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Context: Comprehensive assessment of metabolism in maternal obesity and pregnancy disorders can provide information about the shared maternal-fetal milieu and give insight into both maternal long-term health and intergenerational transmission of disease burden., Objective: To assess levels, profiles, and change in the levels of metabolic measures during pregnancies complicated by obesity, gestational diabetes (GDM), or hypertensive disorders., Design, Setting and Participants: A secondary analysis of 2 study cohorts, PREDO and RADIEL, including 741 pregnant women., Main Outcome Measures: We assessed 225 metabolic measures by nuclear magnetic resonance in blood samples collected at median 13 [interquartile range (IQR) 12.4-13.7], 20 (IQR 19.3-23.0), and 28 (27.0-35.0) weeks of gestation., Results: Across all 3 time points women with obesity [body mass index (BMI) ≥ 30kg/m2] in comparison to normal weight (BMI 18.5-24.99 kg/m2) had significantly higher levels of most very-low-density lipoprotein-related measures, many fatty and most amino acids, and more adverse metabolic profiles. The change in the levels of most metabolic measures during pregnancy was smaller in obese than in normal weight women. GDM, preeclampsia, and chronic hypertension were associated with metabolic alterations similar to obesity. The associations of obesity held after adjustment for GDM and hypertensive disorders, but many of the associations with GDM and hypertensive disorders were rendered nonsignificant after adjustment for BMI and the other pregnancy disorders., Conclusions: This study shows that the pregnancy-related metabolic change is smaller in women with obesity, who display metabolic perturbations already in early pregnancy. Metabolic alterations of obesity and pregnancy disorders resembled each other suggesting a shared metabolic origin., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Human and animal studies suggest that hypothalamic-pituitary-adrenal axis (HPA-A) function may be programmed in utero; however, these findings are inconsistent. Given the powerful metabolic actions of cortisol, it is important to clarify the influence of early life on adult HPA-A function., Objective: To determine the relationship between fetal growth and HPA-A stress response to a psychosocial stressor in young adults., Design: Multigenerational, prospective cohort study (the Raine Study) conducted between 1989 and 1991., Setting: King Edward Memorial Hospital, Perth, Western Australia, Australia., Participants: A total of 917 participants aged 18 years from Gen2 of the Raine Study., Main Outcome Measures: Measures of hypothalamic-pituitary-adrenal axis function before and after exposure to the Trier Social Stress Test., Results: In fully adjusted models, an inverse linear relationship was observed between birthweight and plasma measures of (1) baseline cortisol (β = -0.90%, 95% CI: -1.73 to -0.07; P = 0.03); (2) peak cortisol (β = -0.78%, 95% CI -1.51 to -0.06; P = 0.03); (3) area under the curve with respect to ground (β = -0.89%, 95% CI -1.60 to -0.18; P = 0.01); and (4) adrenal sensitivity (β = -1.02, 95% CI: -1.85 to -0.18; P = 0.02). Similar results were demonstrated for percent optimal birthweight. No consistent quadratic relationships were identified. No associations were found between measures of fetal adiposity and HPA-A function at age 18 years, or fetal growth and HPA-A response pattern. Removal of anticipatory responders from the models substantially attenuated the observed relationships., Conclusion: We observed an inverse linear relationship between fetal growth and HPA-A function at age 18 years. This differs from the inverse parabolic relationship (inverted U curve) reported in adults of advanced age. Altered adrenal sensitivity may underlie this relationship., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Across pregnancy, maternal serum cortisol levels increase up to 3-fold. It is not known whether maternal peripheral cortisol metabolism and clearance change across pregnancy or influence fetal cortisol exposure and development., Objectives: The primary study objective was to compare maternal urinary glucocorticoid metabolites, as markers of cortisol metabolism and clearance, between the second and third trimester of pregnancy. Secondary objectives were to test associations of total maternal urinary glucocorticoid excretion, with maternal serum cortisol levels and offspring birth weight z score., Design, Participants, and Setting: A total of 151 women with singleton pregnancies, recruited from prenatal clinic at the Pittsburgh site of the Measurement of Maternal Stress (MOMS) study, had 24-hour urine collections during both the second and third trimesters., Results: Between the second and third trimester, total urinary glucocorticoid excretion increased (ratio of geometric means [RGM] 1.37, 95% CI 1.22-1.52, P < .001), and there was an increase in calculated 5β-reductase compared to 5α-reductase activity (RGM 3.41, 95% CI 3.04-3.83, P < .001). During the third trimester total urinary glucocorticoid excretion and serum cortisol were negatively correlated (r = -0.179, P = .029). Mean total urinary glucocorticoid excretion across both trimesters and offspring birth weight z score were positively associated (β = 0.314, P = .001)., Conclusions: The estimated activity of maternal enzymes responsible for cortisol metabolism change between the second and third trimester of pregnancy. Additionally, maternal peripheral metabolism and clearance of cortisol may serve as a novel mechanism affecting fetal cortisol exposure and growth., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Context: Fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular disease in later life., Objective: To develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesized placental 11-β-hydroxysteroid dehydrogenase-type 2 (11β-HSD2) would be the major rate-limiting step in maternal cortisol transfer to the fetus., Design: We used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modeling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus., Participants: Term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery., Intervention: Maternal artery of the isolated perfused placenta was perfused with D4-cortisol., Main Outcome Measures: D4-cortisol, D3-cortisone, and D3-cortisol were measured in maternal and fetal venous outflows., Results: D4-cortisol, D3-cortisone, and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11-β-hydroxysteroid dehydrogenase (11β-HSD) activity was inhibited. At the highest inlet concentration, only 3.0% of the maternal cortisol was transferred to the fetal circulation, whereas 26.5% was metabolized and 70.5% exited via the maternal vein. Inhibiting 11β-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, whereas 92.7% exited via the maternal vein., Conclusions: Our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11β-HSD2 acts as a major "barrier" to cortisol transfer to the fetus., (Copyright © 2017 Endocrine Society)

