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Endocrine Reviews Aug 2017In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution,... (Review)
Review
In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution, metabolism, and biological activity. According to the free hormone hypothesis, which has been debated extensively, only the unbound or free fraction is biologically active in target tissues. Consequently, accurate determination of the partitioning of testosterone between bound and free fractions is central to our understanding of how its delivery to the target tissues and biological activity are regulated and consequently to the diagnosis and treatment of androgen disorders in men and women. Here, we present a historical perspective on the evolution of our understanding of the binding of testosterone to circulating binding proteins. On the basis of an appraisal of the literature as well as experimental data, we show that the assumptions of stoichiometry, binding dynamics, and the affinity of the prevailing models of testosterone binding to sex hormone-binding globulin and human serum albumin are not supported by published experimental data and are most likely inaccurate. This review offers some guiding principles for the application of free testosterone measurements in the diagnosis and treatment of patients with androgen disorders. The growing number of testosterone prescriptions and widely recognized problems with the direct measurement as well as the computation of free testosterone concentrations render this critical review timely and clinically relevant.
Topics: Humans; Serum Albumin, Human; Sex Hormone-Binding Globulin; Testosterone; Transcortin
PubMed: 28673039
DOI: 10.1210/er.2017-00025 -
The Journal of Endocrinology Jul 2016Biologically active steroids are transported in the blood by albumin, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG). These plasma... (Review)
Review
Biologically active steroids are transported in the blood by albumin, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG). These plasma proteins also regulate the non-protein-bound or 'free' fractions of circulating steroid hormones that are considered to be biologically active; as such, they can be viewed as the 'primary gatekeepers of steroid action'. Albumin binds steroids with limited specificity and low affinity, but its high concentration in blood buffers major fluctuations in steroid concentrations and their free fractions. By contrast, SHBG and CBG play much more dynamic roles in controlling steroid access to target tissues and cells. They bind steroids with high (~nM) affinity and specificity, with SHBG binding androgens and estrogens and CBG binding glucocorticoids and progesterone. Both are glycoproteins that are structurally unrelated, and they function in different ways that extend beyond their transportation or buffering functions in the blood. Plasma SHBG and CBG production by the liver varies during development and different physiological or pathophysiological conditions, and abnormalities in the plasma levels of SHBG and CBG or their abilities to bind steroids are associated with a variety of pathologies. Understanding how the unique structures of SHBG and CBG determine their specialized functions, how changes in their plasma levels are controlled, and how they function outside the blood circulation provides insight into how they control the freedom of steroids to act in health and disease.
Topics: Animals; Estradiol; Glucocorticoids; Humans; Progesterone; Serum Albumin; Sex Hormone-Binding Globulin; Testosterone; Transcortin
PubMed: 27113851
DOI: 10.1530/JOE-16-0070 -
Journal of Pediatric Endocrinology &... Jan 2018Cortisol is a hydrophobic molecule that is largely bound to corticosteroid-binding globulin (CBG) in the circulation. In the assessment of adrenal insufficiency, many... (Review)
Review
Cortisol is a hydrophobic molecule that is largely bound to corticosteroid-binding globulin (CBG) in the circulation. In the assessment of adrenal insufficiency, many clinicians measure a total serum cortisol level, which assumes that CBG is present in normal concentrations and with a normal binding affinity for cortisol. CBG concentration and affinity are affected by a number of common factors including oral contraceptive pills (OCPs), fever and infection, as well as rare mutations in the serine protease inhibitor A6 (SERPINA6) gene, and as such, total cortisol levels might not be the ideal way to assess adrenal function in all clinical circumstances. This paper reviews the limitations of immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the measurement of total cortisol, the challenges of measuring free serum cortisol directly as well as the difficulties in calculating an estimated free cortisol from total cortisol, CBG and albumin concentrations. Newer approaches to the evaluation of adrenal insufficiency, including the measurement of cortisol and cortisone in the saliva, are discussed and a possible future role for these tests is proposed.
