Both obesity and type 2 diabetes are significant health burdens in our society. The prevention of these conditions is vital to individual health and to the health care system, which is inordinately stressed by these chronic diseases. Due to variations in individual response to interventions, prevention strategies may require some tailoring based on heritable traits.The objective of this study was to determine whether insulin sensitivity could be altered by resistance training, and further if body composition or insulin sensitivity response to resistance training in postmenopausal women may be influenced by adrenergic receptor genetic variants and gene-gene interactions.Completers of a 12-month randomized controlled trial of resistance training in sedentary post-menopausal (PM) women, using or not using hormone therapy, were measured for fasting plasma glucose, insulin, and non-esterified fatty acids (NEFA) at baseline and one year. These biomarkers were used to compute models of insulin sensitivity. Body composition was measured by dual x-ray absorptiometry. Subjects were also re-consented for genotyping of adrenergic receptor (ADR) gene variants, ADRA2B Glu9/12, ADRB3 Trp64Arg, ADRB2 Gln27Glu.The resistance training intervention did not have an overall effect on insulin sensitivity in the largest sample and change in insulin sensitivity was largely dependent body composition. There were small favorable effects of genotype on initial measures of both body composition and insulin sensitivity in the ADRA2B Glu9+ carriers versus non-carriers. The effects of ADRA2B alone were no longer present following intervention, but ADRB3 Arg64+ and ADRB2 Glu27+ contribute to improved insulin sensitivity with exercise, when accounting for body composition. ADRB2 Glu27+ was the key to improved biomarkers of insulin sensitivity when in combination with ADRA2B Glu9+ or ADRB3 Arg64+ and a model of insulin sensitivity was most improved by the combination ADRB3 Arg64+ by ADRB2 Glu27+, compared to other ADRB3 by ADRB2 combinations.This is the first trial of ADRA2B, ADRB3, and ADRB2 genetic variation combinations and resistance training in postmenopausal women relative to body composition and insulin sensitivity. Some specific genotypes were identified as responders and non-responders to exercise. These data support independent associations between body composition and insulin sensitivity and the ADR gene variants.

Whole-body vibration (WBV) was recently introduced as a potential modality for strengthening bones, and this thesis was set out to investigate whether it plays a role in the prevention of postmenopausal bone loss. First, effects of WBV on bone mineral density (BMD) were systematically evaluated in previous randomized controlled trials (RCTs) in postmenopausal women. Second, a RCT of 202 postmenopausal women with primary osteopenia not on bone medications was conducted to investigate the effects of WBV at 0.3g and 90 Hz versus 0.3g and 30 Hz versus controls on various bone outcomes, as measured by dual-energy x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and quantitative ultrasound (QUS). In the systematic evaluation of previous RCTs, statistically significant increase in areal BMD (aBMD) at the hip was found in postmenopausal women receiving WBV versus controls, but the effect was small and may have been due to study bias. Also, WBV was not found to influence aBMD at the lumbar spine or volumetric BMD (vBMD) at the distal tibia in the systematic evaluation. In the RCT conducted in this thesis, no statistically significant effects of WBV were found on aBMD at the femoral neck, total hip or lumbar spine, as measured by DXA, or on vBMD or bone structure parameters at the distal tibia or distal radius, as measured by HR-pQCT. Further in this RCT, a statistically significant decrease was observed in QUS attenuation at the calcaneus in women receiving 90 Hz or 30 Hz WBV compared to controls. This may have been due to heel bone or soft tissue damage, although the effect was small and may not be clinically important. In conclusion, this investigation of postmenopausal women did not find clinically relevant benefits of WBV on osteoporotic-prone skeletal sites, including the hip, spine, tibia or radius, while potentially harmful effects on heel bone and/or soft tissue was observed in response to WBV. Thus based on this thesis, WBV is currently not recommended for the prevention of bone loss in community-dwelling postmenopausal women with primary osteopenia.

