Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.

Testosterone treatment, weight loss and health-related quality of life and psychosocial function in men: a two-year RCT.

OBJECTIVE: To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of a 2-year, randomised controlled, testosterone therapy trial for prevention, or reversal of newly diagnosed, type 2 diabetes, enrolling men > 50 years at high risk for type 2 diabetes from six Australian centers. INTERVENTIONS: Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES: Self-reported measures of HR-QOL/psychosocial function. RESULTS: Of 1007 participants randomised into T4DM, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and two years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and less depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSIONS: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

Sex steroids and androgen biomarkers in the healthy man study: within-person variability and impact of fasting.

OBJECTIVE: Serum testosterone measurements in clinical practice mostly utilize "direct" (non-extraction) immunoassays which have method-specific bias due to steroid cross-reactivity and nonspecific matrix artifacts. Although more accurate, sensitive, and specific liquid chromatography-mass spectrometry (LCMS) dominates in clinical research, the within-person variability of serum testosterone in healthy men using LCMS measurement is not reported. DESIGN: Longitudinal multi-sampling observational study of men in excellent health over 3 months. METHODS: Elite healthy men (n = 325) over 40 years of age in excellent, asymptomatic health provided 9 blood samples over 3 months with serum testosterone, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) measured by validated LCMS with conventional biochemical and anthropometric variables. RESULTS: Quantitative estimates of within-person variability within day and between day, week, month, and quarter were stable other than an increase due to fasting. The androgen biomarkers most sensitive to age and testosterone among widely used biochemical and anthropometric variables in middle-aged and older men were identified. CONCLUSIONS: This study provides estimates of variability in serum testosterone and the best androgen biomarkers that may prove useful for future studies of androgen action in male ageing.

Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial.

OBJECTIVE: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant hand-grip, oestradiol (E2), and sex hormone-binding globulin (SHBG). DESIGN: Mediation analysis of a randomised placebo-controlled trial of testosterone. METHODS: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥95 cm, serum total testosterone ≤14 nmol/L (immunoassay), and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle programme and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2 years (OGTT ≥ 11.1 mmol/L and change in 2-h glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG, were performed. RESULTS: For type 2 diabetes at 2 years, the unadjusted OR for treatment was 0.53 (95% CI:.35-.79), which became 0.48 (95% CI:.30-.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; P < .001). CONCLUSION: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass.

Familial Hypocalciuric Hypercalcemia in Pregnancy: Diagnostic Pitfalls.

Familial hypocalciuric hypercalcemia (FHH) is a group of autosomal dominant disorders caused by dysfunction of the calcium sensing receptor (CaSR) and its downstream signaling proteins, leading to generally asymptomatic hypercalcemia. During pregnancy, distinguishing FHH from primary hyperparathyroidism (PHPT) is important, as the latter is associated with adverse outcomes and can be treated surgically during pregnancy, whereas the former is benign. This case report highlights the difficulties in diagnosing FHH during pregnancy. A 32-year-old woman was found to have asymptomatic hypercalcemia at 14-weeks' gestation. Investigations showed a corrected calcium (cCa) of 2.61 mmol/L (2.10 to 2.60), ionized Ca (iCa) of 1.40 mmol/L (1.15 to 1.28), 25OHD of 33 nmol/L (75 to 250), and PTH of 9.5 pmol/L (1.5 to 7.0). The patient was treated with 2000 IU cholecalciferol daily with normalization of 25OHD. The urine calcium / creatinine clearance ratio (CCCR) was 0.0071, and neck US did not visualize a parathyroid adenoma. Upon a retrospective review of the patient's biochemistry from 2 years prior, hypercalcemia was found that was not investigated. The patient was monitored with serial iCa levels and obstetric US. She delivered a healthy boy at 38-weeks' gestation. Postnatal iCa was 1.48 mmol/L and remained elevated. Her son had elevated iCa at birth of 1.46 mmol/L (1.15 to 1.33), which rose to 1.81 mmol/L by 2 weeks. He was otherwise well. Given the familial hypercalcemia, a likely diagnosis of FHH was made. Genetic testing of the son revealed a missense mutation, NM_000388.3(CASR):c.2446A > G, in exon 7 of the CaSR, consistent with FHH type 1. To our knowledge, there are only three existing reports of FHH in pregnancy. When differentiating between FHH and PHPT in pregnancy, interpretation of biochemistry requires an understanding of changes in Ca physiology, and urine CCCR may be unreliable. If the decision is made to observe, clinical symptoms, calcium levels, and fetal US should be monitored, with biochemistry and urine CCCR performed postpartum, once lactation is completed © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Normal foetal kidney volume in offspring of women treated for gestational diabetes.

