Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography-tandem mass spectrometry

In severely ill patients low concentrations of the corticosteroid binding globulin are typically found; the aim of this study was to quantify directly free bioactive cortisol concentrations in the sera of postoperative cardiosurgical patients. Serum samples of 12 consecutive patients undergoing aortocoronary bypass surgery taken preoperatively and on the postoperative days 1 to 4 were analyzed. Total serum cortisol was quantified using liquid chromatographytandem mass spectrometry with an online sample extraction system and trideuterated cortisol as the internal standard, and free serum cortisol was measured after overnight equilibrium dialysis. Whereas on the first postoperative day, the median total serum cortisol concentration was approximately twofold increased compared to preoperative samples (preoperatively, 245 nmol/l (interquartile range (IQR) 203293 nmol/l); first postoperative day, 512 nmol/l (IQR 410611 nmol/l)), median dialyzable free cortisol concentration was almost sevenfold increased (preoperatively, 14.2 nmol/l (IQR 10.920.7 nmol/l); first postoperative day, 98.3 nmol/l (IQR 81.3134 nmol/l)). On the fourth postoperative day, median free cortisol was still significantly increased compared to baseline sampling (p < 0.05), whereas median total cortisol was not. A median of 5.7% (IQR 5.47.0%) of total cortisol was found as free cortisol on the preoperative day, 21.2% (IQR 18.9 23.5%) on the first postoperative day and 10.5% (IQR 9.814.0%) on the fourth postoperative day. It is concluded that during the postoperative period the freeto bound ratio of cortisol is highly variable and that during the acute phase response direct quantification of free bioactive cortisol concentrations seems to be biologically more appropriate than the measurement of total cortisol concentrations

A Child with Resistance to Thyroid Hormone without Thyroid Hormone Receptor Gene Mutation: A 20-Year Follow-Up

We report here the 20-year follow-up study of a male subject diagnosed at 15 months of age as a sporadic case of pituitary resistance to thyroid hormone on the combination of clinical hyperthyroidism, elevated serum thyroid hormone (TH) levels and inappropriate thyrotropin (TSH). On d-thyroxine (D-T4) therapy from 30 months of age to 12.5 years, hyperactivity and hyperthyroid signs and symptoms as well as growth abnormalities improved, serum l-thyroxine (L-T4) enantiomer normalized, and basal and stimulated TSH decreased significantly without complete suppression. After 8 years off D-T4, at 20 years of age, clinical status was normal despite persisting high TH levels and inappropriate TSH. Evolution of serum markers of TH action and echocardiography measurements followed up from 15 months to 20 years of age either in basal condition or on triiodothyronine (T3), as well as the sequential determination of bone mineral density suggest differences in the tissue responses to T3: normal in bone with a high remodelling rate, heterogeneity for various hepatic markers, and decreased at heart level. No mutations were found in the coding sequence of TRβ1, TRβ2, TRα1, RXRγ, SMRT, NCoR1, and NCoA1. In this patient the putative long-term effects of the persisting high bone resorption are unknown

Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients An adaptive phenomenon?

OBJECTIVE—Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women. RESEARCH DESIGN AND METHODS—Ten glucose-normotolerant, fertile, obese women (BMI >40 kg/m2, aged 38.66 ± 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method. RESULTS—No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P = 0.05) and postobese women (P ≤ 0.01) as was the decrease in dehydroepiandrosterone (P ≤ 0.05 and P ≤ 0.01, respectively). CBG decreased from 51.50 ± 12.76 to 34.33 ± 7.24 mg/l (P ≤ 0.01) following BPD. FCI increased from 11.15 ± 2.85 to 18.16 ± 6.82 (P ≤ 0.05). Insulin secretion decreased (52.04 ± 16.71 vs. 30.62 ± 16.32 nmol/m−2; P ≤ 0.05), and insulin sensitivity increased by 163% (P ≤ 0.0001). Serum CBG was related to BMI (r0 = 0.708; P = 0.0001), body weight (r0 = 0.643; P = 0.0001), body fat percent (r0 = 0.462; P = 0.001), C-reactive protein (r0 = 0.619; P = 0.004), and leptin (r0 = 0.579; P = 0.007) and negatively to M value (r0 = −0.603; P = 0.005). CONCLUSIONS—After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity

Role of sex steroids, intrahepatic fat and liver enzymes in the association between SHBG and metabolic features

BACKGROUND: SHBG and liver enzymes levels are both associated with the risk of type 2 diabetes. However, the relationship between SHBG with liver enzymes and intrahepatic fat content remain poorly understood. OBJECTIVE: To investigate whether SHBG is correlated with glucose and lipids levels and whether this association depends on fatty liver content, liver enzymes or sex hormone concentrations. DESIGN AND PATIENTS: We studied 233 dysmetabolic men with measures of plasma SHBG, total testosterone, 17β-oestradiol, glucose, adiponectin, liver enzymes and hepatokines. Intrahepatic liver fat and visceral fat contents were measured by magnetic resonance imaging in 108 of these individuals. RESULTS: After adjustment for age, SHBG concentration was inversely correlated with fasting glucose (βstandardized  = -0·21, P = 0·0007), HbA1c (βstandardized  = -0·27, P < 0·0001), triglycerides (βstandardized  = -0·19, P = 0·003) and positively correlated with HDL-Cholesterol (βstandardized  = 0·14, P = 0·03). These correlations persisted after adjustment for either total testosterone or 17β-oestradiol levels. SHBG was not related to either fetuin A or FGF 21 concentrations. The inverse association of SHBG with HbA1c and glycaemia was not altered after adjusting for liver markers but was no longer significant after adjustment for hepatic fat content. CONCLUSION: The significant association between SHBG and fasting glycaemia, HbA1c and lipid levels in dysmetabolic men was not related to either sex hormones or markers of liver function, but was dependent on intrahepatic fat. This suggests that intrahepatic fat, but not alterations in liver function markers, may be involved in the association between SHBG and glucose and lipid metabolism