Context: Circadian variation is a fundamental characteristic of plasma glucocorticoids, with a postprandial rise in cortisol an important feature. The diurnal rhythm is presumed to reflect alterations in hypothalamic-pituitary-adrenal axis activity; however, cortisol is produced not only by the adrenal glands but also by regeneration from cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 1, mainly in liver and adipose tissue., Objective: We tested the contribution of peripheral cortisol regeneration to macronutrient-induced circadian variation of plasma cortisol in humans., Design: This was a randomized, single-blinded, crossover study., Setting: The study was conducted at a hospital research facility., Participants: Eight normal-weight healthy men participated in the study., Interventions: Subjects were given isocaloric energy isodense flavor-matched liquid meals composed of carbohydrate, protein, fat, or low-calorie placebo during infusion of the stable isotope tracer 9,11,12,12-[2H]4-cortisol., Outcome Measures and Results: Plasma cortisol increased similarly after all macronutrient meals (by ∼90 nmol/L) compared with placebo. Carbohydrate stimulated adrenal secretion and extra-adrenal regeneration of cortisol to a similar degree. Protein and fat meals stimulated adrenal cortisol secretion to a greater degree than extra-adrenal cortisol regeneration. The increase in cortisol production by 11β-hydroxysteroid dehydrogenase type 1 was in proportion to the increase in insulin. The postprandial cortisol rise was not accounted for by decreased cortisol clearance., Conclusions: Food-induced circadian variation in plasma cortisol is mediated by adrenal secretion and extra-adrenal regeneration of cortisol. Given that the latter has the more potent effect on tissue cortisol concentrations and that effects on adrenal and extra-adrenal cortisol production are macronutrient specific, this novel mechanism may contribute to the physiological interplay between insulin and glucocorticoids and the contrasting effects of certain diets on postprandial metabolism.

