Multiple doses of pegylated long‐acting growth hormone are well tolerated in healthy male volunteers and possess a potential once‐weekly treatment profile

Objectives Recombinant human growth hormone (rhGH) replacement therapy in children and adults currently requires daily subcutaneous injections for several years or lifelong. The current study examined safety, tolerability, pharmacokinetic and pharmacodynamic response parameters after single and multiple doses of a long‐acting rhGH preparation (NNC126‐0083). Design Randomized, double‐blinded, placebo‐controlled, multiple‐dose, dose‐escalating (0·02, 0·04, 0·08 and 0·16 mg protein/kg), sequential dose group trial. Subjects Forty adult Japanese healthy male volunteers (aged 20–45; body mass index: 18·0–27·0 kg/m²). Five groups (n = 8) were randomized to receive multiple doses of NNC126‐0083 (n = 6) or placebo (n = 2). Methods Primary outcome was safety, and tolerability of multiple doses of NNC126‐0083 compared with placebo. Blood samples for the assessment of pharmacokinetics (PK) and pharmacodynamics response [insulin‐like growth factor I (IGF‐I) and IGF binding protein 3 (IGFBP‐3)] were taken after multiple ascending doses. Results NNC126‐0083 was well tolerated and not associated with any local injection‐site reactions or lipoatrophy. Following administration, NNC126‐0083 levels increased rapidly and remained elevated for several days, returning to baseline before each weekly injection. Steady‐state PK was achieved after the third dosing. A more than dose‐proportional exposure was observed at the highest NNC126‐0083 dose (0·16 mg protein/kg). A strong dose‐dependent pharmacodynamic response in circulating concentrations of both IGF‐I and IGFBP‐3 compared with placebo (P < 0·0001) was observed during the administration of all doses. Conclusions Multiple administration of NNC126‐0083 in healthy male volunteers indicates that NNC126‐0083 has the potential for an efficacious, well‐tolerated, once‐weekly rhGH compound in the treatment of GH deficiency.     

Gender and the use of hormonal contraception in women are not associated with cerebral cortical 5-HT 2A receptor binding

Gender influences brain function including serotonergic neurotransmission, which may play a role in the well-known gender variations in vulnerability to mood and anxiety disorders. Even though hormonal replacement therapy in menopause is associated with globally increased cerebral 5-HT_2A receptor binding it is not clear if gender or use of hormonal contraception exhibits associations with 5-HT_2A receptor binding. We found no significant effect of gender on cortical 5-HT_2A receptor binding (P=0.15, n=132). When adjusting for the personality trait neuroticism, known to be positively correlated to frontolimbic 5-HT_2A receptor binding and to be more pronounced in women, again, the effect of gender was not significant (P=0.42, n=127). Also, the use of hormonal contraception (n=14) within the group of pre-menopausal women (total n=29) was not associated with cortical 5-HT_2A receptor binding (P=0.31). In conclusion, neither gender, nor the use of hormonal contraception in premenopausal women was associated with cortical 5-HT_2A receptor binding.     

Endocrine systems in juvenile anadromous and landlocked Atlantic salmon (Salmo salar): seasonal development and seawater acclimation