With the average female life expectancy in Canada currently at 82 years, women are now spending approximately one-third of their lives in a hypoestrogenic state. Numerous studies from the basic sciences have shown that estrogen is neuroprotective in a variety of ways. The findings from the clinical studies of the effects of estrogen replacement on cognition in postmenopausal women are more inconsistent, though current research suggests that the timing of initiation of estrogen replacement relative to menopause is a major contributing factor to the discrepant findings in this literature. Reproductive and biological variables that affect levels of endogenous estrogen throughout a woman's lifespan may also influence cognitive function later in life as well as modify a woman's response to exogenous estrogen. The present study looked at the effects of cumulative estrogen exposure on the performance of a measure of prospective memory in a group of older postmenopausal women. Cumulative estrogen exposure was estimated using a mathematical index that included variables known to influence estrogen levels across the life span such as age at menarche and menopause, parity, duration of breastfeeding and estrogen replacement therapy, body mass index and time since menopause. Prospective memory is memory for future intentions and it was chosen because of its relevance for independent function and possible utility as an early indicator of dementia. Imaging studies link prospective memory to the prefrontal cortex, an area of the brain that is known to be influenced by estrogen so it was hypothesized that women with higher levels of cumulative estrogen exposure would perform better on a measure of prospective memory than women with lower levels of endogenous estrogen. Measures of verbal memory were also included in the study for comparative purposes as verbal memory is the cognitive function reported most consistently in the previous literature to be affected by postmenopausal estrogen replacement use. The results of the multivariate analyses indicated a significant positive correlation between prospective memory scores and cumulative estrogen exposure but only when women who had initiated estrogen replacement more than five years after menopause were excluded from the analysis. The significant positive correlation between cumulative estrogen exposure and prospective memory performance remained significant when only women who had never used estrogen were included in the analysis. No relationships were observed between levels of cumulative estrogen exposure and performance on measures of verbal memory. While the study was limited by the fact that it was observational in nature and the sample size was small, the results are consistent with recent findings from the hormone literature, in that they suggest that the timing of hormone replacement as well as the influence of variables that affect endogenous estrogen levels over a woman's lifespan need to be considered when studying relationships between cognitive performance and estrogen. In addition, the finding that performance on a measure of prospective memory but not performance on a measure of verbal memory was associated with levels of cumulative estrogen exposure adds further support to the theory that the frontal cortex may be especially sensitive to estrogen.

The function of skeletal adaptation to mechanical load is to adjust the amount and distribution of bone tissue (geometry); such that stresses experienced within the bone are kept within certain physiological limits and fractures are prevented. Genetic, environmental or hormonal factors may cause heterogeneity in this adaptive response, altering geometry and consequently fragility. The purpose of this thesis was to explore the skeletal response to load in vivo, by evaluating stress at the hip under three different conditions: FRACTURE (Study 1), DIABETES (Study 2) and ESTROGEN deficiency (STUDY 3). We studied women 25 years of age or older who participated in the Canadian Multicentre Osteoporosis Study and had available Hip Structure Analysis (HSA) data from baseline dual energy x-ray absorptiometry (DXA) scans. Women were categorized according to fracture status (fracture or no fracture), diabetes status (diabetes or no diabetes) and estrogen use (current users or never users). We computed stress (megapascals=MPa) at the infero-medial margin of the femoral neck in a one-legged iii stance using a 2-D engineering beam analysis. We used linear regression to determine associations between femoral neck stress and each categorical variable. Study 1 (n=2168) demonstrated higher stresses in postmenopausal women with fractures compared to women without fractures (10.57 ± 2.19 vs. 10.30 ± 2.03 MPa; p=0.0031). Study 2 (n=3665) demonstrated higher stresses in women with Type 2 Diabetes Mellitus compared to non-diabetic women (10.98 ± 2.33 vs. 10.57 ± 2.20 MPa; p=0.0194). Study 3 (n=2447) demonstrated higher stresses in postmenopausal women not on estrogen than in premenopausal women (10.66 ± 2.14 vs. 10.09 ± 2.01 MPa; p<0.0001), but no differences in stresses between postmenopausal women on estrogen and premenopausal women (10.16 ± 2.00 vs. 10.09 ± 2.01 MPa; p=0.6102). Since stress is an indicator of underlying geometry, and geometry should be adapted to prevalent loads, higher stress indicates weaker geometry and suggests an impaired modeling response in these three conditions. Compromised modeling has important clinical implications in terms of treatment selection, as individuals with reduced load sensitivity may respond best to metabolic agents that would improve modeling responses to load stimuli.

