Hypothyroidism is characterized by hypometabolism, and may be seen as a part of secondary failure due to pituitary insufficiency or tertiary due to hypothalamic disease. Secondary and tertiary ...failures are also referred to as central hypothyroidism. Whereas overt primary hypothyroidism has a well-known affection on the heart and cardiovascular system, and may result in cardiac failure, cardiovascular affection is less well recognized in central hypothyroidism. Studies on central hypothyroidism and cardiovascular outcome are few and given the rarity of the diseases often small. Further, there are several limitations given vast difficulties in diagnosing the condition correctly biochemically, and difficulties monitoring the treatment because normal thyroid–pituitary feedback interrelationships are disrupted. The present review summarizes available studies of central adult hypothyroidism and its possible influence on the cardiovascular system, describe differences from primary thyroid failure and seek evidence for performing guidelines for clinical management of this particular thyroid and hypothalamo-pituitary disorder.
Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas ...hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objective Patients receiving long-term glucocorticoid treatment are at risk of developing adrenal insufficiency during treatment. We investigated the prevalence of prednisolone-induced adrenal ...insufficiency in the particular clinical situation where patients receive ongoing low-dose (5 mg/day) prednisolone treatment, a dose by itself too low to cover glucocorticoid needs during stress. Design and methods Cross-sectional study in 42 patients with rheumatoid arthritis (29 women, aged 36–86 years) treated with 5 mg prednisolone/day, who had received prednisolone for ≥6 months (median: 66, range: 6–444 months). Adrenal function was evaluated by a 250 μg Synacthen test performed after mean 48.7 h prednisolone pause. Local assay-specific cut-off for normal adrenal function was P-cortisol ≥420 nmol/L 30 min after Synacthen injection. Results Overall, 20 of the 42 patients (48%, 95% CI: 33–62%) had an insufficient adrenal response to the Synacthen test. Including only patients who had not received concomitant treatment with any other glucocorticoid formulas within the last 3 months, 13 of 33 patients (39%, 95% CI: 25–56%) had an insufficient response. Adrenocorticotrophic hormone (ACTH) concentrations were generally low and anti-adrenal antibodies were negative indicating secondary adrenal insufficiency as the most likely diagnosis. There was no correlation between duration of treatment and 30 min P-cortisol (P = 0.62). Adrenal function did not depend on sex or seropositivity of rheumatoid arthritis. Conclusion We demonstrate a high prevalence of adrenal insufficiency during ongoing low-dose prednisolone treatment. The results urge to increase focus on the condition to ensure identification and correct management of insufficient patients during stress and withdrawal. Strategies for adrenal function evaluation during ongoing low-dose glucocorticoid treatment need to be established.
Central hypothyroidism is defined as low circulating free thyroxine (free T4) with inappropriately low circulating thyrotropin (TSH), in context of a hypothalamic pituitary pathology. Rare cases of ...idiopathic central hypothyroidism caused by a functional defect may occur, and the condition is often overlooked due to difficulty in achieving the correct diagnosis, sparse symptomatology of the condition and a high risk of misinterpretion of the biochemical changes in central hypothyroidism. Central hypothyroidism is mainly seen in patients with hypothalamic–pituitary pathology due to one of many possible aetiologies, where other hormone deficiencies often co-exist, and both the presence of other deficiencies and their replacement have a strong influence on the measurement of the thyroid-related hormones and thereby interpretation of the thyroid function variables in relation to the clinical impact of thyroid hormone substitution therapy. Conversely, lack of thyroid hormone has a similar strong influence on the interpretation of other pituitary hormone axes, as well as their replacement. Undertreating patients with central hypothyroidism may have serious metabolic consequences with a potentially increased risk of cardiovascular morbidity. The present review thus aims at describing central hypothyroidism, by an overview of interactions of hypothyroidism with other pituitary hormones, diagnosing/testing for central hypothyroidism, and focusing on consequences of undertreatment. Finally, it is mentioned how to deal with new diagnostic settings with lower a priori likelihood of hypopituitarism, particularly in view of the importance of stringent diagnostic testing in order to avoid overdiagnosing central hypothyroidism.
To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer ...and mortality.
Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation.
Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time.
Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.
Context: The normal cortisol response to an ACTH test remains inconsistently defined, possibly caused by various subject- and test- condition-related factors.
Objective: Our objective was to evaluate ...the impact of newer automated immunoassays; gender, age, body composition, and endogenous sex-hormone levels; corticosteroid-binding globulin levels; and test conditions (fasting/nonfasting, rest/intermittent exercise).
Methods: A 250-μg ACTH test (0800–1000 h) was performed in 100 unmedicated subjects, 13 women taking oral contraception (OC), and six men with nephrotic syndrome. Tests were performed fasting supine (n = 119), nonfasting supine (n = 38), and fasting with intermittent exercise (n = 45). Serum cortisol was analyzed by three immunoassays.
Results: Even with a negligible between-assay mean bias, individual samples from unmedicated subjects differed by as much as 110 nmol/liter. The normative 2.5th percentile for total cortisol ranged from 475–523 nmol/liter when analyzed by the three assays. In multivariate analyses, 30-min total cortisol was predicted by baseline cortisol (men plus women) and central adiposity (men) but not by gender, age, and endogenous sex hormones, corticosteroid-binding globulin, fasting/nonfasting, and exercise. Compared with unmedicated subjects, OC women had 2-fold elevated 30-min cortisol (P < 0.001) but lowered calculated free cortisol (P < 0.001), whereas nephrotic syndrome patients had lowered 30-min cortisol (P < 0.01) in two of three assays, but similar calculated free cortisol (P > 0.1).
