Diverse presentations of Cushing's syndrome during pregnancy - A case series.

BACKGROUND: Cushing's syndrome (CS) encompasses various causes of hypercortisolism including adrenocorticotropic hormone (ACTH) secreting pituitary adenoma with or without bilateral adrenal hyperplasia, an adrenal adenoma or carcinoma, ectopic ACTH or corticotrophin-releasing hormone (CRH) secretion by a neoplasm or exogenous corticosteroid therapy. The diagnosis of CS in pregnancy presents a challenge due to overlapping clinical features of pregnancy (weight gain, striae, acne). If untreated, CS in pregnancy is associated with increased risk of maternal and fetal complications. AIMS: With fewer than 250 cases currently published, we aim to review the clinical presentations, diagnostic methods, management, and outcomes of patients with CS in pregnancy to help optimise our clinical practice. MATERIALS AND METHODS: This is a single-centre, retrospective review of woman with documented hypercortisolism receiving antenatal care at a tertiary maternity hospital in Perth between 2006 to 2022. Data were collated from electronic and chart reviews. OMNI calculator was used for birthweight calculations. Local ethics and patient consent were obtained. RESULTS: Five women and seven pregnancies were identified. Four women had a pituitary source of ACTH-dependent CS as confirmed by brain magnetic resonance imaging. One woman had an ectopic source of ACTH. Two women were diagnosed during pregnancy. All pregnancies occurring prior to treatment of the Cushing's disease were complicated by secondary hypertension and diabetes. CONCLUSION: CS represents a rare and difficult to diagnose condition in pregnancy. When untreated, maternal and fetal outcomes are compromised. Close monitoring of the associated complications with involvement of a multidisciplinary team are recommended.

Anti-Müllerian hormone concentration is associated with central adiposity and reproductive hormones in expectant fathers.

OBJECTIVE: The role of the anti-Müllerian hormone (AMH) as an indicator of physical and reproductive health in men is unclear. We assessed the relationships between AMH and follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and metabolic parameters, in a cohort of expectant fathers. DESIGN: ORIGINS Project prospective cohort study. SETTING: Community-dwelling men. PARTICIPANTS: Partners of pregnant women attending antenatal appointments. MAIN OUTCOME MEASURES: Serum AMH, FSH, LH, testosterone, and metabolic parameters. RESULTS: In 485 expectant fathers, median age 33 years, median AMH was 40 pmol/L (quartiles 29, 56). AMH was inversely correlated with FSH, age, and body mass index (BMI) (correlation coefficients: -.32, -.24, and -.17 respectively). The age association was nonlinear, with peak AMH between 20 and 30 years, a decline thereafter, and somewhat steady levels after 45 years. The inverse association of AMH with FSH was log-linear and independent of age and BMI (ß: -.07, SE: 0.01, p < .001). AMH was inversely correlated with waist circumference and directly associated with sex hormone-binding globulin. Testosterone was moderately correlated with AMH (correlation coefficient: .09, ß: .011, SE: 0.004, p = .014): this association was mediated by an inverse relationship with BMI (mediated proportion 0.49, p < .001). CONCLUSIONS: In reproductively active men, lower AMH is a biomarker for advancing age, and for poorer metabolic and reproductive health. The inverse association between AMH and FSH is independent of age and BMI, whereas the association of AMH and testosterone is mediated via BMI. The utility of AMH to predict reproductive and cardiometabolic outcomes in men warrants further investigation.

Decreased Immunoglobulin G Core Fucosylation, A Player in Antibody-dependent Cell-mediated Cytotoxicity, is Associated with Autoimmune Thyroid Diseases.

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.

In infants with sufficient vitamin D status at birth, vitamin D supplementation does not impact immune development.

