Hip fractures in patients with primary aldosteronism - a Swedish nationwide study.

In this large population-based matched cohort study, patients with primary aldosteronism were at increased risk of hip fracture, particularly subgroups traditionally considered at higher risk of osteoporosis such as women, patients older than 56 years at diagnosis, patients with established cardiovascular disease at diagnosis, and patients treated with MRA. PURPOSE: Previous studies suggest that primary aldosteronism (PA) is associated with dysregulated bone homeostasis. The aim of this study was to evaluate the incidence of hip fractures in patients with PA. METHODS: We studied a nationwide cohort of 2419 patients with PA (1997-2019) and 24 187 age and sex matched controls from the general population. Hip fractures were identified by ICD codes in the Swedish National Patient Register. We estimated hazard ratios (HRs) for incident hip fractures, adjusted for prior fractures, socioeconomic factors, diabetes, osteoporosis, hyperparathyroidism, and cardiovascular disease (CVD). Pairwise subgroup comparisons were performed by age (18-56 and > 56 years), sex, CVD at baseline, and treatment for PA. RESULTS: During a mean follow up of 8 ± 5 years, 64 (2.6%) patients had a hip fracture after being diagnosed with PA, compared to 401 (1.7%) controls. After adjustments, PA was associated with a 55% increased risk of hip fracture compared to controls (HR 1.55 [1.18-2.03]). HRs were increased in women (HR 1.76 [95% CI 1.24-2.52]), patients aged > 56 years (HR 1.62 [95% CI 1.21-2.17]), and patients with CVD at diagnosis (HR 2.15 [95% CI 1.37-3.37]). PA patients treated with adrenalectomy did not have higher risk than controls (HR 0.84 [95% CI 0.35-2.0]), while patients treated with mineralocorticoid receptor antagonists (MRA) retained a greater risk (HR 1.84 [95% CI 1.20-2.83]). CONCLUSION: PA is associated with increased hip fracture risk, especially in women, patients diagnosed after the age of 56 years and patients with established CVD at diagnosis. Also, patients treated with MRA seem to have an increased risk of hip fractures, while adrenalectomy may be protective.

Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Diabetes mellitus in patients with acromegaly: pathophysiology, clinical challenges and management.

Acromegaly is a rare endocrine disease caused by hypersecretion of growth hormone, most commonly arising due to a pituitary adenoma. Diabetes mellitus is a common complication of acromegaly, occurring in approximately one-third of patients. The risk of diabetes mellitus in acromegaly is driven by increased exposure to growth hormone, which directly attenuates insulin signalling and stimulates lipolysis, leading to decreased glucose uptake in peripheral tissues. Acromegaly is a unique human model, where insulin resistance occurs independently of obesity and is paradoxically associated with a lean phenotype and reduced body adipose tissue mass. Diabetes mellitus in patients with acromegaly is associated with an increased risk of cardiovascular morbidity and mortality. Therefore, preventive measures and optimized treatment of diabetes mellitus are essential in these patients. However, specific recommendations for the management of diabetes mellitus secondary to acromegaly are lacking due to limited research on this subject. This Review explores the underlying mechanisms for diabetes mellitus in acromegaly and its effect on morbidity and mortality. We also discuss treatment modalities for diabetes mellitus that are suited for patients with acromegaly. Improved understanding of these issues will lead to better management of acromegaly and its associated metabolic complications.

Headache in patients with non-functioning pituitary adenoma before and after transsphenoidal surgery - a prospective study.

