A case report of growth attenuation during methionyl human growth hormone treatment

A 10-year-old child with idiopathic growth hormone deficiency was treated with recombinant methionyl human growth hormone (m-hGH, Somatonorm) at a dose of 14 IU/week. Height increased from 122.3 to 126.5 cm during the first 9 months of treatment (5.6 cm/y), but only from 126.5 to 126.6 cm during the next 3 month of treatment (0.4 cm/y). Anti-hGH antibody was detected at 2 months of treatment, reached its maximum at the end of 9 months with a titer of 10(6) and a binding capacity of 2.0 mg/L. After switching from m-hGH to pituitary extracted hGH (p-hGH) treatment, his height increased again from 126.6 to 132.2 cm during the next 12 months of p-hGH treatment (5.6 cm/y). The cause of growth attenuation during m-hGH treatment was concluded to be the high titer of anti-hGH antibody. This is the first case in Japan and one of only three cases in which growth attenuation occurred during m-hGH treatment.     

Deaths in children with Prader-Willi syndrome. A contribution to the debate about the safety of growth hormone treatment in children with PWS

Irrespective of GH treatment, children with Prader-Willi syndrome (PWS) suffer more frequently and more seriously from respiratory problems than healthy children. The pathogenesis of such respiratory problems in PWS seems to be multifactorial in origin, but mainly related to insufficiency of respiratory muscles and pharyngeal narrowness. Deaths of children with PWS are reported among GH treated as well as untreated children. Our data show that also disturbed body composition plays an important role in fatal outcomes, possibly enhancing the ventilation disorder. For several years, in our recommendations we have pointed out the secondary risks of increasing obesity. In addition, it is recommended for all children with PWS, in particular before institution of GH therapy, to have polysomnography and an otorhinolaryngologic examination performed, and tonsillectomy in the case of enlarged tonsils. Furthermore, upper airway infections should be treated aggressively.     

Growth hormone secretion during sleep. II. Interrelationships between growth hormone secretion, insulin-like growth factor I and sex steroids

The serum levels of insulin-like growth factor I (IGF I), dehydroepiandrosterone sulfate (DHAS), testosterone (T) and estradiol (E2) have been measured in 78 prepubertal and 57 early pubertal patients referred for short stature, at the same time when their secretion of GH was evaluated both during nocturnal sleep and by two conventional stimulation tests. According to the results of GH measurements they were considered as having a normal secretion of GH (group I), a complete GH deficiency (group II), a partial GH deficiency (group III), low responses to stimuli with normal secretion during sleep (group IV) or a nocturnal neurosecretory dysfunction (group V). Though widely scattered, the IGF I levels showed the following characteristics: a significant increase at puberty from 0.77 to 1.29 U/ml (p less than 0.001) in the so-called endocrinologically normal patients of group I, not in the other groups; in the prepubertal patients of group I, a correlation of IGF I with chronological age (r = 0.47, p less than 0.005) and bone age (r = 0.52, p less than 0.002); significantly reduced IGF I levels in patients of group II having complete GH deficiency (p less than 0.001); no significant differences between prepubertal patients with partial or atypical GH deficiency from groups III, IV, V and prepubertal patients from group I; lower pubertal levels in groups III, IV, V than in pubertal patients from group I (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of growth hormone deficiency and growth hormone replacement therapy on bone. A meeting report

Recently, several reports have described the effects of growth hormone (GH) deficiency (GHD) on bone and the associated potential benefits of GH therapy. Not all of these reports have, however, been consistent and the results are debated. Some of the contention surrounding this issue reflects disagreement about which bone parameters are the best indicators of bone strength and fracture risk. In November 1999, a meeting was held in Taormina, Italy, to discuss the assessment of bone in patients with GHD and the effects of GH therapy on the skeleton. The participants included endocrinologists, orthopaedists and biophysicists from around the world. During the meeting, the advantages and disadvantages of the various indicators of bone strength were defined. In considering GH therapy, the delegates agreed that it had beneficial effects on bone in adults with GHD, but that further studies were needed in GH-deficient children. Finally, the participants stressed the need for more data to clarify which indicator of bone strength is the most appropriate to use in adults and children with GHD, and to define fully the role of GH therapy in bone metabolism. It was recognized that pharmacoepidemiological surveys, such as KIGS (Pharmacia International Growth Database) and KIMS (Pharmacia International Metabolic Database), are valuable sources of such data, and are, therefore, important in the development of evidence-based medicine.     