Context: The prevalence of obesity among women of childbearing age is increasing. Emerging evidence suggests that this has long-term adverse influences on offspring health., Objective: The aim was to examine whether maternal body composition and gestational weight gain have persisting effects on offspring adiposity in early adulthood., Design and Setting: The Motherwell birth cohort study was conducted in a general community in Scotland, United Kingdom., Participants: We studied 276 men and women whose mothers' nutritional status had been characterized in pregnancy. Four-site skinfold thicknesses, waist circumference, and body mass index (BMI), were measured at age 30 yr; sex-adjusted percentage body fat and fat mass index were calculated., Main Outcome Measure: Indices of offspring adiposity at age 30 yr were measured., Results: Percentage body fat was greater in offspring of mothers with a higher BMI at the first antenatal visit (rising by 0.35%/kg/m2; P<0.001) and in offspring whose mothers were primiparous (difference, 1.5% in primiparous vs. multiparous; P=0.03). Higher offspring percentage body fat was also independently associated with higher pregnancy weight gain (7.4%/kg/wk; P=0.002). There were similar significant associations of increased maternal BMI, greater pregnancy weight gain, and parity with greater offspring waist circumference, BMI, and fat mass index., Conclusions: Adiposity in early adulthood is influenced by prenatal influences independently of current lifestyle factors. Maternal adiposity, greater gestational weight, and parity all impact on offspring adiposity. Strategies to reduce the impact of maternal obesity and greater pregnancy weight gain on offspring future health are required.

Context: Lipophilic plasma glucocorticoids are thought to gain rapid access to intracellular compartments in adipose tissue. In other organs, transport can be regulated in a steroid- and tissue-specific manner. Moreover, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) generates additional cortisol within adipose., Aim: The aim was to measure the rate of exchange of cortisol between plasma and adipose for comparison with rates of intracellular cortisol generation by 11βHSD1., Participants and Interventions: With ethical approval, otherwise healthy females (n = 6) undergoing hysterectomy for benign indications were infused with tracer 9,11,12,12-[(2)H](4)cortisol (d4-cortisol). Adipose biopsies and peripheral venous samples were obtained during surgery after 3.9-5.5 h of infusion. Glucocorticoids were quantified using liquid chromatography tandem mass spectrometry., Results: In plasma, d4-cortisol concentrations and appearance rates of cortisol and d3-cortisol (reflecting 11βHSD1 activity) did not change during surgery. In both omental and sc adipose, cortisol concentrations were lower than in plasma, consistent with differences in corticosteroid binding globulin, and enrichment with d4-cortisol was low (sc, 7.2 ± 0.6%; omental, 7.4 ± 0.7%; vs. plasma, 15.5 ± 1.0%). The rate of accumulation of d4-cortisol in adipose depots was 0.5 ± 0.1 (sc) and 0.4 ± 0.1 (omental) nmol/kg · h, and the proportion of intraadipose cortisol replaced each hour only 10.7 ± 1.0 and 10.4 ± 0.7%, respectively. The contribution of 11βHSD1 to this turnover could not be quantified because very little substrate d3-cortisone accumulated in adipose during infusion., Conclusions: Slow turnover of the adipose glucocorticoid pool suggests that rapid acute fluctuations in circulating cortisol are not reflected in adipose, so that 11βHSD1 activity (previously estimated to generate 9 nmol cortisol/kg · h in sc adipose) may play a relatively important role in modulating activation of glucocorticoid receptors.

Context: Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the metabolic syndrome, but whether circulating cortisol levels predict cardiovascular end points is less clear. People with type 2 diabetes are at increased cardiovascular disease risk and thus are suitable to study associations of plasma cortisol with cardiovascular risk., Objective: We aimed to assess whether altered HPA axis activity was associated with features of the metabolic syndrome and ischemic heart disease in people with type 2 diabetes., Design and Setting: We conducted a cross-sectional cohort study in the general community, including 919 men and women aged 67.9 (4.2) yr with type 2 diabetes (the Edinburgh Type 2 Diabetes Study)., Intervention: We measured fasting morning plasma cortisol., Main Outcome Measurement: Associations between cortisol levels, features of the metabolic syndrome, obesity, and ischemic heart disease were determined., Results: Elevated plasma cortisol levels were associated with raised fasting glucose and total cholesterol levels (P < 0.001). These findings remained significant after adjustment for potential confounding factors (P < 0.001). Elevated cortisol levels were associated with prevalent ischemic heart disease (>800 vs. <600 nmol/liter; odds ratio, 1.58; P = 0.02). This association remained significant after adjustment for duration and control of diabetes and other cardiovascular risk factors (P = 0.03)., Conclusions: The previously described associations between HPA axis activation and features of the metabolic syndrome are present among people with type 2 diabetes. Elevated plasma cortisol is also associated with a greater prevalence of ischemic heart disease, independent of conventional risk factors. Understanding the role of cortisol in the pathogenesis of ischemic heart disease merits further exploration.