Topics: Adrenal Insufficiency; Algorithms; Child; Cortisone; Endocrinology; Humans; Hydrocortisone; Hydrophobic and Hydrophilic Interactions; Hypothalamo-Hypophyseal System; Mutation; Pediatrics; Pituitary-Adrenal System; Practice Guidelines as Topic; Reproducibility of Results; Saliva; Serum Albumin, Human; Transcortin
PubMed: 29194043
DOI: 10.1515/jpem-2017-0270 -
The Journal of Thoracic and... May 2017Hypothalamic-pituitary-adrenal (HPA) axis dysfunction may be partially responsible for the hemodynamic instability experienced by infants after cardiopulmonary bypass... (Observational Study)
Observational Study
BACKGROUND
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction may be partially responsible for the hemodynamic instability experienced by infants after cardiopulmonary bypass (CPB). We report the full spectrum of the HPA response surrounding CPB for infant congenital cardiac surgery.
METHODS
We enrolled 84 infants who received 1 mg/kg of dexamethasone before initiation of CPB. Total cortisol (TC), free cortisol (FC), adrenocorticotropic hormone (ACTH), and corticosteroid-binding globulin (CBG) were measured at 3 time points: immediately before CPB (TP1), on intensive care unit arrival (TP2), and at 24 hours after surgery (TP3). A 1-μg ACTH stimulation test was performed at each time point to evaluate adrenal responsiveness.
RESULTS
Sixty-eight infants completed all study procedures. Levels of TC, FC, CBG, and ACTH decreased significantly between the preoperative and 24-hour postoperative measurements. There were no significant associations between preoperative FC responses and clinical outcomes after adjusting for weight and Risk-Adjusted Scores for Congenital Heart Surgery. Infants with subnormal TC responses to ACTH stimulation (<9 μg/dL) at TP2 had greater fluid requirements (P < .001) and greater chest tube output (P < .001) during the first 24 hours, as well as longer length of stay (LOS) (P = .007). Except for LOS, these differences persisted for infants with subnormal stimulation tests at TP3.
CONCLUSIONS
We observed a significant decline in all aspects of the HPA axis throughout the first 24 hours after infant CPB. TC and FC levels were not associated with clinical outcomes. Subnormal (Δ <9 μg/dL) TC response to cosyntropin stimulation during the postoperative period was associated with increased fluid resuscitation and greater LOS.
Topics: Adrenal Cortex; Adrenal Cortex Function Tests; Adrenocorticotropic Hormone; Age Factors; Biomarkers; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child, Preschool; Cosyntropin; Dexamethasone; Female; Heart Defects, Congenital; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Infant; Infant, Newborn; Male; Pituitary-Adrenal System; Prospective Studies; Time Factors; Transcortin; Treatment Outcome; United States
PubMed: 28024808
DOI: 10.1016/j.jtcvs.2016.11.030 -
Trends in Endocrinology and Metabolism:... Mar 2023Corticosteroid-binding globulin (CBG) is a 50-60 kDa circulating glycoprotein with high affinity for cortisol. CBG is adapted for sepsis; its cortisol binding is reduced... (Review)
Review
Corticosteroid-binding globulin (CBG) is a 50-60 kDa circulating glycoprotein with high affinity for cortisol. CBG is adapted for sepsis; its cortisol binding is reduced reversibly by pyrexia and acidaemia, and reduced irreversibly by neutrophil elastase (NE) cleavage, converting high cortisol-binding affinity CBG to a low affinity form. These characteristics allow for the targeted delivery of immunomodulatory cortisol to tissues at the time and body site where cortisol is required in sepsis and septic shock. In addition, high titer inflammatory cytokines in sepsis suppress CBG hepatic synthesis, increasing the serum free cortisol fraction. Recent clinical studies have highlighted the importance of CBG in septic shock, with CBG deficiency independently associated with mortality.
Topics: Humans; Hydrocortisone; Shock, Septic; Transcortin; Sepsis; Fever
PubMed: 36681594
DOI: 10.1016/j.tem.2023.01.002 -
Pharmaceutics May 2022Patients with adrenal insufficiency are treated with oral hydrocortisone (HC) to compensate for the loss of endogenous cortisol production. Intrinsic imperfections of...
