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Open access

Eva Novoa, Marcel Gärtner, and Christoph Henzen

Objective

The study aimed to assess the possible systemic effects of intratympanic dexamethasone (IT-Dex) on the hypothalamic–pituitary–adrenal (HPA) axis, inflammation, and bone metabolism.

Design

A prospective cohort study including 30 adult patients of a tertiary referral ENT clinic treated with 9.6 mg IT-Dex over a period of 10 days was carried out.

Methods

Effects on plasma and salivary cortisol concentrations (basal and after low-dose (1 μg) ACTH stimulation), peripheral white blood cell count, and biomarkers for bone turnover were measured before (day 0) and after IT-Dex (day 16). Additional measurements for bone turnover were performed 5 months after therapy. Clinical information and medication with possible dexamethasone interaction were recorded.

Results

IT-Dex was well tolerated, and no effect was detected on the HPA axis (stimulated plasma and salivary cortisol concentration on day 0: 758±184 and 44.5±22.0 nmol/l; day 16: 718±154 and 39.8±12.4 nmol/l; P=0.58 and 0.24 respectively). Concentrations of osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP) did not differ after dexamethasone (OC on days 0 and 16 respectively: 24.1±10.5 and 23.6±8.8 μg/l; BSAP on day 0, 16, and after 5 months respectively: 11.5±4.2, 10.3±3.4, and 12.6±5.06 μg/l); similarly, there was no difference in the peripheral white blood cell count (5.7×1012/l and 6.1×1012/l on days 0 and 16 respectively).

Conclusions

IT-Dex therapy did not interfere with endogenous cortisol secretion or bone metabolism.

Open access

Pablo Abellán-Galiana, Carmen Fajardo-Montañana, Pedro Riesgo-Suárez, Marcelino Pérez-Bermejo, Celia Ríos-Pérez, and José Gómez-Vela

Objectives

To analyze the usefulness of plasma ACTH in predicting CD remission after surgery and to evaluate the prognostic usefulness of ACTH measurement after the cortisol and ACTH nadir (48 h prior to discharge).

Design

A prospective study was made of 65 patients with CD operated upon between 2005 and 2016.

Methods

Postsurgery plasma ACTH and cortisol were measured every 6 h, in the absence of corticosteroid coverage. Hydrocortisone was started in the presence of adrenal insufficiency or cortisol <55.2 nmol/L. Plasma ACTH was again determined before discharge.

Main outcome measure

Usefulness of plasma ACTH in predicting CD remission.

Results

Remission at 3 months of CD was achieved in 56 of 65 cases, with late recurrence in 18 of 58 cases. Following resection, the ACTH nadir was significantly lower referred to late remission (2.8 vs 6.5 pmol/L; P = 0.031) and higher for recurrence (2.1 vs 4.8 pmol/L; P < 0.001), and identical results were obtained for the ACTH values before discharge. In the analysis of the ROC curves, nadir and before discharge ACTH values <1.9 pmol/L and <2.6 pmol/L were respectively indicative of early remission (AUC 0.827; P < 0.001); <6.2 pmol/L of remission at 3 months (AUC 0.847; P = 0.001) and >3.2 pmol/L of recurrence (AUC 0.810; P < 0.001) in both ACTH values. A time to ACTH nadir <46 h was indicative of early remission (AUC 0.751; P = 0.001), while a time >39 h was indicative of recurrence (AUC 0.773; P = 0.001).

Conclusions

We propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate.

Open access

Karim Gariani and François R Jornayvaz

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. NAFLD encompasses a whole spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The latter can lead to hepatocellular carcinoma. Furthermore, NASH is the most rapidly increasing indication for liver transplantation in western countries and therefore represents a global health issue. The pathophysiology of NASH is complex and includes multiple parallel hits. NASH is notably characterized by steatosis as well as evidence of hepatocyte injury and inflammation, with or without fibrosis. NASH is frequently associated with type 2 diabetes and conditions associated with insulin resistance. Moreover, NASH may also be found in many other endocrine diseases such as polycystic ovary syndrome, hypothyroidism, male hypogonadism, growth hormone deficiency or glucocorticoid excess, for example. In this review, we will discuss the pathophysiology of NASH associated with different endocrinopathies.