Changes in serum thyroid hormone autoantibody concentrations during pregnancy: a case report.

A 29-year-old female patient with Graves' disease who developed thyroid hormone autoantibodies (THAA) under treatment with methimazole is presented. THAA were identified as IgG-kappa. During a first pregnancy that ended by miscarriage in the 3rd month, the titer of anti-thyroxine autoantibodies decreased by about 30%. Relapse of Graves' disease occurred 2 months later and an increase in serum THAA concentration to the initial titer was observed. THAA titer remained unchanged during treatment with methimazole and afterwards during thyroxine supplementation for radioiodine-induced hypothyroidism. During a second pregnancy, a decrease in anti-thyroxine autoantibody titer reached 45% at the time of delivery and an increase by 20% was noted 5 months later. A similar decline in THAA concentration was shown during a third pregnancy. The changes in THAA concentrations observed during pregnancy suggest an immunological influence of pregnancy on the THAA production, as previously demonstrated in other autoimmune diseases, like Hashimoto's thyroiditis.     

Simultaneous sleep study and nasoendoscopic investigation in a patient with obstructive sleep apnoea syndrome refractory to continuous positive airway pressure: a case report

Introduction

There seem to be no published data concerning the clinical impact of populations of hepatitis B virus (HBV) in the hepatic and extrahepatic compartments of HIV-infected people with severe acute hepatitis.

Case presentation

A 26-year-old Caucasian man presenting to our hospital with clinical symptoms suggesting acute hepatitis was found to have an acute hepatitis B profile upon admission. He developed fatal fulminant hepatitis and was found to be heavily immunocompromised due to HIV-1 infection. He had a high plasma HBV and HIV load, and analysis of the partial pre-S1/pre-S2 domain showed the presence of mixed infection with D and F genotypes. Analysis of the point mutations within this region revealed the presence of HBV strains with amino acid substitutions at the immunodominant epitopes involved in B or T cell recognition. A homogeneous population of a pre-core mutant strain harbouring the A1896G and A1899G affecting HBeAg expression was invariably found in the liver tissue, plasma and peripheral blood mononuclear cells despite active HBeAg secretion; it was the dominant strain in the liver only, and was characterised by the presence of two point mutations in the direct repeat 1 domain involved in HBV replication activity. Taken together, these mutations are indicative of a highly replicative virus capable of evading immune responses.

Conclusion

This case report provides clinical evidence of a possible association between the rapid spread of highly replicative escape mutants and the development of fulminant hepatitis in a heavily immunocompromised patient. Virological surveillance of severe acute hepatitis B may be important in establishing an early treatment strategy involving antiviral drugs capable of preventing liver failure, especially in individuals for whom liver transplantation is not accepted as a standard indication.     

Bone markers and bone mineral density during growth hormone treatment in children with growth hormone deficiency

Growth hormone (GH) has a positive impact on muscle mass, growth and bone formation. It is known to interact with the bone-forming unit, with well-documented increases in markers of bone formation and bone resorption within weeks of the start of GH therapy. These changes relate significantly to short-term growth rate, but it is not evident that they predict long-term response to GH therapy. The consequences of GH deficiency (GHD) and GH replacement therapy on bone mineral density (BMD) have been difficult to interpret in children because of the dependency of areal BMD on height and weight. Some studies have tried to overcome this problem by calculating volumetric BMD, but results are conflicting. The attainment of a normal peak bone mass in an individual is considered important for the future prevention of osteoporosis. From the limited data available, it appears difficult to normalize bone mass totally in GH-deficient individuals, despite GH treatment for long periods. Studies to date examining the interaction between GH and bone have included only small numbers of individuals, making it difficult to interpret the study findings. It is hoped that these issues can be clarified in future research by the direct measurement of bone density (using quantitative computer tomography). Mineralization is only one facet of bone strength, however; other important components (e.g. bone structure and geometry) should be addressed in future paediatric studies. Future studies could also address the importance of the degree of GHD in childhood; how GH dose and insulin-like growth factor-I levels achieved during therapy relate to the final outcome; whether or not the continuation of GH therapy after the attainment of final height may further enhance bone mass; whether the timing and dose of other treatments (e.g. sex hormone replacement therapy) are critical to the outcome; and whether GHD in childhood is associated with an increased risk of fracture.     