PURPOSE: To study the long-term effect of transsphenoidal surgery (TSS) on headache in patients with non-functioning pituitary adenoma (NFPA) and identify factors predicting headache relief following TSS. METHODS: We evaluated headache in 101 consecutive patients with NFPA who underwent TSS from September 2015 to December 2021, preoperatively and 12-months post-surgery, by using the Migraine Disability Assessment (MIDAS) questionnaire. Health-related quality of life (QoL) was assessed using the EQ-5D visual analogue scale (EQ-VAS). RESULTS: Of 101 patients, 27 (27%) experienced disabling preoperative headache. Among these, the median total MIDAS score improved from 60 (interquartile range (IQR): 19-140) to 10 (IQR: 0-49) (P = 0.004). Additionally, headache frequency over a 90-day period decreased from 45 (IQR: 25-83) to 6 (IQR: 3-36) days (P = 0.002), and headache intensity decreased from 5 (IQR: 4-7) to 4 (IQR: 2-7) (P = 0.016) at 12-months post-surgery. At 12 months post-surgery, 18 (67%) of 27 patients with preoperatively disabling headache showed clinically relevant improvement of their headache, 4 (15%) showed deterioration, and 5 (19%) remained unchanged. In patients with clinically relevant improvement of their headache, the EQ-VAS score improved from 50 (IQR: 30 - 7) to 80 (IQR: 65-86) (P < 0.001). Of the 74 patients with no preoperative headache, 11 (15%) developed postoperative headache. We identified no clinical factors predicting postoperative headache relief. CONCLUSION: The study supports that clinically significant and long-lasting improvements of disabling headache and QoL can be achieved with TSS in a substantial number of patients with NFPA.

Sex steroid levels in women with hypopituitarism: A case-controlled observational study.

CONTEXT: Women with hypopituitarism remain at increased risk of morbidity and mortality. Insufficient replacement of sex steroids has been suggested as a contributing factor, but sex steroid levels in women with hypopituitarism have not been comprehensively mapped. OBJECTIVE: To quantify sex steroids in women with hypopituitarism by a high-sensitivity assay. METHODS: Using a combination of clinical and biochemical criteria, women with hypopituitarism (n = 104) who started growth hormone replacement 1995-2014 at a single center were categorized as eugonadal or having hypogonadotropic hypogonadism (HH). A population-based cohort of women (n = 288) served as controls. Eugonadal women and controls were categorized as pre-/postmenopausal and HH women as younger/older (≤ or >52 years). Dehydroepiandrosterone (DHEA), androstenedione, testosterone, dihydrotestosterone, progesterone, 17αOH-progesterone, estradiol and estrone were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. RESULTS: Among both premenopausal/younger and postmenopausal/older women, women with HH had lower levels of sex steroid precursors (DHEA, androstenedione) and androgens (testosterone and dihydrotestosterone) than controls. Progesterone, 17αOH-progesterone, estrone and estradiol showed similar patterns. Women with HH and adrenocorticotropic hormone (ACTH) deficiency had markedly lower concentrations of all sex hormones than those without ACTH deficiency. CONCLUSION: This study demonstrates for the first time a broad and severe sex steroid deficiency in both younger and older women with HH, particularly in those with combined gonadotropin and ACTH deficiency. The health impact of low sex steroid levels in women with hypopituitarism requires further study and women with combined gonadotropin and ACTH deficiency should be a prioritized group for intervention studies with sex hormone replacement.

Undiagnosed adrenal insufficiency as a cause of premature death in glucocorticoid users.

Objective: It is unknown whether glucocorticoid (GC)-induced adrenal insufficiency may cause premature mortality in GC users. We conducted a retrospective cohort study to investigate if undiagnosed and undertreated GC-induced adrenal insufficiency is a contributor to premature death in GC users. Methods: Information on dispensed prescriptions in West Sweden from 2007 to 2014 was obtained from the Swedish Prescribed Drug Register. Cause of death was collected from the Swedish Cause of Death Register. Of 223,211 patients who received oral GC prescriptions, 665 died from sepsis within 6 months of their last prescription. Three hundred of these patients who had died in hospital were randomly selected for further investigation. Medical records were initially reviewed by one investigator. Furthermore, two additional investigators reviewed the medical records of patients whose deaths were suspected to be caused by GC-induced adrenal insufficiency. Results: Of 300 patients (121 females, 40%), 212 (75%) were prescribed GC treatment at admission. The mean age was 76 ± 11 years (range 30-99). Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a probable contributor to death by at least two investigators in 11 (3.7%) patients. In five of these 11 cases, long-term GC therapy was abruptly discontinued during hospitalization. Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a possible contributing factor to death in a further 36 (12%) patients. Conclusion: GC-induced adrenal insufficiency is an important contributor to premature death in GC users. Awareness of the disorder during intercurrent illness and following cessation of GC treatment is essential.

