Associations between bone mass, hormone levels, and body composition in postmenopausal women.

OBJECTIVES: The aim of this study was to explore body composition parameters and hormone levels as risk factors for low bone mass (osteopenia/osteoporosis) in postmenopausal women. METHODS: We analyzed biorepository samples from 139 postmenopausal women with no clinical evidence of cardiovascular disease. Inclusion criteria were menopause occurring after 40 years of age and no use of hormone therapy in the past 3 months. Bone mineral density and body composition were assessed by dual-energy x-ray absorptiometry. Sex hormone-binding globulin (SHBG) and follicle-stimulating hormone (FSH) levels were measured in all participants. Serum estradiol was measured by gas chromatography/tandem mass spectrometry in a subset of 57 participants. Free estrogen index was calculated by dividing estradiol by SHBG × 100. RESULTS: Body mass index (25.0 [22.5-26.5] vs 27.7 [26.6-31.9] kg/m 2 , P < 0.001), estradiol (3.0 [2.7-4.5] vs 6.0 [2.7-15.0] pg/mL, P = 0.006), waist circumference (84 ± 9 vs 93 ± 12 cm, P < 0.001), appendicular lean mass (ALM) (15.739 ± 2.129 vs 17.184 ± 2.104 kg, P = 0.001), and fat mass index (9.36 [7.29-11.43] vs 11.38 [9.95-15.33] kg/m 2 , P < 0.001) were lower in women with low bone mass by dual-energy x-ray absorptiometry. Univariate analysis showed that free estrogen index, time since menopause, SHBG, and fat mass were significant predictors of low bone mass, and ALM was a significant predictor against low bone mass. Appendicular lean mass persisted as an independent predictor against low bone mass in multivariate models with fat mass and SHBG. In turn, fat mass was no longer significant in this multivariate model after inclusion of SHBG. No association of FSH with low bone mass was observed. CONCLUSIONS: Appendicular lean mass was a significant independent predictor against low bone mass in postmenopausal women. Further prospective studies are needed to investigate whether lean mass, fat mass, and FSH have a direct effect on bone mass in postmenopausal women, adding to the consequences of hypoestrogenism in this group.

Are vitamin D deficiency and VDR gene polymorphisms associated with high blood pressure as defined by the ACC/AHA 2017 criteria in postmenopausal women?

OBJECTIVES: To assess the vitamin D levels, prevalence of vitamin D deficiency and genotypes of Fok-I, Bsm-I, Apa-I and Taq-I polymorphisms in the VDR gene and to determine whether vitamin D deficiency and VDR gene variants are associated with blood pressure levels and systemic arterial hypertension as defined by the 2017 ACC/AHA criteria. STUDY DESIGN: A cross-sectional study of biobanked blood samples from 339 postmenopausal women. MAIN OUTCOME MEASURES: Blood pressure strata were defined according to the 2017 ACC/AHA cutoffs. Circulating 25(OH)D levels were considered deficient if <20 ng/mL. RESULTS: Mean serum total 25(OH)D levels were 22.99 ± 8.54 ng/mL, and 40.1% of participants were deficient in vitamin D. Overall, 7.7% had elevated blood pressure, 36.6% had stage 1 and 37.8% had stage 2 hypertension. Mean total (p = 0.014) and free 25(OH)D levels (p = 0.029) were lower in women with stage 2 hypertension than in those with normal blood pressure. A higher prevalence rate of stage 2 hypertension was associated with age (PR 1.058; 95%CI 1.033-1.083; p < 0.001), BMI (PR 1.046; 95%CI 1.025-1.068; p < 0.001), vitamin D deficiency (PR 1.333; 95%CI 1.016-1.749; p = 0.038) and Taq-I polymorphism (PR 1.764; 95%CI 1.030-3.019; p = 0.039). Women with vitamin D deficiency and the AA+AG genotype of Taq-I polymorphism were 33% and 76% more likely to have stage 2 hypertension, respectively, but these associations lost significance when adjusted for age and BMI. CONCLUSION: The results suggest that vitamin D deficiency and Taq-I polymorphism are associated with stage 2 hypertension, depending on age and BMI, in postmenopausal women.