BACKGROUND
Patients with adrenal insufficiency are treated with oral hydrocortisone (HC) to compensate for the loss of endogenous cortisol production. Intrinsic imperfections of cortisol replacement strategies in mimicking normal cortisol secretion are the underlying cause of the increased morbidity and mortality of patients suffering from secondary adrenal insufficiency (SAI). To improve oral hydrocortisone substitution therapy, a better understanding of its pharmacokinetics (PK) is necessary. The previous PK model did not include protein binding. It is known that protein binding can impact hydrocortisone pharmacokinetics. The aim of this study is to describe HC pharmacokinetics including the protein-binding state using Edsim++ (Mediware, Prague) pharmacokinetic modeling software, paving the way for an in-silico tool suitable for drug delivery design.
METHODS
A total of 46 patients with SAI participated in a randomized double-blind crossover study Patients randomly received a low dose of HC (0.2-0.3 mg/kg body weight/day) for 10 weeks, followed by a high dose (0.4-0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. Plasma samples were obtained and analyzed for free and total hydrocortisone. Single compartment population pharmacokinetic analysis was performed using an extended Werumeus-Buning model built in Edsim++. This model includes a mathematical approach for estimating free cortisol by Nguyen et al., taking the protein binding of HC to albumin and hydrocortisone-binding globulin (CBG, transcortin) into consideration, as well as different states of CBG which affect binding kinetics to HC. The goodness of fit for observed versus predicted values was calculated.
RESULTS AND CONCLUSIONS
Nguyen's formula for free cortisol estimation was successfully implemented in a pharmacokinetic model. The model shows high Spearman's correlation for observed versus predicted hydrocortisone concentrations. Significantly higher correlations (Spearman's r, 0.901 vs. 0.836) between total and free hydrocortisone AUC (area-under the curve over 24 h) are found when comparing new and old models. This new model was used to simulate the plasma concentration-time behavior of a more suitable hydrocortisone formulation.
PubMed: 35745734
DOI: 10.3390/pharmaceutics14061161 -
ISRN Inflammation May 2012Acute phase reaction is a systemic response which usually follows a physiological condition that takes place in the beginning of an inflammatory process. This... (Review)
Review
Acute phase reaction is a systemic response which usually follows a physiological condition that takes place in the beginning of an inflammatory process. This physiological change usually lasts 1-2 days. However, the systemic acute phase response usually lasts longer. The aim of this systemic response is to restore homeostasis. These events are accompanied by upregulation of some proteins (positive acute phase reactants) and downregulation of others (negative acute phase reactants) during inflammatory reactions. Cardiovascular diseases are accompanied by the elevation of several positive acute phase reactants such as C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, white blood cell count, secretory nonpancreatic phospholipase 2-II (sPLA2-II), ferritin, and ceruloplasmin. Cardiovascular disease is also accompanied by the reduction of negative acute phase reactants such as albumin, transferrin, transthyretin, retinol-binding protein, antithrombin, and transcortin. In this paper, we will be discussing the biological activity and diagnostic and prognostic values of acute phase reactants with cardiovascular importance. The potential therapeutic targets of these reactants will be also discussed.
PubMed: 24049653
DOI: 10.5402/2012/953461 -
Critical Care Medicine Mar 2015Cortisol clearance is reduced in sepsis and may contribute to the development of impaired adrenocortical function that is thought to contribute to the pathophysiology of...
OBJECTIVE
Cortisol clearance is reduced in sepsis and may contribute to the development of impaired adrenocortical function that is thought to contribute to the pathophysiology of critical illness-related corticosteroid insufficiency. We sought to assess adrenocortical function using computer-assisted numerical modeling methodology to characterize and compare maximal cortisol secretion rate and free cortisol half-life in septic shock, sepsis, and healthy control subjects.
DESIGN
Post hoc analysis of previously published total cortisol, free cortisol, corticosteroid-binding globulin, and albumin concentration data.
