute breast cancer risks using the Gail Model showed that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the variables in the Gail Model. Compared to Caucasians, recent Chinese migrants had lower average total physical activity over lifetime, and also spent less time on moderate- and vigorous-intensity activity. Compared to Caucasians, recent Chinese migrants consumed per day on average 175 fewer calories, 6 more grams of energy-adjusted protein, 16 more grams of energy-adjusted carbohydrates, and 5 fewer grams of energy-adjusted fat. Also, recent Chinese migrants consumed higher amounts of grains, fruits, vegetables, fish, and soy products, and lower amounts of alcohol, meat, dairy products, and sweets than Caucasians. Western born Chinese and early Chinese migrants had values intermediate between the other two groups for most of the variables. These results suggest that in addition to the established risk factors, some dietary factors may also contribute to the lower breast cancer risk in urban Chinese women.

Striking differences exist between countries in the incidence of breast cancer, with rates higher in the West than in Asian countries. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The objective of this thesis was to compare established breast cancer risk factors, physical activity, and diet in three groups of postmenopausal women at substantially different risks of developing breast cancer – Caucasians (N = 413), Chinese born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants, 99% of whom coming from urban China (N = 421). In this cross-sectional study, information on risk factors and diet were collected by telephone, and physical activity and anthropometric data were obtained at a home visit. Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, and less often had a family history of breast cancer or a benign breast biopsy. Estimating 5-year absolute breast cancer risks using the Gail Model showed that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the variables in the Gail Model. Compared to Caucasians, recent Chinese migrants had lower average total physical activity over lifetime, and also spent less time on moderate- and vigorous-intensity activity. Compared to Caucasians, recent Chinese migrants consumed per day on average 175 fewer calories, 6 more grams of energy-adjusted protein, 16 more grams of energy-adjusted carbohydrates, and 5 fewer grams of energy-adjusted fat. Also, recent Chinese migrants consumed higher amounts of grains, fruits, vegetables, fish, and soy products, and lower amounts of alcohol, meat, dairy products, and sweets than Caucasians. Western born Chinese and early Chinese migrants had values intermediate between the other two groups for most of the variables. These results suggest that in addition to the established risk factors, some dietary factors may also contribute to the lower breast cancer risk in urban Chinese women.

Type 2 diabetes (T2D) is increasing in the United States, currently affecting 11.3% of the nation. The Developmental Origins of Health and Disease Hypothesis suggests that environmental stresses in utero and in early stages of life, such as preterm birth (age), can lead to development of adulthood diseases, including T2D. However, research on the association between preterm birth and T2D is sparse and predominantly based on European ancestry populations. We examined this association in postmenopausal women (N = 85,356) from the Women’s Health Initiative, a nationwide prospective cohort. Logistic regression models were used to examine the association between self-reported preterm birth and T2D status, adjusting for demographic and lifestyle covariates. Preterm birth was significantly and positively associated with odds of T2D at baseline (unadjusted: OR=1.51, 95% CI 1.24, 1.83; P

Recent studies have shown that postmenopausal follicle stimulating hormone (FSH) levels may be predictive of future cardiovascular disease risk. However, little is known about postmenopausal FSH levels, including the level of variation between women and factors associated with this variation. We assessed the relationship of multiple reproductive factors with FSH levels among 588 postmenopausal women in the Kuopio Ischemic Heart Disease Risk Factor Study. Participants were aged 53 to 73 years and not using hormone therapy at baseline (1998-2001). Reproductive factors were assessed at baseline, along with FSH levels. After adjustment for sex steroids, adiposity measures, plasma lipids, blood pressure, and behavioral factors, we observed that women with 3 or more births and an age at first birth of 25 or later had mean FSH levels that were significantly 7.6 IU/L lower than those of women with a 1 to 2 births and an age at first birth of 24 or less. Number of miscarriages was inversely correlated with FSH levels. Women reporting a 7 or more years of OC use and 4-6 or 7 or more years of HT use each had significantly higher mean FSH levels than women who had never used OCs or HT. In summary, multiple reproductive factors were associated with postmenopausal FSH levels, independent of estradiol, adiposity, and other factors. These findings warrant replication and further exploration of potential underlying mechanism.