C-reactive protein gene rs1205 polymorphism is associated with low-grade chronic inflammation in postmenopausal women.

BACKGROUND: Cardiovascular disease is the leading cause of death in postmenopausal women, and inflammation is a key mechanism involved in the pathogenesis of atherosclerosis. High-sensitivity C-reactive protein (hs-CRP) has been used as a biomarker of inflammation. Considering that CRP gene rs1205 polymorphism has been associated with hs-CRP circulating levels, we evaluated whether rs1205 genotypes influence the presence of low-grade chronic inflammation, acting as a marker of cardiovascular risk. METHODS: We performed a cross-sectional study with biobanked blood samples from 327 postmenopausal women with no evidence of clinical disease. Genotyping for rs1205 C > T SNP of the CRP gene was done by real-time polymerase chain reaction with allelic discrimination assays. RESULTS: Mean age was 55.6 ± 5.6 years. Mean body mass index (BMI) was 27.3 ± 4.7. Participants were divided according to hs-CRP levels: ≥3 mg/l (low-grade chronic inflammation) or < 3 mg/l. The frequency of allele C at rs1205 was 74.2% in the hs-CRP ≥ 3 mg/l group vs. 59% in the hs-CRP < 3 mg/l. In a multivariable model, higher prevalence of hs-CRP ≥ 3 mg/l was associated with CC genotype (PR 1.53; 95%CI 1.07-2.18; p = 0.018) and waist circumference ≥ 88 cm (PR 2.45; 95%CI 1.66-3.60; p < 0.001). CONCLUSIONS: CRP rs1205 CC homozygotes may be at higher risk of a low-grade chronic inflammatory status compared to individuals carrying the T allele.

Prevalence of vitamin D deficiency in women from southern Brazil and association with vitamin D-binding protein levels and GC-DBP gene polymorphisms.

Vitamin D deficiency is highly prevalent worldwide, and vitamin D-binding protein (DBP) a major regulator of serum vitamin D levels. The rs4588 and rs7041 polymorphisms of the GC gene constitute the genetic basis of the three major isoforms of circulating DBP (GC1s, GC1f, and GC2), while the rs2282679 variant is located in an important regulatory region of the GC gene. The aim of this study was to assess the prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency and to ascertain whether it is associated with DBP levels and with GC gene variants. Biorepository samples of 443 women aged 20 to 72 years, with no evidence of clinical disease, were analyzed. Circulating levels of 25(OH)D were considered sufficient if ≥20 ng/mL and deficient if <20 ng/mL. Genotype analysis was performed by RT-PCR. Mean age was 53.4±9.4 years; mean BMI was 27.8±5.8 kg/m2. The overall sample had mean 25(OH)D levels of 22.8±8.3 ng/mL; 39.7% of participants had deficient circulating 25(OH)D levels. Higher prevalence ratios (PR) of 25(OH)D deficiency were found for the CC genotype of rs2282679 (PR 1.74; 95%CI 1.30 to 2.24; p<0.001), GC2 isoform (PR 1.66; 95%CI 1.17 to 2.38; p = 0.005), time since menopause (PR 1.02; 95%CI 1.003 to 1.03, p = 0.016), and HOMA-IR (PR 1.02; 95%CI 1.01 to 1.03, p = 0.004). DBP levels (per 30 µg/mL increase in DBP) were associated with lower PR for 25(OH)D deficiency (PR 0.89; 95%CI 0.80;0.99; p = 0.027). Except for HOMA-IR, these prevalence ratios remained significant after adjustment for age and BMI. In conclusion, the rs2282679 polymorphism and the GC2 isoform of DBP were associated with lower serum DBP levels and with susceptibility to 25(OH)D deficiency in Brazilian women with no evidence of clinical disease.

Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis.

INTRODUCTION: Hormone therapy (HT) is an effective treatment for climacteric symptoms. Nevertheless, combined estrogen-progestin therapy and the oral route seem to entail higher risk of venous thromboembolism (VTE) than estrogen-only therapy and transdermal administration. The present study aimed to investigate the risk of thromboembolic events in postmenopausal women using non-oral estrogen compared to women using oral estrogen and control groups (women receiving placebo or non-users of HT), as well as to assess the thrombotic impact of estrogens alone vs. combined estrogen-progestin therapy. MATERIALS AND METHODS: Systematic review of MEDLINE, Cochrane CENTRAL, EMBASE, and ClinicalTrials.gov according to PRISMA guidelines. RESULTS: Twenty-two studies were included in the meta-analyses (9 case-control studies, 9 cohort studies, and 4 randomized controlled trials). As compared to control groups, VTE risk was not increased with non-oral HT, including users of estrogens and estrogens plus progestins (OR 0.97 [0.9-1.06]), non-oral estrogen therapy (ET)-only (OR 0.95 [0.81-1.10]), and non-oral combined estrogen-progestin therapy (OR 0.92 [0.77-1.09]). Conversely, increased risk of VTE was observed as compared with control groups in users of oral HT, including users of estrogens and estrogens plus progestins HT (OR 1.72 [1.47-2.01]), oral ET-only (OR 1.43 [1.34-1.53]), and combined oral estrogen-progestin HT (OR 2.35 [1.9-2.9]). The comparison of non-oral vs. oral HT showed increased VTE risk with oral HT (OR 1.66 [1.39-1.98]). CONCLUSIONS: VTE risk was increased in postmenopausal women with no previous thromboembolic events using oral HT. Non-oral HT did not significantly affect this risk. The quality of the evidence produced in our meta-analyses is low to moderate, and further clinical trials are needed to sort out the impact of different types of progestin and different estrogen doses and administration routes on VTE risk.

Effects of low-dose versus placebo or conventional-dose postmenopausal hormone therapy on variables related to cardiovascular risk: a systematic review and meta-analyses of randomized clinical trials.

CONTEXT: Hormone therapy (HT), the most efficient treatment for menopausal symptoms, might have deleterious cardiovascular (CV) effects. OBJECTIVE: This study aimed to evaluate the effects of low-dose estrogen HT on CV risk factors vs conventional-dose HT and placebo in postmenopausal women with no established CV disease. DATA SOURCES: MEDLINE, Cochrane Central, and EMBASE were searched for trials published in 1990-2013; a hand search of reference lists of selected articles was performed; and ClinicalTrials.gov was searched for unpublished trials. STUDY SELECTION: Within randomized controlled trials of healthy postmenopausal women comparing low-dose HT to placebo or conventional-dose HT, 11 418 studies were initially identified. DATA EXTRACTION: Data were independently extracted by two investigators. Disagreements were resolved by a third author. DATA SYNTHESIS: Twenty-eight trials (3360 patients) were included. Low-dose HT vs placebo or conventional-dose HT did not effect weight, body mass index (BMI), blood pressure, C-reactive protein, or high-density lipoprotein cholesterol (HDL-C). Low-dose HT was associated with lower levels of total cholesterol (-12.16 mg/dL, 95% confidence interval [CI], -17.41 - -6.92) and low-density lipoprotein cholesterol (LDL-C) (-12.16 mg/dL; 95% CI, -16.55 - -7.77) vs placebo. Compared with conventional-dose HT, low-dose HT was associated with higher total cholesterol (5.05 mg/dL; 95% CI, 0.88-9.21) and LDL-C (4.49 mg/dL; 95% CI, 0.59-8.39). Low-dose HT was not associated with differences in triglycerides vs placebo. Oral, low-dose HT was associated with lower triglycerides vs conventional-dose HT (-14.09 mg/dL; 95% CI, -24.2 - -3.93). CONCLUSION: In this population of apparently healthy postmenopausal women, the effect of low-dose HT did not differ from that of placebo or conventional-dose HT regarding weight, BMI, blood pressure, CRP, or HDL-C. In contrast, low-dose HT was associated with better lipid profile vs placebo, and induced higher total and LDL-C and lower triglycerides vs conventional-dose HT.

