Growth hormone receptor and insulin-like growth factor-I immunoreactivity in osteoclast-like cells during tooth eruption in the toothless (Osteopetrotic) rat following treatment with colony-stimulating factor-1

In the toothless (tl/tl) osteopetrotic rat, teeth form but fail to erupt. Treatment of tl/tl rats with colony-stimulating factor-1 (CSF-1) activates bone resorption by osteoclasts, permits tooth eruption, and up-regulates the immunoreactivity of bone marrow mononuclear cells to growth hormone receptor (GHr) and insulin-like growth factor (IGF)-I. This study examined the distribution of tartrate-resistant acid phosphatase (TRAP) and immunoreactivity for GHr and IGF-I in osteoclast-like cells located on the alveolar bone margin, adjacent to the lower first molar crown, in 14-day-old normal and tl/tl rats, following treatment with CSF-1. Osteoclast-like cells demonstrated a positive reaction for TRAP, GHr, and IGF-I in all groups. However, in tl/tl tissue, osteoclast-like cells were generally negative for GHr. There was no significant difference in the total number of TRAP, GHr, and IGF-I-positive osteoclast-like cells on the adjacent bone margin in normal, normal treated with CSF-1, and tl/tl rats. CSF-1 treatment of the tl/tl rat significantly increased the total number of osteoclast-like cells, which were positive for TRAP (p < 0.001), GHr (p < 0.05) and IGF-I (P < 0.01)

Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency

Adults with childhood onset GH deficiency (GHD) have reduced bone mass, increased fat mass, and disorders of lipid metabolism. The aim of the present study was to evaluate bone mineral density (BMD), bone metabolism, body composition, and lipid metabolism in GHD children before and during 2-3 yr of GH treatment (GHRx). Forty children with GHD, mean age 7.9 yr, participated in the study of bone metabolism and body composition; and an additional group of 17 GHD children, in the study of lipid metabolism. Lumbar spine BMD, total body BMD, and body composition were measured with dual-energy x-ray absorptiometry. Volumetric BMD (bone mineral apparent density, BMAD) was calculated to correct for bone size. BMD, BMAD, lean tissue mass, bone mineral content, fat mass, and percentage body fat were expressed as SD scores (SDS), in comparison with normative data of the same population. Lumbar spine BMD and BMAD and total body BMD were all decreased at baseline. All BMD variables increased significantly during GHRx, lumbar spine BMD SDS, already after 6 months of treatment. Lean tissue mass SDS increased continuously. Bone mineral content SDS started to increase after 6 months GHRx. Fat mass SDS decreased during the first 6 months of GHRx and remained stable thereafter. Biochemical parameters of bone formation and bone resorption did not differ from normal at baseline and increased during the first 6 months of GHRx. Serum 1,25 dihydroxyvitamin D increased continuously during GHRx, whereas PTH and serum calcium remained stable. Lipid profile was normal at baseline: Atherogenic index had decreased and apolipoprotein A1(Apo-A1) had increased after 3 yr of treatment. In conclusion, children with GHD have decreased bone mass. BMD, together with height and lean tissue mass, increased during GHRx. GHRx had a beneficial effect on lipid metabolism

Bone health and cardiovascular risk in hypopituitary patients on complete hormone replacement, including GH

Growth hormone deficiency (GHD) is associated with decreased bone mineral density (BMD). Low BMD is correlated to increased fracture risk. There are no studies on fracture risk in GHD patients on GH therapy and no studies on BMD in adults with childhood onset (CO) craniopharyngioma (CP) on GH therapy. We have shown a doubled fracture incidence in CO GHD women and decreased incidence of fractures in adult onset (AO) GHD men. We have also shown decreased BMD in adult women with CO CP on GH therapy, in comparison to matched controls, but not in CO CP men. The cause is not known but insufficient sex steroid and GH replacements, particularly during adolescence, in CO GHD and CP women, and an adequate substitution rate of testosterone and GH in AO GHD and CO CP men are possible explanations. GHD is also associated with increased cardiovascular mortality and morbidity. The impact of long-term GH replacement on cerebral- and cardiovascular diseases and diabetes mellitus (DM) in hypopituitary patients and the prevalence of cardiovascular morbidity and risk factors in adults with childhood onset (CO) craniopharyngioma (CP) are unknown. We have shown that the life-long incidence of non-fatal stroke was tripled in GHD women and doubled in men, but a decline was seen among both genders during the periods where most patients had GH replacement. Life-long incidence of non-fatal cardiac events was similar in the patient and control cohorts, but declined in GHD men during the periods where most patients had GH replacement. GHD women had higher prevalence of type 2 DM and lipid-lowering medication, whereas GHD men had higher prevalence of antihypertensive medication. This cardio-protective medication, together with the GH therapy may have resulted in the decline in non-fatal stroke risk, particularly noted in GHD women, and in significantly lower non-fatal cardiac risk that was seen in GHD men. We have also shown that patients with a CO CP, on GH therapy, had increased cardiovascular morbidity and particularly women were at risk. Of CP women 60% had increased risk for cardiovascular disease. Insulin tolerance test (ITT) is the recommended test for diagnosing GHD. We have shown that GHD patients during an ITT had very low nadir blood glucose levels and few symptoms of hypoglycemia and in 31% unawareness was seen. If the ITT is still going to be recommended, we ask for more uniform recommendations