BACKGROUND: Low vitamin D levels have been associated with allergic diseases. Vitamin D has potent immunomodulatory properties, but the mechanisms remain unclear. We have investigated the effect of oral vitamin D supplementation on circulating immune cell phenotypes in infants. METHOD: A double-blinded randomised controlled trial was conducted to investigate the effect of oral vitamin D supplementation (400 IU/d) on eczema and immune development. A subset of 78 infants was included in this analysis. Phenotypic analysis of immune cell subsets was performed using flow cytometry. RESULTS: Vitamin D supplementation resulted in median 25(OH)D levels of 80.5 vs 59.5 nmol/L in the placebo group at 3 months of age (P = .002) and 87.5 vs 77 nmol/L at 6 months of age (P = .08). We observed significant changes in immune cell composition from birth (cord blood) to 6 months of age. Vitamin D supplementation did not impact these changes, nor did immune cell composition correlate with plasma 25(OH)D levels. Through exploratory analysis, we identified possible associations with eczema development and increased abundance of naïve CD4- T cells at birth, as well as associations with basophils, iNKT and central memory CD4+ T cells, and altered expression patterns of IgE receptor (FcεR1) on monocytes and dendritic cells with eczema at 6 months. CONCLUSIONS: Vitamin D supplementation in infants who were vitamin D sufficient at birth did not affect developmental changes in immune cells during the first 6 months of life. However, immune cell profiles at birth and at 6 months of age were associated with early life eczema.

Direct infant UV light exposure is associated with eczema and immune development.

BACKGROUND: Suboptimal vitamin D levels during critical periods of immune development have emerged as an explanation for higher rates of allergic diseases associated with industrialization and residing at higher latitudes. OBJECTIVE: We sought to determine the effects of early postnatal vitamin D supplementation on infant eczema and immune development. METHODS: By using a double-blind randomized controlled trial, newborn infants were randomized to receive vitamin D supplementation (400 IU/d) or a placebo until 6 months of age. Some infants also wore personal UV dosimeters to measure direct UV light (290-380 nm) exposure. Infant vitamin D levels were measured at 3 and 6 months of age. Eczema, wheeze, and immune function outcomes were assessed at 6 months of age. RESULTS: At 3 (P < .01) and 6 (P = .02) months of age, vitamin D levels were greater for the vitamin D-supplemented group than the placebo group, but there was no difference in eczema incidence between groups. Infants with eczema were found to have had less UV light exposure (median, 555 Joules per square meter [J/m2; interquartile range, 322-1210 J/m2]) compared with those without eczema (median, 998 J/m2 [interquartile range, 676-1577 J/m2]; P = .02). UV light exposure was also inversely correlated with IL-2, GM-CSF, and eotaxin production to Toll-like receptor ligands. CONCLUSION: This study is the first to demonstrate an association between greater direct UV light exposures in early infancy with lower incidence of eczema and proinflammatory immune markers by 6 months of age. Our findings indicate that UV light exposure appears more beneficial than vitamin D supplementation as an allergy prevention strategy in early life.

Serum 25-hydroxyvitamin D as a predictor of mortality and cardiovascular events: A 20-year study of a community-based cohort.

OBJECTIVE: Prospective studies, mostly from Europe and North America, suggest that serum 25-hydroxyvitamin D (25(OH)D) is inversely associated with mortality and cardiovascular disease (CVD) risk. Data from other regions are limited, and threshold levels for adverse cardiovascular outcomes are uncertain. We examined serum 25(OH)D as a predictor of total mortality and cardiovascular outcomes in an Australian cohort. DESIGN: A 20-year, community-based cohort study. PATIENTS: Participants in the 1994/1995 Busselton Health Survey (n = 3946, baseline age 25-84 years). MEASUREMENTS: Baseline serum 25(OH)D and mortality and cardiovascular outcomes to 2014 obtained by record linkage. RESULTS: The mean serum 25(OH)D concentration was 60.6 ± 18.0 nmol/L. During 20-year follow-up (excluding the first 2 years), 889 participants died (including 363 from CVD) and 944 experienced a CVD event (including 242 with heart failure). In the full cohort, controlling for Framingham risk score variables, higher baseline 25(OH)D was associated with significantly reduced all-cause mortality (adjusted HR 0.83 per SD increment of 25(OH)D, 95% CI 0.77-0.90), CVD death (HR 0.85, 95% CI 0.74-0.96) and heart failure (HR 0.81, 95% CI 0.69-0.94), but not CVD events (HR 0.99, 0.92-1.07). In restricted cubic spline regression models, serum 25(OH)D below 65 and 55 nmol/L was associated with higher total mortality and higher CVD mortality/heart failure, respectively. In participants without CVD at baseline (n = 3220), results were similar, but hazard ratios were attenuated and associations with CVD mortality no longer significant. CONCLUSIONS: In an Australian community-based cohort, baseline vitamin D levels below 55-65 nmol/L are predictive of all-cause mortality, CVD death and heart failure.