Human growth hormone release is decreased during sleep in temporal isolation (free-running)

Growth hormone (hGH) secretion was measured during sleep in 10 healthy male subjects isolated from all time cues. HGH concentrations following sleep onset were compared between scheduled sleep episodes (entrainment) and self-selected sleep episodes (free-running). Peak sleep-related hGH values were decreased significantly during free-running. The duration of the first slow wave sleep (SWS) episode and the latency to the first REM sleep episode also decreased significantly during free-running. The latencies from sleep onset to SWS and to peak hGH secretion did not differ between entrainment and free-running. These results suggest that sleep-related hGH secretion begins 'on time' during free-running, but is terminated earlier. Thus, while sleep onset facilitates hGH release, the timing of other stages of sleep such as REM may alter the magnitude of sleep-related hGH secretion.     

Pulsatile secretion pattern of growth hormone during the luteal phase and mid-anoestrus in beagle bitches

The pulsatile secretion pattern of growth hormone was investigated during four stages of the luteal phase and during mid-anoestrus in six cyclic beagle bitches. Plasma samples were obtained via jugular venepuncture at 10 min intervals for 12 h at 19 +/- 2 (mean +/- SEM; luteal phase 1), 38 +/- 2 (luteal phase 2), 57 +/- 2 (luteal phase 3), 78 +/- 2 (luteal phase 4) and 142 +/- 4 days (mid-anoestrus) after ovulation. During all stages, growth hormone was secreted in a pulsatile fashion. The mean basal plasma growth hormone concentration during luteal phase 1 (2.2 +/- 0.3 microgram l(-1)) was significantly higher than that during luteal phase 4 (1.5 +/- 0.1 microgram l(-1)) and mid-anoestrus (1.4 +/- 0.2 microgram l(-1)). The mean area under the curve (AUC) above zero during luteal phase 1 (27.3 +/- 2.7 microgram l(-1) in 12 h) tended to be higher than that during luteal phase 4 (20.8 +/- 1.8 microgram l(-1) in 12 h) and mid-anoestrus (19.2 +/- 2.5 microgram l(-1) in 12 h). In contrast, the mean AUCs above the baseline during luteal phase 1 (1.1 +/- 0.5 microgram l(-1) in 12 h) and luteal phase 2 (1.2 +/- 0.5 microgram l(-1) in 12 h) were significantly lower than that during luteal phase 4 (2.8 +/- 0.5 microgram l(-1) in 12 h). In conclusion, the pulsatile secretion pattern of growth hormone changes during the luteal phase in healthy cyclic bitches: basal growth hormone secretion is higher and less growth hormone is secreted in pulses during stages in which the plasma progesterone concentration is high. It is hypothesized that this change is caused by a partial suppression of pituitary growth hormone release by progesterone-induced growth hormone production in the mammary gland. The progesterone-induced production of growth hormone in the mammary gland may promote the physiological proliferation and differentiation of mammary gland tissue during the luteal phase of the bitch by local autocrine-paracrine effects. In addition, progesterone-induced mammary growth hormone production may exert endocrine effects, such as hyperplastic changes in the uterine epithelium and insulin resistance.     

Comparison of spontaneous growth hormone secretion during daytime and sleep in children with short stature

The authors compared diurnal growth hormone (GH) secretion with GH secretion during sleep in 24 children with delayed growth. In group I (children with normal response to provocative tests), the level of daytime secretion was lower than that of nocturnal secretion. In 3 of 9 cases, daytime secretion was abnormal, whereas nocturnal secretion was normal. In 2 cases, both diurnal and nocturnal secretion were abnormal, but response to provocative stimuli was normal. In group II (children with a false partial GH deficiency, i.e. with inadequate response to provocative tests, GH peak less than 11 ng/ml and normal nocturnal secretion), the results were comparable with those of group I, with extremely low diurnal secretion in 6 of 9 cases. In group III (children presenting true partial GH deficiency, i.e. GH less than 11 ng/ml in response to provocative tests together with abnormal nocturnal secretion), both diurnal and nocturnal GH secretion were insufficient, with nonexistent diurnal secretion in 5 of 6 cases. Diurnal secretion does not seem to be a reliable indicator of 24-hour spontaneous secretion.     

Cell movements during the initial phase of gastrulation in the sea urchin embryo.