Untersuchungen zur Wachstumshormonsubstitution bei Patienten mit Wachstumshormonmangel im Erwachsenenalter

Ein Wachstumshormonmangel im Erwachsenenalter führt sowohl im Stoffwechsel als auch in der Psyche zu negativen Veränderungen, die Genese des GH-Mangels spielt keine Rolle. Die vorliegende Arbeit untersuchte, ob es bei Patienten mit einem GH-Mangel im Erwachsenenalter durch die Substitution mit rekombinantem humanen Wachstumshormon zu Beeinflussungen der in der vorliegenden Studie untersuchten Parameter kommt. Diese Patienten wurden zum Teil (80%) als Kind mit WH behandelt und in einem Zeitraum von 12 Monaten bis zu 18 Jahren nach Abbruch der Therapie erneut diagnostisch getestet (Insulin Hypoglykämie Test, L-Arginin-Test, Pyridostigmin Plus Releasing Hormone[GHRH]-Test) und resubstituiert. Um der Frage nachzugehen, welche Auswirkungen GH auf diese Patienten hat, wurden 10 Patienten in der endokrinologischen Ambulanz in Frankfurt/ Main über einen Zeitraum von 2-3 Jahren unter ansteigender GH-Substitution beobachtet. Diese Patienten waren zwischen 20-40 Jahre alt und wurden zum Teil zuvor in der Pädiatrie der Johann Wolfgang Goethe-Universität Frankfurt/Main betreut. Es wurden Laborparameter des Fettstoffwechsels (Triglyceride, Gesamtcholesterin, LDL-Cholesterin, HDL-Cholesterin), des Kohlenhydratstoffwechsels (HbA1c) und des Knochenstoffwechsels (Osteocalcin, C1CP, BAP) vor und alle 6 Monate nach Substitution von WH untersucht. Es zeigte sich eine positive Beeinflussung sowohl des Fett- (s. 3.2.10.) als auch des Knochenstoffwechsels (s. 3.2.7.). Die positiven Auswirkungen auf den Fettstoffwechsel im Sinne einer Vorbeugung kardiovaskulärer Erkrankungen wurden durch eine Senkung des Gesamtcholesterins und LDL-Cholesterin-Wertes und Anhebung des HDL-Cholesterin-Wertes erreicht. Durch eine Steigerung des Osteocalcins, des C1CP-Wertes und des BAP-Wertes mit einer Zunahme der Knochendichte im Sinne einer Prophylaxe osteoporotischer Erkrankungen über eine GH-Substitution, erklärt sich der günstige Einfluss auf den Knochenstoffwechsel. Der HbA1c-Wert (s. 3.2.6.) wurde zwar gesenkt, eine Aussage über die klinische Relevanz kann im Rahmen der vorliegen Studie nicht gemacht werden. Weitere Untersuchungen in größeren Studien sind hierfür notwendig. Zu Veränderungen im Bereich der Gerinnung und des Blutbildes kam es nicht (s. 3.2.3. u. 3.2.4.). Ein anderer Aspekt dieser Studie war die Prüfung von Veränderungen der Körperzusammensetzung durch GH. Diese Messungen wurden anhand der BIA (Bioelektrische Impedanzanalyse, s. 2.2.5.) durchgeführt. Es bestätigten sich frühere Ergebnisse, die eine Beeinflussung der Körperzusammensetzung unter GH-Substitution beschrieben (s. 3.2.2.). Die psychische Komponente wurde durch Fragebögen zur Beurteilung der Lebensqualität anhand soziologischer, psychischer und auch physischer Komponenten geprüft. Eine Tendenz zur positiven Beeinflussung der körperlichen und geistigen Leistungsfähigkeit sowie der Konzentrationsleistungen lässt sich erkennen (s. 3.2.8.), obwohl die Ergebnisse stark variieren. Zu diskutieren wäre, inwieweit es sich um primäre oder sekundäre Effekte durch positive somatische Einflüsse der GH-Substitution handelt. Das EKG wurde in dieser Studie als Beurteilungsparameter für eventuelle kardiomorphologische Veränderungen während der GH-Substitution herangezogen; im Gegensatz zu anderen Studien konnten keine Einflüsse beobachtet werden (s. 3.2.9.). In ihrer Gesamtheit zeigen die Ergebnisse, dass eine GH-Substitution im Erwachsenenalter bei GH-Mangel einen positiven Effekt auf die Körperzusammensetzung, den Kohlenhydratstoffwechsel, den Knochenstoffwechsel, die Lebensqualität und den Fettstoffwechsel hat. Eine teilweise große Divergenz in den Resultaten der Prüfwerte erklärt sich durch zufällig auftretende Faktoren bzw. interindividuelle Unterschiede in einer kleinen Prüfgruppe. Weitere Studien in größerem Rahmen wären zur Klärung der aufgetretenen Divergenzen notwendig