Impact of chronic oral glucocorticoid treatment on mortality in patients with COVID-19: analysis of a population-based cohort.

OBJECTIVES: While glucocorticoid (GC) treatment initiated for COVID-19 reduces mortality, it is unclear whether GC treatment prior to COVID-19 affects mortality. Long-term GC use raises infection and thromboembolic risks. We investigated if patients with oral GC use prior to COVID-19 had increased mortality overall and by selected causes. DESIGN: Population-based observational cohort study. SETTINGS: Population-based register data in Sweden. PARTICIPANTS: All patients infected with COVID-19 in Sweden from January 2020 to November 2021 (n=1 200 153). OUTCOME MEASURES: Any prior oral GC use was defined as ≥1 GC prescription during 12 months before index. High exposure was defined as ≥2 GC prescriptions with a cumulative prednisolone dose ≥750 mg or equivalent during 6 months before index. GC users were compared with COVID-19 patients who had not received GCs within 12 months before index. We used Cox proportional hazard models and 1:2 propensity score matching to estimate HRs and 95% CIs, controlling for the same confounders in all analyses. RESULTS: 3378 deaths occurred in subjects with any prior GC exposure (n=48 806; 6.9%) and 14 850 among non-exposed (n=1 151 347; 1.3%). Both high (HR 1.98, 95% CI 1.87 to 2.09) and any exposure (1.58, 1.52 to 1.65) to GCs were associated with overall death. Deaths from pulmonary embolism, sepsis and COVID-19 were associated with high GC exposure and, similarly but weaker, with any exposure. High exposure to GCs was associated with increased deaths caused by stroke and myocardial infarction. CONCLUSION: Patients on oral GC treatment prior to COVID-19 have increased mortality, particularly from pulmonary embolism, sepsis and COVID-19.

Androgen deficiency in hypopituitary women: its consequences and management.

Women with hypopituitarism have various degrees of androgen deficiency, which is marked among those with combined hypogonadotrophic hypogonadism and secondary adrenal insufficiency. The consequences of androgen deficiency and the effects of androgen replacement therapy have not been fully elucidated. While an impact of androgen deficiency on outcomes such as bone mineral density, quality of life, and sexual function is plausible, the available evidence is limited. There is currently no consensus on the definition of androgen deficiency in women and it is still controversial whether androgen substitution should be used in women with hypopituitarism and coexisting androgen deficiency. Some studies suggest beneficial clinical effects of androgen replacement but data on long-term benefits and risk are not available. Transdermal testosterone replacement therapy in hypopituitary women has shown some positive effects on bone metabolism and body composition. Studies of treatment with oral dehydroepiandrosterone have yielded mixed results, with some studies suggesting improvements in quality of life and sexual function. Further research is required to elucidate the impact of androgen deficiency and its replacement treatment on long-term outcomes in women with hypopituitarism. The lack of transdermal androgens for replacement in this patient population and limited outcome data limit its use. A cautious and personalized treatment approach in the clinical management of androgen deficiency in women with hypopituitarism is recommended while awaiting more efficacy and safety data.

Mortality in patients with adrenal insufficiency: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Adrenal insufficiency (AI) is a rare disorder characterised by an impaired secretion of glucocorticoids from the adrenal glands. Treatment strategies for AI have developed over time with reduced glucocorticoid replacement doses and improved circadian exposure regimens, but whether this has resulted in better survival is unknown. The main purpose of this systematic review is to gather and synthesise available evidence on long-term mortality in patients with AI. The secondary aim is to study causes of death, with focus on cardiovascular and infectious diseases, in AI patients. METHODS AND ANALYSIS: Studies published from the inception of respective databases (Medline, Embase, Cochrane and Web of Science) until the end of May 2023 will be systematically synthetised. Observational studies with a reference population will be included, and their quality will be assessed using the Newcastle-Ottawa scale. Data collected will be narratively integrated and a meta-analysis will be performed to pool data from studies considered homogeneous. The systematic review will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This will be the first systematic review assessing mortality and causes of death in AI patients. The findings of this systematic review will be of value for both patients and healthcare providers. ETHICS AND DISSEMINATION: This systematic review does not require ethical approval or informed consent because it will be based on previously published data only and does not implicate any direct contact with individual patients. The research results will be presented at scientific conferences and submitted for publication in an internationally recognised peer-reviewed scientific journal. PROSPERO REGISTRATION NUMBER: CRD42023416253.