AIMS: The worldwide prevalence of gestational diabetes mellitus (GDM) is increasing. Studies in rodent models indicate that hyperglycaemia during pregnancy alters kidney development, yet few studies have examined if this is so in humans. The objective of this study was to evaluate the association of treated GDM with foetal kidney size. MATERIALS AND METHODS: Participants were recruited from an Australian tertiary hospital, and clinical data were collected from women without GDM and women diagnosed and treated for GDM and their offspring. Participants underwent an obstetric ultrasound at 32-34 weeks gestation for foetal biometry and foetal kidney volume measurement. RESULTS: Sixty-four non-GDM and 64 GDM women participated in the study. Thirty percent of GDM women were diagnosed with fasting hyperglycaemia, while 89% had an elevated 2-hour glucose level. Maternal age, weight and body mass index were similar in women with and without GDM. Estimated foetal weight, foetal kidney dimensions, total foetal kidney volume and birth weight were similar in offspring of women with and without GDM. CONCLUSIONS: We conclude that a period of mild hyperglycaemia prior to diagnosis of GDM and treatment initiation, which coincides with a period of rapid nephron formation and kidney growth, does not alter kidney size at 32-34 weeks gestation.

Minimal-trauma ankle fractures predominate during pregnancy: a 17-year retrospective study.

This study assessed all fractures occurring in pregnancy at a tertiary referral centre over a 17-year period. Most fractures were due to minimal trauma, and those involving the ankle were the most common. Women tended to fracture during their second and third trimesters and most required surgical intervention during pregnancy. PURPOSE: To characterise fractures in pregnancy over a 17-year period at a tertiary referral health service. METHODS: Medical records at the Monash Health in Australia were examined from 2000-2016 for fractures in pregnancy using the birthing outcome system database and the tenth revision of the International Statistical Classification of Diseases and Related Health Problems coding. Site, mechanism, investigations, management and outcomes were documented. RESULTS: Of the 114,673 live births during this period, 33 women (mean age 30.3 ± 1.9 years) were identified with fracture in pregnancy (~ 2.9 maternal fractures/10,000 live births). Minimal-trauma fractures (MTFs) occurred in 28 women whilst 5 were due to motor vehicle accidents. Of the MTF, 2/28 (7.1%), 13/28 (46.4%) and 13/28 (46.4%) occurred in the first, second and third trimesters, respectively. MTF involved the lower limb (60.7%), upper limb (25.0%), ribs (10.7%) and clavicle (3.6%). The ankle was involved in 39.3% of MTFs. Diabetes (14.3%), asthma (10.7%) and thyroid dysfunction (7.1%) affected these women with MTF; vitamin D levels were not routinely measured. Surgical interventions requiring anaesthesia were required in 57.1% with MTF: 50.0% during their second, 31.3% in their third and 12.5% in their first trimesters; 6.3% had surgery post partum. Pre-term birth and emergency caesarean section complicated 6/28 (21.4%) of MTF pregnancies. One patient received post-partum bisphosphonate therapy; only two 2/32 (6.25%) received medical follow-up. CONCLUSIONS: Fractures in pregnancy are uncommon. Lower limb fractures are frequently due to minimal trauma, and surgical intervention is often required. The low rate of medical follow-up in MTF is of concern and reinforces the need for greater recognition of potential osteoporosis in this population.

