Jens Sandahl Christiansen

AMITRIPTYLINE PLASMA-CONCENTRATION AND CLINICAL EFFECT: A World Health Organisation Collaborative Study

54 patients in five centres participated in a study of the relationship between steady-state plasma-levels of amitriptyline (AT) and its active metabolite nortriptyline (NT) and therapeutic response. The participants were inpatients who, after a 7-12 day period of assessment, were rated greater than or equal to 16 on the Hamilton rating scale for depression. They were given 75 mg of amitriptyline for 3 days and then 150 mg daily for an active-treatment period of 6 weeks. Clinical ratings and plasma-samples were obtained at baseline then at 2, 4, and 6 weeks after starting therapy. Contrary to the findings of three previous trials, no important correlations were found between steady-state plasma-levels and therapeutic outcome or corrected side-effects. Corrected side-effects correlated negatively with therapeutic outcome. There seems little advantage in routine monitoring of AT and NT, since variations in plasma-levels do not account for the considerable variation in therapeutic outcome.

Weight loss increases circulating levels of ghrelin in human obesity

objective Ghrelin, a novel endogenous ligand for the GH secretagogue receptor, has been reported to have adipogenic actions and induce weight gain in addition to its GH‐releasing properties. Interestingly, recent data indicate that ghrelin is downregulated in human obesity, which is also known to be accompanied by reduced GH levels.

Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models

Animal models are fundamentally important in our quest to understand the genetic, epigenetic, and environmental factors that contribute to human aging. In comparison to humans, relatively short-lived mammals are useful models as they allow for rapid assessment of both genetic manipulation and environmental intervention as related to longevity. These models also allow for the study of clinically relevant pathologies as a function of aging. Data associated with more distant species offers additional insight and critical consideration of the basic physiological processes and molecular mechanisms that influence lifespan. Consistently, two interventions, caloric restriction and repression of the growth hormone (GH)/insulin-like growth factor-1/insulin axis, have been shown to increase lifespan in both invertebrates and vertebrate animal model systems. Caloric restriction (CR) is a nutrition intervention that robustly extends lifespan whether it is started early or later in life. Likewise, genes involved in the GH/IGF-1 signaling pathways can lengthen lifespan in vertebrates and invertebrates, implying evolutionary conservation of the molecular mechanisms. Specifically, insulin and insulin-like growth factor-1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for CR individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages. In this review, we will provide an overview of how the manipulation of the GH/IGF axis influences lifespan, highlight the invertebrate and vertebrate animal models with altered lifespan due to modifications to the GH/IGF-1 signaling cascade or homologous pathways, and discuss the basic phenotypic characteristics and healthspan of these models.

Clinical and epidemiological description of aortic dissection in Turner's syndrome.

BACKGROUND Women with Turners syndrome have an increased risk of congenital cardiac malformations, ischaemic heart disease, hypertension and stroke. Aortic dissection seems to occur with increased frequency. AIM To describe in more detail aortic dissection as encountered in Turners syndrome, giving attention to clinical, histological and epidemiological aspects. MATERIALS AND METHODS Based on a retrospective study, we describe the clinical, karyotypic, and epidemiological aspects of aortic dissection as encountered in cases of Turners syndrome seen in Denmark and Sweden. RESULTS The median age at onset of aortic dissection in 18 women was 35 years, ranging from 18 to 61 years. Fourteen of 18 women had a 45,X karyotype, while 2 patients had 45,X/45,XY, and 2 had the 45,X/46,X+r(X) complement, respectively. Echocardiography was performed in 10 of 18 patients before their acute illness, and showed signs of congenital cardiac disease, with either bifoliate aortic valves, dilation of the aortic root, or previous aortic coarctation evident in most patients. In 5 patients evidence of a bifoliate aortic valve was conclusive. Hypertension was present in 5 of 18 patients, while 10 of the patients died from aortic dissection, of so-called type A in 6, type B in 3, while in the final case the origin of dissection could not be determined. Biochemical analysis showed altered ratio between type I and type III collagen. Histology showed cystic medial necrosis in 3 of 7 cases. We estimated an incidence of dissection of 36 per 100,000 Turners syndrome years, compared with an incidence of 6 per 100,000 in the general population, and a cumulated rate of incidence of 14, 73, 78, and 50 per 100,000 among 0-19, 20-29, 30-39, and 40+ year olds, respectively. CONCLUSION Aortic dissection is extremely common in the setting of Turners syndrome, and occurs early in life. Patients with Turners syndrome should be offered a protocol for clinical follow-up similar to that provided for patients with Marfan syndrome, and each clinic should embrace a programme for follow-up.

Glucose Metabolism, Lipid Metabolism, and Cardiovascular Risk Factors in Adult Turner's Syndrome: The impact of sex hormone replacement

