| 1. |
- Barbosa, Edna J L, 1961, et al.
(författare)
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Influence of the Exon 3-deleted/full-length Growth Hormone Receptor Polymorphism on the Response to Growth Hormone Replacement Therapy in Adults with Severe Growth Hormone Deficiency. : d3-GHR isoform in GHD adults
- 2009
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:2, s. 639-644
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Tidskriftsartikel (refereegranskat)abstract
- Context: There is considerable individual variation in the clinical response to growth hormone (GH) replacement therapy in GH deficient (GHD) adults. Useful predictors of treatment response are lacking. Objective: To assess the influence of the exon 3-deleted (d3-GHR) and full-length (fl-GHR) GH receptor isoforms on the response to GH replacement therapy in adults with severe GHD. Design, Patients: 124 adult GHD patients (79 men, median age 50 years) were studied before and after 12 months of GH therapy. GHD patients were divided into those bearing fl/fl alleles (Group 1) and those bearing at least one d3-GHR allele (Group 2), and the genotype was related to the effects of GH therapy on IGF-I levels and total body fat (BF). Intervention: GH dose was individually titrated to obtain normal serum IGF-I levels. Main Outcome Measures: GHR genotype was determined by PCR amplification, IGF-I levels by immunoassay, and BF by a four-compartment model. Results: Seventy-two (58%) patients had fl/fl genotype and were classified as Group 1, while 52 (42%) had at least one d3-GHR allele and were classified as Group 2 (40 were heterozygous and 12 were homozygous). At baseline, there were no significant differences in the study groups. Changes in IGF-I and BF after 12 months of GH treatment did not differ significantly between the two genotype groups. Conclusion: The presence of d3-GHR allele did not influence the response to GH replacement therapy in our cohort of adults with severe GHD.
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| 2. |
- Bergthorsdottir, Ragnhildur, 1971, et al.
(författare)
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Premature mortality in patients with Addison's disease: a population-based study.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:12, s. 4849-53
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The survival rate of patients with primary adrenal insufficiency (Addison's disease) undergoing currently accepted replacement therapy is not known, although well-informed patients are considered to have a normal survival rate. In this study, we evaluated the mortality of patients with Addison's disease in Sweden. METHODS: A population-based, retrospective, observational study was performed, using the National Swedish Hospital and Cause of Death Registers, covering the period from 1987-2001. After a diagnosis of Addison's disease, each patient was followed until the end of follow-up or death. Mortality was compared with that of the Swedish background population. FINDINGS: We identified 1675 patients (995 women and 680 men) diagnosed with primary adrenal insufficiency. The average follow-up from initial diagnosis was 6.5 yr. Five hundred seven patients died during the study period compared with an expected 199. The risk ratio for all-cause mortality was 2.19 (confidence interval 1.91-2.51) for men and 2.86 (confidence interval 2.54-3.20) for women. The excess mortality in both men and women was attributed to cardiovascular, malignant, and infectious diseases. Concomitant diabetes mellitus was observed in 12% of the patients, but only contributed to the increased mortality to a minor extent. INTERPRETATION: Compared with the background population, we observed that the risk ratio for death was more than 2-fold higher in patients with Addison's disease. Cardiovascular, malignant, and infectious diseases were responsible for the higher mortality rate.
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| 3. |
- Berryman, Darlene E, et al.
(författare)
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Role of the GH/IGF-1 axis in lifespan and healthspan: Lessons from animal models.
- 2008
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Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - : Elsevier BV. - 1096-6374. ; 18:6, s. 455-71
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Burt, Morton G, et al.
(författare)
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Impact of acute and chronic low-dose glucocorticoids on protein metabolism.