Open access

Rachel K Rowe, Benjamin M Rumney, Hazel G May, Paska Permana, P David Adelson, S Mitchell Harman, Jonathan Lifshitz, and Theresa C Thomas

As many as 20–55% of patients with a history of traumatic brain injury (TBI) experience chronic endocrine dysfunction, leading to impaired quality of life, impaired rehabilitation efforts and lowered life expectancy. Endocrine dysfunction after TBI is thought to result from acceleration–deceleration forces to the brain within the skull, creating enduring hypothalamic and pituitary neuropathology, and subsequent hypothalamic–pituitary endocrine (HPE) dysfunction. These experiments were designed to test the hypothesis that a single diffuse TBI results in chronic dysfunction of corticosterone (CORT), a glucocorticoid released in response to stress and testosterone. We used a rodent model of diffuse TBI induced by midline fluid percussion injury (mFPI). At 2months postinjury compared with uninjured control animals, circulating levels of CORT were evaluated at rest, under restraint stress and in response to dexamethasone, a synthetic glucocorticoid commonly used to test HPE axis regulation. Testosterone was evaluated at rest. Further, we assessed changes in injury-induced neuron morphology (Golgi stain), neuropathology (silver stain) and activated astrocytes (GFAP) in the paraventricular nucleus (PVN) of the hypothalamus. Resting plasma CORT levels were decreased at 2months postinjury and there was a blunted CORT increase in response to restraint induced stress. No changes in testosterone were measured. These changes in CORT were observed concomitantly with altered complexity of neuron processes in the PVN over time, devoid of neuropathology or astrocytosis. Results provide evidence that a single moderate diffuse TBI leads to changes in CORT function, which can contribute to the persistence of symptoms related to endocrine dysfunction. Future experiments aim to evaluate additional HP-related hormones and endocrine circuit pathology following diffuse TBI.

Open access

Earn H Gan, Wendy Robson, Peter Murphy, Robert Pickard, Simon Pearce, and Rachel Oldershaw

Background

The highly plastic nature of adrenal cortex suggests the presence of adrenocortical stem cells (ACSC), but the exact in vivo identity of ACSC remains elusive. A few studies have demonstrated the differentiation of adipose or bone marrow-derived mesenchymal stem cells (MSC) into steroid-producing cells. We therefore investigated the isolation of multipotent MSC from human adrenal cortex.

Methods

Human adrenals were obtained as discarded surgical material. Single-cell suspensions from human adrenal cortex (n = 3) were cultured onto either complete growth medium (CM) or MSC growth promotion medium (MGPM) in hypoxic condition. Following ex vivo expansion, their multilineage differentiation capacity was evaluated. Phenotype markers were analysed by immunocytochemistry and flow cytometry for cell-surface antigens associated with bone marrow MSCs and adrenocortical-specific phenotype. Expression of mRNAs for pluripotency markers was assessed by q-PCR.

Results

The formation of colony-forming unit fibroblasts comprising adherent cells with fibroblast-like morphology were observed from the monolayer cell culture, in both CM and MGPM. Cells derived from MGPM revealed differentiation towards osteogenic and adipogenic cell lineages. These cells expressed cell-surface MSC markers (CD44, CD90, CD105 and CD166) but did not express the haematopoietic, lymphocytic or HLA-DR markers. Flow cytometry demonstrated significantly higher expression of GLI1 in cell population harvested from MGPM, which were highly proliferative. They also exhibited increased expression of the pluripotency markers.

Conclusion

Our study demonstrates that human adrenal cortex harbours a mesenchymal stem cell-like population. Understanding the cell biology of adrenal cortex- derived MSCs will inform regenerative medicine approaches in autoimmune Addison’s disease.