Prevalence and prognosis of a low serum testosterone in men with type 2 diabetes: the Fremantle Diabetes Study Phase II.

BACKGROUND: Because published studies have usually involved imprecise assays and selected patients with limited additional data and follow-up, the consequences of a low serum testosterone in diabetes are unclear. This study assessed the prevalence, associates and prognosis of a low testosterone in community-dwelling men with type 2 diabetes. DESIGN: Longitudinal observational study. PATIENTS: 788 men (mean ± SD age: 65·8 ± 11·3 years) followed for 4·0 ± 1·1 years. MEASUREMENTS: Serum testosterone, SHBG, erectile dysfunction (ED; Sexual Health Inventory for Men score <22), anaemia (haemoglobin <130 g/l), all-cause mortality. RESULTS: The mean ± SD total serum testosterone by liquid chromatography/mass spectrometry was 13·1 ± 5·9 nmol/l (30·6% <10 nmol/l). Most men with a total testosterone <10 nmol/l (67·0%) had a normal/low serum LH. Serum testosterone was independently associated with anaemia (P < 0·001), but not ED (P = 0·80), in logistic regression models. The optimal cut-point (Youden Index) for anaemia was 9·8 nmol/l (sensitivity 53·6%, specificity 75·4%). During the follow-up, 102 men (12·9%) died. There was a U-shaped relationship between total serum testosterone quintiles and death (P = 0·003, log rank test). The middle quintile (>11·1 to ≤13·7 nmol/l) had the lowest risk and there was a 78% increased risk for highest (>16·9 nmol/l) vs lowest (≤8·6 nmol/l) quintile in Cox proportional hazards modelling (P = 0·036). Free serum testosterone and SHBG quintiles were not associated with death. CONCLUSIONS: These data provide some support for the general conventional serum testosterone <10 nmol/l cut-point in identifying an increased risk of anaemia and the subsequent death in men with type 2 diabetes, but indicate that high-normal levels are also an adverse prognostic indicator.

Vitamin D and cancer mortality in elderly women.

BACKGROUND: There is increasing evidence that vitamin D deficiency is a risk factor for cancer, however it remains uncertain whether vitamin D deficiency also predisposes to death from cancer. The aim of the study was to determine the association between serum 25-hydroxy-vitamin D (25 (OH) D) concentrations and cancer-specific mortality in a community-based cohort of older post-menopausal women. METHODS: Cox proportional regression analyses were conducted to examine the association between serum 25 (OH) D concentrations and the risk of overall and site-specific cancer mortality in a cohort of elderly women. RESULTS: Over a median follow-up time of 10 years, a total of 84 cancer deaths were observed. Women with lower serum 25 (OH) D concentrations were at an increased risk of cancer death, but not for incident cancer. The excess risk for cancer death was observed with serum 25 (OH) D concentration less than 64 nmol/L (the median value) [adjusted HR: 1.61 (95% CI: 1.02 - 2.54, p = 0.04]. For every 30 nmol/L reduction in serum 25 (OH) D concentrations, there was a 30% increase in the overall risk of cancer death [adjusted HR: 1.33; 95% CI: 1.03 - 1.72, p = 0.02]. The excess risk appeared to be site-specific and greatest in those with haematological cancers [adjusted HR: 2.13: 95% CI: 1.0 - 4.55, p = 0.05]. CONCLUSIONS: In elderly women, lower serum 25 (OH) D concentrations appear to be an independent risk factor for cancer-specific mortality, but not a risk factor for the development of cancer.