- 2007
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:10, s. 3923-9
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: High-dose glucocorticoids cause acute protein loss by increasing protein breakdown and oxidation. Whether lower glucocorticoid doses, typical of therapeutic use, induce sustained catabolism has not been studied. OBJECTIVE: Our objective was to assess the effect of acute and chronic therapeutic glucocorticoid doses on protein metabolism. DESIGN AND SETTING: We conducted an open longitudinal and a cross-sectional study at a clinical research facility. PATIENTS AND INTERVENTION: Ten healthy subjects were studied before and after a short course of prednisolone (5 and 10 mg/d sequentially for 7 d each). Twelve subjects with inactive polymyalgia rheumatica receiving chronic (>12 months) prednisone (mean = 5.0 +/- 0.8 mg/d) were compared with 12 age- and gender-matched normal subjects. MAIN OUTCOME MEASURE: Whole-body protein metabolism was assessed using a 3-h primed constant infusion of 1-[(13)C]leucine, from which rates of leucine appearance (leucine Ra, an index of protein breakdown), leucine oxidation (Lox, index of protein oxidation) and leucine incorporation into protein (LIP, index of protein synthesis) were estimated. RESULTS: Prednisolone induced an acute significant increase in Lox (P = 0.008) and a fall in LIP (P = 0.08) but did not affect leucine Ra. There was no significant difference between the effects of the 5- and 10-mg prednisolone doses on leucine metabolism. In subjects receiving chronic prednisone therapy, leucine Ra, Lox, and LIP were not significantly different from normal subjects. CONCLUSION: Glucocorticoids stimulate protein oxidation after acute but not chronic administration. This time-related change suggests that glucocorticoid-induced stimulation of protein oxidation does not persist but that a metabolic adaptation occurs to limit protein loss.
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| 5. |
- Burt, Morton G, et al.
(författare)
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Impact of growth hormone and dehydroepiandrosterone on protein metabolism in glucocorticoid-treated patients.
- 2008
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 93:3, s. 688-95
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Chronic pharmacological glucocorticoid (GC) use causes substantial morbidity from protein wasting. GH and androgens are anabolic agents that may potentially reverse GC-induced protein loss. OBJECTIVE: Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. DESIGN: This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). SETTING: The studies were performed at a clinical research facility. PATIENTS AND INTERVENTION: In study 1, six subjects (age 69+/-4 yr) treated with long-term (>6 months) GCs (prednisone dose 8.3+/-0.8 mg/d) were studied before and after two sequential GH doses (0.8 and 1.6 mg/d) for 2 wk each. In study 2, 10 women (age 71+/-3 yr) treated with long-term GCs (prednisone dose 5.4+/-0.5 mg/d) were studied at baseline and after 2-wk treatment with GH 0.8 mg/d, DHEA 50 mg/d, or GH and DHEA (combination treatment). MAIN OUTCOME MEASURE: Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance, leucine oxidation, and leucine incorporation into protein were estimated. RESULTS: In study 1, GH 0.8 and 1.6 mg/d significantly reduced leucine oxidation by 19% (P=0.03) and 31% (P=0.02), and increased leucine incorporation into protein by 10% (P=0.13) and 19% (P=0.04), respectively. The lower GH dose did not cause hyperglycemia, whereas GH 1.6 mg/d resulted in fasting hyperglycemia in two of six subjects. In study 2, DHEA did not significantly change leucine metabolism alone or when combined with GH. Blood glucose was not affected by DHEA. CONCLUSION: GH, at a modest supraphysiological dose of 0.8 mg/d, induces protein anabolism in chronic GC users without causing diabetes. DHEA 50 mg/d does not enhance the effect of GH. GH may safely prevent or reverse protein loss induced by chronic GC therapy.
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| 6. |
- Clayton, P E, et al.
(författare)
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Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society.
