Vasomotor symptoms and the risk of incident venous thrombosis in postmenopausal women.

Essentials Vasomotor symptoms have been proposed as markers of changing cardiovascular risk. In this cohort study, we evaluated these symptoms as markers of venous thrombosis (VT) risk. We found no evidence that vasomotor symptom presence or severity were associated with VT risk. Among these postmenopausal women, vasomotor symptoms are not a useful marker of VT risk. SUMMARY: Background Vasomotor symptoms may be markers of changes in cardiovascular risk, but it is unknown whether these symptoms are associated with the risk of venous thrombosis (VT). Objective To evaluate the association of vasomotor symptom presence and severity with incident VT risk among postmenopausal women, independent of potential explanatory variables. Methods This cohort study included participants of the Women's Health Initiative (WHI) Hormone Therapy Trials (n = 24 508) and Observational Study (n = 87 783), analyzed separately. At baseline, women reported whether hot flashes or night sweats were present and, if so, their severity. Using Cox proportional hazards models, we estimated the VT risk associated with vasomotor symptom presence and severity, adjusted for potential explanatory variables: age, body mass index, smoking status, race/ethnicity, and time-varying current hormone therapy use. Results At baseline, WHI Hormone Therapy Trial participants were aged 64 years and WHI Observational Study participants were aged 63 years, on average. In the WHI Hormone Therapy Trials over a median of 8.2 years of follow-up, 522 women experienced a VT event. In the WHI Observational Study, over 7.9 years of follow-up, 1103 women experienced a VT event. In adjusted analyses, we found no evidence of an association between vasomotor symptom presence (hazard ratio [HR]adj  0.91, 95% confidence interval [CI] 0.75-1.1 in the WHI Hormone Therapy Trials; HRadj  1.1, 95% CI 0.99-1.3 in the WHI Observational Study) or severity (HRadj for severe versus mild 0.99, 95% CI 0.53-1.9 in the WHI Hormone Therapy Trials; HRadj  1.3, 95% CI 0.89-2.0) in the WHI Observational Study) and the risk of incident VT. Conclusions Although vasomotor symptoms have been associated with the risk of other cardiovascular events in published studies, our findings do not suggest that vasomotor symptoms constitute a marker of VT risk.

Long-term treatment of Cushing's disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial.

BACKGROUND: Treating hypercortisolism in patients with Cushing's disease after failed surgery often requires chronic medication, underlining the need for therapies with favourable long-term efficacy and safety profiles. METHODS: In a randomised, double-blind study, 162 adult patients with persistent/recurrent or de novo Cushing's disease received pasireotide. Patients with mean urinary free cortisol at/below the upper limit of normal or clinical benefit at month 12 could continue receiving pasireotide during an open-ended, open-label phase, the outcomes of which are described herein. RESULTS: Sixteen patients received 5 years of pasireotide treatment. Among these, median (95% confidence interval) percentage change from baseline in mean urinary free cortisol was -82.6% (-89.0, -41.9) and -81.8% (-89.8, -67.4) at months 12 and 60. Eleven patients had mean urinary free cortisol ≤ upper limit of normal at month 60. Improvements in clinical signs were sustained during long-term treatment. The safety profile of pasireotide at 5 years was similar to that reported after 12 months. Fifteen of 16 patients experienced a hyperglycaemia-related adverse event; glycated haemoglobin levels were stable between months 6 and 60. Adverse events related to hyperglycaemia, bradycardia, gallbladder/biliary tract, and liver safety were most likely to first occur by month 6; adverse event severity did not tend to worsen over time. CONCLUSIONS: This represents the longest prospective trial of a medical therapy for Cushing's disease to date. A subset of patients treated with pasireotide maintained biochemical and clinical improvements for 5 years, with no new safety signals emerging. These data support the use of pasireotide as an effective long-term therapy for some patients with Cushing's disease.

Cross-sectional association of endogenous steroid hormone, sex hormone-binding globulin, and precursor steroid levels with hemostatic factor levels in postmenopausal women.