OBJECTIVE To examine glucose metabolism, blood pressure, physical fitness, and lipid metabolism in adult untreated women with Turners syndrome compared with a group of normal women and to examine the effects of female sex hormone substitution on these factors. RESEARCH DESIGN AND METHODS A total of 26 patients with Turners syndrome were examined before and during sex hormone replacement with 17β-estradiol and norethisterone, and an age-matched control group (n = 24) was examined once. A frequently sampled intravenous glucose tolerance test was applied with minimal model assessment. We also performed an oral glucose tolerance test, measurement of 24-h ambulatory blood pressure, and assessment of physical fitness and lipid metabolism. RESULTS Insulin sensitivity (SI) and glucose effectiveness (SG) were similar in Turners syndrome patients and control subjects, whereas the acute insulin response (P = 0.03) was lower in Turners syndrome patients, and no change was seen during sex hormone treatment. Abnormal glucose tolerance was found in 50% of Turners syndrome patients before and 78% during treatment with sex hormones. Fat-free mass (FFM; P = 0.0005) and physical fitness (P = 0.002) were lower in Turner=s syndrome subjects compared with control subjects. During treatment, an increase in FFM (P = 0.001) and physical fitness (P = 0.02) was seen in Turners syndrome patients. Blood pressure was increased in Turners syndrome, and a decrease was seen in diastolic blood pressure during treatment with sex hormones. CONCLUSIONS Turners syndrome is associated with glucose intolerance, diminished first-phase insulin response, elevated blood pressure, reduced FFM, and physical fitness. Sex hormone administration causes a deterioration in glucose tolerance, increases FFM and physical fitness, and has beneficial effects on blood pressure. The deleterious effect on glucose tolerance may be mediated by norethisterone, a gestagen known to have androgenic effects.

Insulin-like growth factor I stimulates lipid oxidation, reduces protein oxidation, and enhances insulin sensitivity in humans.

To elucidate the effects of insulin-like growth factor I (IGF-I) on fuel oxidation and insulin sensitivity, eight healthy subjects were treated with saline and recombinant human (IGF-I (10 micrograms/kg.h) during 5 d in a crossover, randomized fashion, while receiving an isocaloric diet (30 kcal/kg.d) throughout the study period. On the third and fourth treatment days, respectively, an L-arginine stimulation test and an intravenous glucose tolerance test were performed. A euglycemic, hyperinsulinemic clamp combined with indirect calorimetry and a glucose tracer infusion were performed on the fifth treatment day. IGF-I treatment led to reduced fasting and stimulated (glucose and/or L-arginine) insulin and growth hormone secretion. Basal and stimulated glucagon secretion remained unchanged. Intravenous glucose tolerance was unaltered despite reduced insulin secretion. Resting energy expenditure and lipid oxidation were both elevated, while protein oxidation was reduced, and glucose turnover rates were unaltered on the fifth treatment day with IGF-I as compared to the control period. Enhanced lipolysis was reflected by elevated circulating free fatty acids. Moreover, insulin-stimulated oxidative and nonoxidative glucose disposal (i.e., insulin sensitivity) were enhanced during IGF-I treatment. Thus, IGF-I treatment leads to marked changes in lipid and protein oxidation, whereas, at the dose used, carbohydrate metabolism remains unaltered in the face of reduced insulin levels and enhanced insulin sensitivity.

Continuous glucose monitoring: an Endocrine Society Clinical Practice Guideline.

OBJECTIVE The aim was to formulate practice guidelines for determining settings where patients are most likely to benefit from the use of continuous glucose monitoring (CGM). PARTICIPANTS The Endocrine Society appointed a Task Force of experts, a methodologist, and a medical writer. EVIDENCE This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, the Diabetes Technology Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS The Task Force evaluated three potential uses of CGM: 1) real-time CGM in adult hospital settings; 2) real-time CGM in children and adolescent outpatients; and 3) real-time CGM in adult outpatients. The Task Force used the best available data to develop evidence-based recommendations about where CGM can be beneficial in maintaining target levels of glycemia and limiting the risk of hypoglycemia. Both strength of recommendations and quality of evidence were accounted for in the guidelines.

Ghrelin immunoreactivity in human plasma is suppressed by somatostatin

objective Ghrelin was recently identified as a specific endogenous ligand for the growth hormone secretagogue receptor (GHS‐R). This new hormone was isolated from rat and human stomach and was reported to circulate in human plasma, but the regulation and physiological significance of ghrelin in humans have not been clarified. The present study was undertaken to test the following hypotheses: (1) prolonged fasting, which is known to stimulate GH secretion, is associated with changes in ghrelin immunoreactivity; (2) somatostatin in the systemic circulation regulates ghrelin secretion; and (3) GH affects ghrelin levels.

Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose‐dependent manner and suppresses circadian thyrotrophin levels: studies in GH‐deficient adults

OBJECTIVE The impact of exogenous GH on thyroid function remains controversial although most data add support to a stimulation of peripheral T4 to T3 conversion. For further elucidation we evaluated iodothyronine and circadian TSH levels in GH‐deficient patients as part of a GH dose‐response study.

Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans.

Insulin-like growth factor-I (IGF-I) is considered to be the mediator of the growth-promoting effects of growth hormone (GH). The metabolic effects of these two hormones, however, are different. Whereas GH treatment leads to elevated insulin and glucose levels, reduced insulin sensitivity, and impaired glucose tolerance, IGF-I treatment leads to reduced insulin and GH levels and enhanced insulin sensitivity. IGF-I may, therefore, not only be the mediator of the growth-promoting effects of GH but also a modulator of the effects of GH on insulin action and glucose metabolism. To study the influence of GH and IGF-I on substrate metabolism and insulin sensitivity (assessed by euglycemic, hyperinsulinemic clamping combined with indirect calorimetry and glucose tracer infusion), we have treated eight GH-deficient adults with GH (2 IU/m2 daily subcutaneously [s.c.]), IGF-I (10 micrograms/kg.h s.c.), or both hormones together for 7 d, respectively, and compared the effects of these treatment regimens with a control phase. Our findings suggest that (a) both GH and IGF-I promote lipolysis and lipid oxidation, albeit by different mechanisms; (b) treatment with either hormone is followed by enhanced energy expenditure and reduced protein oxidation; and (c) IGF-I reverses the insulin resistance induced by GH.