Investigating thyroid nodules.

Thyroid nodules are common clinically and even more common as an incidental finding during ultrasonography. Routine screening of thyroid nodules in patients with hyperthyroidism or hypothyroidism without risk factors for thyroid cancer is not recommended. Most thyroid nodules are benign. Sonographic risk-stratification systems should be used to estimate the risk of malignancy and the need for fine-needle aspiration biopsy. Malignant thyroid nodules require surgical management. Most thyroid cancers are well-differentiated papillary or follicular thyroid neoplasms, which have an excellent prognosis with a low mortality rate.

Plasma, salivary and urinary cortisol levels following physiological and stress doses of hydrocortisone in normal volunteers.

BACKGROUND: Glucocorticoid replacement is essential in patients with primary and secondary adrenal insufficiency, but many patients remain on higher than recommended dose regimens. There is no uniformly accepted method to monitor the dose in individual patients. We have compared cortisol concentrations in plasma, saliva and urine achieved following "physiological" and "stress" doses of hydrocortisone as potential methods for monitoring glucocorticoid replacement. METHODS: Cortisol profiles were measured in plasma, saliva and urine following "physiological" (20 mg oral) or "stress" (50 mg intravenous) doses of hydrocortisone in dexamethasone-suppressed healthy subjects (8 in each group), compared to endogenous cortisol levels (12 subjects). Total plasma cortisol was measured half-hourly, and salivary cortisol and urinary cortisol:creatinine ratio were measured hourly from time 0 (between 0830 and 0900) to 5 h. Endogenous plasma corticosteroid-binding globulin (CBG) levels were measured at time 0 and 5 h, and hourly from time 0 to 5 h following administration of oral or intravenous hydrocortisone. Plasma free cortisol was calculated using Coolens' equation. RESULTS: Plasma, salivary and urine cortisol at 2 h after oral hydrocortisone gave a good indication of peak cortisol concentrations, which were uniformly supraphysiological. Intravenous hydrocortisone administration achieved very high 30 minute cortisol concentrations. Total plasma cortisol correlated significantly with both saliva and urine cortisol after oral and intravenous hydrocortisone (P <0.0001, correlation coefficient between 0.61 and 0.94). There was no difference in CBG levels across the sampling period. CONCLUSIONS: An oral dose of hydrocortisone 20 mg is supraphysiological for routine maintenance, while stress doses above 50 mg 6-hourly would rarely be necessary in managing acute illness. Salivary cortisol and urinary cortisol:creatinine ratio may provide useful alternatives to plasma cortisol measurements to monitor replacement doses in hypoadrenal patients.

High cortisol levels in hyperglycaemic myocardial infarct patients signify stress hyperglycaemia and predict subsequent normalization of glucose tolerance.

CONTEXT: It is unclear if people who develop stress hyperglycaemia have underlying abnormal glucose metabolism, an exaggerated hormonal response to stress, or both. Similarly, it is unknown whether stress hyperglycaemia predicts future glucose intolerance. OBJECTIVE: To determine the relationship between illness severity and plasma cortisol concentration with the degree of hyperglycaemia in subjects experiencing acute myocardial infarction (AMI), and their later glucose metabolic status. PATIENTS AND DESIGN: This analysis comprised 55 patients from the HI-5 Study--a randomized control trial of insulin-glucose infusion therapy for AMI patients with hyperglycaemia. MAIN OUTCOME MEASURES: Blood glucose level (BGL) as well as total and free cortisol levels on admission were measured. Patients not previously known to have diabetes were assessed for abnormal glucose metabolism following discharge. RESULTS: Patients with ST segment-elevation myocardial infarction (STEMI) and higher peak creatinine kinase level had a higher mean admission total and free cortisol level. As many as 38.5% of subjects were found to have newly diagnosed glucose intolerance at follow up. After multiple logistic regression, admission BGL was found to be a positive predictor (P = 0.027) whereas total cortisol level (P = 0.01) was a negative predictor for glucose intolerance. CONCLUSIONS: Both the level of hyperglycaemia and cortisol levels on admission are predictive for the subsequent abnormal glucose tolerance development in hyperglycaemic AMI patients. Hyperglycaemia in patients who are more unwell (i.e. higher cortisol) reflects the stressed state rather than underlying glucose intolerance. Conversely, if the patient is less sick (i.e. lower cortisol), hyperglycaemia is more likely to reflect underlying glucose intolerance.