Antecedent hypoglycaemia does not diminish the glycaemia-increasing effect and glucoregulatory responses of a 10 s sprint in people with type 1 diabetes.

AIMS/HYPOTHESIS: A 10 s sprint has been reported to provide a means to prevent acute post-exercise hypoglycaemia in young adults with type 1 diabetes because of its glycaemia-raising effect, but it is unclear whether this effect is impaired by antecedent hypoglycaemia. The purpose of this study was to investigate whether antecedent hypoglycaemia impairs the glycaemia-raising effect of a 10 s sprint in individuals with type 1 diabetes. METHODS: Eight individuals underwent a hyperinsulinaemic-hypoglycaemic or hyperinsulinaemic-euglycaemic clamp on two separate mornings. Thereafter, the participants underwent a basal insulin-euglycaemic clamp before performing a 10 s sprint on a cycle ergometer. The levels of blood glucose and glucoregulatory hormones and rates of glucose appearance (Ra) and disappearance (Rd) were compared between conditions. RESULTS: During the morning clamps, blood glucose levels were significantly different between conditions of hypoglycaemia (2.8 ± 0.1 mmol/l) and euglycaemia (5.4 ± 0.2 mmol/l; p < 0.001). Mean glycaemia prior to sprinting was similar (5.6 ± 0.4 and 5.5 ± 0.3 mmol/l for hypoglycaemic and euglycaemic conditions, respectively; p = 0.83). In response to the afternoon sprint, the pattern of increase in blood glucose levels did not differ between conditions, reaching similar maximal levels 45 min after exercise (6.5 ± 0.4 and 6.6 ± 0.3 mmol/l, respectively; p = 0.43). The early post-exercise patterns in glucose Ra and Rd and increases in plasma adrenaline (epinephrine), growth hormone and cortisol levels did not differ between conditions. CONCLUSIONS/INTERPRETATION: Hypoglycaemia in the morning does not diminish the glycaemia-raising effect of an afternoon 10 s sprint in young adults with type 1 diabetes, suggesting that sprinting is a useful strategy for opposing hypoglycaemia, regardless of prior hypoglycaemia.

How good is a morning cortisol in predicting an adequate response to intramuscular synacthen stimulation?

CONTEXT: Previous studies have demonstrated that a morning serum cortisol of <100 nmol/l makes further dynamic testing such as the Synacthen stimulation test (SST) unnecessary to confirm adrenal insufficiency. The morning cortisol level that reliably predicts adrenal sufficiency (AS) is less well established, and values ranging from 300 to 500 nmol/l have been proposed. OBJECTIVE: The aim of this study was to determine the ambulatory morning cortisol level that predicts adrenal sufficiency, as defined by an adequate response to SST, using a receiver operating characteristics (ROC) curve. DESIGN: Observational retrospective cross-sectional study. METHOD & SUBJECTS: We conducted a retrospective audit of SST performed at PathWest Laboratory QEII from January 2006 to August 2008. A total of 761 results were obtained. Patients who were acutely ill or in intensive care, on glucocorticoid therapy, and those with inadequate data or multiple records were excluded from the analysis leaving 505 available for analysis. Baseline serum was obtained prior to intramuscular injection of 250 mcg Synacthen, and a second sample was obtained 30 min post-Synacthen. AS was defined as a 30-min post-Synacthen cortisol of >550 nmol/l; values ≤550 nmol/l were considered inadequate. RESULTS: Based on SST criteria, of the 505 patients included in the study, 350 patients (69%) were adrenal sufficient and 155 (31%) had adrenal insufficiency. Using the minimum ROC distance criterion, a basal cortisol value of >236 nmol/l was identified to predict AS with sensitivity 84% and specificity 71%. However, to increase the specificity to 95%, we recommend a basal cortisol cut-off of >375 nmol/l. For patients with known pituitary disease (n = 152), basal cortisol of >214 nmol/l (sensitivity 85% and specificity 71%) may obviate the need for SST in the appropriate clinical context, although 330 nmol/l gives a specificity of 95%. CONCLUSION: Basal morning cortisol is a viable first step in the evaluation of patients with suspected adrenal insufficiency.

