OBJECTIVE

Hyperandrogenemia is associated with cardiovascular risk factors in women but evidence about the relationship of testosterone levels with mortality is sparse. We aimed to evaluate whether total testosterone (TT), free testosterone (FT), and sex hormone–binding globulin (SHBG) are associated with all-cause and cardiovascular mortality in a cohort of postmenopausal women.

RESEARCH DESIGN AND METHODS

We measured TT and SHBG levels in 875 postmenopausal women who were referred for coronary angiography (during 1997–2000). FT was calculated according to the Vermeulen method. The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes and from cardiovascular causes.

RESULTS

After a median follow-up time of 7.7 years, 179 women (20.5%) had died. There were 101 deaths due to cardiovascular disease (56.4% of all deaths). We found no association of FT, TT, and SHBG levels with mortality in all postmenopausal women. In postmenopausal diabetic women, multivariable-adjusted HRs (with 95% CIs) in the fourth compared with the first FT quartile for all-cause and cardiovascular mortality were 0.38 (0.08–0.90), P = 0.025, and 0.28 (0.08–0.90), P = 0.032, respectively. We found no association of TT and SHBG with mortality in diabetic postmenopausal women.

CONCLUSIONS

In postmenopausal diabetic women referred for coronary angiography, low FT levels are independently associated with increased all-cause and cardiovascular mortality.

Context

Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.

Objective

To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.

Design and Setting

Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.

Main Outcome Measures

Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.

Results

The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n =25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P=3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P=2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P =3.8 × 10−5) and 8 mg/cm2 (P=5.0×10−6) for the Met667 and Val1330 alleles, respectively (n=25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08–1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01–1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05–1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01–1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.

Conclusions

Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P<10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

Aims

Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients.

Methods and results

25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD (n = 146), myocardial infarction (MI, n = 174), stroke (n = 89), cardiovascular events (CVE, n = 414), death due to heart failure (n = 37), fatal infection (n = 111), and all-cause mortality (n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28–55). Patients with severe vitamin D deficiency [25(OH)D of≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39–6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18–2.69, and HR: 1.74, 95% CI: 1.22–2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected.

Conclusion

Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D supplementation decreases adverse outcomes requires further evaluation.

Hirsutism represents a primary clinical indicator of androgen excess. The most common endocrine condition causing hirsutism is polycystic ovary syndrome (PCOS). Diagnosing PCOS is not easy as the signs and symptoms are heterogenous. The newest diagnostic guideline made by the Androgen Excess and PCOS Society in 2006, claims the presence of hyperandrogenism, and ovarian dysfunction (oligo / anovulation and / or polycystic ovaries). Obesity associated reproductive and metabolic dysfunctions may aggravate the symptoms of PCOS. PCOS might be underdiagnosed in non obese women because lean PCOS phenotypes might be underestimated for the syndrome. Effective medical treatment of PCOS and associated hirsutism depends on the endocrinological expertise and experience of the therapist in each individual case. An algorithm for the treatment has not been established yet.

Background

Primary aldosteronism (PA) affects approximately 5 to 10% of all patients with arterial hypertension and is associated with an excess rate of cardiovascular complications that can be significantly reduced by a targeted treatment. There exists a general consensus that the aldosterone to renin ratio should be used as a screening tool but valid data about the accuracy of the aldosterone to renin ratio in screening for PA are sparse. In the Graz endocrine causes of hypertension (GECOH) study we aim to prospectively evaluate diagnostic procedures for PA.

Methods and design

In this single center, diagnostic accuracy study we will enrol 400 patients that are routinely referred to our tertiary care center for screening for endocrine hypertension. We will determine the aldosterone to active renin ratio (AARR) as a screening test. In addition, all study participants will have a second determination of the AARR and will undergo a saline infusion test (SIT) as a confirmatory test. PA will be diagnosed in patients with at least one AARR of ≥ 5.7 ng/dL/ng/L (including an aldosterone concentration of ≥ 9 ng/dL) who have an aldosterone level of ≥ 10 ng/dL after the saline infusion test. As a primary outcome we will calculate the receiver operating characteristic curve of the AARR in diagnosing PA. Secondary outcomes include the test characteristics of the saline infusion test involving a comparison with 24 hours urine aldosterone levels and the accuracy of the aldosterone to renin activity ratio in diagnosing PA. In addition we will evaluate whether the use of beta-blockers significantly alters the accuracy of the AARR and we will validate our laboratory methods for aldosterone and renin.

Conclusion

Screening for PA with subsequent targeted treatment is of great potential benefit for hypertensive patients. In the GECOH study we will evaluate a standardised procedure for screening and diagnosing of this disease.

Background

Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.

Methods and Findings

Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm 2 (CI, 16 to 34 mg/cm 2) lower in TT homozygotes than the other genotype groups ( p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm 2 (CI, 1 to 42 mg/cm 2), ( p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses.

Conclusions

Allowing for the inevitable heterogeneity between participating teams, this study—which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene—demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

A large collaborative European study finds only weak links between a much studied potential genetic risk factor and bone mineral density or fracture risk.

OBJECTIVE

To investigate via the vitamin D status whether patients with peripheral arterial disease (PAD) tend to develop vitamin D deficiency that in turn influences their clinical symptoms.

DESIGN

Cross-sectional.

SETTING

University hospital.

PATIENTS AND PARTICIPANTS

Three hundred twenty-seven patients were evaluated; subjects with secondary causes of bone disease or bone active medication were excluded. One hundred sixty-one patients with either PAD stage II (n = 84) or stage IV (n = 77) were enrolled and compared to 45 age- and sex-matched healthy controls.

MEASUREMENTS AND MAIN RESULTS

All patients underwent determinations of serum chemistry, 25-hydroxyvitamin D (vitamin D3) intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and osteocalcin and were further stratified according to an individual restriction score into 3 groups: mildly, moderately, or severely restricted in daily life due to the underlying disease. Patients with PAD IV showed significantly lower vitamin D3 (P = .0001), and calcium (P = .0001) values and significantly higher iPTH (P = .0001), osteocalcin (P = .0001) and ALP (P = .02) levels as compared to patients with PAD II. Patients considering themselves as severely restricted due to the underlying disease showed lower vitamin D3 and higher iPTH levels than those who described only a moderate (vitamin D3: P < .001; iPTH: P < .01) or mild (vitamin D3: P < .001; iPTH: P < .001) restriction in daily life.

CONCLUSION

Patients with PAD IV, especially those who feel severely restricted due to the disease, are at high risk of developing vitamin D deficiency, secondary hyperparathyroidism, and ultimately osteomalacia due to immobilization and subsequent lack of exposure to sunlight, all of which in turn lead to further deterioration. Monitoring of vitamin D metabolism and vitamin D replacement therapy could be a simple, inexpensive approach to mitigating clinical symptoms and improving quality of life in patients with advanced PAD.