Achondroplasia with SRY-positive 46, XX disorder of sex development: an extremely rare association.

A 40-year-old man with achondroplasia presented with symptoms of hypogonadism, low libido and gynaecomastia. He was found to have hypergonadotropic hypogonadism, and karyotype and fluorescent in situ hybridisation analysis showed SRY-positive 46, XX disorder of sex development (DSD). He was tested to have the common activating mutation of the FGFR3 gene implicated in achondroplasia, indicating that he had the two rare conditions independently, with an extremely low incidence of 1 in 400 million. This, to the best of our knowledge, is the first report of an individual having these two rare conditions concurrently. This case highlights that individuals with achondroplasia should have normal sexual development, and in those presenting with incomplete sexual maturation or symptoms of hypogonadism should prompt further evaluation. We also propose a plausible link between achondroplasia and 46, XX DSD through the intricate interactions between the SRY, SOX9 and FGFR9 gene pathways. LEARNING POINTS: The SOX9 and FGF9 genes, which are upregulated by the SRY gene, are important in both sex determination in the embryo, as well as endochondral bone growth.Patients with achondroplasia should have normal sexual development and function in the absence of other confounding factors.Patients with achondroplasia who present with symptoms and signs of abnormal sexual development and/or hypogonadism should be appropriately investigated for other causes.

Free and total plasma cortisol measured by immunoassay and mass spectrometry following ACTH1₋24 stimulation in the assessment of pituitary patients.

CONTEXT: Measurement of plasma cortisol by immunoassay after ACTH1₋24 stimulation is used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Liquid chromatography-tandem mass spectrometry (LCMS) has greater analytical specificity than immunoassay and equilibrium dialysis allows measurement of free plasma cortisol. OBJECTIVE: We investigated the use of measuring total and free plasma cortisol by LCMS and total cortisol by immunoassay during an ACTH1₋24 stimulation test to define HPA status in pituitary patients. DESIGN AND SETTING: This was a case control study conducted in a clinical research facility. PARTICIPANTS: We studied 60 controls and 21 patients with pituitary disease in whom HPA sufficiency (n = 8) or deficiency (n = 13) had been previously defined. INTERVENTION: Participants underwent 1 µg ACTH(1-24) intravenous and 250 µg ACTH1₋24 intramuscular ACTH1₋24 stimulation tests. MAIN OUTCOME MEASURES: Concordance of ACTH1₋24-stimulated total and free plasma cortisol with previous HPA assessment. RESULTS: Total cortisol was 12% lower when measured by immunoassay than by LCMS. Female sex and older age were positively correlated with ACTH1₋24-stimulated total and free cortisol, respectively. Measurements of total cortisol by immunoassay and LCMS and free cortisol 30 minutes after 1 µg and 30 and 60 minutes after 250 µg ACTH1₋24 were concordant with previous HPA axis assessment in most pituitary patients. However, free cortisol had greater separation from the diagnostic cutoff than total cortisol. CONCLUSIONS: Categorization of HPA status by immunoassay and LCMS after ACTH1₋24 stimulation was concordant with previous assessment in most pituitary patients. Free cortisol may have greater clinical use in patients near the diagnostic threshold.

A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum.