Essentials Endogenous hormone levels' influence on hemostatic factor levels is not fully characterized. We tested for associations of endogenous hormone with hemostatic factor levels in postmenopause. Estrone levels were inversely associated with the natural anticoagulant, protein S antigen. Dehydroepiandrosterone sulfate levels were inversely associated with thrombin generation. SUMMARY: Background Oral use of exogenous estrogen/progestin alters hemostatic factor levels. The influence of endogenous hormones on these levels is incompletely characterized. Objectives Our study aimed to test whether, among postmenopausal women, high levels of estradiol (E2), estrone (E1), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione, and low levels of sex hormone-binding globulin (SHBG), are positively associated with measures of thrombin generation (TG), a normalized activated protein C sensitivity ratio (nAPCsr), and factor VII activity (FVIIc), and negatively associated with antithrombin activity (ATc) and total protein S antigen (PSAg). Methods This Heart and Vascular Health study cross-sectional analysis included 131 postmenopausal women without a prior venous thrombosis who were not currently using hormone therapy. Adjusted mean differences in TG, nAPCsr, FVIIc, ATc and PSAg levels associated with differences in hormone levels were estimated using multiple linear regression. We measured E2, E1, total T, DHEAS, DHEA and androstenedione levels by mass spectrometry, SHBG levels by immunoassay, and calculated the level of free T. Results One picogram per milliliter higher E1 levels were associated with 0.24% lower PSAg levels (95% Confidence Interval [CI]: -0.35, -0.12) and 1 µg mL-1 higher DHEAS levels were associated with 40.8 nm lower TG peak values (95% CI: -59.5, -22.2) and 140.7 nm×min lower TG endogenous thrombin potential (ETP) (95% CI: -212.1, -69.4). After multiple comparisons correction, there was no evidence for other associations. Conclusions As hypothesized, higher E1 levels were associated with lower levels of the natural anticoagulant PSAg. Contrary to hypotheses, higher DHEAS levels were associated with differences in TG peak and ETP that suggest less generation of thrombin.

Recovery of adrenal function after chronic secondary adrenal insufficiency in patients with hypopituitarism.

OBJECTIVE: Previous studies have reported recovery of secondary adrenal insufficiency (SAI) in patients with pituitary disorders, generally immediately after pituitary surgery; however, data regarding recovery of long-term SAI are lacking. We conducted a study to assess the longer term recovery rate of SAI in patients with pituitary disorders. METHODS: We identified all SAI patients in the Halifax Neuropituitary Database from 1 November 2005 to 30 September 2014, who had required glucocorticoid therapy for ≥3 months, and had a minimum follow-up of 6 months. Patients with ACTH-secreting adenomas, those receiving glucocorticoids only in the routine peri-operative period for pituitary surgery and those on glucocorticoids for nonpituitary conditions were excluded. SAI was defined as either basal serum cortisol < 130 nm and/or a subnormal cortisol response to ACTH-(1-24) stimulation test or insulin tolerance test response. RESULTS: Fifty-one patients fulfilled the criteria. Nine (17·6%) patients had complete recovery of SAI over a median of 20 months (range: 8-51) after initiating glucocorticoid replacement. Patients with smaller tumour size had increased likelihood of hypothalamic-pituitary-adrenal (HPA) axis recovery, whereas those with secondary hypogonadism or growth hormone deficiency were less likely to recover. Those with initial cortisol >175 nm had an almost one in two chance of recovery. CONCLUSION: Results from our study show that approximately one in six patients with SAI recover adrenal function, even up to 5 years after diagnosis. We recommend that patients with SAI undergo regular testing to assess recovery in order to prevent unnecessary glucocorticoid therapy.

MsFLASH participants' priorities for alleviating menopausal symptoms.

OBJECTIVE: To describe self-reported menopausal symptom priorities and their association with demographics and other symptoms among participants in an intervention trial for vasomotor symptoms (VMS). METHODS: Cross-sectional study embedded in the MsFLASH 02 trial, a three-by-two factorial design of yoga vs. exercise vs. usual activity and omega-3-fatty acid vs. placebo. At baseline, women (n = 354) completed hot flush diaries, a card sort task to prioritize symptoms they would most like to alleviate, and standardized questionnaires. RESULTS: The most common symptom priorities were: VMS (n = 322), sleep (n = 191), concentration (n = 140), and fatigue (n = 116). In multivariate models, women who chose VMS as their top priority symptom (n = 210) reported significantly greater VMS severity (p = 0.004) and never smoking (p = 0.012), and women who chose sleep as their top priority symptom (n = 100) were more educated (p ≤ 0.001) and had worse sleep quality (p < 0.001). ROC curves identified sleep scale scores that were highly predictive of ranking sleep as a top priority symptom. CONCLUSIONS: Among women entering an intervention trial for VMS and with relatively low prevalence of depression and anxiety, VMS was the priority symptom for treatment. A card sort may be a valid tool for quickly assessing symptom priorities in clinical practice and research.

