Married but lonely. Impact of poor marital quality on diurnal cortisol patterns in older people: findings from the cross-sectional KORA-Age study.

Despite well-established evidence on marriage as a psychosocial support for adults, there are studies that indicate loneliness may affect even married adults. Loneliness provokes a dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Thus, the study aims to examine the sex-specific association of loneliness and cortisol levels in the married older population. A cross-sectional analysis was conducted among 500 married participants (316 male and 184 female) aged 65-90 years (mean age = 73.8 ± 6.4 years) of the population-based KORA (Cooperative Health Research in the Region of Augsburg) - Age study. Linear regression analyses were employed to examine the association between cortisol measurements (salivary cortisol upon waking (M1), 30 min after awakening (M2), late night (LNSC), cortisol awakening response (CAR), diurnal cortisol slope (DCS)) and loneliness (assessed by UCLA Loneliness Scale) in married participants with adjustments for potential confounders. In total sample population, lonely married participants displayed a significantly flatter DCS after M2 peak than their not lonely counterparts. In sex-specific analyses, lonely married men showed flatter DCS and reduced CAR than non-lonely counterparts. The association between loneliness and DCS was robust even after adjustment for lifestyle and psychosocial factors. In married women, no significant associations between loneliness and cortisol levels were observed. These findings suggest a differential impact of loneliness on HPA axis dynamics in lonely married men. Our findings highlight the importance to address loneliness even in married people.

Diurnal 11-ketotestosterone and 17-hydroxyprogesterone saliva profiles in paediatric classical congenital adrenal hyperplasia.

OBJECTIVES: The most suitable biochemical markers for therapy adjustment in patients with congenital adrenal hyperplasia are controversial. 11-Oxygenated androgens are a promising new approach. The objective of this study was to investigate the diurnal rhythm of 11-ketotestosterone in children and adolescents in saliva and to correlate it with salivary 17-hydroxyprogesterone. METHODS: Fifty-one samples of steroid day-profiles from 17 patients were additionally analysed for 11-ketotestosterone, retrospectively. All patients were treated in our university outpatient clinic for paediatric endocrinology between 2020 and 2022. Steroid day-profiles of 17 patients could be examined. The cohort showed a balanced sex ratio. The median age was 13 years. The measurements for 17-hydroxyprogesterone were carried out during routine care by immunoassay. The measurements of 11-ketotestosterone were performed from frozen saliva samples using an implemented in-house protocol for liquid chromatography-tandem mass spectrometry (LC-MS/MS). The most important outcome were the absolute values for 11-ketotestosterone, their diurnal rhythmicity and the correlation with 17-hydroxyprogesterone. RESULTS: Both steroids show a circadian diurnal rhythm. 17-hydroxyprogesterone and 11-ketotestosterone correlate significantly. 11-Ketotestosterone showed a positive correlation with BMI at all times of the day. CONCLUSIONS: 11-Ketotestosterone shows circadian rhythmicity in our cohort and correlates with 17-hydroxyprogesterone. These findings serve as an important basis for prospective research into 11-oxygenated androgens as therapeutic markers in paediatrics. However, 11-ketotestosterone appears to be very dependent on BMI.

Altered psychobiological responsiveness in women with irritable bowel syndrome.

OBJECTIVE: Although stress has been considered an important pathophysiological factor in irritable bowel syndrome (IBS), there is incomplete understanding of its physiological mechanisms. The current study was designed to compare diurnal hypothalamic-pituitary-adrenal (HPA) axis activity in IBS patients and controls and their psychobiological response to a psychosocial stressor. METHODS: Basal and stimulated HPA axis activity was assessed in 57 women with IBS and 20 matched controls. Psychiatric comorbidity was assessed using a standardized clinical interview. Salivary morning cortisol and diurnal profile were obtained, and the Trier Social Stress Test (TSST) was administered. Levels of cortisol and adrenocorticotropic hormone (ACTH) were measured before and within 1 hour after the stressor. Overall stress experience and stress related to the TSST were assessed using standardized questionnaires. RESULTS: All subjects showed intact circadian variation of cortisol. However, IBS patients with predominant diarrhea exhibited substantially heightened cortisol levels at awakening (p < .03) and a blunted cortisol awakening response. In response to the TSST, patients exhibited significantly blunted cortisol (p < .05) and slightly attenuated ACTH secretion compared with controls. During the recovery period, ACTH levels were significantly lower (p < .04) in patients than those in healthy subjects. Women with IBS perceived higher stress susceptibility than control subjects did (p < .01). CONCLUSIONS: The enhanced morning cortisol levels in one subgroup of IBS patients may indicate an association between basal HPA axis activity and predominant bowel habit. The downregulated HPA axis reactivity in IBS after the TSST suggests a downregulated sensitivity of the endocrine system. On the contrary, all subjective stress ratings were increased in the IBS group, which may indicate increased stress susceptibility.

