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Background: The evidence on the effects of metformin and insulin in type 2 diabetes patients on quality of life, patient satisfaction, and cardiovascular outcomes is unclear., Methods: The Copenhagen Insulin and Metformin Therapy (CIMT) trial is an investigator-initiated multicentre, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. Participants with type 2 diabetes were randomised to metformin (n = 206) versus placebo (n = 206); in combination with open-label biphasic insulin aspart one to three times daily (n = 137) versus insulin aspart three times daily in combination with insulin detemir once daily (n = 138) versus insulin detemir once daily (n = 137).We present a detailed description of the methodology and statistical analysis of the clinical CIMT outcomes including a detailed description of tests of the assumptions behind the statistical analyses. The outcomes are quality of life (Short Form Health Survey (SF-36)), Diabetes Medication Satisfaction Questionnaire, and Insulin Treatment Satisfaction Questionnaire (assessed at entry and 18 months after randomisation) and cardiovascular outcomes including time to a composite of either myocardial infarction, stroke, peripheral amputation, coronary revascularisation, peripheral revascularisation, or death., Discussions: This statistical analysis plan ensure the highest possible quality of the subsequent post-hoc analyses., Trial Registration: The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency (EudraCT: 2007-006665-33 CIMT), and registered within ClinicalTrials.gov (NCT00657943, 8 th of April 2008)., Competing Interests: Sten Madsbad: Advisory boards: AstraZeneca; Boehringer Ingelheim; Eli Lilly; Intarcia Therapeutics; Merck Sharp & Dohme; Novartis; Novo Nordisk; Sanofi. Lecture fees: AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. Research Grant Recipient: Novo Nordisk; Boehringer Ingelheim. Leif Breum: Advisory boards: AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. Lecture fees: AstraZeneca; Lundbeck, Otsuka. Louise Lundby-Christensen, Christian Ovesen, Thomas Almdal: own shares in Novo Nordisk A/S. Elisabeth R Mathiesen: Advisory board: Novo Nordisk. Markus Harboe Olsen. Janus C Jakobsen, Christian Gluud, Simone B Sneppen, Christoffer Hedetoft, Michael E. Røder, Henrik Vestergaard, Niels Wiinberg, Thure Krarup: none declared., (© 2023 The Authors.)

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: -9.6% (95% CI: -14.4% to -4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: -0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: -2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: -9.9% (95% CI: -14.4% to -5.2%)) than basal-bolus insulin (within group effect: -1.2% (95% CI: -6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes., Introduction: Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus., Methods: This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months., Results: Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) - 2.4 [- 3.5, - 1.4] kg, p value < 0.001) and FM (- 1.5 [- 2.3, - 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group., Conclusion: Metformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Background: Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM)., Methods: The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed., Results: After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI - 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference - 0.33 V (95% CI - 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA 1c did not confound the associations., Conclusions: Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA 1c . Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

Preclinical studies have shown a potential osteoanabolic effect of metformin but human studies of how metformin affects bone turnover are few. A post hoc sub-study analysis of an 18-month multicenter, placebo-controlled, double-blinded trial in type 2 diabetes mellitus (T2DM), randomizing participants to metformin versus placebo both in combination with different insulin analogue regimens (Metformin + Insulin vs. Placebo + Insulin). Patients were not treatment naive at baseline, 83% had received metformin, 69% had received insulin, 57.5% had received the combination of metformin and insulin before entering the study. Bone formation and resorption were assessed by measuring, N-terminal propeptide of type I procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX) at baseline and end of study. The influence of gender, age, smoking, body mass index (BMI), T2DM duration, glycosylated hemoglobin A1c (HbA1c), c-reactive protein (CRP) and insulin dosage was also included in the analyses. The levels of bone formation marker P1NP and bone resorption marker CTX increased significantly in both groups during the trial. P1NP increased less in the Metformin + Insulin compared to the placebo + insulin group (p = 0.001) (between group difference change), while the increases in CTX levels (p = 0.11) were not different. CRP was inversely associated (p = 0.012) and insulin dosage (p = 0.011) was positively related with change in P1NP levels. BMI (p = 0.002) and HbA1C (p = 0.037) were inversely associated with change in CTX levels. During 18 months of treatment with metformin or placebo, both in combination with insulin, bone turnover increased in both groups. But the pattern was different as the bone formation marker (P1NP) increased less during Metformin + Insulin treatment, while change in bone resorption (CTX) was not significantly different between the two groups.

Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo., Introduction: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS)., Methods: This was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up., Results: Four hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, - 0.041 [- 0.055, - 0.027]; placebo group - 0.046 [- 0.058, - 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non-significant. HbA 1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively)., Conclusions: Eighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups., Trial Registration: ClinicalTrials.gov (NCT00657943).

Objective: To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes., Design and Setting: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design, conducted at 8 hospitals in Denmark., Participants and Interventions: Participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol), body mass index >25 kg/m(2)) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1-3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c ≤ 7.0% (≤ 53 mmol/mol)., Outcomes: Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes., Results: Carotid IMT change did not differ between groups (biphasic -0.009 mm (95% CI -0.022 to 0.004), aspart+detemir 0.000 mm (95% CI -0.013 to 0.013), detemir -0.012 mm (95% CI -0.025 to 0.000)). HbA1c was more reduced with biphasic (-1.0% (95% CI -1.2 to -0.8)) compared with the aspart+detemir (-0.4% (95% CI -0.6 to -0.3)) and detemir (-0.3% (95% CI -0.4 to -0.1)) groups (p<0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p<0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ., Conclusions: Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA1c, weight gain and insulin doses. The trial only reached 46% of planned sample size and lack of power may therefore have affected our results., Trial Registration Number: NCT00657943., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes., Design and Setting: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark., Participants and Interventions: 412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤ 7.0% (≤ 53 mmol/mol)., Outcomes: The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes., Results: Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI -0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference -0.42% (95% CI -0.62% to -0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference -2.6 kg (95% CI -3.3 to -1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001)., Conclusions: Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results., Trial Registration Number: NCT00657943; Results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Patients with type 2 diabetes (T2DM) have an increased mortality rate primarily because of macrovascular disease. Where T2DM patients cannot be managed sufficiently through diet, exercise and peroral antidiabetic drugs, that is when haemoglobin A1c (HbA1c) is above 7.0%, it is yet unknown whether a combination of metformin and insulin analogues is superior to insulin analogues alone. Nor is it known which insulin analogue regimen is the optimal., Objective: The primary objective of this trial is to evaluate the effect of an 18-month treatment with metformin vs. placebo in combination with one of three insulin analogue regimens, the primary outcome measure being carotid intima-media thickness (CIMT) in T2DM patients., Design: A randomized, stratified, multicentre trial having a 2 x 3 factorial design. The metformin part is double masked and placebo controlled. The insulin treatment is open. The intervention period is 18 months., Patient Population: Nine hundred and fifty patients with T2DM and HbA1c > or = 7.5% on treatment with oral hypoglycaemic agents or on insulin treatment and deemed able, by the investigator, to manage once-daily insulin therapy with a long-acting insulin analogue., Randomization: Central randomization stratified for age (above 65 years), previous insulin treatment and treatment centre., Interventions: Metformin 1 g x two times daily vs. placebo (approximately 475 patients vs. 475 patients) in combination with insulin detemir before bedtime (approximately 315 patients) or biphasic insulin aspart 30 before dinner with the possibility to increase to two or three injections daily (approximately 315 patients) or insulin aspart before the main meals (three times daily) and insulin detemir before bedtime (approximately 315 patients). Intervention follows a treat-to-target principle in all six arms aiming for an HbA1c < or = 7.0%., Outcome Measures: Primary outcome measure is the change in CIMT from baseline to 18 months. Secondary outcome measures comprises the composite outcome of death, acute myocardial infarction, stroke or amputation assessed by an adjudication committee blinded to intervention, other cardiovascular clinical outcomes, average postprandial glucose increment from 0 to 18 months, hypoglycaemia and any inadvertent medical episodes. In addition, change in plaque formation in the carotids, HbA1c, cardiovascular biomarkers, body composition, progression of microvascular complications and quality of life will be assessed as tertiary outcome measures. TIME SCHEDULE: Patient enrolment started May 2008. Follow-up is expected to finish in March 2011., Conclusion: CIMT is designed to provide evidence as to whether metformin is advantageous even during insulin treatment and to provide evidence regarding which insulin analogue regimen is most advantageous with regard to cardiovascular disease.