Management of patients with Cushing's disease: a Canadian cost of illness analysis.

BACKGROUND: Cushing's disease (CD) is a rare disorder caused by increased pituitary secretion of adrenocorticotropic hormone (ACTH) resulting in elevated production of cortisol. It is associated with multiple adverse cardiovascular, metabolic, musculoskeletal and mental consequences. Patients with CD require substantial health care resources both in terms of treatments with a curative intent and control of disease related co-morbidities. In this study, a cost of illness analysis was conducted to estimate the direct cost of CD care in Canada. METHODS: This was a retrospective cohort study of 86 CD patients. Data collection included patient demographic and disease related information, existing comorbidities, treatments received and all clinical outcomes. In addition, healthcare resource utilization to manage CD was also collected. Once the mean cost per patient was determined, the overall disease prevalence was used to estimate the total direct cost of illness in Canada. RESULTS: The sample included 86 CD patients, with a mean age of 43 years at diagnosis, 72% were female. All received a first line intervention consisting of transsphenoidal pituitary surgery (78%), bilateral adrenalectomy (5%), radiation therapy (5%) or medical therapy ± radiation (13%). In addition, 18 and 14 patients subsequently received a second and third line intervention, respectively. The mean cost was $85,946 per patient over the first three lines of therapy. Combining this estimate with the reported disease prevalence (5.5 patients per 100,000 [95%CI: 4.2 to 6.8]), the total direct cost of CD in Canada was estimated to be approximately $80.6 million (95%CI: $61.5 to $99.6 million) over the first 3 lines of therapy. CONCLUSIONS: CD is a debilitating condition that is associated with substantial health care costs. Strategies that provide clinical cure or long term disease control need to be identified to reduce patient morbidity and to save health care costs in patients who remain uncontrolled.

Non-hip, non-spine fractures drive healthcare utilization following a fracture: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We evaluated healthcare utilization associated with treating fracture types in >51,000 women aged ≥55 years. Over the course of 1 year, there were five times more non-hip, non-spine fractures than hip or spine fractures, resulting in twice as many days of hospitalization and rehabilitation/nursing home care for non-hip, non-spine fractures. INTRODUCTION: The purpose of this study is to evaluate medical healthcare utilization associated with treating several types of fractures in women ≥55 years from various geographic regions. METHODS: Information from the Global Longitudinal Study of Osteoporosis in Women (GLOW) was collected via self-administered patient questionnaires at baseline and year 1 (n = 51,491). Self-reported clinically recognized low-trauma fractures at year 1 were classified as incident spine, hip, wrist/hand, arm/shoulder, pelvis, rib, leg, and other fractures. Healthcare utilization data were self-reported and included whether the fracture was treated at a doctor's office/clinic or at a hospital. Patients were asked if they had undergone surgery or been treated at a rehabilitation center or nursing home. RESULTS: During 1-year follow-up, there were 195 spine, 134 hip, and 1,654 non-hip, non-spine fractures. Clinical vertebral fractures resulted in 617 days of hospitalization and 512 days of rehabilitation/nursing home care; hip fractures accounted for 1,306 days of hospitalization and 1,650 days of rehabilitation/nursing home care. Non-hip, non-spine fractures resulted in 3,805 days in hospital and 5,186 days of rehabilitation/nursing home care. CONCLUSIONS: While hip and vertebral fractures are well recognized for their associated increase in health resource utilization, non-hip, non-spine fractures, by virtue of their 5-fold greater number, require significantly more healthcare resources.

Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study.

SUMMARY: The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D(3) daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer. INTRODUCTION: This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality. METHODS: WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS). RESULTS: Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive. CONCLUSION: Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.

Renal function and nonvertebral fracture risk in multiethnic women: the Women's Health Initiative (WHI).