Effects of micronized progesterone added to non-oral estradiol on lipids and cardiovascular risk factors in early postmenopause: a clinical trial.

BACKGROUND: Much attention has been drawn to the deleterious effects of adding progestins to estrogen as hormone therapy (HT) in postmenopausal women. Some widely prescribed progestins have been shown to partially oppose the beneficial effects of estrogens on surrogate markers of cardiovascular disease (CVD) risk. Progestins with higher androgenic activity may interfere with lipid profile and glucose tolerance, and could affect mechanisms of estrogen-induced C-reactive protein (CRP) stimulation. Recent data have shown that norpregnane derivatives, but not micronized progesterone, increase the risk of venous thromboembolism among transdermal estrogens users. The aim of the present study was to assess the effects of combining micronized progesterone with non-oral estrogen therapy on lipid profile and cardiovascular risk factors in a sample of early postmenopausal women. METHODS: Clinical trial including 40 women receiving intranasal 17ß estradiol 3 mg/day for two months and 46 women receiving percutaneous 17ß estradiol gel 1.5 mg/day for three months (E2). Both groups received an additional 200 mg/day of micronized progesterone by vaginal route 14 days/month (E2+P). Outcome measures included body weight, waist circumference, body mass index (BMI), lipid profile and ultra-sensitive C-reactive protein (usCRP) at baseline and during the E2 or E2+P portions of treatment. RESULTS: Mean age was 51±3 years. Mean time since menopause was 22.2±10 months. Most participants were overweight; HT did not change BMI. E2 and E2+P did not affect waist circumference and weight. Menopausal symptoms improved after HT. The effects of intranasal and percutaneous estradiol were similar, regardless of the addition of progesterone. Similarly, for the overall group of 86 women, micronized progesterone did not alter the response to E2. Blood pressure, glucose, insulin, HDL-c, triglycerides, and usCRP remained constant with or without micronized progesterone. Total cholesterol decreased after E2, and progesterone maintained this reduction. LDL-c levels were similar at baseline and with E2, and lower during E2+P in relation to baseline. CONCLUSIONS: Cyclic, short term exposure to vaginal micronized progesterone did not alter the metabolic and cardiovascular effects of non-oral E2 in early, apparently healthy, postmenopausal women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01432028.

Fat mass and obesity-associated gene polymorphisms do not affect metabolic response to hormone therapy in healthy postmenopausal women.

OBJECTIVE: To determine whether fat mass and obesity-associated gene polymorphisms rs9939609 T>A and rs8050136 A>C or their haplotypes influence anthropometric and metabolic variables in recently postmenopausal women receiving hormone therapy. STUDY DESIGN: In this randomized crossover study carried out in a university clinic, 86 postmenopausal women consulting for symptoms of estrogen deficiency were genotyped by real-time polymerase chain reaction for single nucleotide polymorphisms rs9939609 T>A and rs8050136 A>C of the fat mass and obesity-associated gene. Haplotypes were constructed from the combination of polymorphisms rs9939609 and rs8050136, and their frequencies were inferred using the PHASE 2.1.1 program. Participants were clinically evaluated before and after 6 months of hormone therapy to determine body mass index (current kg/m(2)) and waist circumference, blood pressure, lipid profile (total cholesterol, HDL cholesterol and triglycerides) plasma glucose (oral glucose tolerance test), and insulin. Blood samples were also drawn for ultra sensitive C reactive protein. The lipid accumulation product index was calculated as (waist [cm] - 58) × triglyceride concentration (mmol/L). Non-normally distributed parameters were log10 transformed before statistical analysis. Measurements at baseline and at follow-up were compared with ANOVA for repeated measures. Data were considered significant at P<0.05. RESULTS: In women with the homozygous polymorphic AA genotype of the single nucleotide polymorphisms rs9939609 and the wild AA genotype of the single nucleotide polymorphisms rs8050136, lipid accumulation product index and ultra sensitive C reactive protein were higher before hormone therapy in comparison with women with other genotypes from the same single nucleotide polymorphisms group. There was no worsening of any of the anthropometric or metabolic variables, and lipid accumulation product index improved slightly after hormone therapy in SNP rs9939609 (P=0.03) and haplotype AAAA. No changes were observed after hormone therapy in SNP rs8050136. CONCLUSIONS: The presence of fat mass and obesity-associated gene risk variants in healthy early postmenopausal women does not adversely affect their response to hormone therapy.