CONTEXT: There is a paucity of longitudinal data on plasma and urinary cortisol levels during pregnancy using modern assays. Furthermore, conflicting data exist as to the effect of the low-dose oral contraceptive pill (OCP) on cortisol. DESIGN, SUBJECTS, AND MEASUREMENTS: We conducted a prospective longitudinal study on morning plasma cortisol (total and free), corticosteroid-binding globulin (CBG), and 24-h urinary free cortisol (UFC) levels in 20 pregnant women during the first, second, and third trimesters and 2-3 months postpartum compared with 12 subjects on low-dose OCP and 15 nonpregnant subjects not taking the OCP (control group). RESULTS: A progressive rise in total plasma cortisol, CBG, and 24-h UFC was demonstrated during pregnancy, peaking during the third trimester (mean 3-fold rise compared with controls). Plasma free cortisol increased 1.6-fold by the third trimester. In the OCP group, total plasma cortisol and CBG were 2.9- and 2.6-fold elevated, respectively, whereas 24-h UFC and plasma free cortisol were not significantly different from controls. Compared with liquid chromatography-mass spectrometry, a commercial immunoassay underestimated mean total plasma cortisol concentrations by 30% during second and third trimesters and in OCP users and overestimated UFC levels by 30-35% during pregnancy. CONCLUSIONS: Our study demonstrated elevations in total plasma cortisol and CBG concentrations during pregnancy and with low-dose OCP use. Pregnancy was also associated with significant increases in plasma free cortisol and UFC, suggesting that the rise in total plasma cortisol is contributed to by up-regulation of the maternal hypothalamic-pituitary-adrenal axis in addition to elevated CBG.

Clinical manifestations of highly prevalent corticosteroid-binding globulin mutations in a village in southern Italy.

CONTEXT: Corticosteroid-binding globulin (CBG) is the binding protein for cortisol. Rare kindreds with CBG mutations reducing CBG levels or altering binding affinity have been described, along with clinical manifestations encompassing fatigue, chronic pain, and hypotension. The largest kindred, exhibiting two mutations (null and Lyon) were Australian immigrants from Italy. OBJECTIVE: Our objective was to determine the prevalence of the null/Lyon mutations in the village where the original null/Lyon family emigrated and compare subjects with and without CBG mutations, without previous knowledge of their mutation status. DESIGN, SETTING, AND PARTICIPANTS: We conducted a survey field study that included 495 adult residents. MAIN OUTCOMES: We assessed clinical history, CBG mutation analysis, plasma CBG, salivary cortisol, body mass index, waist circumference, blood pressure, and the Krupp fatigue scale. RESULTS: Eighteen of 495 participants (3.6%, seven males and 11 females) had one of two function-altering CBG mutations. All were heterozygous for the null (n = 6) or Lyon mutations (n = 12). Of 12 Lyon participants (four males and eight females), eight (two males and six females) had chronic widespread pain and five osteoarthritis with associated pain (one male and four females). Of six null participants (three males and three females), three (one male and two females) had chronic pain and four osteoarthritis with associated pain (two males and two females). CONCLUSIONS: A high combined prevalence (3.6%) of these two CBG mutations was detected. The presence of either mutation conferred a propensity to chronic pain. In other communities, individuals with the same genetic background complain more of fatigue than pain, suggesting an environmental effect on the phenotype. These findings, combined with animal CBG gene knockout and human CBG single-nucleotide polymorphism haplotype studies, suggest that CBG influences the endocrine and neurobehavioral response to stress, including the development of pain/fatigue syndromes.

Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations.

Corticosteroid-binding globulin (CBG) is the specific high-affinity plasma transport glycoprotein for cortisol. Stress-induced falls in CBG levels may heighten hypothalamic-pituitary-adrenal axis responses and CBG:tissue interactions may allow targeted cortisol delivery. Three genetic variants of CBG have been identified that reduce cortisol binding affinity and/or CBG levels. These include the Leuven and Lyon mutations which reduce CBG:cortisol binding affinity 3- and 4-fold, respectively, and the null mutation resulting in a 50% (heterozygote) or 100% (homozygote) reduction in CBG levels. The three reported null homozygotes demonstrate that complete CBG deficiency is not lethal, although it may be associated with hypotension and fatigue. The phenotype of a CBG null murine model included fatigue and immune defects. One community-based study revealed that severe CBG mutations are rare in idiopathic fatigue disorders. The mechanisms by which CBG mutations may cause fatigue are unknown. There are preliminary data of altered CBG levels in hypertension and in the metabolic syndrome; however, the nature of these associations is uncertain. Further studies may clarify the functions of CBG, and clinical observations may validate and/or extend the phenotypic features of various CBG mutations.