UNLABELLED: To examine the association between renal function and fracture in multiethnic women, we studied postmenopausal women enrolled in the Women's Health Initiative. Postmenopausal White women with mild renal dysfunction were at increased risk of nonvertebral fracture; this association was at least partially explained by effects of renal dysfunction on chronic inflammation. Reduced renal function appeared to increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups. INTRODUCTION: The purpose of this study was to determine whether renal function is associated with fracture risk within racial/ethnic groups. METHODS: A nested case-control study was conducted among 93,673 postmenopausal women; incident nonvertebral fractures were identified in 362 Black, 183 Hispanic, 110 Asian, and 45 American-Indian women. A random sample of 395 White women with incident nonvertebral fracture was chosen. One nonfracture control for each case was selected (matched on age, race/ethnicity, and blood draw date). Cystatin C levels were measured using baseline serum, and estimated glomerular filtration rate calculated (eGFR(cys-c)). RESULTS: Each 1 SD increase in cystatin C was associated with a 1.2-fold increased risk of fracture among White women (adjusted odds ratios [OR], 1.23; 95% confidence intervals [CI], 1.04-1.46). The OR of fracture was 1.16 (95% CI, 0.85-1.58) among women with eGFR(cys-c) 60-90 mL/min/1.73 m(2) and 2.46 (95% CI, 1.16-5.21) among those with eGFR(cys-c) <60 mL/min/1.73 m(2) compared to the reference group (eGFR(cys-c) >90 mL/min/1.73 m(2)) (p trend = 0.05). The association was reduced after adjustment for cytokine TNFα soluble receptors (OR, 1.62; 95% CI, 0.59-4.46 for eGFR(cys-c) <60 mL/min/1.73 m(2)). Among Blacks, there was an association between cystatin C and fracture risk (OR per 1 SD increase, 1.15; 95% CI, 1.00-1.32); after adjustment, this association was only modestly attenuated, but no longer statistically significant. There was no evidence of significant associations among Hispanic, Asian, or American-Indian women. CONCLUSION: Postmenopausal White women with mild renal dysfunction are at increased risk of nonvertebral fracture. Effects of renal function on chronic inflammation may mediate this association. Reduced renal function may increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups.

Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome.

We studied a 55-year old woman presenting with features of Cushing's syndrome associated with metabolic abnormalities including severe hypertension and type 2 diabetes. Urinary free cortisol excretion was within normal limits, but an unusual diurnal cortisol rhythm was observed with low morning and high postprandial levels, associated with the absence of cortisol suppression after dexamethasone, suggesting the possibility of GIP-dependent Cushing's syndrome. The diagnosis was confirmed by further investigations, showing significant plasma cortisol responses after a mixed meal test and after oral, but not intravenous glucose administration, as well as ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH). An aberrant increase in cortisol was also observed after glucagon and terlipressin injections. The patient was first treated with octreotide 100-250 µg thrice daily for 6 months, then with the new multi-ligand somatostatin analogue (SOM 230) 450-900 µg twice daily for 3 months. Although inducing a significant acute suppression of post-prandial cortisol response, both drugs had no effects on the clinical and metabolic abnormalities associated with Cushing's syndrome and new tests performed at the end of each treatment period confirmed escape of post-meal cortisol suppression to therapy. The patient finally underwent a bilateral adrenalectomy, which markedly improved her medical condition and allowed in vitro confirmation by real time RT-PCR quantification of a high aberrant expression of GIP receptor mRNA in adrenal tissue. This case report illustrates the lack of sustained efficacy of somatostatin analogues on GIP-dependent Cushing's syndrome, independent of their affinity for the different somatostatin receptor subtypes.

Aberrant hormone receptors in primary aldosteronism.

The mechanisms involved in the renin-independent regulation of aldosterone secretion in primary aldosteronism are poorly understood. In ACTH-independent Cushing's syndrome, cortisol secretion can be regulated by the aberrant expression of G-protein coupled receptors (GPCRs) in unilateral tumors and bilateral macronodular adrenal hyperplasia. By analogy, some recent studies identified overexpression or function of several GPCR as a potential cause for excess aldosterone production in some aldosteronomas and in bilateral idiopathic hyperaldosteronism. Initial studies have used in vitro techniques, while the clinical aldosterone responses were not assessed. More recently, several receptors have been shown to be expressed in aldosterone-producing adrenal tumors in vitro and to regulate aberrantly renin-independent aldosterone secretion in vivo. The prevalence of aberrant hormone receptors in primary aldosteronism could be elevated, but larger systematic studies are required to establish its true frequency. The identification of aberrant adrenal GPCRs by in vivo functional studies offers the potential for novel pharmacological therapies that either suppress the endogenous ligands or block the receptor with specific antagonists.

Clinical and biochemical features of seven adult adrenal ganglioneuromas.