Context: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie disorders including obesity, depression, cognitive decline, and the metabolic syndrome. Conventional tests of HPA axis negative feedback rely on glucocorticoid receptor (GR) agonists such as dexamethasone but do not test feedback by endogenous cortisol, potentially mediated by both GR and mineralocorticoid receptors (MR)., Objective: The objective of the study was to use a combination of GR (RU38486, mifepristone) and MR (spironolactone) antagonists to explore the poorly understood activation of the HPA axis that occurs in obesity., Design: This was a double-blind, placebo-controlled, randomized, crossover study., Setting: The study was conducted at a clinical research facility., Participants: Participants included 15 lean (body mass index 22.0 +/- 1.6 kg/m(2)) and 16 overweight/obese (body mass index 30.1 +/- 3.5 kg/m(2)) men., Intervention: Subjects attended on four occasions for blood and saliva sampling every 30 min between 1800 and 2200 h. At 1100 and 1600 h before visits, subjects took 200 mg spironolactone, 400 mg RU38486, 200 mg spironolactone + 400 mg RU38486, or placebo orally., Main Outcome Measures: Serum cortisol levels after drug or placebo were measured., Results: Cortisol levels did not differ between lean and obese after placebo. Spironolactone and RU38486 alone had modest effects, increasing cortisol by less than 50% in both groups. However, combined spironolactone plus RU38486 elevated cortisol concentrations substantially, more so in lean than obese men [2.9- (0.3) vs. 2.2 (0.3)-fold elevation, P = 0.002]., Conclusions: Combined receptor antagonist stimulation of the HPA axis reveals redundancy of MR and GR in negative feedback in humans. Obese men have impaired responses to combined receptor antagonist stimulation, suggesting impaired negative feedback by endogenous cortisol. Such an approach may be useful to dissect abnormal HPA axis control in neuropsychiatric and other disorders.

Context: Men and women whose mothers ate an unbalanced high-protein, low-carbohydrate diet in late pregnancy have raised blood pressure. We recently showed that they also have raised fasting plasma cortisol concentrations. Because raised fasting cortisol concentrations probably reflect a greater response to the stress of fasting and venesection, we suspected that this diet may have led to increased stress responsiveness in the adult offspring., Objective: The aim was to determine whether an unbalanced high-protein diet during pregnancy is associated with increased cortisol secretion in response to psychological stress in the offspring., Design and Participants: Salivary cortisol concentrations were measured during a modified Trier Social Stress Test in 70 men and women aged 36.3 yr whose mothers had taken part in a dietary intervention in which they were advised to eat 1 pound (0.45 kg) of red meat daily during pregnancy and to avoid carbohydrate-rich foods., Results: The offspring of women who reported greater consumption of meat and fish in the second half of pregnancy had higher cortisol concentrations during the Trier Test. Compared with the offspring of mothers who had reported eating no more than 13 meat/fish portions per week, the average cortisol concentrations were raised by 22% (95% confidence interval, 13 to 71%) and 46% (5 to 103%) in the offspring of those eating 14-16 and at least 17 portions per week, respectively., Conclusions: These findings provide the first human evidence that an unbalanced high protein maternal diet during late pregnancy leads to increased cortisol secretion in response to psychological stress in the offspring.