Endocrine Society of Australia position statement on male hypogonadism (part 2): treatment and therapeutic considerations.

INTRODUCTION: Part 1 of this position statement dealt with the assessment of male hypogonadism, including the indications for testosterone therapy. This article, Part 2, focuses on treatment and therapeutic considerations for male hypogonadism and identifies key questions for future research. MAIN RECOMMENDATIONS: Key points and recommendations are:Excess cardiovascular events have been reported in some but not all studies of older men without pathological hypogonadism who were given testosterone treatment. Additional studies are needed to clarify whether testosterone therapy influences cardiovascular risk.Testosterone is the native hormone that should be replaced in men being treated for pathological hypogonadism. Convenient and cost-effective treatment modalities include depot intramuscular injection and transdermal administration (gel, cream or liquid formulations).Monitoring of testosterone therapy is recommended for efficacy and safety, focusing on ameliorating symptoms, restoring virilisation, avoiding polycythaemia and maintaining or improving bone mineral density.Treatment aims to relieve an individual's symptoms and signs of androgen deficiency by administering standard doses and maintaining circulating testosterone levels within the reference interval for eugonadal men.Evaluation for cardiovascular disease and prostate cancer risks should be undertaken as appropriate for eugonadal men of similar age. Nevertheless, when there is a reasonable possibility of substantive pre-existing prostate disease, digital rectal examination and prostate-specific antigen testing should be performed before commencing testosterone treatment.Changes in management as result of the position statement: Treatment aims to relieve symptoms and signs of androgen deficiency, using convenient and effective formulations of testosterone. Therapy should be monitored for efficacy and safety.

Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy.

INTRODUCTION: This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.) MAIN RECOMMENDATIONS: Key points and recommendations are:Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Measurement of sex hormone-binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.Currently, there are limited data from high-quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non-specific consequences of non-reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.Changes in management as result of the position statement: Men with pathological hypogonadism should be identified and considered for testosterone therapy, while further research is needed to clarify whether there is a role for testosterone in these other settings.

Proportion of Undercarboxylated Osteocalcin and Serum P1NP Predict Incidence of Myocardial Infarction in Older Men.

CONTEXT: Undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity in mice, and higher ucOC is associated with lower prevalence of diabetes in men. The influence of ucOC distinct from other markers of bone turnover on incidence of cardiovascular events is unclear. PARTICIPANTS: Community-dwelling men aged 70-89 years resident in Perth, Western Australia. MAIN OUTCOME MEASURES: Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. The ratio ucOC/TOC was calculated. Hospital admissions and deaths from myocardial infarction (MI) and stroke were ascertained. RESULTS: There were 3384 men followed for 7.0 years, during which 293 experienced an MI, 251 stroke, and 2840 neither. In multivariate analyses, higher ratio of ucOC/TOC (expressed as %) was associated with lower incidence of MI (quartiles Q2-4, ≥ 49% versus Q1,<49%, hazard ratio 0.70, 95% confidence interval = 0.54-0.91), but not of stroke (0.99, 0.73-1.34). Higher P1NP was associated with higher incidence of MI (Q2-4, ≥ 28.2 µg/L versus Q1, <28.2 µg/L, hazard ratio 1.45, 95% confidence interval = 1.06-1.97), but not of stroke (0.94, 0.70-1.26). CTX was not associated with incident MI or stroke. CONCLUSIONS: A reduced proportion of undercarboxylated osteocalcin or higher P1NP are associated with increased incidence of MI. UcOC/TOC ratio and P1NP predict risk of MI but not stroke, in a manner distinct from CTX. Further studies are needed to investigate potential mechanisms by which bone turnover markers related to metabolic risk and to collagen formation could modulate cardiovascular risk.

Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men.