Objective: We tested the impact of commencement of GH replacement therapy in GH-deficient (GHD) adults on the circulating levels of other anterior pituitary and peripheral hormones and the need for re-evaluation of other hormone replacement therapies, especially the need for dose changes., Methods: 22 GHD patients were investigated in a double-blind randomized study and 90 GHD patients in an open study at baseline and after 6 and 12 months of GH replacement therapy., Results: In the placebo-controlled trial, the FT(3) levels increased after 6 months in the GH-treated group, and in the open study the FT(3) levels tended to increase. Other hormone concentrations did not change in either part of the study. Four patients required an increase in thyroxine dose, while 2 patients needed dose reduction. One originally euthyroid patient required thyroxine replacement. Two patients with originally conserved pituitary-adrenal function developed ACTH insufficiency. The hydrocortisone dose was increased in 1 and decreased in 1 of the 66 patients with secondary hypocortisolism. None of the females required any adjustment of sex hormone replacement therapy. Two of 37 males needed dose increase of testosterone, while 1 needed dose reduction., Conclusion: GH replacement therapy required dose adjustments regarding other hormone replacement therapies in 12.2% (n = 11), while initiation of new hormone replacement was performed in 3.3% (n = 3) of the 90 patients during the 1-year follow-up. Monitoring of pituitary hormone axes is advisable after commencement of GH replacement therapy, since changes of hormone replacement therapy was observed in a small but clinically significant number of patients., (Copyright 2004 S. Karger AG, Basel)

Objective: The aim of the present study was to investigate natural killer (NK) cell function and lymphocyte subsets in GH-deficient (GHD) adults, before and during long-term GH treatment., Study Design: We investigated immune function in 19 adults with severe GHD, before and during 18 months of randomized treatment with GH or placebo. Measurement of lymphocyte subsets and NK cell activity was performed. Data obtained from 110 healthy adults served as reference values., Results: NK cell activity, both unstimulated and stimulated by interferon-a or interleukin-2, was significantly impaired in GHD patients. Similarly, NK cell concentration and the proportion of NK cells (CD16+) were reduced in GHD patients compared to controls. Both total and proportional CD4 + cells were increased in patients compared with controls. IGF-I increased significantly during treatment, but the immune functions investigated were unaltered., Conclusions: GH deficiency was associated with changes in lymphocyte subsets and impaired unstimulated and stimulated natural killer cell activity, but these remained abnormal during 18 months of GH replacement therapy. Extra-pituitary GH gene expression in, e.g. lymphoid tissues may serve as an autocrine/paracrine factor in immunomodulation and explain the clinical normal immune function in adult GH-deficient patients.

Objective: To characterise the effect of long-term low-dose growth hormone (GH) treatment on cardiac anatomy and function., Methods: 20 patients with multiple pituitary hormone deficiencies, including severe acquired GH deficiency (GHD), were randomly assigned to GH or placebo (P) for 18 months. Echocardiographic measurements were performed at baseline and after 6, 12 and 18 months., Results: At baseline, 8 of 20 patients had diastolic dysfunction (6 severe and 2 borderline), while only 1 had systolic dysfunction. None of the investigated parameters of diastolic or systolic function changed during treatment., Conclusion: In adult onset GHD, diastolic dysfunction was present in 40% of the patients. None of the investigated values were different after 18 months of GH compared to placebo., (Copyright 2002 S. Karger AG, Basel)