The function of skeletal adaptation to mechanical load is to adjust the amount and distribution of bone tissue (geometry); such that stresses experienced within the bone are kept within certain physiological limits and fractures are prevented. Genetic, environmental or hormonal factors may cause heterogeneity in this adaptive response, altering geometry and consequently fragility. The purpose of this thesis was to explore the skeletal response to load in vivo, by evaluating stress at the hip under three different conditions: FRACTURE (Study 1), DIABETES (Study 2) and ESTROGEN deficiency (STUDY 3). We studied women 25 years of age or older who participated in the Canadian Multicentre Osteoporosis Study and had available Hip Structure Analysis (HSA) data from baseline dual energy x-ray absorptiometry (DXA) scans. Women were categorized according to fracture status (fracture or no fracture), diabetes status (diabetes or no diabetes) and estrogen use (current users or never users). We computed stress (megapascals=MPa) at the infero-medial margin of the femoral neck in a one-legged iii stance using a 2-D engineering beam analysis. We used linear regression to determine associations between femoral neck stress and each categorical variable. Study 1 (n=2168) demonstrated higher stresses in postmenopausal women with fractures compared to women without fractures (10.57 ± 2.19 vs. 10.30 ± 2.03 MPa; p=0.0031). Study 2 (n=3665) demonstrated higher stresses in women with Type 2 Diabetes Mellitus compared to non-diabetic women (10.98 ± 2.33 vs. 10.57 ± 2.20 MPa; p=0.0194). Study 3 (n=2447) demonstrated higher stresses in postmenopausal women not on estrogen than in premenopausal women (10.66 ± 2.14 vs. 10.09 ± 2.01 MPa; p<0.0001), but no differences in stresses between postmenopausal women on estrogen and premenopausal women (10.16 ± 2.00 vs. 10.09 ± 2.01 MPa; p=0.6102). Since stress is an indicator of underlying geometry, and geometry should be adapted to prevalent loads, higher stress indicates weaker geometry and suggests an impaired modeling response in these three conditions. Compromised modeling has important clinical implications in terms of treatment selection, as individuals with reduced load sensitivity may respond best to metabolic agents that would improve modeling responses to load stimuli.

Whole-body vibration (WBV) was recently introduced as a potential modality for strengthening bones, and this thesis was set out to investigate whether it plays a role in the prevention of postmenopausal bone loss. First, effects of WBV on bone mineral density (BMD) were systematically evaluated in previous randomized controlled trials (RCTs) in postmenopausal women. Second, a RCT of 202 postmenopausal women with primary osteopenia not on bone medications was conducted to investigate the effects of WBV at 0.3g and 90 Hz versus 0.3g and 30 Hz versus controls on various bone outcomes, as measured by dual-energy x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and quantitative ultrasound (QUS). In the systematic evaluation of previous RCTs, statistically significant increase in areal BMD (aBMD) at the hip was found in postmenopausal women receiving WBV versus controls, but the effect was small and may have been due to study bias. Also, WBV was not found to influence aBMD at the lumbar spine or volumetric BMD (vBMD) at the distal tibia in the systematic evaluation. In the RCT conducted in this thesis, no statistically significant effects of WBV were found on aBMD at the femoral neck, total hip or lumbar spine, as measured by DXA, or on vBMD or bone structure parameters at the distal tibia or distal radius, as measured by HR-pQCT. Further in this RCT, a statistically significant decrease was observed in QUS attenuation at the calcaneus in women receiving 90 Hz or 30 Hz WBV compared to controls. This may have been due to heel bone or soft tissue damage, although the effect was small and may not be clinically important. In conclusion, this investigation of postmenopausal women did not find clinically relevant benefits of WBV on osteoporotic-prone skeletal sites, including the hip, spine, tibia or radius, while potentially harmful effects on heel bone and/or soft tissue was observed in response to WBV. Thus based on this thesis, WBV is currently not recommended for the prevention of bone loss in community-dwelling postmenopausal women with primary osteopenia.