CONTEXT: In mice, undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity and increases testosterone (T) secretion from Leydig cells, but human data are lacking. We hypothesized that ucOC is associated with diabetes risk and modulates sex hormone concentrations in older men, distinct from other bone turnover markers. PARTICIPANTS: PARTICIPANTS were community-dwelling men aged 70 to 89 years resident in Perth, Western Australia. MAIN OUTCOME MEASURES: Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. Plasma total T, DHT, and estradiol (E2) were assayed by mass spectrometry. RESULTS: Excluding men with osteoporosis or conditions affecting sex hormones or on bisphosphonates, glucocorticoids, or warfarin, 2966 men were included. In multivariate analyses, higher ucOC was associated with reduced diabetes risk (odds ratio [OR] per 1 SD increase = 0.55, P < .001). Similar results were seen for TOC (OR = 0.60, P < .001), P1NP (OR = 0.64, P < .001), and CTX (OR = 0.60, P < .001) but not ucOC/TOC. When all 4 markers were included in the fully adjusted model, higher ucOC (OR = 0.56, P < .001) and CTX (OR = 0.76, P = .008) remained associated with reduced diabetes risk. E2 was inversely associated with ucOC (coefficient -0.04, P = .031), TOC (-0.05, P = .001) and CTX (-0.04, P = .016); and positively with ucOC/TOC (0.05, P = .002). DHT was inversely associated with ucOC/TOC (-0.04, P = .040). T was not associated with bone turnover. CONCLUSIONS: Higher bone remodeling rates are associated with reduced diabetes risk in older men. Higher ucOC is both a marker of bone remodeling and an independent predictor of reduced diabetes risk. E2 is inversely associated with bone turnover markers. We found no evidence ucOC modulates circulating T in older men.

Androgen deprivation therapy complications.

Androgen deprivation therapy (ADT) is increasingly used to treat advanced prostate cancer and is also utilised as adjuvant or neo-adjuvant treatment for high-risk disease. The resulting suppression of endogenous testosterone production has deleterious effects on quality of life, including hot flushes, reduced mood and cognition and diminished sexual function. Cross-sectional and longitudinal studies show that ADT has adverse bone and cardio-metabolic effects. The rate of bone loss is accelerated, increasing the risk of osteoporosis and subsequent fracture. Fat mass is increased and lean mass reduced, and adverse effects on lipid levels and insulin resistance are observed, the latter increasing the risk of developing type 2 diabetes. ADT also appears to increase the risk of incident cardiovascular events, although whether it increases cardiovascular mortality is not certain from the observational evidence published to date. Until high-quality evidence is available to guide management, it is reasonable to consider men undergoing ADT to be at a higher risk of psychosexual dysfunction, osteoporotic fracture, diabetes and cardiovascular disease, especially when treated for extended periods of time and therefore subjected to profound and prolonged hypoandrogenism. Health professionals caring for men undergoing treatment for prostate cancer should be aware of the potential risks of ADT and ensure appropriate monitoring and clinical management.

Sex steroids and glucose metabolism.

Testosterone levels are lower in men with metabolic syndrome and type 2 diabetes mellitus (T2DM) and also predict the onset of these adverse metabolic states. Body composition (body mass index, waist circumference) is an important mediator of this relationship. Sex hormone binding globulin is also inversely associated with insulin resistance and T2DM but the data regarding estrogen are inconsistent. Clinical models of androgen deficiency including Klinefelter's syndrome and androgen deprivation therapy in the treatment of advanced prostate cancer confirm the association between androgens and glucose status. Experimental manipulation of the insulin/glucose milieu and suppression of endogenous testicular function suggests the relationship between androgens and insulin sensitivity is bidirectional. Androgen therapy in men without diabetes is not able to differentiate the effect on insulin resistance from that on fat mass, in particular visceral adiposity. Similarly, several small clinical studies have examined the efficacy of exogenous testosterone in men with T2DM, however, the role of androgens, independent of body composition, in modifying insulin resistance is uncertain.

Patterns of weight gain in pregnant women with and without gestational diabetes mellitus: an observational study.