Conclusion: The normal response to an ACTH test is assay specific, even with newer methods, and this also applies to calculated free cortisol. Both total cortisol and calculated free cortisol were severely affected by OC, and the test is therefore only reliable if OC has been discontinued. The ACTH test is, however, robust for most of the other evaluated subject- and test-condition-related factors.
While hypopituitarism after traumatic brain injury (TBI) was previously considered rare, it is now thought to be a major cause of treatable morbidity among TBI survivors. Consequently, ...recommendations for assessment of pituitary function and replacement in TBI were recently introduced. Given the high incidence of TBI with more than 100 pr. 100,000 inhabitants, TBI would be by far the most common cause of hypopituitarism if the recently reported prevalence rates hold true. The disproportion between this proposed incidence and the occasional cases of post-TBI hypopituitarism in clinical practice justifies reflection as to whether hypopituitarism has been unrecognized in TBI patients or whether diagnostic testing designed for high risk populations such as patients with obvious pituitary pathology has overestimated the true risk and thereby the disease burden of hypopituitarism in TBI. The findings on mainly isolated deficiencies in TBI patients, and particularly isolated growth hormone (GH) deficiency, raise the question of the potential impact of methodological confounding, determined by variable test-retest reproducibility, appropriateness of cut-off values, importance of BMI stratified cut-offs, assay heterogeneity, pre-test probability of hypopituitarism and lack of proper individual laboratory controls as reference population. In this review, current recommendations are discussed in light of recent available evidence.
Context:
NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration.
Objectives:
The objective of the study was to evaluate safety, local tolerability, ...pharmacodynamics, and pharmacokinetics of multiple, once-weekly doses of NNC0195-0092, compared with daily GH.
Design and Setting:
This was a phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial.
Patients:
Thirty-four GH-treated adult subjects (male, n = 25) with GH deficiency participated in the study.
Interventions and Main Outcome Measures:
Subjects were sequentially assigned into four cohorts of eight subjects, randomized within each cohort (3:1) to once-weekly NNC0195-0092 (n = 6) for 4 weeks (0.02, 0.04, 0.08, and 0.12 mg/kg) or daily injections of Norditropin NordiFlex (n = 2) for 4 weeks with a dose replicating the pretrial dose of somatropin. A safety assessment was performed prior to initiating treatment at the next dose level of NNC0195-0092. Daily GH treatment was discontinued 14 days before the trial start. Blood samples were drawn for assessment of safety, pharmacokinetics, pharmacodynamics (IGF-1 and IGF-binding protein-3) profiles, and immunogenicity studies.
Results:
Numbers of adverse events were similar at the dose levels of 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 vs daily injections of Norditropin NordiFlex, whereas the number of adverse events was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (area under the curve0–168h) and peak plasma concentration) increased in a dose-dependent manner, and a dose-dependent increase in IGF-1 levels was observed. IGF-1 profiles were elevated for at least 1 week, and for the 0.02-mg/kg and 0.04-mg/kg NNC0195-0092 doses, the observed IGF-1 levels were similar to the levels for the active control group.
Conclusion:
Four once-weekly doses of NNC0195-0092 (dose range 0.02–0.12 mg/kg) administered to adult patients with GH deficiency were well tolerated, and IGF-1 profiles were consistent with a once-weekly treatment profile. No clinically significant safety and tolerability signals causally related to NNC0195-0092 were identified, nor were any immunogenicity concerns revealed.
The prognosis and impact of different prognostic factors in pancreatic neuroendocrine neoplasms (pNEN) remain controversial.
To investigate prognostic factors for recurrence-free survival and ...disease-specific survival in patients with pNEN, divided into three groups: patients undergoing surveillance (tumor size < 2 cm, group 1), patients followed after curative-intended surgery (group 2), and patients with unresectable disease or residual tumors after resection (group 3).
A single-center retrospective study including consecutive patients over a 20-year period. Multivariate Cox regression analyses were performed to identify risk factors.
413 patients were included, with a mean (SD) age of 62 ± 14 years. In group 1 (n = 51), median (IQR) follow-up was 29 (21-34) months, and tumor size was 1.0 (0.8-1.4) cm. One progressed and had a tumor resection. In group 2 (n = 165), follow-up 59 (31-102) months, median tumor size 2 (1.2-3.4) cm, median Ki-67 index 5 (3-10)%, the 5-year recurrence rate was 21%. Tumor size (
< 0.001), Ki-67 index (
= 0.02), and location in the pancreatic head (
< 0.001) were independent risk factors. In group 3 (n = 197), follow-up 19 (6-46) months, median tumor size 4.2 (2.6-7.0) cm, Ki-67 index 17 (9-64)%, the median disease-specific survival was 22 (6-75) months-99 in NET G1; 54 in NET G2; 14 in NET G3; and 6 months in neuroendocrine carcinomas (NEC). Age (
= 0.029), plasma chromogranin A (
= 0.014), and proliferation, expressed by grade (
= 0.001) and Ki-67 index (
< 0.001), were risk factors.
Growth in pNET < 2 cm requiring surgery was observed in 1/51. Tumor size, Ki-67 index, and location in the head were prognostic factors for disease recurrence, while age, plasma chromogranin A, and proliferation predicted mortality in patients with unresectable disease or residual tumors after resection.
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