Semaglutide treatment of hypothalamic obesity - a real-life data study.

PURPOSE: Patients with tumors involving the hypothalamic region are at high risk of developing morbid obesity due to disturbances in the appetite regulative nuclei in hypothalamus. We evaluated the effect of the Glucagon-like peptide 1 (GLP-1) analogue semaglutide in patients with hypothalamic obesity. METHODS: We recorded weight changes from real-time data before and after treatment with semaglutide in patients with hypothalamic obesity from our outpatient clinic at the Department of Endocrinology at Rigshospitalet, from September 2020 to November 2023. RESULTS: A total of 26 patients were included in this study (15 females, median age at initiation of semaglutide was 52 (range 18-65) years). Body mass index (BMI) at initial diagnosis was median 25 (range 20-38) kg/m2 while BMI at initiation of semaglutide was median 38 (range 28-58) kg/m2. All but one patient lost weight during semaglutide treatment with a mean weight loss of 13.4 kg (95% CI 10.3-16.5 kg, p = < 0.001) after 12 months corresponding to a loss in BMI of 4.4 kg/m2 (95% CI 3.4-5.4 kg/m2, p = < 0.001) with a median dosage of semaglutide of 1.6 (range 0.5-2.5) mg. Fifteen patients (58%) lost more than 10% and two patients (8%) lost more than 20% of initial body weight, respectively. CONCLUSION: Treatment with semaglutide shows promising results in reducing body weight in patients with acquired hypothalamic obesity. Whether the weight reduction remains stable after long time follow-up needs further investigation.

A nationwide registry-based observational study of thyroid disease incidence in the Faroe Islands.

OBJECTIVE: The occurrence of thyroid disease varies among populations. While the iodine nutrition level of the Faroese seems to have been decreasing over the past decades, there is no systematic evaluation of the thyroid disease pattern in the Faroe Islands. Such knowledge of thyroid disease occurrence in the North Atlantic region may support healthcare planning and prevention. To investigate incidence rates, including subtypes of thyroid diseases, and demographic characteristics of thyroid disease patients in the Faroe Islands, to improve understanding of the patterns and trends of these disorders. DESIGN AND METHOD: A registry-based observational study was conducted over 10 years, encompassing all adult Faroese individuals. PATIENTS AND MEASUREMENTS: Health records from general practitioners and hospitals were used to identify incident cases of thyroid diseases. Validation was performed using multiple data sources. The incidence rates were standardised using population data from the middle of the study period 2006-2018. RESULTS: Among the 1152 individuals diagnosed with thyroid disease, the standardised incidence rates per 100,000 person-years were 55 for hyperthyroidism and 112 for hypothyroidism, and around four times higher in women than in men. Hashimoto's thyroiditis was the dominant cause of hypothyroidism, while Graves' disease was the leading cause of hyperthyroidism. The incidence of hypothyroidism increases with age. A decreasing trend was observed over time for both hypothyroidism and hyperthyroidism. CONCLUSION: Considering the decrease in iodine nutrition levels over the past decades, we were surprised by the high incidence of autoimmune thyroid disease. The findings highlight the need for continuous monitoring of thyroid disease occurrence in coastal areas of the North Atlantic Ocean.

Desmopressin Dose Requirements in Adults with Congenital and Acquired Central Diabetes Insipidus.

Central diabetes insipidus is a rare disorder characterized by a deficiency of vasopressin. The first line drug to treat this disorder is a synthetic analogue of vasopressin, desmopressin.The primary aim of this retrospective register study was to compare desmopressin dose requirements in patients with acquired and congenital DI, and secondly to assess the influence of BMI on dose requirement and risk of hyponatremia with different drug administrations. We included all patients with suspected DI attending the endocrine department at Rigshospitalet, Copenhagen, Denmark in 2022. We identified 222 patients who were included whereof 130/222 (58.6%) were females and median age was 53 years (IQR 35 to 63). The etiology included 7/222 (3.2%) congenital and 215/222 (96.8%) acquired. After converting nasal and sublingual doses to equivalent oral doses, the median daily dose requirement was 600 µg in patients with congenital etiology compared to 200 µg in patients with acquired etiology (p=0.005). We found no association between BMI and desmopressin dose requirements (p=0.6). During the past 12 months, 66/215 (30.7%) had sodium levels<136 mmol/l including 20/215 (9.3%) with sodium levels<131 mmol/l. No increased risk of hyponatremia was found, when nasal and oral were compared (p=0.9). Daily desmopressin dose requirements were higher in patients with congenital DI compared to patients with acquired DI. However, this result was associated with uncertainty due to the small congenital group. BMI did not influence daily dose requirements and nor did type of administration influence the risk of hyponatremia.