Effect of continuous positive airway pressure therapy on sexual function and serum testosterone in males with type 2 diabetes and obstructive sleep apnoea.

OBJECTIVE: There have been no studies of the effect of continuous positive airway pressure (CPAP) therapy on erectile dysfunction (ED) and serum testosterone in men with type 2 diabetes and obstructive sleep apnoea (OSA), a patient group at increased risk of ED and hypogonadism. The aim of this study was to determine whether CPAP improves sexual and gonadal function in males with type 2 diabetes and a pre-CPAP apnoea-hypopnoea index >15/h. DESIGN: Substudy of a trial assessing the effect of 3 months of CPAP on cardiovascular risk in type 2 diabetes. PATIENTS: Of 35 males starting CPAP, 27 (mean ± SD age 65.4 ± 9.6 years, median [interquartile range] diabetes duration 12.1 [5.2-15.3] years) completed the trial. MEASUREMENTS: Serum total and free testosterone, responses to the Androgen Deficiency in the Aging Aale (ADAM) and Sexual Health Inventory for Men (SHIM) questionnaires. RESULTS: There were no significant changes in mean total or free testosterone (baseline concentrations 12.7 ± 4.5 nm and 0.26 ± 0.07 pm, respectively), or SHIM score (baseline 13 [5-17]), after 3 months of CPAP (P > 0.20). The ADAM score (baseline 6.2 ± 2.1) fell after 1 month (to 5.0 ± 2.6) and was maintained at this level at 3 months (P = 0.015). The Epworth Sleepiness Scale score decreased and self-reported physical activity increased over 3 months (P ≤ 0.017) without a change in body mass index (P = 1.00). CONCLUSIONS: These findings imply that CPAP therapy improves somnolence and promotes exercise in men with type 2 diabetes, but that there is no direct benefit for gonadal or sexual function.

Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial.

IMPORTANCE: Hypoglycemia is a critical obstacle to the care of patients with type 1 diabetes. Sensor-augmented insulin pump with automated low-glucose insulin suspension has the potential to reduce the incidence of major hypoglycemic events. OBJECTIVE: To determine the incidence of severe and moderate hypoglycemia with sensor-augmented pump with low-glucose suspension compared with standard insulin pump therapy. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial involving 95 patients with type 1 diabetes, recruited from December 2009 to January 2012 in Australia. INTERVENTIONS: Patients were randomized to insulin pump only or automated insulin suspension for 6 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the combined incidence of severe (hypoglycemic seizure or coma) and moderate hypoglycemia (an event requiring assistance for treatment). In a subgroup, counterregulatory hormone responses to hypoglycemia were assessed using the hypoglycemic clamp technique. RESULTS: Of the 95 patients randomized, 49 were assigned to the standard-pump (pump-only) therapy and 46 to the low-glucose suspension group. The mean (SD) age was 18.6 (11.8) years; duration of diabetes, 11.0 (8.9) years; and duration of pump therapy, 4.1 (3.4) years. The baseline rate of severe and moderate hypoglycemic events in the pump-only group was 20.7 vs 129.6 events per 100 patient months in the low-glucose suspension group. After 6 months of treatment, the event rates decreased from 28 to 16 in the pump-only group vs 175 to 35 in the low-glucose suspension group. The adjusted incidence rate per 100 patient-months was 34.2 (95% CI, 22.0-53.3) for the pump-only group vs 9.5 (95% CI, 5.2-17.4) for the low-glucose suspension group. The incidence rate ratio was 3.6 (95% CI, 1.7-7.5; P <.001). There was no change in glycated hemoglobin in either group: mean, 7.4 (95% CI, 7.2-7.6) to 7.4 (95% CI, 7.2-7.7) in the pump-only group vs mean, 7.6 (95%, CI, 7.4-7.9) to 7.5 (95% CI, 7.3-7.7) in the low-glucose suspension group. Counterregulatory hormone responses to hypoglycemia were not changed. There were no episodes of diabetic ketoacidosis or hyperglycemia with ketosis. CONCLUSIONS AND RELEVANCE: Sensor-augmented pump therapy with automated insulin suspension reduced the combined rate of severe and moderate hypoglycemia in patients with type 1 diabetes. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12610000024044.