Open access

Bjørn O Åsvold, Valdemar Grill, Ketil Thorstensen, and Marit R Bjørgaas

It has been suggested that comparison of posttest dexamethasone and cortisol concentrations may improve the evaluation of the dexamethasone suppression test (DST) for Cushing's syndrome. In particular, this would be reasonable if posttest cortisol differs by dexamethasone levels within the range that is usually attained in the DST. Using fractional polynomial regression, we therefore studied the association between posttest 0800 h dexamethasone and cortisol levels in 53 subjects without Cushing's syndrome who were tested with the 1 mg overnight DST. Plasma dexamethasone was associated with plasma cortisol (P<0.001), and the regression line suggested a strong negative association related to dexamethasone levels <5 nmol/l. However, among the 94% of subjects with plasma dexamethasone >5.0 nmol/l, there was no association between dexamethasone and cortisol levels (P=0.55). In conclusion, subjects tested with the 1 mg overnight DST usually attain an 0800 h plasma dexamethasone >5 nmol/l, and plasma cortisol does not differ by plasma dexamethasone in these subjects. This suggests that routine comparison of dexamethasone and cortisol levels may not be a useful approach to improve the performance of the 1 mg DST. However, dexamethasone measurements may identify subjects with inadequately low plasma dexamethasone and may therefore be of value when retesting subjects with possibly false-positive DST results.

Open access

Fahim Ebrahimi, Sandrine A Urwyler, Philipp Schuetz, Beat Mueller, Luca Bernasconi, Peter Neyer, Marc Y Donath, and Mirjam Christ-Crain

Background

Anti-inflammatory treatment with interleukin-1 (IL-1) antagonism decreases both cortisol and adrenocorticotropin hormone (ACTH) levels in individuals with obesity in short term. However, it remains unknown whether these effects persist upon prolonged treatment.

Methods

In this double-blind, parallel-group trial involving patients with features of the metabolic syndrome, 33 patients were randomly assigned to receive 100 mg of anakinra (recombinant human IL-1 receptor antagonist) subcutaneously twice-daily and 34 patients to receive placebo for 4 weeks. For this analysis, change in cortisol and ACTH levels from baseline to 4 weeks were predefined end points of the trial.

Results

The mean age was 54 years, baseline cortisol levels were 314 nmol/L (IQR 241–385) and C-reactive protein (CRP) levels were 3.4 mg/L (IQR 1.7–4.8). Treatment with anakinra led to a significant decrease in cortisol levels at day 1 when compared to placebo with an adjusted between-group difference of 28 nmol/L (95% CI, −7 to −43; P = 0.03). After 4 weeks, the cortisol-lowering effect of anakinra was attenuated and overall was statistically not significant (P = 0.72). Injection-site reactions occurred in 21 patients receiving anakinra and were associated with higher CRP and cortisol levels.

Conclusions

IL-1 antagonism decreases cortisol levels in male patients with obesity and chronic low-grade inflammation on the short term. After prolonged treatment, this effect is attenuated, probably due to injection-site reactions (ClinicalTrials.gov, NCT02672592).

Open access

Ferdinand Roelfsema, Diana van Heemst, Ali Iranmanesh, Paul Takahashi, Rebecca Yang, and Johannes D Veldhuis

Context

Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol levels, often restricted to one or a few samples, are well recognized, but conflicting.

Objective

To investigate cortisol dynamics in 143 healthy men and women, spanning 7 decades and with a 2-fold body mass index (BMI) range with different analytic tools.

Setting

Clinical Research Unit.

Design

Cortisol concentrations in 10-min samples collected for 24 h. Outcomes were mean levels, deconvolution parameters, approximate entropy (ApEn, regularity statistic) and 24-h rhythms.

Results

Total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. Mean 24-h cortisol concentrations were lower in premenopausal women than those in men of comparable age (176 ± 8.2 vs 217 ± 9.4 nmol/L, P = 0.02), but not in subjects older than 50 years. This was due to lower daytime levels in women, albeit similar in the quiescent overnight period. Aging increased mean cortisol by 10 nmol/L per decade during the quiescent secretory phase and advanced the acrophase of the diurnal rhythm by 24 min/decade. However, total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. ApEn of 24-h profiles was higher (more random) in premenopausal women than those in men (1.048 ± 0.025 vs 0.933 ± 0.023, P = 0.001), but not in subjects older than 50 years. ApEn peaked during the daytime.