Ecological momentary assessments (EMAs) did not improve responsiveness of patient-reported outcomes on quality of life.

OBJECTIVES: Clinical practice guidelines recommend questionnaires with short recall. We compare responsiveness of ecological momentary assessments (EMAs) and retrospective assessments of thyroid-related quality of life. STUDY DESIGN AND SETTING: Patients with newly diagnosed thyrotoxicosis completed retrospective Thyroid-related Patient-Reported Outcome measures (ThyPROs) with 4-week and 1-week recall, respectively, and three daily EMAs for 4 weeks at time of inclusion and again after treatment (N = 115). Magnitude of change and statistical power (F-test statistics) were compared. Two designs were applied to the same data: Design 1 mimicked the practical realities of clinical trials by comparing 4-week recall ThyPRO administered at time of inclusion with EMA initiated at time of inclusion and collected prospectively for 1 week, thus not covering the same time frame or duration. Design 2 compared assessments covering the same 4 weeks after inclusion. RESULTS: Design 1: the estimated change and statistical power were significantly larger for 4-week ThyPRO compared with EMAs. Design 2: retrospective assessments and EMAs had comparable change and power. Repeated 1-week ThyPRO administrations increased the statistical power. CONCLUSION: Selecting the optimal time frame for evaluation proved crucial for responsiveness. EMAs did not provide higher responsiveness than retrospective measures in either design. Repeated 1-week ThyPRO administrations increased statistical power.

Shorter Recall Period for the Thyroid-Related Patient-Reported Outcome Measure ThyPRO Did Not Change the Accuracy as Evaluated by Repeated Momentary Measurements.

Background: The thyroid-related patient-reported outcome measure ThyPRO has become the gold standard for measuring thyroid-related quality of life and uses a 4-week recall period. The impact of the length of recall is unresolved. To minimize recall bias, the US Food and Drug Administration has argued in favor of short recall periods or measures describing current states. We investigated whether a 1-week recall version of ThyPRO was less prone to recall bias than the original ThyPRO, using averaged momentary ThyPRO measurements as the hypothesized true mean of patients' symptoms. Methods: Patients newly diagnosed with thyrotoxicosis were included (N = 122). During a 28-day study period, participants answered momentary questions three times daily via a smartphone, weekly retrospective surveys with a 1-week recall period, and the original survey with a 4-week recall period on day 28. Twelve ThyPRO items from four multi-item scales were used. Mean momentary ratings for each scale were compared with recall ratings of 1- and 4-week periods, respectively. Results: The mean momentary ratings were highly correlated with retrospective ratings and remained rather constant when altering the reporting period from four weeks to one week. We found consistently lower scores (i.e., better thyroid-related quality of life) on momentary ratings compared with retrospective ratings. The mean differences between momentary ratings and retrospective ratings were similar for both recall periods. The original 4-week ThyPRO accurately summarized the mean of all 1-week ThyPROs. Conclusions: Shortening the recall period of ThyPRO from four weeks to one week was not associated with less recall bias within this subset of items. Nor did 1-week recall seem to compromise the accuracy of ThyPRO. Thus, either version of ThyPRO can be used in future studies.

Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself.

Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years. Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor the duration of treatment can be used reliably to predict adrenal function after glucocorticoid withdrawal. Also the recovery rate of the adrenal glands shows individual variation, which may be why there is currently insufficient evidence to prove the efficacy and safety of different withdrawal regimens. Whether a patient with an insufficient response to an adrenal stimulating test develops clinically significant adrenal insufficiency depends on the presence of stress and resulting glucocorticoid demand and it is thus totally unpredictable and can change relative fast. Adrenal insufficiency should therefore always be taken seriously. Individual variation in hypothalamic-pituitary-adrenal axis function might be due to differences in glucocorticoid sensitivity and might be genetic. Further awareness of the potential side effect of withdrawal of glucocorticoid and further research are urgently needed.