BACKGROUND: Adrenal ganglioneuroma (GN) is seldom considered in the differential diagnosis of adrenal lesions, and its clinical presentation is not well known. OBJECTIVE: Our aim was to describe the clinical, biochemical, and radiological features of adrenal GNs in adults. METHODS: Seven adults underwent endocrine investigation for adrenal lesions that were confirmed to be adrenal GNs. RESULTS: Mean age of the seven patients was 49 yr (range, 23 to 71 yr). Average tumor diameter was 5.0 cm (range, 1.5 to 10.4 cm). In five patients, the adrenal lesions were found incidentally. A 49-yr-old female carried a germline mutation in MSH2 gene. A 57-yr-old female presented with mild virilization and increased testosterone levels. Bilateral adrenal venous sampling revealed testosterone production from her right adrenal lesion. All tumors showed nonenhanced attenuation between 25 and 40 Hounsfield units on computed tomography scan. Magnetic resonance imaging revealed low- to iso-signal intensity on T1-weighted imaging and high-signal intensity on T2-weighted imaging. [(18)F]-2-Fluoro-deoxy-d-glucose-positron emission tomography scan (n = 5) disclosed a mean standard uptake value of 2.4. Three tumors were composite pheochromocytoma-GN. Microsatellite instability study and immunohistochemical analysis of MSH2 protein in a patient carrying a MSH2 mutation showed normal MSH2 protein expression and low microsatellite instability, indicating that the adrenal GN was not related to the patient's MSH2 germline defect. CONCLUSIONS: We describe one of the largest series of adult adrenal GNs. Adrenal GNs may secrete testosterone or be part of a composite tumor with pheochromocytoma. The association of adrenal GN with MSH2 mutation seems to be a coincidental finding.

Baseline serum estradiol and fracture reduction during treatment with hormone therapy: the Women's Health Initiative randomized trial.

INTRODUCTION: The purpose of the study was to test the hypothesis that the reduction in fractures with hormone therapy (HT) is greater in women with lower estradiol levels. METHODS: We conducted a nested case-control study within the Women's Health Initiative HT Trials. The sample included 231 hip fracture case-control pairs and a random sample of 519 all fracture case-control pairs. Cases and controls were matched for age, ethnicity, randomization date, fracture history, and hysterectomy status. Hormones were measured prior to randomization. Incident cases of fracture were identified over an average follow-up of 6.53 years. RESULTS: There was no evidence that the effect of HT on fracture differed by baseline estradiol (E2) or sex hormone binding globulin (SHBG). Across all quartiles of E2 and SHBG, women randomized to HT had about a 50% lower risk of fracture, including hip fracture, compared to placebo. CONCLUSION: The effect of HT on fracture reduction is independent of estradiol and SHBG levels.

Food-dependent Cushing's syndrome.

It has recently been proposed that other hormones than ACTH can control cortisol production in Cushing's syndrome with bilateral adrenal hyperplasia. We present a case of food-dependent Cushing's syndrome. After a positive response of cortisol production during mixed meals, several tests identified glucose-dependent insulinotropic polypeptide (GIP) as the driving hormone responsible for the cortisol overproduction. Identification of aberrant hormone receptor expression is of importance because it may create a possibility for pharmacological treatment.

Obesity and risk of pancreatic cancer among postmenopausal women: the Women's Health Initiative (United States).

A total of 138,503 women in the Women's Health Initiative in the United States were followed (for an average of 7.7 years) through 12 September 2005 to examine obesity, especially central obesity in relation to pancreatic cancer (n=251). Women in the highest quintile of waist-to-hip ratio had 70% (95% confidence interval 10-160%) excess risk of pancreatic cancer compared with women in the lowest quintile.

Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement.

OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations. EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

Cross-sectional correlates of fasting hyperinsulinaemia in post-menopausal women of different ethnic origin.