La relative immunité des femmes vis-à-vis du risque cardiovasculaire a longtemps été attribuée aux hormones sexuelles. Néanmoins, le rôle protecteur des estrogènes dans le développement de l’athérosclérose et de ses complications a été récemment remis en cause chez les femmes ménopausées. A partir de la cohorte française des Trois Cités incluant environ 10.000 sujets de plus de 65 ans, j’ai évalué l’association entre les estrogènes endogènes et le risque de maladies cardiovasculaires chez des femmes n’utilisant pas de traitement hormonal. J’ai montré pour la première fois que des taux élevés d’estradiol plasmatique étaient associés à une augmentation du risque artériel ischémique à 4 ans, indépendamment des facteurs de risque cardiovasculaire traditionnels, notamment l’obésité ou le diabète. Dans une deuxième partie, j’ai étudié le rôle modulateur des polymorphismes génétiques des récepteurs des estrogènes α (ESR1) et β (ESR2). J’ai montré que le risque cardiovasculaire augmentait avec les taux élevés d’estradiol chez les femmes porteuses du génotype rs9340799-AA mais pas chez celles avec le génotype rs9340799-AG/GG. Des analyses complémentaires m’ont également permis de suggérer que l’effet des estrogènes était lié en partie à une hypercoagulabilité et un état inflammatoire. Dans une dernière étape, j’ai évalué le rôle prédicteur à long terme des estrogènes endogènes. J’ai confirmé la relation indépendante entre les taux élevés d’estrogènes et la survenue d’un évènement cardiovasculaire après 10 ans de suivi. Globalement, ces résultats suggèrent un effet délétère des estrogènes dans le développement des maladies artérielles ischémiques chez les femmes ménopausées après 65 ans . Si ces résultats étaient confirmés, une meilleure stratification du risque artériel pourrait être proposée chez les femmes ménopausées avec des implications potentielles dans la prévention des maladies cardiovasculaires. / The low incidence of coronary heart disease among women has often been attributed to sex hormones. However, adverse effects of estrogens on arterial disease have been recently reported in older postmenopausal women. In the French Three-City prospective cohort study of subjects over 65 years of age, I investigated the association of endogenous estradiol with cardiovascular risk among postmenopausal women who did not use any hormone therapy. In a first part, I showed that high levels of plasma estradiol were related to the 4-year incidence of ischemic arterial disease (IAD), independently of traditional cardiovascular risk factors such as obesity or diabetes. Then, I reported that the relation between estrogens and IAD risk could be modulated by estrogen receptor-α (ESR1) polymorphisms. Indeed, endogenous estrogens were positively associated with IAD risk in women carrying the ESR1 rs9340799-AA genotype but not in those carrying the ESR1 rs9340799-AG/GG genotype. Further analyses revealed that both hypercoagulability and inflammatory state might act as mediators. Finally, I assessed the long-term predictor role of endogenous estrogens in arterial disease. I showed a positive and independent association of estrogens levels with the 10-year incidence of cardiovascular disease. Overall, high plasma levels of endogenous estradiol emerge as a new significant predictor of cardiovascular disease in older postmenopausal women. If confirmed, these findings could have the potential to improve the stratification of IAD risk in postmenopausal women.

Introduction: About 80% of those affected by osteoporosis are postmenopausal women. Therefore, identifying beneficial or harmful dietary factors for postmenopausal osteoporosis may have a significant public health impact. Objectives: The overall objective of this thesis was to examine the relations between various dietary factors and bone health in postmenopausal women aged ≥ 45 years using different analytical approaches. Methods: First, the associations between fruit and vegetables (F&V) intake and indicators of bone health were assessed using a systematic review approach. Electronic databases were searched and peer-reviewed observational and interventional studies published in English with F&V intake as a main dietary exposure were included. Data selection, extraction and evaluation of risk of bias were performed independently by two reviewers. Second, the associations between an overall diet quality index (HEI-2005) and its components with bone turnover markers (BTMs) were examined. Third, the relationships between alpha-tocopherol intake, serum alpha- and gamma-tocopherol, two concentration biomarkers of vitamin E intake, and their ratio and BTMs were assessed. For the second and third studies, cross-sectional data from the National Health and Nutrition Examination Survey 1999-2002 were used. Weighted multiple regression models with adjustments for relevant confounders were used to examine the relationship between exposures and serum bone-specific alkaline phosphatase (BAP), a biomarker of bone formation, and urinary N-Telopeptides/Creatinine (uNTx/Cr), a biomarker of bone resorption. Results: There was significant between-study heterogeneity in design, definition and amount of F&V intake, outcomes, analyses and reporting of results in the eight included studies. Overall, cross-sectional and case-control analyses reported protective associations between F&V intake and bone health, whereas interventional and prospective cohort analyses did not. There were no associations between total HEI-2005 scores and BTMs. However, the Milk Group component of HEI-2005 had a significant inverse relationship with uNTx/Cr. Higher serum gamma-tocopherol and lower ratio of serum alpha- to gamma-tocopherol were associated with higher BAP concentrations but had no associations with NTx/Cr concentrations. Conclusions: The results confirm the existing knowledge that a diet with adequate intake of dairy may reduce bone loss. Further research is needed to examine the potential anabolic effects of gamma-tocopherol on bone in postmenopausal women.

Hormone replacement therapy (HRT) has been studied as a protective factor for cognitive decline and dementia. However, study findings have been inconsistent. Variation in study findings may be due to differences in study designs, small sample size, exposure ascertainment, diagnostic procedures, and inclusion of relevant risk and confounding factors. Moreover, there may be significant differences between the characteristics of women choosing to use HRT and those opting not to use the therapy. Using a large-scale, population-based, cohort study, we examined the relationship between HRT and cognition while paying particular attention to moderating and confounding factors. The main outcomes of interest were to assess differences in risk for cognitive impairments and dementia between HRT user and never user groups; examine HRTs impact on age of onset of dementia; and explore the relationship between duration of HRT and cognitive decline. Logistic regression and Cox Proportional Hazards models were used to test HRT as a predictor for cognitive impairments, Alzheimers disease and vascular dementia, as well as to assess the effect of duration. Linear regression was used to consider the putative relationship between age at onset of dementia and HRT status. HRT use was found to be a statistically significant predictor for Alzheimers disease and vascular dementia. Overall, HRT use did not significantly predict for milder cognitive impairments, although significant interaction effects indicate that HRT may be protective at least for specific sub-groups of women. No durational effect was found for any of the outcomes. Neither did HRT appear to predict for age at onset of dementia. Notably, a large proportion of women in the current study reported using estrogen-only hormone supplements, and therefore generalizations regarding the findings are likely limited to estrogen-only preparations, not combination estrogen-progestin therapies. These findings must be considered within the context of the other known and potential risks and benefits that HRT may afford.