Conclusion

Sex and age jointly determine the 24-h cortisol secretory profile. Sex effects are largely restricted to age <50 years, whereas age effects elevate concentrations in the late evening and early night and advance the timing of the peak diurnal rhythm.

Open access

Emmanuelle Motte, Anya Rothenbuhler, Stephan Gaillard, Najiba Lahlou, Cécile Teinturier, Régis Coutant, and Agnès Linglart

To investigate whether low-dose mitotane (up to 2 g/day) could be a temporary therapeutic alternative to transsphenoidal surgery (TSS) in pediatric Cushing’s disease (CD). Twenty-eight patients with CD aged 12.2 years (± 2.2) were referred to our center. We compared nine patients treated with mitotane alone for at least 6 months to 13 patients cured after surgery. Primary outcomes were changes in growth velocity, BMI and pubertal development. The following results were obtained: (1) Mitotane improved growth velocity z-scores (−3.8 (±0.3) vs −0.2 (±0.6)), BMI z-scores (2.1 (±0.5) vs 1.2 (±0.5) s.d.) and pubertal development. After 1 year on mitotane, the mean BMI z-score was not significantly different in both groups of patients. (2) Control of cortisol secretion was delayed and inconsistent with mitotane used as monotherapy. (3) Side effects were similar to those previously reported, reversible and dose dependent: unspecific digestive symptoms, concentration or memory problems, physical exhaustion, adrenal insufficiency and hepatitis. (4) In one patient, progressive growth of a pituitary adenoma was observed over 40 months of mitotane treatment, allowing selective adenomectomy by TSS. In conclusions, low-dose mitotane can restore growth velocity and pubertal development and decrease BMI in children with CD, even without optimal control of cortisol secretion. It may promote pituitary tumor growth thus facilitating second-line TSS. However, given its possibly life-threatening side effects (transient adrenal insufficiency and hepatitis), and in the absence of any reliable follow-up procedures, this therapy may be difficult to manage and should always be initiated and monitored by specialized teams.

Open access

L M Mongioì, R A Condorelli, S La Vignera, and A E Calogero

Objective

Adrenal insufficiency (AI) is a chronic condition associated with increased mortality and morbidity. The treatment of AI in the last years has been object of important changes due to the development of a dual-release preparation of hydrocortisone. It differs from previous therapeutic strategy as it contemplates a once-daily tablet that allows more closely mimicking the physiological circadian cortisol rhythm. The aim of the study was to evaluate the effects of dual-release hydrocortisone treatment on the glycometabolic profile and health-related quality of life of patients with AI.

Design and Methods

In this clinical open trial, we enrolled ten patients with primary AI (41 ± 2.67 years) and nine patients with AI secondary to hypopituitarism (53.2 ± 17.7 years). We evaluated the glycometabolic profile before and 3, 6, 9 and 12 months after dual-release hydrocortisone administration. We also evaluated health-related quality of life, estimated by the AddiQol questionnaire. The mean dose administered of dual-release hydrocortisone was 28.33 ± 6.68 mg/day.

Results

One female hypopituitary patient dropped out from the study. After 12 months of treatment, the mean dosage administered of dual-release hydrocortisone was significantly lower (P < 0.05) and all patients reported improved quality of life and well-being. The glycometabolic profile improved and the glycosylated hemoglobin decreased significantly in patients with primary AI (6.25 ± 0.2 vs 5.35 ± 0.17, P < 0.05). In contrast, hypopituitary patients had worse glycometabolic profile and a trend toward hypertriglyceridemia.

Conclusions

Dual-release hydrocortisone treatment improved the quality of life of patients with AI, and it allowed a decrease of cortisol dosage administered in the absence of side effects. The glycometabolic profile worsened in hypopituitary patients.