Serum 21-Deoxycortisol for Diagnosis of Nonclassic Congenital Adrenal Hyperplasia in Women With Androgen Excess.

CONTEXT: Nonclassic congenital adrenal hyperplasia (NCCAH) requires exclusion before diagnosing polycystic ovary syndrome (PCOS). Increasing use of liquid chromatography and tandem mass spectrometry (LC-MS/MS) necessitates revision of immunoassay-based criteria for NCCAH. Measurement of 21-deoxycortisol (21DF) may simplify the diagnosis of heterozygosity (HTZ), the presence of 1 affected CYP21A2 allele, which currently relies on complex molecular studies. OBJECTIVE: We aimed to determine LC-MS/MS-specific criteria for NCCAH and HTZ and compare the diagnostic accuracy of 21DF and 17-hydroxyprogesterone (17OHP). METHODS: A cross-sectional study involving 99 hyperandrogenic females was performed. We identified females who had undergone both a synacthen stimulation test (SST) and CYP21A2 genotyping from 2010 to 2017, and prospectively recruited females referred for an SST to investigate hyperandrogenic symptoms from 2017 to 2021. Steroids were compared between genetically confirmed NCCAH, HTZ, and PCOS. Optimal 17OHP and 21DF thresholds for HTZ and NCCAH were determined by receiver operating characteristic analysis. RESULTS: Basal 17OHP, stimulated 17OHP, and 21DF were measured in 99, 85, and 42 participants, respectively. Optimal thresholds for NCCAH were 3.0 nmol/L and 20.7 nmol/L for basal and stimulated 17OHP, respectively. Basal and stimulated 21DF thresholds of 0.31 nmol/L and 13.3 nmol/L provided 100% sensitivity with specificities of 96.8% and 100% for NCCAH, respectively. Diagnostic thresholds for HTZ of 8.0 nmol/L, 1.0 nmol/L, and 13.6 for stimulated 17OHP, 21DF, and the ratio (21DF + 17OHP)/cortisol each provided 100% sensitivity with specificities of 80.4%, 90.5%, and 85.0%, respectively. CONCLUSION: LC-MS/MS-specific 17OHP thresholds for NCCAH are lower than those based on immunoassay. LC-MS/MS-quantified 17OHP and 21DF accurately discriminate HTZ and NCCAH from PCOS.

Estimated glomerular filtration rate as an independent predictor of atherosclerotic vascular disease in older women.