- 2007
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:3, s. 804-10
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Low birth weight remains a major cause of morbidity and mortality in early infancy and childhood. It is associated with an increased risk of health problems later in life, particularly coronary heart disease and stroke. A meeting was convened to identify the key health issues facing a child born small for gestational age (SGA) and to propose management strategies. PARTICIPANTS: There were 42 participants chosen for their expertise in obstetrics, peri- and neonatal medicine, pediatrics, pediatric and adult endocrinology, epidemiology, and pharmacology. EVIDENCE: Written materials were exchanged, reviewed, revised, and then made available to all. This formed the basis for discussions at the meeting. Where published data were not available or adequate, discussion was based on expert clinical opinions. CONSENSUS PROCESS: Each set of questions was considered by all and then discussed in plenary sessions with consensus and unresolved issues identified. The consensus statement was prepared in plenary sessions and then edited by the group chairs and shared with all participants. CONCLUSIONS: The diagnosis of SGA should be based on accurate anthropometry at birth including weight, length, and head circumference. We recommend early surveillance in a growth clinic for those without catch-up. Early neurodevelopment evaluation and interventions are warranted in at-risk children. Endocrine and metabolic disturbances in the SGA child are recognized but infrequent. For the 10% who lack catch-up, GH treatment can increase linear growth. Early intervention with GH for those with severe growth retardation (height sd score, <-2.5; age, 2-4 yr) should be considered at a dose of 35-70 microg/kg x d. Long-term surveillance of treated patients is essential. The associations at a population level between low birth weight, including SGA, and coronary heart disease and stroke in later life are recognized, but there is inadequate evidence to recommend routine health surveillance of all adults born SGA outside of normal clinical practice.
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| 7. |
- Filipsson, Helena, 1966, et al.
(författare)
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Exploring the use of recombinant human TSH in the diagnosis of central hypothyroidism.
- 2008
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X. ; 159:2, s. 153-60
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The diagnosis of central hypothyroidism (CH) is often difficult to establish as serum TSH levels may be low, normal, or slightly increased. OBJECTIVE: To explore the use of recombinant human TSH (rhTSH) in the diagnosis of CH. DESIGN: Randomized single-blind clinical trial. SETTING: Outpatient clinic of a tertiary care referral center. INTERVENTION: A single intramuscular injection of 0.1 and 0.9 mg rhTSH in random order with 1-week interval. PARTICIPANTS: Eighteen adult patients with pituitary insufficiency and six healthy age-, sex-, and body mass index-matched controls. Six patients had untreated CH (newCH), six had treated CH (CH), and six patients were TSH sufficient (nonCH). Five weeks before TSH stimulation, levothyroxine was replaced with tri-iodothyronine (T(3)) for 4 weeks. One week before stimulation, treatment was withdrawn. MAIN OUTCOME MEASURES: Thyroid hormones and thyroglobulin (Tg) before and 2, 3(1/2), 7, 24, 48, and 72 h after each injection. RESULTS: In the newCH group, basal free thyroxine (FT(4)) levels were lower than in controls (P<0.05). After 0.9 mg rhTSH, the increases in FT(4) and reverse T(3) (rT(3)) were less marked in the newCH group than in controls (FT(4)+/-s.e.m. 9.2+/-0.5 to 19.7+/-1.2 vs 11.3+/-0.5 to 27.8.2+/-2.4 pmol/l, P<0.05). The CH group exhibited reduced basal and stimulated FT(4) compared with the TSH-sufficient groups. Tg increased similarly among all study groups after rhTSH injection. CONCLUSION: In this pilot study, patients with untreated CH had lower response to 0.9 mg rhTSH in FT(4) and rT(3) than controls. An rhTSH test may be useful in the diagnosis of CH, but further studies are required.
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| 8. |
- Filipsson, Helena, 1966, et al.
(författare)
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GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies.
- 2009
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X. ; 161 Suppl 1
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Tidskriftsartikel (refereegranskat)abstract
- Severe GH deficiency (GHD) in adults has been described as a clinical entity. However, some of the features associated with GHD could be due to unphysiological and inadequate replacement of other pituitary hormone deficiencies. This may be true for glucocorticoid replacement that lacks a biomarker making dose titration and monitoring difficult. Moreover, oral estrogen replacement therapy decreases IGF1 levels compared with the transdermal route, which attenuates the responsiveness to GH replacement therapy in women. In addition, in untreated female hypogonadism, oral estrogen may augment the features associated with GHD in adult women. Important interactions between the hormones used for replacing pituitary hormone deficiency occur. Introducing GH replacement may unmask both an incipient adrenal insufficiency and central hypothyroidism. Therefore, awareness and proper monitoring of these hormonal interactions are important in order to reach an optimal replacement therapy. This review will focus on the complex hormonal interactions between GH and other pituitary hormones in GHD and in GH replacement.