Response to GH treatment in adult GH deficiency is predicted by gender, age, and IGF1 SDS but not by stimulated GH-peak.

OBJECTIVE: We studied whether the severity of GH deficiency (GHD) defined as i) GH-peak on stimulation tests (insulin tolerance test (ITT), arginine, and glucagon), ii) number of additional pituitary deficits, or iii) baseline IGF1 SDS could impact the response to GH treatment. We further explored whether iv) IGF1 SDS after 24 months of GH replacement or v) ΔIGF1 SDS from baseline to 24 months was related to the phenotypic response to GH treatment. DESIGN, PATIENTS, AND MEASUREMENTS: The patient cohort (n=1752; 50% women) was obtained from KIMS (Pfizer International Metabolic Database). The patients were divided into three groups of approximately equal size (tertiles) according to the stimulated GH-peak values and baseline IGF1 SDS and were studied at baseline, 12, and 24 months of GH therapy. RESULTS: Lower baseline IGF1 SDS predicted better response in weight, BMI, total cholesterol, and triglycerides, while IGF1 SDS after 24 months was associated with reduction in waist/hip ratio, total cholesterol, and improved quality of life (QoL). Age-correlated negatively with the response in body weight, BMI, waist, IGF1 SDS, and total and LDL-cholesterol. Response in weight and BMI was greater in men than in women, whereas women showed greater improvement in QoL than men. Patients with more severe GHD as assessed by lower GH-peaks and more pituitary hormone deficiencies had a greater increase in IGF1 SDS. The increase in IGF1 SDS was associated with a reduction in waist/hip ratio and an increase in weight, BMI, and triglycerides. There was no correlation with other lipids, blood pressure, or glucose. CONCLUSION: Our findings indicate that baseline and 24 months, IGF1 and its degree of increase during GH replacement were more important than stimulated peak GH to predict the phenotypic response.

Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy?

Maternal euthyroidism during pregnancy is crucial for normal development and, in particular, neurodevelopment of the foetus. Up to 3.5 percent of pregnant women suffer from hypothyroidism. Industrial use of various chemicals-endocrine disrupting chemicals (EDCs)-has been shown to cause almost constant exposure of humans with possible harmful influence on health and hormone regulation. EDCs may affect thyroid hormone homeostasis by different mechanisms, and though the effect of each chemical seems scarce, the added effects may cause inappropriate consequences on, for example, foetal neurodevelopment. This paper focuses on thyroid hormone influence on foetal development in relation to the chemicals suspected of thyroid disrupting properties with possible interactions with maternal thyroid homeostasis. Knowledge of the effects is expected to impact the general debate on the use of these chemicals. However, more studies are needed to elucidate the issue, since human studies are scarce.

Iodine and tri-iodo-thyronine reduce the incidence of type 1 diabetes mellitus in the autoimmune prone BB rats.

Thyroid hormones modulate the immune system and metabolism, influence insulin secretion, and cause decreased glucose tolerance. Thyroid hormones have been described to change the incidence of spontaneous autoimmune thyroiditis in Bio-Breeding/Worcester (BB) rats but it is unknown how these hormones affect the development of type 1 diabetes mellitus (T1DM). The aim was to investigate the influence of changes in thyroid function during postnatal development on the prevalence of T1DM in BB rats and the influence of T3 on the beta cell mass in non-diabetic Wistar rats. BB rats were treated with sodium iodine (NaI) or thyroid stimulating hormone (TSH) neonatally or with tri-iodo-thyronine (T3) during adolescence. At the age of 19 weeks the incidence of T1DM and the degree of insulitis were evaluated. The influence of T3 treatment on the beta cell mass was evaluated in Wistar rats by unbiased stereological methods. The incidence of T1DM in control BB rats was 68% at the age of 19 weeks. NaI and T3 reduced the incidence, whereas TSH had no effect. In Wistar rats T3 treatment increased the beta cell mass per bodyweight. The modulation of thyroid function during postnatal development may thus affect the precipitation of T1DM in genetically susceptible individuals.

Factors influencing the adrenocorticotropin test: role of contemporary cortisol assays, body composition, and oral contraceptive agents.

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-microg 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.