An ancient founder mutation in PROKR2 impairs human reproduction

Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ∼123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproductio

Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society

Background: Hirsutism, defined by the presence of excessive terminal hair in androgen-sensitive areas of the female body, is one of the most common disorders in women during reproductive age.Methods: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of hirsutism.Results: The prevalence of hirsutism is about 10% in most populations, with the important exception of Far-East Asian women who present hirsutism less frequently. Although usually caused by relatively benign functional conditions, with the polycystic ovary syndrome leading the list of the most frequent etiologies, hirsutism may be the presenting symptom of a life-threatening tumor requiring immediate intervention.Conclusions: Following evidence-based diagnostic and treatment strategies that address not only the amelioration of hirsutism butalso the treatment of the underlying etiology is essential for the proper management of affected women, especially considering that hirsutismis, in most cases, a chronic disorder needing long-term follow-up. Accordingly, we provide evidence-based guidelines for the etiological diagnosis and for the management of this frequent medical complaint

Endocrine Disrupting Chemicals Interfere With Leydig Cell Hormone Pathways During Testicular Descent in Idiopathic Cryptorchidism

Cryptorchidism, a frequent genital malformation in male newborn, remains in most cases idiopathic. On the basis of experimental, epidemiological, and clinical data, it has been included in the testicular dysgenesis syndrome and believed to be influenced, together with genetic and anatomic factors, by maternal exposure to endocrine disrupting chemicals (EDCs). Here, we analyze how EDCs may interfere with the control of testicular descent, which is regulated by two Leydig cell hormones, testosterone, and insulin like peptide 3 (INSL3)

Branched-chain amino acid database integrated in MEDIPAD software as a tool for nutritional investigation of mediterranean populations

Branched-chained amino acids (BCAA) are essential dietary components for humans and can act as potential biomarkers for diabetes development. To efficiently estimate dietary intake, we developed a BCAA database for 1331 food items found in the French Centre d'Information sur la Qualité des Aliments (CIQUAL) food table by compiling BCAA content from international tables, published measurements, or by food similarity as well as by calculating 267 items from Greek, Turkish, Romanian, and Moroccan mixed dishes. The database embedded in MEDIPAD software capable of registering 24 h of dietary recalls (24HDR) with clinical and genetic data was evaluated based on archived 24HDR of the Saint Pierre Institute (France) from 2957 subjects, which indicated a BCAA content up to 4.2 g/100 g of food and differences among normal weight and obese subjects across BCAA quartiles. We also evaluated the database of 119 interviews of Romanians, Turkish and Albanians in Greece (27⁻65 years) during the MEDIGENE program, which indicated mean BCAA intake of 13.84 and 12.91 g/day in males and females, respectively, comparable to other studies. The MEDIPAD is user-friendly, multilingual, and secure software and with the BCAA database is suitable for conducting nutritional assessment in the Mediterranean area with particular facilities for food administration

Diagnosis and Treatment of Sexual Dysfunctions in Late-Onset Hypogonadism

Testosterone is the principal androgen in the human male. The decline of testosterone with aging was recognized to be associated with a number of symptoms and signs that reduce the quality of life and that may even have severe, debilitating consequences. Clinically, late-onset hypogonadism (LOH) is diagnosed by use of biochemical and clinical measures. Despite published guidelines and recommendations, however, uncertainty surrounds the profile of clinical symptoms as well as the biochemical threshold of diagnosis. Clinicians should be aware of these shortcomings while adhering to the guidelines. Current treatment methods are centered on restoring testosterone to mid to lower levels of young men with natural testosterone replacements. Although recent studies have highlighted possible additional benefits involving improvement of systemic disorders, the goal of treatment is to improve sexual function, while observing for adverse effects in the prostate. Overall, the problem of LOH in debilitating the quality of life and well-being is real, and by following proper guidelines with attentiveness to the results of treatment trials, testosterone replacement therapy presents a safe and effective treatment option

Plasma metabolomics and proteomics profiling after a postprandial challenge reveal subtle diet effects on human metabolic status

We introduce the metabolomics and proteomics based Postprandial Challenge Test (PCT) to quantify the postprandial response of multiple metabolic processes in humans in a standardized manner. The PCT comprised consumption of a standardized 500 ml dairy shake containing respectively 59, 30 and 12 energy percent lipids, carbohydrates and protein. During a 6 h time course after PCT 145 plasma metabolites, 79 proteins and 7 clinical chemistry parameters were quantified. Multiple processes related to metabolism, oxidation and inflammation reacted to the PCT, as demonstrated by changes of 106 metabolites, 31 proteins and 5 clinical chemistry parameters. The PCT was applied in a dietary intervention study to evaluate if the PCT would reveal additional metabolic changes compared to non-perturbed conditions. The study consisted of a 5-week intervention with a supplement mix of anti-inflammatory compounds in a crossover design with 36 overweight subjects. Of the 231 quantified parameters, 31 had different responses over time between treated and control groups, revealing differences in amino acid metabolism, oxidative stress, inflammation and endocrine metabolism. The results showed that the acute, short term metabolic responses to the PCT were different in subjects on the supplement mix compared to the controls. The PCT provided additional metabolic changes related to the dietary intervention not observed in non-perturbed conditions. Thus, a metabolomics based quantification of a standardized perturbation of metabolic homeostasis is more informative on metabolic status and subtle health effects induced by (dietary) interventions than quantification of the homeostatic situation