AIMS: In a large ethnically diverse nationwide sample of post-menopausal women we explored the relationship between fasting insulin levels, ethnicity, and a wide range of anthropometric, socio-economic, and lifestyle factors. METHODS: Subjects were post-menopausal women aged 50-79 years without diagnosed diabetes mellitus comprising a subsample (n = 3500) of the Women's Health Initiative (WHI) Clinical Trial and Observational Study. In a cross-sectional survey at baseline, we analysed the association between ethnicity and fasting insulin using analysis of covariance procedures and identified independent correlates of hyperinsulinaemia, defined by the 75th percentile cut point for each ethnic group. RESULTS: Fasting insulin levels were higher among African-American and Hispanic women than among non-Hispanic White or Asian women. These differences persisted after adjustment for age, educational attainment, total and central body obesity, adult weight change, family history of diabetes, smoking status, alcohol consumption, use of menopausal hormone therapy and physical activity. Higher levels of body mass index, waist-hip ratio, adult weight gain, and lower levels of total and moderate or strenuous recreational activity were independent correlates of fasting hyperinsulinaemia. Habitual walking was also inversely associated with fasting insulin. CONCLUSIONS: In this cross-sectional analysis, fasting insulin levels were higher among African-American and Hispanic post-menopausal women as compared with non-Hispanic White and Asian women. In addition, obesity, adult weight gain, and low levels of moderate or strenuous physical activity were independently associated with hyperinsulinaemia.

Correlation between nutritional biomarkers and breast cancer: a case-control study.

A case-control study to explore associations between retinoids, tocopherols, total and beta-carotenes and breast cancer was conducted by analysing concentrations of these biomarkers in adipose tissue, cheek cells and plasma. A total of 414 French-Canadians in Montreal with new diagnoses of breast cancer were age-matched to 429 population-based controls. Subjects were interviewed using a questionnaire, and biological samples from 287 cases and 112 controls were collected within 3 months of the diagnosis. Mean beta carotene concentrations in cheek cells were significantly lower among controls. Odds ratios (ORs) from logistic regression analysis were used to compare higher and lower tercile concentrations. Significant positive associations were observed in adipose tissue for retinoid [OR=2.11; 95% CI (1.09-4.08)] and beta carotene [OR=3.18; 95% CI (1.70-5.93)]; in cheek cells for beta carotene [OR=2.22; 95% CI (1.21-4.50)] and for total carotenes [OR=2.94; 95% CI (1.59-5.42)] and in plasma for beta carotene [OR=1.53; 95% CI (0.80-2.93)] and total carotenes [OR=1.04; 95% CI (0.53-2.05)]. Among the control groups, significant Pearson correlations were observed between cheek cells and adipose tissue for total carotenes (r=0.27; p=0.01) and cheek cells and plasma (r=0.22; p=0.04). In contrast to previous works, this study shows that high concentrations of retinoids and carotenes in adipose tissue and cheek cells are associated with increased risk of breast cancer. However, all these studies are limited by small sample size. Although our study tested a limited number of controls, important associations were observed. These results suggest that the effect of disease on biomarkers is fundamental to the interpretation of epidemiological data. We suggest either that the high levels of these biomarkers found in cancer patients in this study may be due to the disease process that affects the pharmacokinetics of the biomarker or that the disease causes a change in dietary habits. In addition, in studies involving the application of biomarkers to cancer epidemiology it is imperative that a typical biomarker concentration is not associated with breast cancer risk before further examination of the methodological limitations of epidemiological studies investigating this relationship. Therefore, sample size, selection bias, information bias, and confounding should be considered in the design of studies investigating the aetiological relationship between biomarkers and breast cancer.

Analysis of the putative regulatory region of the gastric inhibitory polypeptide receptor gene in food-dependent Cushing's syndrome.

Gastric inhibitory polypeptide (GIP)-dependent Cushing's syndrome (CS) results from the ectopic expression of non-mutated GIP receptor (hGIPR) in the adrenal cortex. We evaluated whether mutations or polymorphisms in the regulatory region of the GIPR gene could lead to this aberrant expression. We studied 9.0kb upstream and 1.3kb downstream of the GIPR gene putative promoter (pProm) by sequencing leukocyte DNA from controls and from adrenal tissues of GIP- and non-GIP-dependent CS patients. The putative proximal promoter region (800 bp) and the first exon and intron of the hGIPR gene were sequenced on adrenal DNA from nine GIP-dependent CS, as well as on leukocyte DNA of nine normal controls. Three variations found in this region were found in all patients and controls; at position -4/-5, an insertion of a T was seen in four out of nine patients and in five out of nine controls. Transient transfection studies conducted in rat GC and mouse Y1 cells showed that the TT allele confers loss of 40% in the promoter activity. The analysis of the 8-kb distal pProm region revealed eight distal single nucleotide polymorphisms (SNPs) without probable association with the disease, since frequencies in patients and controls were very similar. In conclusion, mutations or SNPs in the regulatory region of the GIPR gene are unlikely to underlie GIP-dependent CS.