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Hepatic focal nodular hyperplasia after pediatric hematopoietic stem cell transplantation: The impact of hormonal replacement therapy and iron overload.
Cattoni, A, Rovelli, A, Prunotto, G, Bonanomi, S, Invernizzi, P, Perego, R, Mariani, AM, Balduzzi, A
Pediatric blood & cancer. 2020;(4):e28137
Abstract
BACKGROUND The advent of techniques for the assessment of iron overload (liver T2*-MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. METHODS We performed a retrospective analysis of the liver T2*-MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. RESULTS Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 ± 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate-to-severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI-T2* values in affected patients were statistically lower than healthy controls (P < .001). CONCLUSIONS We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.
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Leptin-Mediated Changes in the Human Metabolome.
Lawler, K, Huang-Doran, I, Sonoyama, T, Collet, TH, Keogh, JM, Henning, E, O'Rahilly, S, Bottolo, L, Farooqi, IS
The Journal of clinical endocrinology and metabolism. 2020;(8):2541-52
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CONTEXT While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. OBJECTIVE The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. DESIGN Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. RESULTS Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. CONCLUSION Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin's effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.
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Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: results from a phase 2a proof-of-concept study.
Archer, DF, Stewart, EA, Jain, RI, Feldman, RA, Lukes, AS, North, JD, Soliman, AM, Gao, J, Ng, JW, Chwalisz, K
Fertility and sterility. 2017;(1):152-160.e4
Abstract
OBJECTIVE To evaluate the safety and efficacy of elagolix vs. placebo and elagolix with low-dose E2/progestogen add-back therapy. DESIGN Proof-of-concept, dose-ranging, multiple-cohort study. SETTING Clinics. PATIENT(S): Premenopausal women with fibroids and heavy menstrual bleeding (menstrual blood loss [MBL] >80 mL per cycle). INTERVENTION(S): Three months' treatment with elagolix alone: 100 mg twice daily (BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the 600 mg QD arm were placebo controlled); or elagolix plus add-back therapy: 200 mg BID plus continuous low-dose E2 0.5 mg/norethindrone acetate 0.1 mg or elagolix 300 mg BID plus E2 1 mg continuously and cyclical P 200 mg. MAIN OUTCOME MEASURE(S): Least-squares mean percentage change in MBL; adverse events (AEs). RESULT(S): Mean age was 41.8 years; 73.8% were black; mean baseline MBL was 267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment period. The MBL percentage change from baseline to last 28 days was significantly greater with elagolix alone (range, -72% to -98%; dose-dependent reduction was highest with 300 mg BID) vs. placebo (range, -8% to -41%); mean percentage changes with add-back regimens were -80% to -85%. Overall AEs were dose independent (elagolix alone, 70.0%-81.3%) but lower with placebo (56.0%) and add-back regimens (55.6%-70.6%). Hot flush was the most common AE (elagolix alone, 45.5%-62.5%; placebo, 12.0%; add-back regimens, 18.5%-26.5%). CONCLUSION(S): Elagolix significantly reduced heavy menstrual bleeding in women with fibroids. Low-dose add-back regimens substantially reduced flushing. CLINICAL TRIAL REGISTRATION NUMBER NCT01441635.
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MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults.
Strasburger, CJ, Vanuga, P, Payer, J, Pfeifer, M, Popovic, V, Bajnok, L, Góth, M, Olšovská, V, Trejbalová, L, Vadasz, J, et al
European journal of endocrinology. 2017;(3):283-294
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OBJECTIVE Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study's objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults. DESIGN 54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A. RESULTS Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects. CONCLUSIONS Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.
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No Effect of Levothyroxine and Levothyroxine-Induced Subclinical Thyrotoxicosis on the Pharmacokinetics of Sorafenib in Healthy Male Subjects.