Salivary Profiles of 11-oxygenated Androgens Follow a Diurnal Rhythm in Patients With Congenital Adrenal Hyperplasia.

CONTEXT: Several studies have highlighted the importance of the 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as potential biomarkers for monitoring patients with 21-hydroxylase deficiency (21OHD). OBJECTIVE: To analyze circadian rhythmicity of 11oxC19 steroids in saliva profiles and evaluate their relevance as potential monitoring parameters in 21OHD. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional single-center study including 59 patients with classic 21OHD (men = 30; women = 29) and 49 body mass index- and age-matched controls (men = 19; women = 30). OUTCOME MEASURES: Salivary concentrations of the following steroids were analyzed by liquid chromatography-tandem mass spectrometry: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11ß-hydroxyandrostenedione (11OHA4), and 11-ketotestosterone (11KT). RESULTS: Similar to the previously described rhythmicity of 17OHP, 11OHA4 and 11KT concentrations followed a distinct diurnal rhythm in both patients and controls with highest concentrations in the early morning and declining throughout the day (11-OHA4: mean reduction of hormone concentrations between timepoint 1 and 5 (Δ mean) in male patients = 66%; male controls Δ mean = 83%; female patients Δ mean = 47%; female controls Δ mean = 86%; 11KT: male patients Δ mean = 57%; male controls Δ mean = 63%; female patients Δ mean = 50%; female controls Δ mean = 76%). Significant correlations between the area under the curve for 17OHP and 11KT (rpmale = 0.773<0.0001; rpfemale = 0.737<0.0001), and 11OHA4 (rpmale = 0.6330.0002; rpfemale = 0.5640.0014) were observed in patients but not present or reduced in controls. CONCLUSIONS: Adrenal 11oxC19 androgens are secreted following a diurnal pattern. This should be considered when evaluating their utility for monitoring treatment control.

Association of generalized and central obesity with serum and salivary cortisol secretion patterns in the elderly: findings from the cross sectional KORA-Age study.

The study aimed to examine the sex specific association of obesity with cortisol metabolism in a sample of older community dwelling people. The cross-sectional analysis included 394 men and 375 women (aged 65-90 years) of the population-based KORA-Age study. Multivariable regression analyses were employed to examine the association between cortisol samples (serum and salivary samples of morning after awakening (M1), 30 min later (M2) and at late night (LNSC)). Obesity was calculated as waist-to-hip ratio (WHR) and body mass index (BMI). Cortisol levels were not significantly different between obesity measures except for elevated serum cortisol (P = 0.02) levels in individuals with a low WHR. Higher M1 levels were especially apparent in women with normal BMI. Serum cortisol levels were inversely related to WHR (P = 0.004) and CARAUC was inversely associated with BMI (P = 0.007). Sex-stratified analytic models revealed that both obesity measures showed a non-linear association with cortisol diurnal pattern (M1/LNSC) in men. Impaired cortisol patterns emerged at both very ends of the body weight distribution. These findings do not support a cortisol driven obesity etiology in an older population and even point to an inverse association of body weight with cortisol levels. Differences of cortisol secretion patterns in generalized and abdominal fat distribution were marginal.

The relationship between alexithymia and salivary cortisol levels in somatoform disorders.

The purpose of this study was to investigate cortisol levels as a function of the hypothalamic-pituitary-adrenal axis (HPA) in relation to alexithymia in patients with somatoform disorders (SFD). Diurnal salivary cortisol was sampled in 32 patients with SFD who also underwent a psychiatric examination and filled in questionnaires (Toronto Alexithymia Scale, TAS scale; Screening for Somatoform Symptoms, SOMS scale; Hamilton Depression Scale, HAMD). The mean TAS total score in the sample was 55.6+/-9.6, 32% of patients being classified as alexithymic on the basis of their TAS scores. Depression scores were moderate (HAMD=13.2, Beck Depression Inventory, BDI=16.5). The patients' alexithymia scores (TAS scale "Difficulty identifying feelings") correlated significantly positively with their somatization scale scores (Symptom Checklist-90 Revised, SCL-90-R); r=0.3438 (P<0.05) and their scores on the Global Severity Index (GSI) on the SCL-90-R; r=0.781 (P<0.01). Regression analysis was performed with cortisol variables as the dependent variables. Cortisol levels [measured by the area under the curve-ground (AUC-G), area under the curve-increase (AUC-I) and morning cortisol (MCS)] were best predicted in a multiple linear regression model by lower depressive scores (HAMD) and more psychopathological symptoms (SCL-90-R). No significant correlations were found between the patients' alexithymia scores (TAS) and cortisol levels. The healthy control group (n=25) demonstrated significantly higher cortisol levels than did the patients with SFD; in both tests P<0.001 for AUC-G and AUC-I. However, the two groups did not differ in terms of their mean morning cortisol levels (P>0.05). The results suggest that pre-existing hypocortisolism might possibly be associated with SFD.

