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Objective: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies., Design/patients: Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study)., Measurements: Plasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD)., Results: In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores., Conclusions: Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition., (© 2024 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: Hypothalamic-pituitary-adrenal axis (HPA) activity is decreased in obese pregnancy and associates with increased foetal size. Pulsatile release of glucocorticoid hormones regulates their action in target tissues. Glucocorticoids are essential for normal foetal growth, but little is known about glucocorticoid pulsatility in pregnancy. We aimed to investigate the ultradian rhythm of glucocorticoid secretion during obese and lean pregnancy and nonpregnancy., Design: Serum cortisol, cortisone, corticosterone and 11-dehydrocorticosterone were measured by LC-MS/MS from samples obtained at 10-minute intervals between 08.00-11.00 hours and 16.00-19.00 hours, from 8 lean (BMI <25 kg/m 2 ) and 7 obese (BMI > 35 kg/m 2 ) pregnant women between 16-24 weeks gestation and again at 30-36 weeks), and nonpregnant controls (lean n = 3, obese n = 4) during the luteal phase of their menstrual cycle. Interstitial fluid cortisol was measured by ELISA, from samples obtained using a portable microdialysis and automated collection device at 20-minute intervals over 24 hours., Results: Serum cortisol AUC, highest peak and lowest trough increased significantly with gestation in lean and obese pregnant compared with nonpregnant subjects. Pulsatility of cortisol was detected in interstitial fluid. In pregnant subjects, interstitial fluid pulse frequency was significantly lower with advancing gestation in obese, but not in lean., Conclusions: We demonstrate cortisol pulsatility in interstitial fluid. Pulse frequency is altered with increased gestation and BMI. This may be a novel mechanism to explain decreased HPA activity in obese pregnancy., (© 2018 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)

Objectives: Low socio-economic status (SES) is associated with increased disease risk in the involved and the next generation. The effects of low maternal SES on the offspring may be initiated prenatally. We hypothesized that fetoplacental glucocorticoid exposure might mediate the links. We examined associations between maternal level of education and occupational status (used as indices of SES) and placental expression of genes involved in glucocorticoid exposure and transfer between the mother and foetus., Design and Patients: Placental biopsies were obtained from 67 healthy women (age 32.2 ± 5.3 years) with singleton, term pregnancies without obstetric complications who participated in a prospective Prediction and Prevention of Preeclampsia (PREDO) study., Measures: Level of education was self-reported, and occupational status was extracted from hospital records. Relative glucocorticoid receptor (GR; NR3C1), mineralocorticoid receptor (MR; NR3C2) and 11-beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) and 2 (HSD11B2) mRNA levels were quantified by real-time PCR., Results: Placental GR and HSD11B1 expression increased with decreasing maternal education (unadjusted P-values for linear trend = 0.04 and 0.02 and adjusted P-values = 0.06 and 0.09, respectively). Mothers with primary/secondary education had 52.9% (95% CI, 6.2-99.6, P = 0.03, adjusted P = 0.05) and 79.6% (95% CI, 6.5-153.6, P = 0.03, adjusted P = 0.09) higher GR and HSD11B1 mRNA levels compared with mothers with tertiary education. There were no other significant associations., Conclusions: Lower maternal level of education is associated with increased placental GR and HSD11B1 gene expression. This combination may regenerate active glucocorticoids in placenta and increase placental sensitivity to glucocorticoids, potentially leading to greater placental and foetal glucocorticoid exposure., (© 2014 John Wiley & Sons Ltd.)

Development in utero is now recognized as crucial to determining later life disease susceptibility. Whilst mechanisms are poorly understood, there has been considerable interest in the potential role of epigenetic processes in intra-uterine programming of disease. Epigenetic modifications include various mechanisms that influence chromatin structure and gene expression. Here, we review emerging data from human studies that altered DNA methylation links intra-uterine events with later life disease. Further research in this field is needed to determine whether altered DNA methylation in target tissues can be used as a biomarker for the early identification of and intervention in individuals most at risk of later life disease., (© 2013 John Wiley & Sons Ltd.)

The prevalence of maternal obesity has risen dramatically in recent years, with approximately one in five pregnant women in the UK now classed as obese (body mass index ≥ 30 kg/m(2) ) at antenatal booking. Obesity during pregnancy has been hypothesized to exert long-term health effects on the developing child through 'early life programming'. While this phenomenon has been well studied in a maternal undernutrition paradigm, the processes by which the programming effects of maternal obesity are mediated are less well understood. In humans, maternal obesity has been associated with a number of long-term adverse health outcomes in the offspring, including lifelong risk of obesity and metabolic dysregulation with increased insulin resistance, hypertension and dyslipidaemia, as well as behavioural problems and risk of asthma. The complex relationships between the maternal metabolic milieu and the developing foetus, as well as the potential influence of postnatal lifestyle and environment, have complicated efforts to study the programming effects of maternal overnutrition in humans. This review will examine the emerging evidence from human studies linking maternal obesity to adverse offspring outcomes., (© 2012 Blackwell Publishing Ltd.)