Bone mineral mass and bone turnover parameters in osteoporosis

In the past decades osteoporosis has been recognized as an important public health problem. Several causes for this problem can be pointed out. The most probable cause for the development of osteoporosis is the loss of ovarian function in women and the increasing age of people, thereby increasing the incidence of osteoporosis. Other causes or risk factors for the development of osteoporosis are immobilization and dietary deficiencies. Finally, the outcome of osteoporosis is an increased risk for the development of fractures (chapter 1.3). The terminology associated with osteoporosis was developed in the nineteenth century by German pathologists to distinguish diseases of bone. Pommer stated in 1926 that in osteoporosis the formation of bone by osteoblasts was not able to replace the bone resorbed by osteoclasts. Pommer performed extensive histomorphometric analysis of bone, thereby distinguishing various forms of osteoporosis (senile, immobility), osteomalacia and osteitis fibrosa cystica

Avaliaçao da composiçao corporal e de parâmetros laboratoriais em adultos com deficiencia de hormônio de crescimento antes e após 12 meses de tratamento com dose baixa e fixa de hormônio de crescimento.

Orientador : Cesar Luiz BoguszewskiCo-orientadora : Rosana Bento RadominskiDissertaçao (mestrado) - Universidade Federal do Paraná, Setor de Ciencias da SaúdeResumo O objetivo do presente estudo foi avaliar os efeitos de 12 meses de tratamento com dose baixa e fixa (0,56 UI/dia ou 0,186 mg/dia) de GH em adultos com deficiência de GH (DGHA), sobre composição corporal, força muscular e parâmetros laboratoriais. Avaliação clínica, antropométrica e laboratorial foram realizadas em 18 pacientes (11 mulheres e 7 homens, idade 40,6± 11,2 anos) antes e após 12 meses de tratamento com GH. Ultrasonografia (US) foi empregada para aferição de panículo adiposo subcutâneo abdominal, dinamometria para aferição de força muscular e bioimpedância (BLA) e dual-energy X-ray absorptiometry (DXA) para gordura corporal e massa magra. DXA foi empregada para estimar massa óssea (DMO). No tempo basal, 83% dos pacientes apresentavam aumento de circunferência abdominal (CA) de acordo com a classificação de risco cardiovascular. O grupo apresentava aumento de gordura corporal e osteopenia e/ou osteoporose foi encontrada em 58% dos pacientes em pelo menos um dos sítios avaliados. Após o tratamento, houve redução significativa da CA (p=0,03). A gordura corporal total reduziu 1,9% (p=0,004), 2,8% em membros superiores (p=0,002) e 2% em membros inferiores (p=0,001). Em tronco, não houve redução significativa, entretanto 12/18 pacientes tiveram redução nos seus valores. A massa magra aumentou 1,3 kg em corpo total (p=0,02) e 0,9 kg em tronco (p=0,01). Ocorreu aumento na DMO de coluna lombar (p=0,009), fémur total (p=0,001) e colo do fémur (p=0,05), principalmente no grupo feminino. Houve correlação direta entre a aferição de gordura corporal pela DXA com pregas cutâneas, BIA e US. A força muscular não se alterou significativamente. No basal, 65% dos pacientes apresentavam IGF-1 abaixo da faixa normal para a idade, e destes, 54,5% normalizaram os níveis após o tratamento. Nenhum paciente tinha diabete e as glicemias mantiveram-se inalteradas durante o tratamento. O índice de HOMA-1R era >2,5 em 11 % dos casos, observando-se piora significativa com o tratamento (p=0,02). Os valores de LDL eram >130 mg/dL em 83% dos