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| 9. |
- Filipsson, Helena, 1966, et al.
(författare)
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The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:10, s. 3954-61
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hypopituitary patients with untreated GH deficiency and patients on inappropriately high doses of glucocorticoid (GC) share certain clinical features. OBJECTIVE: The aim of the study was to examine the influence of GC substitution on clinical characteristics in hypopituitary patients before and after GH replacement therapy. METHOD: A total of 2424 hypopituitary patients within the KIMS (Pfizer International Metabolic Database) were grouped according to ACTH status. Comparisons were performed between subjects on hydrocortisone (HC) (n = 1186), cortisone acetate (CA) (n = 487), and prednisolone/dexamethasone (n = 52), and ACTH-sufficient patients (AS) (n = 717) before and after 1 yr of GH treatment in terms of body mass index, waist and hip circumference, blood pressure, glucose, glycosylated hemoglobin (HbA1c), serum lipids, IGF-I, and comorbidity. Hydrocortisone equivalent (HCeq) doses were calculated, and measurements were adjusted for sex and age. RESULTS: At baseline, the HC group had increased total cholesterol, triglycerides, waist circumference, and HbA1c, and the prednisolone/dexamethasone group had increased waist/hip ratio as compared with AS. After HCeq dose adjustment, the HC group retained higher HbA1c than the CA group. GC-treated patients showed a dose-related increase in serum IGF-I, body mass index, triglycerides, low-density lipoprotein cholesterol and total cholesterol levels. Subjects with HCeq doses less than 20 mg/d (n = 328) at baseline did not differ from AS in metabolic endpoints. The 1-yr metabolic response to GH was similar in all GC groups and dose categories. All new cases of diabetes (n = 12), stroke (n = 8), and myocardial infarction (n = 3) during GH treatment occurred in GC-treated subjects. CONCLUSION: HCeq doses of at least 20 mg/d in adults with hypopituitarism are associated with an unfavorable metabolic profile. CA replacement may have metabolic advantages compared with other GCs.
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| 10. |
- Franco Ramos, Celina, 1956, et al.
(författare)
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Baseline characteristics and effects of growth hormone therapy over two years in younger and elderly adults with adult onset GH deficiency.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:11, s. 4408-14
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The effects of GH replacement in elderly GH-deficient (GHD) adults are not well known. OBJECTIVE/DESIGN/PATIENTS: In this prospective, single-center, open-label study, baseline characteristics and the effects of 2-yr GH replacement were determined in 24 GHD adults above 65 yr of age and in 24 younger GHD patients (mean age, 37 yr; range, 27-46 yr). All patients had adult onset disease, and both groups were comparable in terms of the number of pituitary hormonal deficiencies, gender, body mass index, and waist/hip ratio. Duration of hypopituitarism was, however, longer in the elderly patients. RESULTS: The mean maintenance dose of GH was 0.31 (sem, 0.03) mg/d in the elderly GHD patients and 0.44 (0.04) mg/d in the younger patients. The less marked response in IGF-I sd score, total body fat, and extracellular water in the elderly patients lost significance when the dose of GH was accounted for in the statistical analyses. Despite the lower dose in the elderly GHD group, these patients had a more marked reduction in waist/hip ratio and serum low-density lipoprotein-cholesterol level, and these differences remained also after correction for duration of hypopituitarism. There was no difference at baseline or in responsiveness in lean mass, bone mineral density, and glucose homeostasis. CONCLUSIONS: This study identifies elderly GHD adults as a GH-sensitive group in whom a low dose of GH can improve body composition and serum lipid profile without any significant impairment of glucose metabolism. GH replacement should therefore be considered in elderly GHD adults.
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