A amamentação representa um período de intensa mobilização óssea para produção de leite. Durante esta fase, a mulher sofre uma grande perda de massa óssea com evidências de recuperação após o desmame. Atualmente este tem sido um período preocupante na vida mulher, pois há suspeitas desta perda óssea na lactação gerar um efeito tardio na densidade mineral óssea (DMO) quando esta mulher está na pós-menopausa. A DMO reduzida é o principal fator de risco para a osteoporose que afeta em torno de 200 milhões de mulheres com mais de cinquenta anos no mundo. O objetivo do presente trabalho foi avaliar o efeito da prática da amamentação na densidade mineral óssea de mulheres na pós-menopausa. Para isto, foi realizada uma revisão sistemática da literatura. A busca de artigos foi feita em bases dados (Lilacs, Medline via Pubmed e Scopus) complementada por checagem manual de referências. Foi identificado um total de 181 artigos e, após aplicação dos critérios de inclusão, selecionados 24 artigos para a revisão sistemática. Os resultados dos diversos estudos são divergentes em questões metodológicas, de classificação da duração da amamentação, quanto às variáveis confundidoras, grupo de idade e etnia, o que dificulta a comparabilidade entre eles. Parte dos estudos referem algum tipo de efeito (positivo ou negativo) e outra parte não, sendo mais frequente a observação de uma correlação inversa entre a amamentação e a densidade mineral óssea em pós-menopausadas. Porém, quando outras variáveis (número de gestações, idade, tempo desde a menopausa, entre outras) são consideradas na análise em conjunto com a amamentação, este último perde a relação de significância. Ainda são necessários mais estudos com melhor rigor metodológico para avaliar se de fato o efeito pode ser atribuído à amamentação ou a outros fatores que também estão relacionados com a densidade mineral óssea na pós-menopausa. / Breastfeeding is a period of intense bone mobilization for milk production. During this phase, women suffer a great loss of bone mass with evidence of recovery after weaning. Currently this has been a worrying period in woman's life as there are suspicions that bone loss during lactation generates a late effect on bone mineral density (BMD) when this woman is postmenopausal. The reduced BMD is a major risk factor for osteoporosis that affects around 200 million women over fifty years worldwide. The aim of this study was to evaluate the effect of breastfeeding on bone mineral density in postmenopausal women. For this, we performed a systematic literature review. The search for articles in databases (Lilacs, Medline via Pubmed and Scopus) were supplemented by manual checking of references. It was identified a total of 181 articles and, after applying the inclusion criteria, 24 articles were selected for the systematic review. The results of several studies are divergent concerning methodological issues, classification of breastfeeding duration, for the variables that cause confusion, age group and ethnicity, which makes comparisons between them difficult. Part of the studies relates some kind of effect (positive or negative) while another part shows, the most frequently, the observation of an inverse correlation between breastfeeding and bone mineral density in postmenopausal. However, when other variables (number of pregnancies, age, time since menopause, etc.) are considered in the analysis in conjunction with breastfeeding, the latter loses significant relationship. More studies with better methodological rigor are still necessary to evaluate if indeed the effect can be attributed to breastfeeding or other factors that are also related to bone mineral density in postmenopausal women.

A amamentação representa um período de intensa mobilização óssea para produção de leite. Durante esta fase, a mulher sofre uma grande perda de massa óssea com evidências de recuperação após o desmame. Atualmente este tem sido um período preocupante na vida mulher, pois há suspeitas desta perda óssea na lactação gerar um efeito tardio na densidade mineral óssea (DMO) quando esta mulher está na pós-menopausa. A DMO reduzida é o principal fator de risco para a osteoporose que afeta em torno de 200 milhões de mulheres com mais de cinquenta anos no mundo. O objetivo do presente trabalho foi avaliar o efeito da prática da amamentação na densidade mineral óssea de mulheres na pós-menopausa. Para isto, foi realizada uma revisão sistemática da literatura. A busca de artigos foi feita em bases dados (Lilacs, Medline via Pubmed e Scopus) complementada por checagem manual de referências. Foi identificado um total de 181 artigos e, após aplicação dos critérios de inclusão, selecionados 24 artigos para a revisão sistemática. Os resultados dos diversos estudos são divergentes em questões metodológicas, de classificação da duração da amamentação, quanto às variáveis confundidoras, grupo de idade e etnia, o que dificulta a comparabilidade entre eles. Parte dos estudos referem algum tipo de efeito (positivo ou negativo) e outra parte não, sendo mais frequente a observação de uma correlação inversa entre a amamentação e a densidade mineral óssea em pós-menopausadas. Porém, quando outras variáveis (número de gestações, idade, tempo desde a menopausa, entre outras) são consideradas na análise em conjunto com a amamentação, este último perde a relação de significância. Ainda são necessários mais estudos com melhor rigor metodológico para avaliar se de fato o efeito pode ser atribuído à amamentação ou a outros fatores que também estão relacionados com a densidade mineral óssea na pós-menopausa. / Breastfeeding is a period of intense bone mobilization for milk production. During this phase, women suffer a great loss of bone mass with evidence of recovery after weaning. Currently this has been a worrying period in woman's life as there are suspicions that bone loss during lactation generates a late effect on bone mineral density (BMD) when this woman is postmenopausal. The reduced BMD is a major risk factor for osteoporosis that affects around 200 million women over fifty years worldwide. The aim of this study was to evaluate the effect of breastfeeding on bone mineral density in postmenopausal women. For this, we performed a systematic literature review. The search for articles in databases (Lilacs, Medline via Pubmed and Scopus) were supplemented by manual checking of references. It was identified a total of 181 articles and, after applying the inclusion criteria, 24 articles were selected for the systematic review. The results of several studies are divergent concerning methodological issues, classification of breastfeeding duration, for the variables that cause confusion, age group and ethnicity, which makes comparisons between them difficult. Part of the studies relates some kind of effect (positive or negative) while another part shows, the most frequently, the observation of an inverse correlation between breastfeeding and bone mineral density in postmenopausal. However, when other variables (number of pregnancies, age, time since menopause, etc.) are considered in the analysis in conjunction with breastfeeding, the latter loses significant relationship. More studies with better methodological rigor are still necessary to evaluate if indeed the effect can be attributed to breastfeeding or other factors that are also related to bone mineral density in postmenopausal women.