Increased risk of hospitalization, intensive care and death due to COVID-19 in patients with adrenal insufficiency: A Swedish nationwide study.

BACKGROUND: Patients with adrenal insufficiency (AI) have excess morbidity and mortality related to infectious disorders. Whether patients with AI have increased morbidity and mortality from COVID-19 is unknown. METHODS: In this linked Swedish national register-based cohort study, patients with primary and secondary AI diagnosis were identified and followed from 1 January 2020 to 28 February 2021. They were compared with a control cohort from the general population matched 10:1 for age and sex. The following COVID-19 outcomes were studied: incidence of COVID-19 infection, rates of hospitalization, intensive care admission and death. Hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for socioeconomic factors and comorbidities were estimated using Cox regression analysis. RESULTS: We identified 5430 patients with AI and 54,300 matched controls: There were 47.6% women, mean age was 57.1 (standard deviation 18.1) years, and the frequency of COVID-19 infection was similar, but the frequency of hospitalization (2.1% vs. 0.8%), intensive care (0.3% vs. 0.1%) and death (0.8% vs. 0.2%) for COVID-19 was higher in AI patients than matched controls. After adjustment for socioeconomic factors and comorbidities, the HR (95% CI) was increased for hospitalization (1.96, 1.59-2.43), intensive care admission (2.76, 1.49-5.09) and death (2.29, 1.60-3.28). CONCLUSION: Patients with AI have a similar incidence of COVID-19 infection to a matched control population, but a more than twofold increased risk of developing a severe infection or a fatal outcome. They should therefore be prioritized for vaccination, antiviral therapy and other appropriate treatment to mitigate hospitalization and death.

Proteomic Profiles Associated With Postsurgical Progression in Nonfunctioning Pituitary Adenomas.

CONTEXT: There is a lack of reliable biomarkers capable of predicting postoperative tumor progression of nonfunctioning pituitary adenomas (NFPAs). OBJECTIVE: To discover proteomic profiles associated with postoperative tumor progression in patients with NFPAs. This was a case-controlled exploratory study at a tertiary university hospital. Tissue samples were obtained from 46 patients with residual tumor following surgery for NFPAs of gonadotroph lineage. Two patient groups were compared: patients requiring reintervention due to residual tumor progression (cases; reintervention group, n = 29) and patients with a residual tumor showing no progression for a minimum of 5 years (controls; radiologically stable group, n = 17). Differentially expressed proteins (DEPs) between patient groups were measured. RESULTS: Global quantitative proteomic analysis identified 4074 proteins, of which 550 were differentially expressed between the 2 groups (fold change >80%, false discovery rate-adjusted P ≤ .05). Principal component analysis showed good separation between the 2 groups. Functional enrichment analysis of the DEPs indicated processes involving translation, ROBO-receptor signaling, energy metabolism, mRNA metabolism, and RNA splicing. Several upregulated proteins in the reintervention group, including SNRPD1, SRSF10, SWAP-70, and PSMB1, are associated with tumor progression in other cancer types. CONCLUSION: This is the first exploratory study analyzing proteomic profiles as markers of postoperative tumor progression in NFPAs. The findings clearly showed different profiles between tumors with indolent postoperative behavior and those with postoperative tumor progression. Both enriched pathways involving DEPs and specific upregulated proteins have previously been associated with tumor aggressiveness. These results suggest the value of proteomic profiling for predicting tumor progression in patients with NFPAs.

Mortality in Patients With Primary Aldosteronism: A Swedish Nationwide Study.