Context: Increasing incidence and improved prognosis of thyroid cancer have led to concern about the development of second primary cancers, especially after radioiodine treatment. Thyroid cancer can also arise as a second primary neoplasm after other cancers., Objective: The objective of the study was to assess the risk of second primary cancer after thyroid cancer and vice versa., Design: This was a multinational record linkage study., Setting: The study was conducted at 13 population-based cancer registries in Europe, Canada, Australia, and Singapore., Patients or Other Participants: A cohort of 39,002 people (356,035 person-yr of follow-up) with primary thyroid cancer were followed up for SPN for up to 25 yr, and 1,990 cases of thyroid cancer were diagnosed after another primary cancer., Main Outcome Measures: To assess any possible excess of second primary neoplasms after thyroid cancer, the observed numbers of neoplasms were compared with expected numbers derived from age-, sex-, and calendar period-specific cancer incidence rates from each of the cancer registries, yielding standardized incidence ratios (SIRs). The SIR of second primary thyroid cancer after various types of cancer was also calculated., Results: During the observation period, there were 2821 second primary cancers (all sites combined) after initial diagnosis of thyroid cancer, SIR of 1.31 (95% confidence interval 1.26-1.36) with significantly elevated risks for many specific cancers. Significantly elevated risks of second primary thyroid cancer were also seen after many types of cancer., Conclusion: Pooled data from 13 cancer registries show a 30% increased risk of second primary cancer after thyroid cancer and increased risks of thyroid cancer after various primary cancers. Although bias (detection, surveillance, misclassification) and chance may contribute to some of these observations, it seems likely that shared risk factors and treatment effects are implicated in many. When following up patients who have been treated for primary thyroid cancer, clinicians should maintain a high index of suspicion for second primary cancers.

Recent evidence suggests that variations in cortisol activity within the physiological range contribute to associations between multiple cardiovascular risk factors. Plasma cortisol measurements during a glucose tolerance test differ in men with hypertension, insulin resistance, and glucose intolerance, but it is unclear whether this reflects altered responses of cortisol to glucose, altered circadian rhythm, or altered habituation to multiple sampling. We performed a single-blind randomized cross-over study comparing 75 g oral glucose with placebo in 39 fasted men (22 glucose intolerant and 17 controls) aged 68-77 yr. In all subjects, plasma cortisol fell during the glucose tolerance test. Subjects with glucose intolerance had significantly higher plasma cortisol following placebo (P = 0.001), suggesting an altered circadian rhythm. Treatment with an oral glucose load blunted the circadian fall in plasma cortisol (P = 0.002), but this response was no different in controls or glucose intolerant subjects. In addition, 0900 h plasma cortisol was higher in the first study phase in controls (P = 0.01) but not in glucose-intolerant subjects (P = 0.18), who showed a lack of habituation to repeated plasma measurements. These data support the hypothesis that alterations in central regulation of the hypothalamic-pituitary-adrenal axis may be important in glucose intolerance.

It has been suggested that increased activity of the hypothalamic-pituitary-adrenal axis may link low birth weight with subsequent development of cardiovascular risk factors and disease. Two hundred and five men, aged 66-77 yr, who were born and still live in East Hertfordshire underwent an overnight very low dose (0.25 mg) dexamethasone suppression test followed by a low dose 1-microgram ACTH-(1-24) stimulation test. A 24-h urine sample was collected for analysis of cortisol metabolites by gas chromatography/electron impact mass spectrometry. Men with lower birth weight had enhanced responses of plasma cortisol to ACTH-(1-24) (P = 0.03), increased total urinary cortisol metabolite excretion (after adjustment for confounding effects of increased obesity and lean body mass in high birth weight men; P = 0.04), but no difference in plasma cortisol after dexamethasone. Features of the metabolic syndrome were independently associated with enhanced adrenal responsiveness to ACTH-(1-24) (raised blood pressure, P = 0.02; glucose intolerance, P = 0.09; hypertriglyceridemia, P = 0.02), with trends to increased urinary cortisol metabolite excretion, but not with differences in plasma cortisol after dexamethasone. Men with low birth weight and/or the metabolic syndrome have increased activity of the hypothalamic-pituitary-adrenal axis. This may be an important mechanism underpinning the effects of events in early life on later cardiovascular disease.