Objective: In epidemiological studies, adverse early-life conditions associate with subsequent cardiometabolic disease. Hypothesized causes include maternal malnutrition, foetal glucocorticoid overexposure and reduced growth factors. Animal studies suggest a role for epigenetic processes in maintaining early-life effects into adulthood, but human relevance is unknown. We aimed to investigate relationships between an unbalanced maternal diet in pregnancy, neonatal and adult anthropometric variables with methylation at key genes controlling tissue glucocorticoid action and foetal growth., Design: We studied 34 individuals aged 40 from the Motherwell cohort study whose mothers ate an unbalanced diet in pregnancy, previously linked with elevated blood pressure and cortisol in adult offspring., Measurements: DNA methylation at 11β-hydroxysteroid dehydrogenase type 2 (HSD2), glucocorticoid receptor (GR) and insulin-like growth factor 2 (IGF2) was measured by pyrosequencing on buffy coat DNA., Results: Methylation at specific CpGs in the HSD2 promoter and at one of the IGF2 differentially methylated regions (H19 ICR) correlated with neonatal anthropometric variables. CpG methylation within HSD2, GR and H19 ICR was positively associated with increased adiposity and blood pressure in adulthood. Methylation at GR (exon 1F) was increased in offspring of mothers with the most unbalanced diets in pregnancy., Conclusions: Alterations in DNA methylation at genes important in regulating circulating cortisol levels, tissue glucocorticoid action, blood pressure and foetal growth are present in adulthood in association with both early-life parameters and cardiometabolic risk factors. The data indicate a persisting epigenetic link between early-life maternal diet and/or foetal growth and cardiovascular disease risk in humans., (© 2012 Blackwell Publishing Ltd.)

Objectives: Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre-eclampsia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay and to determine sensitivity and specificity of the test for pre-eclampsia., Design: Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic., Patients: Severely obese (body mass index, BMI > 40 kg/m(2), n = 194) and lean (BMI < 25 kg/m(2), n = 78) pregnant women., Measurements: A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery and stability in maternal plasma samples at 16, 28 and 36 weeks gestation. Pre-eclampsia, defined using International Society for the Study of Hypertension in Pregnancy guidelines; blood pressure; delivery gestation; birthweight., Results: Kisspeptin concentrations were lower in early pregnancy in obese women (P < 0.001), and in women who later developed pre-eclampsia (P < 0.05), compared with women with uncomplicated pregnancies. For 16-week plasma kisspeptin in prediction of pre-eclampsia, area under the receiver-operator characteristic curve was 0.80 (P < 0.01), positive and negative likelihood ratios were 3.0 and 0.2, and test sensitivity and specificity were 85.7 and 71.4%, respectively. In regression analyses, kisspeptin (16 weeks) associated positively with delivery gestation (P < 0.05) and birthweight (P < 0.0001), and negatively with 28- and 36-week blood pressure (P < 0.0001)., Conclusions: Kisspeptin concentration in early pregnancy is a promising biomarker for pre-eclampsia and low birthweight but cannot be recommended, in isolation, for universal screening because of inadequate test sensitivity and specificity. Large-scale studies are required to assess its potential in a panel of biomarkers., (© 2011 Blackwell Publishing Ltd.)

Objective: The metabolic syndrome is more prevalent in South Asians in Britain than in the general population. Furthering our understanding of the underlying mechanisms is important because of the increased risk of cardiovascular disease associated with the metabolic syndrome. As it has been proposed that increased activity of the hypothalamic pituitary adrenal axis might underlie the metabolic syndrome, we hypothesized that plasma cortisol levels would be higher in South Asians and that increased cortisol levels would be associated with cardiovascular risk factors comprising the metabolic syndrome. The aim of the study was to examine ethnic differences in cortisol levels and to compare the relationships between cortisol levels and cardiovascular risk factors in men from different ethnic groups., Design: Cross-sectional population-based study, Newcastle upon Tyne, UK. (Newcastle Heart project). Participants One hundred men, 40-67 years old, of European and South Asian (Indian, Pakistani, Bangladeshi) ancestry, with and without cardiovascular risk factors of the metabolic syndrome., Measurements: Measurement of plasma cortisol and corticosteroid binding globulin in stored sera., Results: After adjustment for age and the presence of cardiovascular risk factors, mean cortisol was 27% (95% CI, 10%, 40%) lower in South Asians compared to Europeans. Cortisol levels were higher in all men with cardiovascular risk factors than those without., Conclusions: Cortisol levels are lower in South Asian than in European men resident in the UK. Despite lower cortisol levels in South Asians, the relations between cortisol and cardiovascular risk factors remain strong.