The aim was to evaluate, markers of disease activity in acromegaly in relation to perceived disease activity. Thirty-seven consecutively treated, acromegalic patients, classified by clinical symptoms as inactive (n=16), slightly active (n=10) and active (n=11), entered the study. When evaluating the inactive and the active groups, we found that positive and negative predictive values (PV(pos), PV(neg)) for clinical disease activity of total and free insulin-like growth factor-I (IGF-I) were 0.59, 0.90 and 1.00, 0.82 respectively. Acid-labile subunit (ALS) showed diagnostic merit similar to insulin-like growth factor binding protein-3 (IGFBP-3) with PV(pos) of 0.69 and 0.71 and PV(neg) of 0.91 and 0.92 respectively. We conclude that free IGF-I is more closely related than total IGF-I to perceived disease activity and is as such useful when evaluating previously treated acromegaly for disease activity. Total IGF-I, IGFBP-3 and ALS possess a higher PV(neg) for the clinical disease activity. None of the parameters can at present be claimed to be superior to the others and thus all the measured parameters are recommended to be part of the evaluation of acromegalic patients., (Copyright 2001 Elsevier Science Ltd.)

Introduction: The chance of malignancy in scintigraphically cold thyroid nodules is 2-24%. Differentiation between malignant and benign cytology is difficult. The aim of this study was to evaluate the ability of immunostaining (MoAB47--raised against thyroid peroxidase (TPO)) to differentiate between malignant and benign cells taken from cold thyroid nodules by fine needle aspiration biopsy (FNAB) in order to reduce the number of unnecessary thyroid operations., Materials and Methods: One hundred and eighty-one patients (150 female) with a scintigraphically cold, solitary thyroid nodule were entered between 1993 and 1996. Fifty-seven were excluded for various reasons. Material removed by FNAB was stained with MoAB47 and routine staining. Staining of 80% or more of the cells was considered benign, less than 80% was considered malignant. Routine staining of operatively removed material was used as the final diagnosis., Results: A pattern with negative TPO staining was found in all lesions that were subsequently proved to be malignant. In all but one, the lesions subsequently diagnosed as being benign stained positive for TPO. The sensitivity and specificity were respectively 1.0 and 0.99., Conclusion: TPO immunostaining of material removed by FNAB is a powerful tool in the differentiation between benign and malignant tumours.

Background: While increased sweating is a prominent symptom in patients with active acromegaly, reduced sweating is gaining status as part of the growth hormone deficiency (GHD) syndrome., Design and Subjects: Sweat secretion rate (SSR), as measured by pilocarpine iontophoresis represents the maximal capacity for stimulated sweat secretion in a localized skin area. SSR was studied in 37 patients with a history of acromegaly, 20 adult patients with GHD before and during long-term GH substitution of GHD adults, and 58 control subjects., Results: Acromegaly: Patients with acromegaly had significantly higher SSR than healthy controls (Z-score + 1.9 (+/- 1.1) mean (+/- SD) (P < 0.001)). SSR was increased irrespective of current clinical disease activity. Thus, the SSR Z-scores in 16 clinically inactive patients were + 2.1 (+/- 1.2), in 10 slightly or doubtfully active patients + 1.5 (+/- 0.7) and in 11 active patients + 1.8 (+/- 1.3). There was no correlation between SSR and IGF-I. GHD: Twenty adult patients participated in an 18-month randomised, placebo controlled, double blinded study of physiological dose GH substitution, followed by 18 months of open GH treatment. SSR at baseline was reduced in male but not in female GHD patients. Mean SSR (95% confidence interval) for 11 male patients was 89.0 mg/30 minutes (51.9-126.1) as compared to 133.5 mg/30 minutes (59.2-259.9) (P = 0.01) in 24 male controls, and for 11 female patients 48.2 mg/30 minutes (25.9-70.6) as compared to 49.2 mg/30 minutes (12.6-93. 9) in 34 female controls. GH treatment in physiological substitution doses for up to 36 months had no effect on SSR., Conclusion: We have demonstrated that longstanding GH hypersecretion in patients with acromegaly induces irreversible changes of sweat gland function, with persistently elevated SSR despite treatment and clinical cure. In GHD patients, SSR was reduced in males but not in females, which together with the established gender difference in normal controls emphasises the role of androgen deficiency as a cofactor for reduced sweating in hypopituitary patients. Sweat gland development seems to be more susceptible to lack of hormones in childhood and adolescence than in adulthood, whereas growth hormone excess can modify sweat function later in life.