Nomegestrolacetat (NOMAC) är ett progestin, selektivt till progesteronreceptorn, med antigonadotropiska och antiandrogena egenskaper. Det används bland annat i kombination med det naturligt förekommande östrogenet 17β-estradiol (E2) för antikonception eller vid postmenopausal behandling. Det föreligger alltid en förhöjd trombosrisk vid hormonterapi, men NOMAC/E2 tros medföra en lägre risk jämfört med andra terapier. Syftet med detta arbete var därför att undersöka om trombosrisken är högre med NOMAC/E2 vid hormonterapi jämfört med andra terapier. Metoden för arbetet var litteraturstudier. Sökningar gjordes genom PubMed i databasen Medline och sex studier valdes ut. NOMAC/E2 visade sig påverka hemostatiska biomarkörer och lipider i lägre utsträckning än levonorgestrel/etinylestradiol (LNG/EE). SHBG (könshormonbindande globulin) ökade däremot mer med NOMAC/EE än med LNG/EE. Den fördelaktiga effekt, som E2 har på endotelcellernas kväveoxidbildning, påverkades inte av NOMAC, och LNG visade liknande egenskaper. Medroxiprogesteron hämmade istället denna antitrombotiska effekt. Utifrån detta arbete kan ingen slutsats dras om trombosrisken är större eller mindre med NOMAC/E2 jämfört med andra terapier. För att kunna göra detta krävs det stora epidemiologiska studier. Däremot kan trombosrisken med NOMAC/E2 anses vara jämförbar med dagens förstahandsval vid kombinerad antikonception som är LNG/EE. Trombosrisken med NOMAC jämfört med MPA kan möjligtvis vara lägre, men detta behöver undersökas i större kliniska studier.

Phthalates are industrial chemicals added to plastics found in products such as children’s toys, cosmetics, and household items, and some laboratory studies suggest phthalates may increase levels of inflammation. Chronic inflammation is associated with many chronic health conditions, such as diabetes and rheumatoid arthritis. Although research is limited, recent studies suggest a strong positive relationship between mono-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), and monocarboxynonyl phthalate (MCNP) and c-reactive protein (CRP), as well as monoethyl phthalate (MEP) and mono-3-carboxypropyl phthalate (MCPP) and interleukin-6 (IL-6). Additionally, this relationship has not been examined among postmenopausal women, a population that is at higher risk of developing chronic health conditions. Our aim was to examine the association between urinary phthalate biomarkers and inflammation biomarkers among postmenopausal women using baseline data from a subset of participants of the Women’s Health Initiative (WHI) (n=443). Phthalate exposure was assessed using phthalate biomarkers (i.e. phthalate metabolites or their molar sum) from urine samples collected at WHI clinical centers from 1993-1998. We measured 13 phthalate metabolites: MEP, MBP, mono-hydroxybutyl phthalate (MHBP), MiBP, mono-hydroxyisobutyl phthalate (MHiBP), monobenzyl phthalate (MBzP), MCPP, mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-carboxyoctyl phthalate (MCOP), and MCNP. Serum and plasma inflammatory biomarker levels (i.e. CRP, IL-6) were measured in separate WHI ancillary studies, using blood samples collected at baseline. We used multivariable linear regression to analyze associations between each phthalate biomarker and inflammation biomarker, adjusting for important covariates. Phthalate biomarkers MCNP (Model 1: b = 0.523; Model 2: b = 0.362) and MCOP (Model 1: b = 0.384; Model 2: b = 0.240) were positively associated with CRP. Additionally, MCNP (Model 1: b = 0.369; Model 2: b = 0.181) was positively associated with IL-6. Statistically significant associations were not observed among the remaining phthalate biomarkers. Our findings suggest that certain phthalates may be related to increasing levels of inflammation.