BACKGROUND: Estimated glomerular filtration rate (eGFR) levels have been shown to predict atherosclerotic vascular disease hospitalization and mortality. We sought to investigate the role of renal function in the prediction of 10-year atherosclerotic vascular hospitalization and deaths in an unselected population of elderly women and compared these predictions to Framingham equations. METHODS: Complete 10-year verified mortality and hospitalization discharge records for atherosclerotic vascular disease were collected for a prospective study of 1,239 unselected female subject's ≥ 70 from the Calcium Intake Fracture Outcome Study (CAIFOS) with 10 years of follow-up. eGFR was compared to the current Framingham risk scores. RESULTS: The eGFR at baseline using the Modification of Diet in Renal Disease Study (MDRD) equation was 65.2 ± 14.5 mL/min/1.73 m(2) and 66.3 ± 13.5 mL/min/1.73 m(2) using the Chronic Kidney Disease EPIdemiology (CKD-EPI) equation. Over 10 years 30% of participants sustained an ASVD hospitalization or death. For every standard deviation (SD) reduction in eGFR using MDRD the odds ratio (OR) for ASVD hospitalization and deaths increased by 1.34 (1.18-1.53), P < 0.00 and 1.31 (1.14-1.50), P < 0.001 in a model adjusted for Framingham 10-year general cardiovascular risk. Addition of eGFR by the MDRD equation to Framingham risk factors improved the net reclassification index by 5.9%, P = 0.018 and the integrated discrimination improvement by 0.010 ± 0.003, P < 0.001 Similar results were seen using the CKD-EPI equation. CONCLUSION: Estimated glomerular filtration rate predicts ASVD outcomes independently of Framingham risk score predictions in elderly women and improves clinical prediction particularly of early ASVD.

Waiting for an elevated FSH--too late a marker of reduced ovarian reserve?

AIM: To assess age at which median follicle-stimulating hormone (FSH) is elevated above 10 U/L. BACKGROUND: Fertility and ovarian reserve decrease over the 4th decade with evidence that sensitive markers such as anti-Mullerian hormone fall even earlier. Despite its limitations, a basal or day 2-3 FSH is commonly used to assess ovarian reserve with levels over 10 U/L often used as a cut-point for further investigations. METHODS: Women referred to a community laboratory for 'hormone testing', including FSH and oestradiol (n = 40 254), were included in a retrospective analysis. Cases excluded were those with suppressed FSH (<1 U/L) who were likely on the oral contraceptive pill or pregnant and those with increased oestradiol (>500 pmol/L) who were likely approaching mid-cycle or pregnant. Remaining cases (n = 32 445) were analysed in five-year age bands for FSH median, mean, and 2.5 and 97.5 percentiles. RESULTS: Median FSH remained consistently low (≤5 U/L) in women ≤35 years of age and was 6 U/L in 35- to 40-year-olds. The mean FSH and 97.5 percentile increased steadily. The 97.5th percentile was 10 U/L or lower in women up to 30 years of age. CONCLUSIONS: Follicle-stimulating hormone is a late indicator of known reducing ovarian reserve, and in this study, median FSH did not increase over 10 U/L until >45 years of age. FSH levels >9 U/L were above the 97.5th percentile in those <25 years of age. If fertility is a concern, FSH levels persistently above age-specific medians in women under 40 years may prompt earlier follow-up with more sensitive tests for ovarian reserve.

Longitudinal Stability of Vitamin D Status and Its Association With Bone Mineral Density in Middle-aged Australians.

Context: The skeletal effects of vitamin D remain controversial and it is uncertain whether variation in serum 25-hydroxyvitamin D (25OHD) levels over time influences bone mineral density (BMD). Objective: We evaluated longitudinal stability of serum 25OHD and associations with changes in BMD in participants aged 46-70 years at baseline. Methods: We studied 3698 Busselton Healthy Ageing Study participants (2040 female) with serum 25OHD and dual-energy x-ray absorptiometry (DXA) BMD assessments at baseline and at ∼6 years follow-up. Restricted cubic splines were used to evaluate associations between changes in 25OHD and BMD. Results: Mean season-corrected serum 25OHD was 81.3 ± 22.7 and 78.8 ± 23.1 nmol/L at baseline and 6 years, respectively, and showed moderate correlation (intraclass correlation coefficient: 0.724). Significant predictors of change in 25OHD concentration (Δ25OHD) included baseline 25OHD, change in body mass index and vitamin D supplementation at follow-up. Greater decline in serum 25OHD over time was associated with significantly greater reduction in BMD at total hip and femoral neck, but the magnitude of the differences was small (estimated differences 0.004 g/cm2 and 0.005-0.007 g/cm2, respectively, for lowest quartile of Δ25OHD compared with higher quartiles, adjusted for sex, baseline BMD, 25OHD, and demographics). No significant associations between Δ25OHD and lumbar spine BMD were observed. Increase in 25OHD levels was not associated with change in BMD. Conclusions: In this predominantly vitamin D-replete middle-aged cohort, serum 25OHD showed moderate longitudinal stability. Declining serum 25OHD over time was associated with greater reduction in BMD at the total hip and femoral neck.