pacientes, observando-se redução significativa após GH (p=0,05). Colesterol >200 mg/dL, triglicerídeos >150 mg/dL e HDL <40 mg/dL foram observados em 67%, 16,6% e 16,6% dos pacientes, respectivamente, sem alteração significativa destes parâmetros com o tratamento. Hormônios tireoideanos não se alteraram durante o seguimento. Concluímos que 12 meses de tratamento com dose de 0,56 UI GH/dia em pacientes com DGHA resultou em redução da gordura corporal total, aumento da massa íagra, aumento da DMO em coluna lombar, fémur total e colo do fémur, particularmente m mulheres, redução do LDL e piora do índice HOMA-IR. Há grande variabilidade idividual na resposta ao tratamento, que merece ser clinicamente considerada.Abstract: The aim of the present study was to evaluate the effects of a 12-month treatment with a low and fixed dose of GH (0,56 IU/day or 0,186 mg/day) on body composition, muscular strength, and metabolic parameters of adults with GH deficiency (GHDA). Anthropometry, clinical and laboratorial evaluation were performed in 18 patients (11 women and 7 men, age 40,6±11,2 yr) before and 12 months of GH. Ultrasonography (US) was used for estimation of abdominal subcutaneous (SC) fat. Dinamometry was employed for evaluating muscular strength. Bioimpedance (BLA) and dual-energy X-ray absorptiometry (DXA) were used for assessment of body fat mass and lean mass, while DXA was also used for estimation of bone mineral density (BMD). At baseline, 83% of patients had increased abdominal circumference (AC), according to epidemiologic classification of cardiovascular risk. This parameter showed a significant decrease after GH (p=0,03). GHDA patients had increased amount of body fat, and osteopenia/osteoporosis was detected in 58% of patients in at least one of bone sites evaluated. After treatment, total body fat decreased by 1,9% (p=0,004), SC fat in arms by 2,8% (p=0,002) and SC fat in legs by 2% (p=0,001). There was no significant reduction of truncal fat, but 12 out of 18 patients showed a decrease in its values. Lean body mass increased by 1,3 kg (p=0,02), with an increment of 0,9 kg on trunk (p=0,01). BMD increased significantly in lumbar spine (p = 0,009), total femur (p = 0,001) and femural neck (p = 0,046), mainly in women. There were positive correlations on fat mass estimation by DXA, skin folds, US and BIA. Muscular strength did not change significantly after GH treatment. At baseline, IGF-I levels adjusted for age and sex were low in 65% of patients, and 54,5% of them showed a normal IGF-1 level after low GH dose. None of patients had diabetes and glucose levels did not change in the follow-up. HOMA-IR index was >2,5 in 11% of cases at baseline, with a worsening after treatment (p=0,02). LDL > 130 mg/dL was found in 83% of patients, with a significant reduction with GH treatment (p=0,05). Cholesterol >200 mg/dL, triglycerides >150 mg/dL e HDL <40 mg/dL were observed in 67%, 16,6% e 16,6% of patients, respectively, with no significant changes after GH therapy. Thyroid function tests were unchanged during the follow-up. We conclude that 12-month treatment with 0,56 UI of GH/dav in GHDA patients resulted in reduction of total body fat with an increase of lean body mass, increment of BMD in lumbar spine, total femur and femoral neck, mainly in women, reduction of LDL levels and worsening of HOMA-IR index. There was a wide individual variability response to the GH therapeutic regime employed in this study, which needs to be considered on clinical practice