BACKGROUND: Primary aldosteronism (PA) is associated with increased mortality. The extent to which this phenomenon is affected by sex, age, comorbidities at diagnosis, and different treatment modalities is largely unknown. The objective was to determine all-cause and cause-specific mortality in a population-based cohort of patients with PA and the impact of age at diagnosis, sex, comorbidities, and treatment modalities. METHODS: We used national registers to identify patients diagnosed with PA between 1997 and 2019 (n=2419) and controls (n=24 187) from the general population, matched for sex, age, and county of residence. We obtained mortality data from the Cause-of-Death Register. We used Cox regression models, adjusted for socioeconomic factors and diabetes, to estimate adjusted hazard ratios (HRs [95% CI]). RESULTS: Overall, 346 (14.3%) patients with PA and 2736 (11.3%) controls died during a median follow-up time of 8.1 years. PA was associated with increased risk from all-cause mortality (HR, 1.23 [95% CI, 1.10-1.38]), death from cardiovascular disease (HR, 1.57 [95% CI, 1.30-1.89]), and stroke (HR, 1.85 [95% CI, 1.16-2.93]). Patients with cardiovascular disease at diagnosis (HR, 1.53 [1.26-1.85]), age >56 years (HR, 1.28 [95% CI, 1.13-1.45]), patients treated with a low dose of a mineralocorticoid receptor antagonist (HR, 1.30 [95% CI, 1.02-1.66]), and untreated patients (HR, 2.51 [95% CI, 1.72-3.67]) had excess mortality. CONCLUSIONS: Mortality, mainly due to cardiovascular disease, is increased in patients with PA compared with controls from the general population, particularly in patients aged >56 years, patients with preexisting cardiovascular comorbidities, and patients receiving low dose of a mineralocorticoid receptor antagonist.

Intermittent high-dose glucocorticoid treatment does not cause adrenal insufficiency in patients with diffuse large B-cell lymphoma - a prospective study.

Glucocorticoid (GC) treatment suppresses the hypothalamic-pituitary-adrenal axis and can cause GC-induced adrenal insufficiency. In this study we investigated the incidence of GC-induced adrenal insufficiency in patients receiving intermittent short-term high-dose oral GC treatment for newly diagnosed diffuse large B-cell lymphoma. Cosyntropin stimulation test was used to assess adrenal function at study entry (baseline), at 2 months (before the 5th cycle), and 6 months from baseline (3 months after the last cycle). Ten patients were included (40% women). Mean age was 61 years. The mean (range) plasma morning cortisol was 407 (320-530) nmol/L at baseline, 373 (260-610) nmol/L at 2 months, and 372 (230-520) nmol/L 6 months from baseline. All patients had normal response to cosyntropin stimulation at baseline as well as 2 and 6 months from baseline. Thus, none of the patients developed biochemically verified adrenal insufficiency. Therefore, short-term high-dose GC therapy, a commonly used adjuvant treatment in patients with malignant hematological diseases, does not seem to down-regulate the hypothalamic-pituitary-adrenal axis.

Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.

Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.

Hypotension during transsphenoidal pituitary surgery associated with increase in plasma levels of brain injury markers.

BACKGROUND: Patients undergoing pituitary surgery may experience short- and long-term postoperative morbidity. Intraoperative factors such as hypotension might be a contributing factor. Our aim was to investigate the association between intraoperative hypotension and postoperative plasma levels of tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) as markers of perioperative brain injury. METHODS: Between June 2016 and October 2017, 35 patients from the Gothenburg Pituitary Tumor Study were included. For tau, NfL, and GFAP, concentrations were measured in plasma samples collected before and immediately following surgery, and on postoperative days 1 and 5. The difference between the highest postoperative value and the value before surgery was used for analysis (∆taupeak , ∆NfLpeak , ∆GFAPpeak ). Intraoperative hypotension was defined as the area under the curve of an absolute threshold below 70 mmHg (AUC70) and a relative threshold below 20% (AUC20%) of the baseline mean arterial blood pressure. RESULTS: Plasma tau and GFAP were highest immediately following surgery and on day 1, while NfL was highest on day 5. There was a positive correlation between AUC20% and both ∆taupeak (r2 = .20, p < .001) and ∆NfLpeak (r2 = .26, p < .001). No association was found between AUC20% and GFAP or between AUC70 and ∆taupeak , ∆NfLpeak or ∆GFAPpeak . CONCLUSION: Intraoperative relative, but not absolute, hypotension was associated with increased postoperative plasma tau and NfL concentrations. Patients undergoing pituitary surgery may be vulnerable to relative hypotension, but this needs to be validated in future prospective studies.