Variations in the fat mass and obesity-associated (FTO) gene are related to glucose levels and higher lipid accumulation product in postmenopausal women from southern Brazil.

OBJECTIVE: To test the association between polymorphisms rs9939609 T>A and rs8050136 A>C of the fat mass and obesity-associated (FTO) gene and metabolic and cardiovascular variables in postmenopause. DESIGN: Cross-sectional study. SETTING: University hospital. PATIENT(S): A total of 135 postmenopausal women (mean age 52 ± 4 years). INTERVENTION(S): Anthropometric measurements and collection of blood samples. MAIN OUTCOME MEASURE(S): Blood pressure, metabolic variables, and FTO genotype. RESULT(S): The frequency of polymorphism rs9939609 was 43.7% for the wild TT genotype, 43.0% for TA, and 13.3% for AA. The frequency of the rs8050136 polymorphism was 12.6% for the wild AA genotype, 39.3% for AC, and 48.1% for CC. The polymorphic AA genotype of the SNP rs9939609 was associated with higher glucose levels and lipid accumulation product (LAP) index, whereas the wild AA genotype of the SNP rs8050136 was associated with higher LAP. CONCLUSION(S): The rs9939609 polymorphism in the FTO gene is related to abnormal glucose levels and with LAP, a surrogate marker of diabetes and cardiovascular risk in postmenopause. Further studies are needed in different ethnic backgrounds to confirm the clinical relevance of these associations.

Effects of nonoral estradiol-micronized progesterone or low-dose oral estradiol-drospirenone therapy on metabolic variables and markers of endothelial function in early postmenopause.

OBJECTIVE: To evaluate the effects of low-dose oral hormone therapy and nonoral hormone therapy on endothelial function markers and on anthropometric, metabolic, and hormonal variables in early postmenopausal women. DESIGN: Cross-over, randomized clinical trial. SETTING: Gynecological Endocrinology Unit. PATIENT(S): Healthy postmenopausal women. INTERVENTION(S): Twenty patients received oral E(2) 1 mg plus drospirenone 2 mg/d for 2 months. Another group of 20 patients received 3 mg/d 17beta intranasal E(2), and then 200 mg/d vaginal micronized P for 14 days during two 28-day cycles. At the end of this period, the patients were crossed over for another 2 months. MAIN OUTCOME MEASURE(S): Endothelial function markers and anthropometric, metabolic, and hormonal variables before and after hormone therapy. RESULT(S): Mean age was 51.2 +/- 2.7 years. Mean time since menopause was 23.1 +/- 10 months. After low-dose treatment, a reduction in waist circumference, waist-to-hip ratio, and high-density-lipoprotein cholesterol was observed. Triglycerides and von Willebrand factor levels decreased significantly with nonoral treatment. Fasting glucose and insulin levels did not change. In both groups, total and non-high-density-lipoprotein cholesterol levels decreased below basal levels, and endothelin-1, fibrinogen, and C-reactive protein levels remained unchanged. CONCLUSION(S): Neither treatment induced deleterious effects in the short term on variables related to cardiovascular risk in early postmenopausal women.