OBJECTIVE: To quantify late-pregnancy weight gain in women with and without gestational diabetes mellitus (GDM) and to determine factors associated with gestational weight gain. STUDY DESIGN: A prospective clinical audit of 212 women (115 GDM and 97 non-GDM) who were weighed at each antenatal visit from 24-32 weeks gestation until delivery. Women received routine antenatal clinical care. For women with GDM, this included a 2-h lifestyle counselling session, capillary blood glucose testing and frequent clinical review. RESULTS: Women with GDM gained less weight than nondiabetic women (GDM: 1.18 kg (1.6%) [range, 3.8-7.1 kg]; non-GDM: 4.0 kg (4.8%) [range, 0.7-18.5 kg]; P < 0.0001). Weight gain was influenced by body mass index and country of birth. Women with GDM showed reduced weight gain at weeks 1-4 postrecruitment, relative to weeks 4-8 (0.04 kg/week vs 0.45 kg/week; P < 0.0001). Nondiabetic women gained weight at a constant rate. GDM status was the only independent predictor of postrecruitment weight gain. CONCLUSIONS: Application of a model of care for GDM (lifestyle advice and regular clinical review, in addition to home glucose monitoring) may reduce weight gain in women with GDM. The potential for applying a modified version of this model to all women in pregnancy warrants further study.

Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study.

OBJECTIVE: To determine serum concentrations, intra-individual variability and impact of age-related co-morbidities on serum testosterone (T), dihydrotestosterone (DHT), estradiol (E(2)) and estrone (E(1)) in older men. DESIGN: Observational, repeated measures study. PARTICIPANTS: Men (n = 325) with 40 years and older self-reporting very good or excellent health. MEASUREMENTS: Standardized history, physical examination and collection of nine blood samples at fixed time intervals were measured over 3 months (three at 20 min intervals on days 1 (fasting) and 2 (non-fasting), one at days 7, 30 and 90). Serum T, DHT, E(2) and E(1) (n = 2900, > 99% of scheduled samples) measured by liquid chromatography-tandem mass spectrometry (LC-MS) were analysed by linear mixed model analysis with fasting, age and obesity as covariables. RESULTS: Mean serum T did not vary with age (P = 0·76) but obesity (-0·35 nM per body mass index (BMI) unit, P < 0·0001) and ex-smoker status (-1·6 nM, P < 0·001) had significant effects. Serum DHT was increased with age (+0·011 nM per year, P = 0·001) but decreased with obesity (-0·05 nM per BMI unit, P < 0·0001). Serum E(2) did not vary with age (P = 0·31) or obesity (P = 0·12). Overnight fasting increased (by 9-16%, all P < 0·001) and reduced variability in morning serum T, DHT, E(2) and E(1). Non-fasting serum T and DHT were stable over time (day, week, month or 3 months; P > 0·28). CONCLUSIONS: Serum T, DHT and E(2) displayed no decrease associated with age among men over 40 years of age who self-report very good or excellent health although obesity and ex-smoking status were associated with decreased serum androgens (T and DHT) but not E(2). These findings support the interpretation that the age-related decline in blood T accompanying non-specific symptoms in older men may be due to accumulating age-related co-morbidities rather than a symptomatic androgen deficiency state.

Correlation between blood activin levels and clinical parameters of type 2 diabetes.