Validation of a simple method of estimating plasma free cortisol: role of cortisol binding to albumin.

OBJECTIVES: To develop, optimize, and validate a generalized mass action, equilibrium solution that incorporates measured concentrations of albumin as well as cortisol binding globulin (CBG) to estimate free cortisol. DESIGN AND METHODS: Free cortisol was estimated by Coolens method or by cubic equilibrium equation and compared to measured free cortisol, determined by ultrafiltration method, in subjects with septic shock (n=45), sepsis (n=19), and healthy controls (n=10) at 0, 30, and 60 min following administration of cosyntropin (250 mcg). The data set also included repeat testing in 30 subjects following recovery from sepsis/septic shock. The equilibrium dissociation constant for cortisol binding to albumin (K(A)) was optimized by non-linear regression. The cubic equilibrium solution was also used to model the influence of cortisol, CBG, and albumin concentration on free cortisol. RESULTS: Compared to measured free cortisol, the cubic solution, using an optimized K(A) of 137,800 nM, was less biased than Coolens solution, with mean percent error of -23.0% vs. -41.1% (paired t test, P<0.001). Standard deviation values were also significantly lower (Wilks' test, P<0.001) for the cubic solution (SD 35.8% vs. 40.8% for cubic vs. Coolens, respectively). Modeling studies using the cubic solution suggest an interaction effect by which low concentrations of CBG and albumin contribute to a greater increase in free cortisol than the sum of their independent effects. CONCLUSIONS: Mass action solutions that incorporate the measured concentration of albumin as well as CBG provide a reasonably accurate estimate of free cortisol that generalizes to conditions of health as well as a setting of hypercortisolism and low CBG and albumin concentrations associated with septic shock. Modeling studies emphasize the significant contribution of albumin deficiency and albumin-bound cortisol under conditions of CBG-deficiency, and identify a synergistic effect by which combined CBG and albumin deficiency contribute to elevation of free cortisol in septic shock.

Reduced maternal corticosteroid-binding globulin and cortisol levels in pre-eclampsia and gamete recipient pregnancies.

OBJECTIVE: To measure and contrast maternal cortisol and corticosteroid-binding globulin (CBG) levels in pregnancies with normal outcomes, pre-eclampsia, intrauterine growth restriction (IUGR) and in gamete recipients. STUDY DESIGN: Prospective study of 93 women at high risk of pre-eclampsia, including gamete recipients (n = 22) and 33 controls. Plasma total and free cortisol and CBG were measured every 2 weeks from 16 weeks' gestation until delivery. RESULTS: Forty-two per cent of the high-risk group had complications, including pre-eclampsia (n = 11), gestational hypertension (n = 16) and small-for-gestational-age (SGA) neonates (n = 12). There were no complications in the controls. In all groups, plasma CBG concentrations increased progressively across gestation (P < 0.05), in parallel to total cortisol, but fell significantly from 36 weeks' gestation onwards, with a corresponding rise in free cortisol concentrations. In pre-eclampsia and gestational hypertension, plasma CBG, and total and free cortisol concentrations were lower from 36 weeks onwards (P < 0.05). In IUGR, plasma CBG concentrations were suppressed from 28 weeks' gestation until delivery (P < 0.05), but with no significant difference in plasma total and free cortisol. Gamete recipients had significantly lower plasma CBG from 20 weeks' gestation onwards, and plasma total and free cortisol were reduced at 24 and 32 weeks onwards, respectively. CONCLUSIONS: Maternal plasma CBG, total and free cortisol concentrations are reduced in pre-eclampsia/gestational hypertension, and markedly reduced in gamete recipients. Low CBG may be due to reduced synthesis or enhanced inflammation-driven degradation. Low maternal cortisol may be due to a lack of placental corticotropin-releasing hormone or reduced maternal ACTH, driving cortisol production. Low maternal cortisol may influence the foetal hypothalamic-pituitary-adrenal axis and disease patterns later in life following complicated pregnancy.