Sex-related differences in the association of salivary cortisol levels and type 2 diabetes. Findings from the cross-sectional population based KORA-age study.

BACKGROUND: Dysregulation in the cortisol secretion may have a role in the development of type 2 diabetes although conflicting evidence on the particular cortisol secretion patterns and type 2 diabetes demands further investigations. We aim to examine the association of cortisol levels and diurnal secretion patterns with prevalence of type 2 diabetes and HbA1c levels as well as the potential impact of sex and adiposity on this association. METHODS: A cross-sectional analysis was conducted among 757 participants (aged 65-90 years) of the population-based KORA (Cooperative Health Research in the Region of Augsburg)-Age study. Multivariate regression analyses were employed to examine the association between salivary cortisol (measured upon waking (M1), 30min after awakening (M2), and in the late night (LNSC)) and type 2 diabetes as well as glycated hemoglobin (HbA1c) with adjustments for potential confounders. RESULTS: In the total sample population, an elevated LNSC level was observed in type 2 diabetes patients compared to non-patients (P=0.04). In sex-stratified analyses, diabetic men showed a greater Cortisol Awakening Response (CAR) (P=0.02). Diabetic women had significantly elevated LNSC levels (P=0.04). HbA1c was positively associated with both CAR and LNSC levels but was negatively associated with M1 to LNSC ratio. CONCLUSION: In this aged population, type 2 diabetes is associated with dysregulated cortisol secretion characterized by distinct sex specific diurnal patterns.

Lower morning to evening cortisol ratio is associated with cognitive impairment in men but not women: An analysis of 733 older subjects of the cross-sectional KORA-Age study.

BACKGROUND: A dysregulated hypothalamic-pituitary-adrenocortical axis (HPA) is thought to play a role in the pathophysiology of cognitive impairment. Surprisingly, little agreement exists on the association of cortisol and cognitive impairment. Thus, we sought to examine the association between cognitive function and salivary cortisol levels in a representative sample of older men and women. METHODS: A cross-sectional analysis was conducted among 733 study participants (65-90 years old, mean age=74.9) of the population-based KORA (Cooperative Health Research in the Region of Augsburg)-Age study. Associations were examined between cognitive function (determined by telephone interview for cognitive status-modified, TICS-m) and salivary cortisol measured upon waking (M1), 30min after awakening (M2), and in the late evening (E). RESULTS: In a dose response manner, lower morning (M1 and M2), and increased evening levels were observed in participants with probable dementia (4.5%, N=33) and slightly increased in those with mild cognitive impairment (MCI) (13.8%, N=101) compared to healthy individuals. Higher morning to evening ratios were associated with reduced odds of cognitive impairment, even after adjustments for important confounders (M1/E ratio: OR=1.50, 95% CI=1.08-2.07, M2/E ratio: 1.41, 1.01-1.95, per 1 standard deviation (SD) increase). However, the significant association of an increased risk for cognitive impairment was observed among men (M1/E: OR=1.94, 95% CI=1.24-3.02; M2/E=1.74, 1.12-2.71) but not women (M1/E: OR=1.11, 0.69-1.78; M2/E=1.09, 0.67-1.77). CONCLUSION: Our findings suggest that dysregulated HPA axis reactivity, evidenced by blunted diurnal cortisol responses, are associated with impaired cognitive function in an aged population.

Evaluation of a salivary based combined dexamethasone/CRH test in patients with major depression.