SETTING
Single academic medical center.
PATIENTS
Subjects included septic shock (n = 45), sepsis (n = 25), and healthy controls (n = 10).
INTERVENTIONS
I.v. cosyntropin (250 μg).
MEASUREMENTS AND MAIN RESULTS
Solutions for maximal cortisol secretion rate and free cortisol half-life were obtained by least squares solution of simultaneous, nonlinear differential equations that account for free cortisol appearance and elimination as well as reversible binding to corticosteroid-binding globulin and albumin. Maximal cortisol secretion rate was significantly greater in septic shock (0.83 nM/s [0.44, 1.58 nM/s] reported as median [lower quartile, upper quartile]) compared with sepsis (0.51 nM/s [0.36, 0.62 nM/s]; p = 0.007) and controls (0.49 nM/s [0.42, 0.62 nM/s]; p = 0.04). The variance of maximal cortisol secretion rate in septic shock was also greater than that of sepsis or control groups (F test, p < 0.001). Free cortisol half-life was significantly increased in septic shock (4.6 min [2.2, 6.3 min]) and sepsis (3.0 min [2.3, 4.8 min] when compared with controls (2.0 min [1.2, 2.6 min]) (both p < 0.004).
CONCLUSIONS
Results obtained by numerical modeling are consistent with comparable measures obtained by the gold standard stable isotope dilution method. Septic shock is associated with generally not only higher levels but also greater variance of maximal cortisol secretion rate when compared with control and sepsis groups. Additional studies would be needed to determine whether assessment of cortisol kinetic parameters such as maximal cortisol secretion rate and free cortisol half-life is useful in the diagnosis or management of critical illness-related corticosteroid insufficiency.
Topics: Academic Medical Centers; Adrenal Cortex; Adult; Aged; Aged, 80 and over; Cosyntropin; Critical Illness; Female; Humans; Hydrocortisone; Male; Middle Aged; Sepsis; Serum Albumin; Shock, Septic; Transcortin
PubMed: 25365720
DOI: 10.1097/CCM.0000000000000721 -
PloS One 2021Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating...
Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating tissue glucocorticoid activity. CBG polymorphisms affecting its expression or affinity for glucocorticoids are associated with chronic pain, chronic fatigue, headaches, depression, hypotension, and obesity with an altered hypothalamic pituitary adrenal axis. CBG has been localized in hippocampus of humans and rodents, a brain area where glucocorticoids have an important regulatory role. However, the specific CBG function in the hippocampus is yet to be established. The aim of this study was to investigate the effect of the absence of CBG on hippocampal glucocorticoid levels and determine whether pathways regulated by glucocorticoids would be altered. We used cbg-/- mice, which display low total-corticosterone and high free-corticosterone blood levels at the nadir of corticosterone secretion (morning) and at rest to evaluate the hippocampus for total- and free-corticosterone levels; 11β-hydroxysteroid dehydrogenase expression and activity; the expression of key proteins involved in glucocorticoid activity and insulin signaling; microtubule-associated protein tau phosphorylation, and neuronal and synaptic function markers. Our results revealed that at the nadir of corticosterone secretion in the resting state the cbg-/- mouse hippocampus exhibited slightly elevated levels of free-corticosterone, diminished FK506 binding protein 5 expression, increased corticosterone downstream effectors and altered MAPK and PI3K pathway with increased pY216-GSK3β and phosphorylated tau. Taken together, these results indicate that CBG deficiency triggers metabolic imbalance which could lead to damage and long-term neurological pathologies.
Topics: Animals; Corticosterone; Fatigue; Genetic Diseases, Inborn; Glycogen Synthase Kinase 3 beta; Hippocampus; Mice; Phosphorylation; Stress, Psychological; Transcortin
PubMed: 33592009
DOI: 10.1371/journal.pone.0246930 -
The Journal of Clinical Endocrinology... Jan 2012
Topics: Humans; Male; Mutation, Missense; Transcortin
PubMed: 22223768
DOI: 10.1210/jc.2011-3090