AIMS: Activins A and B, and their binding protein, follistatin, regulate glucose metabolism and inflammation. Consequently, their role in type 2 diabetes (T2D) was examined. METHODS: Blood was taken from fasted participants (34 males; 58 females; 50-75 years) with diabetes or during an oral glucose tolerance test (OGTT). Clinical parameters were assessed, and blood assayed for activins, follistatin, and C-reactive protein. RESULTS: Serum levels of activin A (93.3 ± 27.0 pg/mL, mean ± SD), B (81.8 ± 30.8 pg/mL), or follistatin (6.52 ± 3.15 ng/mL) were not different (P > 0.05) between subjects with normal OGTT (n = 39), impaired glucose tolerance and/or fasting glucose (n = 17), or T2D (n = 36). However, activin A and/or activin B were positively correlated with parameters of insulin resistance and T2D, including fasting glucose (P < 0.001), fasting insulin (P = 0.02), glycated hemoglobin (P = 0.003), and homeostasis model assessment of insulin resistance (HOMA-IR; P < 0.001). Follistatin was positively correlated with HOMA-IR alone (P = 0.01). CONCLUSIONS: These data indicate that serum measurements of activin A, B, or follistatin cannot discriminate risk for T2D in individual patients, but the activins display a positive relationship with clinical parameters of the disease.

Gestational diabetes: development of an early risk prediction tool to facilitate opportunities for prevention.

BACKGROUND AND AIM: In the setting of advancing maternal age, escalating obesity and increasing Gestational Diabetes Mellitus (GDM) rates, we aimed to develop a novel risk prediction tool to identify high-risk women in early pregnancy, specifically to facilitate targeted antenatal prevention of GDM. METHODS: In this retrospective, observational study, first-trimester data collected routinely by midwifery staff in 4276 women attending a large tertiary hospital in 2007/2008 was analysed to examine predictive factors for GDM. GDM was diagnosed with a 28-week oral glucose tolerance test. The data set included a derivation group (n=2880, from 2007 deliveries) and a validation group (n = 1396, from 2008). Multivariate analysis generated a scoring system. RESULTS: GDM was significantly correlated with a number of factors: past history of GDM, increasing maternal age and body mass index, Asian descent and family history of diabetes. Validation group clinical scores achieved a sensitivity of 61.3% and specificity of 71.4% for differentiating women according to their risk of developing GDM. CONCLUSIONS: Risk factors for GDM are easily identified at the first-trimester midwifery hospital booking visit. A risk prediction tool, derived from risk factors in early pregnancy, identifies women at high risk of GDM. This represents a novel approach to facilitate targeted early intervention with the potential to prevent development of, or ameliorate, GDM.

Waist-to-height ratio as a predictor of serum testosterone in ageing men with symptoms of androgen deficiency.

The decline in serum testosterone in ageing men may be mediated in part by obesity; however, it is uncertain which measure of adiposity is most closely associated with testosterone levels. We have examined the relationships of age, adiposity and testosterone levels in ageing men with symptoms consistent with hypoandrogenism but who were otherwise in good health. We conducted a cross-sectional study of non-smoking men aged ≥ 54 years recruited from the community and who were free of cancer or serious medical illness. Height (Ht), weight and waist circumference (WC) were measured, and body mass index (BMI) and waist-to-height (WHt) ratio were calculated. Two morning blood samples were collected for measurement of total testosterone (TT), sex hormone binding globulin (SHBG) and luteinizing hormone (LH). Free testosterone (cFT) was calculated. Multivariate linear regression analysis was performed to assess their relationship with measures of adiposity. Two hundred and seven men aged 54-86 years were studied. On univariate analysis WHt ratio was more strongly correlated with TT and cFT than either WC or BMI. Furthermore, in models of TT and cFT, the addition of Ht to WC resulted in an increase in the magnitude of the regression coefficients for both WC (inverse correlate) and Ht (positive correlate), with the contributions of both WC and Ht both being significant (P<0.05 for all). In conclusion, WHt ratio is the best anthropometric predictor of both TT and cFT in this group of healthy but symptomatic ageing men.

Windows of opportunity: a holistic approach to men's health.

Evidence is accruing of associations between male reproductive health disorders and chronic diseases such as coronary heart disease and type 2 diabetes. The links between reproductive health and general health are under-recognised by medical practitioners and the general public. Windows of opportunity exist for a more holistic approach to men's health when men present with reproductive health symptoms (such as erectile dysfunction) or the reproductive implications of chronic disease are recognised. Further men's health research is needed in Australia to guide policy, innovative health promotion, and clinical practice.