The combined dexamethasone/corticotropin releasing hormone (Dex/CRH) test is one of the most reliable neuroendocrine function tests for investigation of hypothalamic-pituitary-adrenocortical (HPA) system dysregulation in depression. Persistent high HPA system activity reflected by an enhanced cortisol secretion during the Dex/CRH test after successful antidepressant treatment is correlated with an enhanced risk for relapse in remitted depressives. Thus, the Dex/CRH test might be a useful neuroendocrinological tool for treatment monitoring. However, the performance of the test requiring multiple blood samplings renders this test difficult for routine clinical use. Thus, a simplified test procedure using a saliva based test without the necessity of multiple blood samplings would be desirable.Therefore, we compared matched saliva and serum probes of Dex/CRH tests of 73 depressed patients who underwent a total of 157 tests. Both saliva and serum cortisol concentrations showed a significant stimulation pattern during the test and were highly correlated. This correlation was not influenced by either antidepressive treatment. In patients with high cortisol secretion patterns during the Dex/CRH test there was a decrease in HPA system activity after successful antidepressant treatment that was reflected by both the saliva and the serum Dex/CRH test.Thus, the saliva based combined Dex/CRH test appears to be a suitable tool for monitoring HPA system activity during the course of depressive illness. The easier performance of the saliva Dex/CRH test in comparison to the standard test procedure for both patients and hospital staff opens the door for routine clinical use of the Dex/CRH test for treatment monitoring and estimation of relapse risk.

Blunted diurnal cortisol pattern is associated with frailty: a cross-sectional study of 745 participants aged 65 to 90 years.

BACKGROUND: The role of neuroendocrine alterations in the etiology of frailty syndrome is still poorly understood. Hypothalamic-pituitary-adrenal axis dysregulation is a plausible candidate pathway contributing to frailty. Thus, we sought to examine the associations of diurnal cortisol secretion with frailty in older adults. METHODS: A cross-sectional analysis was conducted among 745 study participants (age 65-90 years, mean age 75.1 years) of the population-based KORA Age study. Associations between salivary cortisol measures at awakening (morning 1 [M1]), 30 minutes after awakening (M2), and evening (E) and frailty criteria were determined. RESULTS: Lower cortisol levels in the first morning sample (M1) (P = .18) and M2 (P = .14) and increased E levels (P = .004) were observed in prefrail (35.17%, n = 262) and frail (3.36%, n = 25) individuals, in a dose-response manner. Frailty was strongly associated with smaller ratios of morning to evening levels; M1 to E ratio (P = .02) and M2 to E ratio (P = .003). Higher evening cortisol levels were associated with a 24% increased risk of a prefrail state (odds ratio, 1.22; 95% confidence interval, 1.03-1.44). A smaller morning to evening ratio was associated with an increased risk of low grip strength (1.42, 1.09-1.86) and gait speed (1.31, 1.02-1.68). CONCLUSION: Frailty status is associated with blunted cortisol reactivity as demonstrated by lower morning and higher evening salivary cortisol levels.

High prevalence of reduced fecundity in men with congenital adrenal hyperplasia.

CONTEXT: Testicular adrenal rest tumors (TARTs) are regarded to contribute to the high prevalence of subfertility in males with congenital adrenal hyperplasia (CAH). OBJECTIVES: Our objectives were to evaluate reduced fecundity and its possible causes in well-controlled adult males with CAH, and to investigate diagnostic tools for improved treatment monitoring with respect to fertility outcomes. DESIGN: In a cross-sectional study at the Department of Endocrinology at the University Hospital München, Germany, 22 adult male CAH patients (15 salt wasting and seven simple virilizing, age 19-48 yr) were clinically assessed according to their hormonal control. We performed testicular ultrasound (22 of 22), magnetic resonance imaging (18 of 22), and a semen analysis (19 of 22) in the participants. RESULTS: All patients had a pathological semen analysis. TART prevalence was 10 of 22 (eight salt wasting, two simple virilizing). Poor therapy control was present in five patients, and all five had TARTs. Of the other 17 well-controlled patients with normal or suppressed adrenal androgens and 17-hydroxyprogesterone levels, five presented with TARTs. There was a significant correlation between sperm concentration and functional testicular volume (r = 0.70; P = 0.002), TART volume (r = -0.70; P = 0.036), as well as inhibin B levels (r = 0.75; P < 0.0001), respectively. In several men, hormonal control parameters suggested hypogonadism, with glucocorticoid overtreatment as a relevant factor for poor semen quality. CONCLUSIONS: Poor semen parameters are common in male CAH patients. TARTs, most likely reflecting undertreatment, as well as inhibin B are important indicators of fecundity. On the other hand, long-term glucocorticoid overtreatment also seems to contribute to low semen quality.