Purpose The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.Methods Fifty-six acromegaly experts... Show morePurpose The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.Methods Fifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes.Results In a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches.Conclusion Consensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease. Show less
Purpose: Acromegalic arthropathy is a well-known phenomenon, occurring in most patients regardless of disease status. To date, solely hips, knees, hands, and spinal joints have been... Show morePurpose: Acromegalic arthropathy is a well-known phenomenon, occurring in most patients regardless of disease status. To date, solely hips, knees, hands, and spinal joints have been radiographically assessed. Therefore, this study aimed to assess the prevalence of joint symptoms and radiographic osteoarthritis (OA) of new, and established peripheral joint sites in well-controlled acromegaly. Methods: Fifty-one acromegaly patients (56% female, mean age 64 +/- 12 years) in long-term remission for 18.3 years (median, IQR 7.2-25.4) were included. Nineteen patients currently received pharmacological treatment. Self-reported joint complaints were assessed using standardized interviews. Self-reported disability of the upper and lower limbs, and health-related quality of life (HR-QoL) were evaluated using validated questionnaires. Radiographic OA [defined as Kellgren & Lawrence (KL) >= 2] was scored using (modified) KL methods. Results: Radiographic signs of OA were present in 46 patients (90.2%) with >= 2 joints affected in virtually all of these patients (N = 44; 95.7%). Radiographic MTP1 OA was as prevalent as radiographic knee OA (N = 26, 51.0%), and radiographic glenohumeral OA was similarly prevalent as hip OA [N = 21 (41.2%) vs. N = 24 (47.1%)]. Risk factors for radiographic glenohumeral OA were higher pre-treatment IGF-1 levels [OR 1.06 (1.01-1.12), P = 0.021], and current pharmacological treatment [OR 5.01 (1.03-24.54), P = 0.047], whereas no risk factors for MTP1 joint OA could be identified. Conclusion: Similar to previously-assessed peripheral joints, clinical and radiographic arthropathy of the shoulder and feet were prevalent in controlled acromegaly. Further studies on adequate management strategies of acromegalic arthropathy are needed. Show less
Labadzhyan, A.; Nachtigall, L.B.; Fleseriu, M.; Gordon, M.B.; Molitch, M.; Kennedy, L.; ... ; Strasburger, C.J. 2021
Purpose Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly.... Show morePurpose Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. Methods CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. Results Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. Conclusions OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each. Show less
Wit, J.M.; Joustra, S.D.; Losekoot, M.; Duyvenvoorde, H.A. van; Bruin, C. de 2021
The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired... Show moreThe current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak ("GH neurosecretory dysfunction," GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of GH1 or GHSR) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0-3.2 mu g/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to GH1 variants) but less on the role of GHSR variants. Several genetic causes of (partial) GHI are known (GHR, STAT5B, STAT3, IGF1, IGFALS defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes. Show less
Introduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is... Show moreIntroduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. Methods: We assessed the sex-specific contribution of GHS-R1a signaling in the activity of the GH/IGF-1 axis, metabolic parameters, and feeding behavior in adolescent (5-6 weeks old) or adult (10-19 weeks old) GHS-R KO (Ghsr-/-) and WT (Ghsr+/+) male and female mice. Results: Adult Ghsr-/- male and female mice displayed deficits in weight and linear growth that were correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr-/- mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr-/- females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations, or ambulatory activity did not predict differences in GH secretion. Discussion/Conclusion: These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occurring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females. Show less
Acromegaly is a chronic, progressive disease caused by a growth hormone (GH)-producing pituitary adenoma, resulting in elevated GH and insulin-like growth factor 1 concentrations. Following... Show moreAcromegaly is a chronic, progressive disease caused by a growth hormone (GH)-producing pituitary adenoma, resulting in elevated GH and insulin-like growth factor 1 concentrations. Following appropriate therapy (surgery, radiotherapy and/or medical treatment), many systemic GH-induced comorbid conditions improve considerably. Unfortunately, despite biochemical control, acromegaly patients suffer from a high prevalence of late manifestations of transient GH excess, significantly impairing their quality of life. In this overview article, we summarize the pathophysiology, diagnosis, clinical picture, disease course and management of skeletal complications of acromegaly, focusing on vertebral fractures and arthropathy. (C) 2015 S. Karger AG, Basel Show less
The thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day... Show moreThe thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day of SXB administration. SXB was taken 2 times 3g per night for 5 consecutive nights. Both groups underwent 24-h blood sampling and many hormones (prolactin, Growth hormone, melatonin, ghrelin, leptin) were measured and compared before and during SXB treatment. A study using the golden standard on insuline sensitivity is decribed to compare insuline sensitivity between patients and controls, and between patients, before and during satisfactory SXB treatment. ANother study describes body and skintemperature differences between narcolepsy patients and controls. Another chapter describes a rarely described, common feature in narcolepsy, in which patients mistake the memory of a dream for a real experience. In another chapter describes that date of birth is not a risk factor for narcolepsy. Show less
Kempers, M.J.E.; Crabben, S.N. van der; Vroede, M. de; Alfen-van der Velden, J.; Netea-Maier, R.T.; Duim, R.A.J.; ... ; Wit, J.M. 2013