The morphogenetic processes responsible for the initial phase of gastrulation in sea urchin embryos are not known. Here we report observations of the size and position of clones of cells derived from horseradish peroxidase (HRP)-injected mesomeres and macromeres. The displacement of these clones during the initial phase of gastrulation suggests that involution is a mechanism involved in primary invagination. Experiments with embryos marked with vital dyes indicate that movements occur only during a brief phase coincident with the invagination of the vegetal plate. Counts of cells derived from HRP-injected mesomeres and macromeres suggest it unlikely that localized growth in the vegetal plate is involved in gastrulation. An analysis of changes in cell shape during the initial phase of gastrulation indicates that there is a stage-dependent shift from cells being columnar to having their apices skewed toward the vegetal plate and an increase in the proportion of cells having basal processes during gastrulation. When embryos are grown in the presence of monoclonal antibodies to the apical lamina or monovalent fragments of these antibodies, the initial phase of gastrulation is delayed and they form partial exogastrulae. Analysis of embryos marked with HRP indicate that the antibody treatments interfere with the cellular movements observed in untreated embryos. We conclude that directed movements of cells within the blastoderm, probably employing tractoring on components of the hyaline layer, cause the buckling of the vegetal plate and displacement of presumptive endoderm cells seen during the initial phase of gastrulation.     

Growth hormone in blood sampled continuously during pentobarbitone-induced sleep in children.

Growth hormone has been estimated in blood sampled continuously in periods each lasting 30 min during the first 3-4 h of pentobarbitone-induced sleep in 69 children. With only two half-hour samples, almost the same information was obtained as with the estimation of growth hormone in all samples. In this way 95% of normally growing children showed growth hormone levels of 5 muU/ml of more. Children with growth retardation of unknown cause and overweight children showed on the average lower growth hormone levels, not rarely even below 5 muU/ml. Pituitary dwarfs all had maximum growth hormone levels of 3 muU/ml or less. Growth hormone levels during sleep may be normal in children who show negative results on provocation, while subnormal growth hormone levels during sleep have been encountered in some children with retarded growth who had a normal response upon provocation.     

Consequences of brand switches during the course of pediatric growth hormone treatment

ObjectiveTo explore the effects of insurance-mandated brand switches during the course of pediatric recombinant human growth hormone (rhGH) treatment on clinical practice.MethodsWe e-mailed a 9-question, anonymous, Internet-based survey to active members of the Pediatric Endocrine Society. The survey consisted of multiple-choice and yes/no answers. Free-text comments were solicited for further explanation of responses. Quantitative answers were tabulated. Each investigator independently coded the free-text responses; themes based on codes identified by all 3 investigators in a minimum of 5 different respondents’ comments were compiled and organized.ResultsOf the 812 active members of the Pediatric Endocrine Society who were e-mailed the survey, 231 responded. Two hundred eight respondents reported switching a patient’s regimen from one rhGH product to another, and of these, 50% experienced repeated switches.Switches occurred for each commercially available rhGH brand. Frequent concerns noted by respondents involved dosing errors and treatment lapses from having to learn a new device and impaired adherence related to patient-family frustration and anxiety. Anti-GH antibodies, measured by only 3 endocrinologists when switching a patient’s regimen from one brand to another, were negative before and after the product switch. When a patient switched rhGH brands, the most frequently reported time involvement for endocrine office staff was 2 hours for paperwork, 1 hour for device instruction, and 1 hour for “other” (mostly related to telephone reassurance).ConclusionGH brand switches may adversely affect patient care and burden pediatric endocrinology practices. (Endocr Pract. 2012;18:307-316)     

Effects of plasmid growth hormone-releasing hormone treatment during heat stress

A gene therapy treatment with plasmid-based growth hormone-releasing hormone (GHRH) delivered by electroporation (EP) was investigated during heat stress; 32 primiparous cows received 2.5 mg of a GHRH-expressing myogenic plasmid (pSP-HV-GHRH), while 20 were designated as controls. Offspring of treated animals showed a reduction in mortality (47%; p < 0.02), and survival from birth to 260 days was dramatically improved (0% mortality vs. 21% in controls) along with an increase in weight gain (p < 0.05). Milk production was increased compared to controls with an average yield gain of 421 kg/cow (p = 0.028). Prolactin (PRL) levels were also significantly increased compared to controls (p < 0.05). The second pregnancy rate was improved by GHRH treatment (53.3% vs. 30.8%). This study shows that the use of plasmid-mediated therapy delivered by EP can maintain health status during periods of heat stress, important for both animals and potentially humans in hot, challenging climates.