Objective: Assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis following pituitary surgery is necessary to determine the requirement for glucocorticoid replacement therapy, but there remains controversy about the optimum way to measure this., Design and Measurements: Postal questionnaire survey among UK endocrinologists to evaluate the current methods used., Results: The response rate was low (81 out of 598 questionnaires mailed), although 85% were consultants. Fifty-five percent measured 9:00 h plasma cortisol in the immediate postoperative phase. Most carried out definitive testing between 4 and 12 weeks: 36% routinely used the insulin tolerance test (ITT), 59% used the short synacthen test (SST). The 30-min cortisol value was used by 67% as a 'pass' when interpreting the results. Others included cortisol measurement at 60 min (17%) or incremental value (7%). For long-term follow-up of patients not rendered ACTH-deficient by surgery, 64% used the SST for patients who had received radiotherapy. If patients had not had radiotherapy, 42% used the SST, whereas 33% did no routine testing unless the patient was symptomatic or there was evidence of tumour recurrence on imaging. If patients were symptomless but 'failed' the chosen test, 28% still treated the patient with glucocorticoid replacement, 38% retested before treatment and 24% recommended glucocorticoid cover for when unwell or 'stressed'. Fifty-six percent used hydrocortisone at doses of 20 mg/day as replacement therapy., Conclusion: Thus, assessment of the HPA axis remains controversial. Although the SST is becoming more popular, there is still considerable variation in the interpretation of results and, in particular, the decision of whether or not to treat with lifelong glucocorticoid replacement therapy.

Objective: The incidence of thyroid cancer is increasing in several countries. The aim was to investigate trends in the incidence and mortality of thyroid cancer in Scotland, where thyroid cancer is relatively uncommon, between 1960 and 2002., Design: Descriptive epidemiological study., Methods: Thyroid cancer registrations between 1960 and 2000 were obtained from the Scottish Cancer Registry. Mortality data (1960-2002) and population estimates were supplied by the Registrar General for Scotland. Incidence and mortality data are expressed as age-specific rates and European age-standardized rates (EASRs)., Results: Thyroid cancer was three times more common in females than in males and was more common in older than younger age groups. Between 1960 and 2000, the annual EASR of thyroid cancer increased from 1.76 to 3.54 per 100,000 for females (P < 0.001) and from 0.83 to 1.25 per 100,000 in males (P < 0.001). The overall thyroid cancer increase between 1975 and 2000 was primarily caused by an increase in papillary thyroid cancer, particularly over the most recent decade. The incidence of follicular thyroid cancer also increased while the incidence of anaplastic and medullary thyroid cancer did not change significantly. Mortality from thyroid cancer fell progressively between 1960 and 2002. EASR for females decreased from 1.05 to 0.28 (P < 0.001) and in males from 0.73 to 0.34 (P < 0.001). For both sexes, in general, survival at 1-, 5- and 10-year follow-up intervals from diagnosis improved steadily over the study period. In both females and males, survival from thyroid cancer was better if the diagnosis was made under the age of 50 years., Conclusions: Thyroid cancer incidence has increased in Scotland over the past 40 years. This is accompanied by a change in the distribution of histological type with a particular increase in papillary carcinoma. The reasons for this may relate partly to changes in clinical practice and histological criteria. Falling mortality in the face of increasing incidence reflects improvements in survival, which should improve further with the introduction and implementation of standardized treatment protocols.

Background: The low dose dexamethasone suppression test (DST) has been used to detect subtle variations in the feedback suppression of the hypothalamic-pituitary-adrenal axis, which may contribute to the pathogenesis of several diseases including depression, the metabolic syndrome and coronary artery disease. Little is known about the reproducibility of this test, or whether the test can be combined with analysis of salivary cortisol which would offer a significant advantage over plasma in population studies., Subjects and Design: A low dose DST was carried out in 29 healthy subjects (14 men, 15 women), aged 24-54 (mean 35.1) years, on two separate occasions 1-10 weeks apart. Following the administration of 0.25 mg dexamethasone (DXM) at 2200 h, plasma and saliva were sampled at 0830 h the next day. Cortisol was measured by radioimmunoassay in plasma and time-resolved immunofluorescent assay ('DELFIA') in saliva. Bland-Altman plots were produced for post-DXM plasma and salivary cortisol measures and used to derive a coefficient of repeatability for each measure, which describes the range of cortisol measurements within which 95% of repeated measurements will fall., Results: The baseline, pre-DXM cortisol concentrations were far more variable for saliva (mean 16.5, range 4.4-34 nmol/l) than for plasma (mean 407.5; range 232-958 nmol/l). Following DXM both measurements showed an approximately 30% suppression from baseline but the variability of salivary cortisol was much greater. From the Bland-Altman plots the 95% range for the differences about their mean was calculated and used as an indication of repeatability. For plasma 95% of differences were within 0.78 log units, indicating that a repeated measurement was approximately half as small or twice as large as the first. For saliva 95% of differences were within 1.64, indicating that a repeated measurement was approximately five times as small or five times as large as the first., Conclusions: Assessment of dexamethasone suppression by salivary cortisol measurement is far less repeatable than the use of plasma cortisol. In the context of field studies of dexamethasone suppression, salivary cortisol measurements may only be appropriate for large numbers of subjects.