Growth disorders are a major concern for patients, their parents, and health care professionals. our understanding of growth failure in the presence of normal GH secretion remains primitive,... Show moreGrowth disorders are a major concern for patients, their parents, and health care professionals. our understanding of growth failure in the presence of normal GH secretion remains primitive, hampering the development of new treatment strategies for children with short stature. Final height gain in currently available therapeutic regimens is restricted by rapid progression of pubertal development and the associated acceleration of growth plate fusion. Both an intact GH-Insulin-like growth factor I (IGF-I) system and estrogen signaling are of pivotal importance for normal growth. Regulation of normal growth is presumably based on the coordinated interplay between these systems, but the underlying molecular mechanisms are poorly understood. The aims of the work described in this thesis were: (1) to increase the understanding of the roles of GH, IGF-I and estrogen in growth plate biology, using a model system of fetal human mesenchymal stem cells (fhMSC) that are able to differentiate along the chondrogenic lineage in a similar fashion as occurs in the growth plate during growth; (2) to explore potential growth-promoting treatment strategies for children with idiopathic short stature (ISS) as an alternative for currently used growth hormone treatment regimens. Show less
Turner syndrome (TS) is a disorder in females that is caused by the complete or partial absence of the second sex chromosome. The main characteristics are gonadal dysgenesis and short stature, with... Show moreTurner syndrome (TS) is a disorder in females that is caused by the complete or partial absence of the second sex chromosome. The main characteristics are gonadal dysgenesis and short stature, with adult patients being on average 20 cm shorter than healthy women. Growth hormone (GH) therapy increases adult height with 5 to 12 cm and the addition of the weak androgen oxandrolone (Ox) may further increase adult height. This thesis describes the results of the first randomized, double-blind, placebo-controlled study on the question whether GH-treated girls with Turner syndrome would profit from Ox therapy, and if so, which Ox dosage should be given. It was concluded that the conventional Ox dosage (0.06 mg/kg/day) should not be used because of its limited efficacy and virilizing capacity. In contrast, the addition of Ox at a dosage of 0.03 mg/kg/day starting between the age of 8 to 15 years increases height during therapy, modestly increases adult height gain and has a fairly good safety profile, except for a small deceleration in breast development. In patients considering this deceleration less important than the increment in height gain, we therefore suggest to add Ox 0.03 mg/kg/day to GH to increase height. Show less
This thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the... Show moreThis thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the considerable prevalence of diverse morbidity in these patients, during the active phase of the disease but even more so after 17 years of disease cure, we suggest the screening of acromegalic patients on highly frequent comorbidities, such as osteoarthritis, vertebral fractures, colonic polyps, and colonic diverticulae. It is of great concern to recognize the long-term consequences of the disease in order to offer the patients adequate follow-up and multidisciplinary care. The aim should be to control the persisting complex morbidity as much as possible in order to prevent the patients from a further decrease in quality of life. The patients__ physician as well as the patient itself should be aware of the long-term consequences of acromegaly in order to eliminate surreal expectations concerning recovery of certain comorbidities. Show less
Growth is a complex process, regulated by multiple external and internal factors. Deviation from the normal growth pattern can be one of the first manifestations of an underlying disorder,... Show moreGrowth is a complex process, regulated by multiple external and internal factors. Deviation from the normal growth pattern can be one of the first manifestations of an underlying disorder, disrupting the normal growth process. The growth hormone __ IGF-I axis plays a key role in regulating this growth process. This thesis focuses on growth disorders as a result of genetic defects in the GH-IGF-I axis. The aim of the thesis is to study the genotype-fenotype relationship in patients with a documented genetic defect in one of the components of the GH-IGF-I axis and to unravel the role of the GH-IGF-I axis in the complex process of growth and development throughout life. Two patients with a mutation in the GH releasing hormone receptor gene demonstrate that combined treatment of GH and gonadotropin-releasing hormone antagonists is very effective in increasing final height. The characteristics of the first male patient with a STAT5b mutation are described in detail. The fenotype of the first patient with an inactivating mutation of the IGF-I gene is described, as well as functional characteristics of the mutation. Finally the consequences of a genetic defect of the IGF-I receptor gene are discussed. Show less
The evolutionary advantage to conserve energy in the form of adipose issue in order to survive long periods of food shortage in the past, turned into a major health problem in current times of... Show moreThe evolutionary advantage to conserve energy in the form of adipose issue in order to survive long periods of food shortage in the past, turned into a major health problem in current times of plenty. Excess accumulation of body fat, or "obesity", is associated with severely increased co-morbidity and mortality risks and is a global epidemical medical condition which is difficult to manage. The exact pathophysiologic mechanism of obesity remains elusive and various factors such as genetic, social, behavioral and physiological cues are involved in its development. From a biological point of view, obesity might be partly explained by differences in the regulation of energy intake, expenditure and storage (energy homeostasis) between obese and lean individuals. The neuroendocrine system provides a source of humoral messengers, which modulate energy homeostasis. This thesis will focus on changes of the neuroendocrine environment of obese women. First of all, spontaneous diurnal plasma hormone concentrations and secretion of different hormonal systems were studied. Secondly, the effect of weight loss on neuroendocrine perturbations of some of these hormonal axes was evaluated. Finally, the impact of modulation of potential physiological cues (increased circulating FFAs and deficit dopaminergic signaling), which might be involved in the neuroendocrine changes and metabolic alterations, was investigated. Show less