Huang, F, Ajavon, A, Huang, E, Lettieri, J, Liu, R, Peña, C, Berse, M
Thyroid : official journal of the American Thyroid Association. 2017;(9):1118-1127
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BACKGROUND Patients receiving the multikinase inhibitor sorafenib for locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine often receive concomitant levothyroxine for thyrotropin (TSH) suppression. In the Phase 3 DTC trial (DECISION), sorafenib exposure was approximately twofold higher than that observed in other cancers. This study assessed sorafenib pharmacokinetics without and with concomitant levothyroxine to examine whether a levothyroxine interaction or levothyroxine-induced subclinical thyrotoxicosis results in increased sorafenib exposure in patients with DTC. METHODS This was an open-label, two-period sequential treatment study in healthy male subjects. In period 1, day 1, subjects received a single oral dose of sorafenib 400 mg, followed by a minimal 10-day washout. In period 2, day 1, levothyroxine 300 μg was administered orally once daily (q.d.) for 14 days. After 10 days, a single oral concomitant dose of sorafenib 400 mg was given. Blood samples for sorafenib pharmacokinetic analyses were obtained pre-dose and at time points up to 96 hours after sorafenib dosing. Samples for thyroid tests were collected before and after levothyroxine dosing. RESULTS Twenty-five subjects completed the study and were evaluable for pharmacokinetic analysis. Levothyroxine 300 μg q.d. was well tolerated and induced subclinical thyrotoxicosis, producing full suppression of TSH (M ± SD = 0.032 ± 0.027 mIU/L) and increased free thyroxine (from 0.94 ± 0.09 to 1.77 ± 0.33 ng/dL) and free triiodothyronine (from 2.87 ± 0.28 to 4.24 ± 0.66 pg/mL) levels by day 11 of period 2. The geometric mean (%CV) sorafenib maximum concentration (Cmax) without and with levothyroxine was 2.09 (68.1) and 1.78 (63.9) mg/L, respectively, with a corresponding geometric mean area under the curve of 68.1 (68.2) and 64.3 (66.3) mg·h/L. Median (range) time to Cmax was 4.00 (2.98-16.0) and 4.02 (1.98-36.0) hours, respectively. Mean (%CV) half-life was 24.0 (25.3) and 25.7 (21.0) hours. All study drug-related adverse events were mild and included headache and fatigue for sorafenib, and headache, increased alanine aminotransferase and glutamate dehydrogenase, fatigue, and nervousness for levothyroxine. CONCLUSIONS Levothyroxine 300 μg q.d. for 14 days was well tolerated, induced subclinical thyrotoxicosis, and did not affect sorafenib pharmacokinetics. The findings suggest that concomitant use of levothyroxine with sorafenib is not likely responsible for the previously reported increase in sorafenib exposure in patients with DTC. However, the possible effects of long-term levothyroxine dosing were not assessed.
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Effects of parathyroid hormone rhPTH(1-84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study.
Clarke, BL, Vokes, TJ, Bilezikian, JP, Shoback, DM, Lagast, H, Mannstadt, M
Endocrine. 2017;(1):273-282
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Abstract
In hypoparathyroidism, inappropriately low levels of parathyroid hormone lead to unbalanced mineral homeostasis. The objective of this study was to determine the effect of recombinant human parathyroid hormone, rhPTH(1-84), on phosphate and vitamin D metabolite levels in patients with hypoparathyroidism. Following pretreatment optimization of calcium and vitamin D doses, 124 patients in a phase III, 24-week, randomized, double-blind, placebo-controlled study of adults with hypoparathyroidism received subcutaneous injections of placebo or rhPTH(1-84) (50 µg/day, titrated to 75 and then 100 µg/day, to permit reductions in oral calcium and active vitamin D doses while maintaining serum calcium within 2.0-2.2 mmol/L). Predefined endpoints related to phosphate homeostasis and vitamin D metabolism were analyzed. Serum phosphate levels decreased rapidly from the upper normal range and remained lower with rhPTH(1-84) (P < 0.001 vs. placebo). At week 24, serum calcium-phosphate product was lower with rhPTH(1-84) vs. placebo (P < 0.001). rhPTH(1-84) treatment resulted in significant reductions in oral calcium dose compared with placebo (P < 0.001) while maintaining serum calcium. After pretreatment optimization, baseline serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) levels were within the normal range in both groups. After 24 weeks, 1,25(OH)2D levels were unchanged in both treatment groups, despite significantly greater reductions in active vitamin D dose in the rhPTH(1-84) group. In hypoparathyroidism, rhPTH(1-84) reduces serum phosphate levels, improves calcium-phosphate product, and maintains 1,25(OH)2D and serum calcium in the normal range while allowing significant reductions in active vitamin D and oral calcium doses.
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Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial.