Immunoregulatory effects of testosterone supplementation combined with exercise training in men with Inclusion Body Myositis: a double-blind, placebo-controlled, cross-over trial.

Objectives: Sporadic Inclusion Body Myositis (IBM) is an inflammatory muscle disease affecting individuals over the age of 45, leading to progressive muscle wasting, disability and loss of independence. Histologically, IBM is characterised by immune changes including myofibres expressing major histocompatibility complex molecules and invaded by CD8+ T cells and macrophages, and by degenerative changes including protein aggregates organised in inclusion bodies, rimmed vacuoles and mitochondrial abnormalities. There is currently no cure, and regular exercise is currently the only recognised treatment effective at limiting muscle weakening, atrophy and loss of function. Testosterone exerts anti-inflammatory effects, inhibiting effector T-cell differentiation and pro-inflammatory cytokine production. Methods: We conducted a double-blind, placebo-controlled, cross-over trial in men with IBM, to assess whether a personalised progressive exercise training combined with application of testosterone, reduced the inflammatory immune response associated with this disease over and above exercise alone. To assess intervention efficacy, we immunophenotyped blood immune cells by flow cytometry, and measured serum cytokines and chemokines by Luminex immunoassay. Results: Testosterone supplementation resulted in modest yet significant count reduction in the classical monocyte subset as well as eosinophils. Testosterone-independent immunoregulatory effects attributed to exercise included altered proportions of some monocyte, T- and B-cell subsets, and reduced IL-12, IL-17, TNF-α, MIP-1ß and sICAM-1 in spite of interindividual variability. Conclusion: Overall, our findings indicate anti-inflammatory effects of exercise training in IBM patients, whilst concomitant testosterone supplementation provides some additional changes. Further studies combining testosterone and exercise would be worthwhile in larger cohorts and longer testosterone administration periods.

Calculated globulin as a screening tool for hypogammaglobulinaemia or paraproteins in hospitalized patients.

BACKGROUND: Calculated globulin fraction is derived from the liver function tests by subtracting albumin from the total protein. Since immunoglobulins comprise the largest component of the serum globulin concentration, increased or decreased calculated globulins and may identify patients with hypogammaglobulinaemia or hypergammaglobulinaemia, respectively. METHODS: A retrospective study of laboratory data over 2.5 years from inpatients at three tertiary hospitals was performed. Patients with paired calculated globulins and immunoglobulin results were identified and clinical details reviewed. The results of serum electrophoresis testing were also assessed where available. RESULTS: A total of 4035 patients had paired laboratory data available. A calculated globulin ≤20 g/L (<2nd percentile) had a low sensitivity (5.8%) but good positive predictive value (82.5%) for hypogammaglobulinaemia (IgG ≤5.7 g/L), with a positive predictive value of 37.5% for severe hypogammaglobulinaemia (IgG ≤3 g/L). Paraproteins were identified in 123/291 (42.3%) of patients with increased calculated globulins (≥42 g/L) who also had a serum electrophoresis performed. Significantly elevated calculated globulin ≥50 g/L (>4th percentile) were seen in patients with either liver disease (37%), haematological malignancy (36%), autoimmune disease (13%) or infections (9%). CONCLUSIONS: Calculated globulin is an inexpensive and easily available test that assists in the identification of hypogammaglobulinaemia or hypergammaglobulinaemia which may prompt further investigation and reduce diagnostic delays.