Healthcare cost and survival in patients with non-functioning pituitary adenoma.

OBJECTIVE: Pituitary adenomas and their consequences impact mortality and morbidity. We studied the healthcare costs, survival, and cost-effectiveness of growth hormone (GH) vs no GH replacement in patients with non-functioning pituitary adenoma (NFPA). DESIGN AND METHODS: A cohort study including all NFPA patients followed from 1987 or the date of diagnosis until the time of death or December 31, 2019, in the Västra Götaland region, Sweden. Data to assess resource use, costs, survival, and cost-effectiveness were collected from patient records and regional/national healthcare registries. RESULTS: A total of 426 patients with NFPA (274 men) with a follow-up of 13.6 ± 6.8 years (mean ± SD) were included. The total annual healthcare cost was higher in patients receiving GH (€9287) than those without GH (€6770), mainly driven by a higher pharmaceutical cost. Glucocorticoid replacement therapy (P = .02), diabetes insipidus (P = .04), body mass index (BMI) (P < .01), and hypertension (P < .01) were all individually associated with a higher total annual cost. The survival rate was higher in the GH group (HR [hazard ratio] 0.60; P = .01) and reduced in patients with glucocorticoid replacement (HR 2.02; P < .01) or diabetes insipidus (HR 1.67; P = .04). The cost per gained life-year for GH vs no GH replacement was about €37 000. CONCLUSIONS: This healthcare utilization study identified several factors driving the cost of care in NFPA patients, such as GH replacement, adrenal insufficiency, and diabetes insipidus. Life expectancy was increased in those with GH replacement and reduced in patients with adrenal insufficiency and diabetes insipidus.

Diagnosis and testing for growth hormone deficiency across the ages: a global view of the accuracy, caveats, and cut-offs for diagnosis.

Growth hormone deficiency (GHD) is a clinical syndrome that can manifest either as isolated or associated with additional pituitary hormone deficiencies. Although diminished height velocity and short stature are useful and important clinical markers to consider testing for GHD in children, the signs and symptoms of GHD are not always so apparent in adults. Quality of life and metabolic health are often impacted in patients with GHD; thus, making an accurate diagnosis is important so that appropriate growth hormone (GH) replacement therapy can be offered to these patients. Screening and testing for GHD require sound clinical judgment that follows after obtaining a complete medical history of patients with a hypothalamic-pituitary disorder and a thorough physical examination with specific features for each period of life, while targeted biochemical testing and imaging are required to confirm the diagnosis. Random measurements of serum GH levels are not recommended to screen for GHD (except in neonates) as endogenous GH secretion is episodic and pulsatile throughout the lifespan. One or more GH stimulation tests may be required, but existing methods of testing might be inaccurate, difficult to perform, and can be imprecise. Furthermore, there are multiple caveats when interpreting test results including individual patient factors, differences in peak GH cut-offs (by age and test), testing time points, and heterogeneity of GH and insulin-like growth factor 1 assays. In this article, we provide a global overview of the accuracy and cut-offs for diagnosis of GHD in children and adults and discuss the caveats in conducting and interpreting these tests.

Weekly somapacitan had no adverse effects on glucose metabolism in adults with growth hormone deficiency.