Woo, SM, Joo, J, Kim, SY, Park, SJ, Han, SS, Kim, TH, Koh, YH, Chung, SH, Kim, YH, Moon, H, et al
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2016;(6):1099-1105
Abstract
BACKGROUND Weight loss in pancreatic cancer is associated with maldigestion due to pancreatic duct obstruction. Pancreatic exocrine replacement therapy (PERT) may significantly improve fat and protein absorption. OBJECTIVES This prospective, double-blind, randomized, placebo-controlled phase II trial assessed whether PERT could reduce or prevent weight loss in patients with unresectable pancreatic cancer. METHODS Sixty seven patients with unresectable pancreatic cancer were randomized to receive enteric coated PERT, consisting of 6-9 capsules of pancreatin (457.7 mg/capsule), or placebo. Patients took two capsules each three times daily during main meals and one capsule each up to three times daily when having between-meal snacks. The primary endpoint was the percentage change in body weight at eight weeks. RESULTS The mean percentage change in body weight (1.49% [1.12 kg] vs. 2.99% [1.63 kg], P = 0.381) and the mean percent change in Patient-Generated Subjective Global Assessment (PG-SGA) score (8.85% vs. 15.69%, p = 0.18) did not differ significantly between the PERT and placebo groups. There was no improvement in quality of life and overall survival did not differ significantly between the PERT and placebo groups (5.84 months vs 8.13 months, p = 0.744). CONCLUSIONS PERT did not reduce weight loss in patients with unresectable pancreatic cancer. Larger randomized trials are needed to identify those patients who may benefit from PERT. TRIAL REGISTRATION ClinicalTrials.gov Number NCT01587534.
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Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis.
Overvad, S, Bay, K, Bojesen, A, Gravholt, CH
Andrology. 2014;(3):421-7
Abstract
Klinefelter syndrome (KS) is characterized by infertility and hypogonadism associated with increased prevalence of osteoporosis, diabetes and metabolic syndrome. Insulin-like factor 3 (INSL3) is produced in the Leydig cells. INSL3 has been suggested to play a role in bone health. Here, we studied INSL3 in relation to bone markers, body composition, the metabolic syndrome and diabetes. This was a case-control study. Sex hormones, anthropometric measures, vitamin D metabolites, parathyroid hormone, growth factors, muscle strength, maximal oxygen consumption and BMD were measured. We included 70 adult KS patients and 71 age-matched controls. INSL3 was lower in testosterone-treated KS compared with untreated KS. Correlation analyses showed a positive correlation between INSL3 and osteocalcin among KS, but not in controls; a significant positive correlation between INSL3 and testosterone in controls and in untreated KS, but not in treated KS men. Among controls a negative correlation was found between INSL3 and lipids, and glucose, but not in KS. HOMA2-B and impaired fasting glycaemia was positively correlated with INSL3 in controls. Among KS males we found a negative correlation between INSL3 and BMI, weight and waist/hip ratio, as well as positive correlations between INSL3 and FSH, LH, SHBG and testis volume. Multivariate analyses showed that age, testosterone and HDL cholesterol were the principal independent variables among healthy controls, whereas the determinants of INSL3 concentration among KS were age, LH, current testosterone treatment and testicular volume. INSL3 in KS is influenced by testosterone treatment and INSL3 is correlated with measures of bone metabolism, body composition and the metabolic syndrome. This may suggest that low INSL3 concentration is related to the pathogenesis behind an unfavourable change in body composition and bone metabolism among KS patients.
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Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1-84) in patients with hypoparathyroidism: an open-label, single-dose, phase I study.