Objective: To evaluate the value of immunostaining using the monoclonal antibody (MoAB47) against thyroperoxidase (TPO) in distinguishing between benign and malignant tumour cells in fine needle aspiration cytology (FNAC) samples obtained from a solitary cold nodule of the thyroid gland for the purpose of strengthening the indication for thyroid surgery., Design: A prospective, immunocytochemical study of FNACs taken from patients with solitary cold thyroid nodules who presented to Rigshospitalet, Copenhagen, Denmark, during the period April 1993 to May 1996. The first sample series was taken perioperatively in order to test the utility of the method. In the second part of the study samples were obtained preoperatively by ultrasonic guided aspiration. Tissue sections from the nodules obtained during a subsequent operation served as controls., Patients: One hundred and eighty-one patients, 150 women and 31 men, were studied. The age range was 14-89 years with a median age of 44 years. Fifty-seven patients were excluded from the study for various reasons leaving us with a total of 124 nodules from 124 patients for final evaluation., Methods: FNAC cells and corresponding nodular tissue were stained by immunocyto- and immuno-histochemistry using MoAb47 and by routine staining methods. Samples were considered benign if 80% or more of the epithelial-looking cells of both the FNACs and the histological tissue sections of the nodule were stained by TPO. Consequently, samples were considered malignant if more than 20% of the epithelial-looking cells failed to stain for TPO. Routinely stained tissue cells and sections served as diagnostic controls., Results: A pattern with negative TPO staining was found in all lesions which, by conventional histological staining, were subsequently proven to be malignant. A universal and reliable, positive TPO staining pattern was found in all subsequently proven benign lesions, with the exception of one out of 26 follicular adenomas. This gave the method a sensitivity of 1.0 (negative TPO staining = malignancy in 27 out of 27) and a specificity of 0.99 (positive TPO staining = benign lesion, in 96 out of 97). Positive and negative predictive values were 0.96 and 1.00 respectively., Conclusion: Thyroperoxidase immunostaining of fine needle aspirates from solitary, scintigraphically cold nodules of the thyroid gland has proved to be an important and reliable diagnostic tool for distinguishing between benign and malignant nodules. Thus, patients might be spared further surgery if not otherwise indicated.

Many studies have shown the beneficial, anabolic effects of growth hormone (GH) replacement therapy in GH deficient adults with childhood onset or adult onset disease. It is becoming increasingly evident, however, that these two groups of patients differ in many respects. Patients with adult onset GH deficiency represent fully developed individuals who have various organic, cerebral defects. By contrast, patients with childhood onset disease represent a heterogenous group comprising individuals with conditions, such as idiopathic isolated GH deficiency, genetic defects and organic defects. It is generally accepted that all children treated with GH should be retested in adulthood before adult replacement is started, as around 40% have a normal retest. It is unclear whether continued treatment with GH in childhood onset GH deficiency will yield results as positive as those seen in trials where GH is re-instituted after longer periods without treatment. Similarly, it is unknown at what timepoint cessation of GH treatment will cause a worsening in the physical state of the patient. In our placebo-controlled trial where GH was discontinued in 19 patients treated with GH during childhood, we determined exercise capacity, body composition, muscle mass and strength, cardiac function, sweating capacity, thyroid function and glucose metabolism before and after 12 months of continued treatment with GH.