PURPOSE: The long-term effects of long-acting growth hormone (LAGH) analogues on glucose metabolism in adult growth hormone deficiency (AGHD) are not known. We investigated the impact of LAGH somapacitan, administered once-weekly, on glucose metabolism in patients with AGHD. METHODS: In post hoc-defined analyses, we compared the effects of somapacitan with daily growth hormone (GH) and placebo on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-ß) in patients with AGHD across a unique data set from three phase 3 randomized controlled trials (REAL 1, REAL 2 and REAL Japan). RESULTS: No new cases of diabetes mellitus were reported with somapacitan. Among GH-naïve patients (n = 120 somapacitan, n = 119 daily GH), higher changes from baseline in FPG, HOMA-IR and fasting insulin levels were observed with daily GH versus somapacitan at 34 weeks, but not at 86 weeks. HbA1c and HOMA-ß did not differ between groups at either timepoint. Among treatment-naïve patients, sex, age, fasting insulin, glucose tolerance status and body mass index did not influence changes in glucose metabolism. In previously treated patients (REAL 1 extension: n = 51 somapacitan, n = 52 daily GH; REAL 2: n = 61 and n = 31, respectively; REAL Japan: n = 46 and n = 16, respectively), the difference in changes from baseline were not statistically significant between somapacitan and daily GH for any glucose metabolism parameters. CONCLUSIONS: Somapacitan, compared with daily GH, did not adversely affect glucose metabolism up to 86 weeks in a large cohort of treatment-naïve or previously treated patients with AGHD. Trial registrations (date of registration): NCT02229851 (2 September 2014), NCT02382939 (3 March 2015), NCT03075644 (7 March 2017).

Illness perspectives in patients with primary aldosteronism.

OBJECTIVE: The burden of symptoms and treatment in patients with primary aldosteronism (PA), as well as the patients' experience of the health care is sparsely studied. The objectives of this study were to describe symptoms considered to be the most troublesome by patients with PA, and to explore health related worries and expectations following treatment. METHODS: This was an explorative qualitative study where 25 patients with PA, diagnosed between 2017 and 2019, were included; 13 patients who had undergone adrenalectomy and 12 who were receiving medical treatment. Data was collected during six group interviews and analyzed using a thematic approach. RESULTS: Three main themes were identified: 1) Distress of the past, where the most important issues were struggle to receive a correct diagnosis, impaired well-being and the consumption of a large number of tablets, 2) Satisfaction after receiving a correct diagnosis, both in patients with unilateral and bilateral disease, but also dissatisfaction with lack of information about the disease, and 3) Future concerns, where worries about the long-term effects of PA on health in general dominated. CONCLUSIONS: Our findings illustrate several important issues related to PA where improvements in patient care are needed, including actions aiming at shortening the long diagnostic delay, a thorough information to the patients about the disease is of great importance, and that all patients with PA, regardless of treatment, would benefit from a structured long-term follow-up.

Effects of 18 months of GH replacement on cardiovascular risk factors and quality of life in GH deficient adults; a randomized controlled trial using a fixed very low and a standard dose of GH.

OBJECTIVE: Little is known of the effects of a fixed very low dose of growth hormone (GH) replacement on cardiovascular risk factors, bone mass, muscle strength and quality of life (QoL) in hypopituitary patients. DESIGN/PATIENTS/METHODS: This was an open-label randomized study performed at a single center. Consecutive hypopituitary patients with adult onset GH deficiency (GHD) and BMI ≥ 27 kg/m2 were randomized to receive a very low fixed dose of GH (LG, n = 9) or a standard dose of GH (SG, n = 9). Body composition, glucose and lipid metabolism, bone mineral content (BMC) and density (BMD), muscle strength, and QoL were measured at baseline and after 6, 12 and 18 months. RESULTS: The fixed GH dose in LG was 0.1 mg/day. In SG, the mean baseline GH dose of 0.13 mg/day was gradually increased to 0.31 mg/day at study end. Lean body mass (LBM) as measured using DEXA as well as total body water (TBW) and extracellular water (ECW) were increased only in SG (P < 0.01, P < 0.05, and P < 0.01 vs. LG, respectively). There were no between-groups differences in BMD, BMC, insulin sensitivity, lipids, or muscle strength. Finally, although not significant compared with SG, a sustained improvement in QoL was seen in LG according to the QoL-AGHDA questionnaire. CONCLUSION: In this pilot study, a fixed very low GH dose improved QoL in GHD adults without any induction of fluid retention. Other effects were comparable to those produced by the standard GH dose. Replacement with a very low GH dose could therefore be a treatment option in hypopituitary patients, especially in patients who do not tolerate higher GH dosage. Trial registration This study is registered at ClinicalTrials.gov, EU-nr 2009-016783-37.