Clarke, BL, Kay Berg, J, Fox, J, Cyran, JA, Lagast, H
Clinical therapeutics. 2014;(5):722-36
Abstract
BACKGROUND Impaired mineral homeostasis affecting calcium, phosphate, and magnesium is a result of parathyroid hormone (PTH) deficiency in hypoparathyroidism. The current standard of treatment with active vitamin D and oral calcium does not control levels of these major minerals. Recombinant full-length human PTH 1-84 (rhPTH[1-84]) is being developed for the treatment of hypoparathyroidism. OBJECTIVE The goal of this study was to investigate the pharmacokinetics and pharmacodynamics of a single subcutaneous injection of rhPTH(1-84) in patients with hypoparathyroidism. METHODS This was an open-label, dose-escalating study of single subcutaneous administration of 50 µg and then 100 µg of rhPTH(1-84). Enrolled patients (age range, 25-85 years) had ≥12 months of diagnosed hypoparathyroidism defined according to biochemical evidence of hypocalcemia with concomitant low-serum intact PTH and were taking doses ≥1000 mg/d of oral calcium and ≥0.25 µg/d of active vitamin D (oral calcitriol). The patient's prescribed dose of calcitriol was taken the day preceding but not on the day of or during the 24 hours after rhPTH(1-84) administration. Each patient received a single 50-µg rhPTH(1-84) dose, had at least a 7-day washout interval, and then received a single 100-µg rhPTH(1-84) dose. The following parameters were assessed: plasma PTH; serum and urine total calcium, magnesium, phosphate, and creatinine; and urine cyclic adenosine monophosphate. RESULTS After administration of rhPTH(1-84) 50 µg (n = 6) and 100 µg (n = 7), the approximate t½ was 2.5 to 3 hours. Plasma PTH levels increased rapidly, then declined gradually back to predose levels at ~12 hours. The median AUC was similar with calcitriol and rhPTH(1-84) for serum 1,25-dihydroxyvitamin D (calcitriol, 123-227 pg · h/mL; rhPTH[1-84], 101-276 pg · h/mL), calcium (calcitriol, 3.3-3.7 mg · h/dL; rhPTH[1-84], 3.3-7.6 mg · h/dL), and magnesium (calcitriol, 0.7-0.9 mg · h/dL; rhPTH[1-84], 1.3-2.8 mg · h/dL). In contrast, the median AUC for phosphate was strongly negative with rhPTH(1-84) (calcitriol, -1.0 to 0.8 mg · h/dL; rhPTH[1-84], -21.3 to -26.5 mg · h/dL). Compared with calcitriol, rhPTH(1-84) 50 µg reduced 24-hour calcium excretion and calcium-to-creatinine ratios by 12% and 23%, respectively, and rhPTH(1-84) 100 µg reduced them by 26% and 27%. There was little overall impact on urine magnesium levels. Compared with calcitriol, rhPTH(1-84) 50 µg increased urinary phosphate excretion and phosphate-to-creatinine ratios by 53% and 54%, respectively, and rhPTH(1-84) 100 µg increased them by 45% and 42%. Urine cyclic adenosine monophosphate-to-creatinine ratio increased with rhPTH(1-84) by 2.3-fold (50 µg) and 4.4-fold (100 µg) compared with calcitriol. CONCLUSIONS PTH replacement therapy with rhPTH(1-84) regulated mineral homeostasis of calcium, magnesium, phosphate, and vitamin D metabolism toward normal in these study patients with hypoparathyroidism.
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Effects of leptin deficiency and replacement on cerebellar response to food-related cues.
Berman, SM, Paz-Filho, G, Wong, ML, Kohno, M, Licinio, J, London, ED
Cerebellum (London, England). 2013;(1):59-67
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Leptin affects eating behavior partly by altering the response of the brain to food-related stimuli. The effects of leptin on brain structure have been observed in the cerebellum, where leptin receptors are most densely expressed, but the function of leptin in the cerebellum remains unclear. We performed a nonrandomized, prospective interventional study of three adults with genetically mediated leptin deficiency. FMRI was recorded three times each year during years 5 and 6 of leptin replacement treatment. Session 1 of each year occurred after 10 months of continuous daily replacement, session 2 after 33-37 days without leptin, and session 3 at 14-23 days after daily replacement was restored. Statistical parametric mapping software (SPM5) was employed to contrast the fMRI blood oxygenation level-dependent response to images of high-calorie foods versus images of brick walls. Covariate analyses quantified the effects of the duration of leptin replacement and concomitant changes in body mass on the cerebral responses. Longer duration of replacement was associated with more activation by food images in a ventral portion of the posterior lobe of the cerebellum, while simultaneous decreases in body mass were associated with decreased activation in a more dorsal portion of the same lobe. These findings indicate that leptin replacement reversibly alters neural function within the posterior cerebellum and modulates plasticity-dependent brain physiology in response to food cues. The results suggest an underexplored role for the posterior cerebellum in the regulation of leptin-mediated processes related to food intake.