The present study compares developmental changes in plasma levels of growth hormone (GH), insulin-like growth factor I (IGF-I) and cortisol, and mRNA levels of their receptors and the prolactin receptor (PRLR) in the gill of anadromous and landlocked Atlantic salmon during the spring parr-smolt transformation (smoltification) period and following four days and one month seawater (SW) acclimation. Plasma GH and gill GH receptor (GHR) mRNA levels increased continuously during the spring smoltification period in the anadromous, but not in landlocked salmon. There were no differences in plasma IGF-I levels between strains, or any increase during smoltification. Gill IGF-I and IGF-I receptor (IGF-IR) mRNA levels increased in anadromous salmon during smoltification, with no changes observed in landlocked fish. Gill PRLR mRNA levels remained stable in both strains during spring. Plasma cortisol levels in anadromous salmon increased 5-fold in May and June, but not in landlocked salmon. Gill glucocorticoid receptor (GR) mRNA levels were elevated in both strains at the time of peak smoltification in anadromous salmon, while mineralocorticoid receptor (MR) mRNA levels remained stable. Only anadromous salmon showed an increase of gill 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) mRNA levels in May. GH and gill GHR mRNA levels increased in both strains following four days of SW exposure in mid-May, whereas only the anadromous salmon displayed elevated plasma GH and GHR mRNA after one month in SW. Plasma IGF-I increased after four days in SW in both strains, decreasing in both strains after one month in SW. Gill IGF-I mRNA levels were only increased in landlocked salmon after 4days in SW. Gill IGF-IR mRNA levels in SW did not differ from FW levels in either strain. Gill PRLR mRNA did not change after four days of SW exposure, and decreased in both strains after one month in SW. Plasma cortisol levels did not change following SW exposure in either strain. Gill GR, 11beta-HSD2 and MR mRNA levels increased after four days in SW in both strains, whereas only the anadromous strain maintained elevated gill GR and 11beta-HSD2 mRNA levels after one month in SW. The results indicate that hormones and receptors of the GH and cortisol axes are present at significantly lower levels during spring development and SW acclimation in landlocked relative to anadromous salmon. These findings suggest that attenuation of GH and cortisol axes may, at least partially, result in reduced preparatory upregulation of key gill ion-secretory proteins, possibly a result of reduced selection pressure for marine adaptations in landlocked salmon.     

Hypercholesterolemia in pregnant mice does not affect atherosclerosis in adult offspring

In humans, maternal hypercholesterolemia during pregnancy promotes microscopical fatty streaks in the children. The mechanism is unknown. Fatty streaks are clinically silent, and many of them regress and never develop into advanced atherosclerosis. The aim of this study was to investigate whether hypercholesterolemia in pregnant mice induced more advanced atherosclerosis in their adult progeny. Hypercholesterolemic (HC) apolipoprotein E knockout (apoE(-/-)) female mice were mated with normocholesterolemic (NC) wild-type (apoE(+/+)) males and vice versa. All parents were almost identical genetically except for apoE. Therefore, all progeny became genetically identical and heterozygous apoE(+/-). They were born of either HC (i.e. apoE(-/-)) or NC (i.e. apoE(+/+)) mothers. The progeny were killed 6 months after birth and the amount of atherosclerosis in the aortic root was assessed. Females developed more atherosclerosis than males (P<0.001) but, regardless of sex, maternal hypercholesterolemia during pregnancy had no influence on the amount of atherosclerosis in adult progeny. Males of HC mothers had lower plasma cholesterol levels than males of NC mothers. Thus, in mice, maternal hypercholesterolemia during pregnancy does not promote the development of advanced atherosclerosis in their adult progeny.     

The role of cortisol and growth hormone in seawater adaptation and development of hypoosmoregulatory mechanisms in sea trout parr (Salmo trutta trutta)

The role of growth hormone (GH) and cortisol in the development of hypoosmoregulatory mechanisms in sea trout parr, Salmo trutta trutta, was investigated by injecting freshwater (FW) yearlings every second day with saline, ovine growth hormone (oGH, 2.0 micrograms/g), cortisol (hydrocortisone hemisuccinate, 8.0 micrograms/g), or oGH + cortisol for a maximum of 14 days. Subgroups of the treated fish were transferred to three-fourths seawater (SW) after 7 or 15 days of treatment and the effects on plasma Na+, Cl-, muscle water content, gill Na+/K(+)-ATPase activity, and gill interlamellar chloride cell density were examined. In FW, gill Na+/K(+)-ATPase chloride cell density, and chloride cell apical to basal length increased by all hormone treatments, most significant by oGH + cortisol treatment. Plasma ions and muscle water content were unaffected in FW. Both SW transfers resulted in considerable mortality (50%) in control fish, whereas few cortisol-treated and no GH-treated or GH + cortisol-treated fish died. Plasma Na+ and Cl- levels increased dramatically (greater than 50%) in control fish and muscle water content decreased (8%) on Day 2 after both transfers. All hormone-treated groups regulated plasma ions and muscle water significantly better than controls in SW, indicating the physiological significance of the treatment. Notably, the oGH + cortisol-treated fish showed only insignificant changes in ion-osmotic homeostasis after SW transfer, suggesting a synergistic effect of the two hormones. It is concluded that treatment with the two hormones increases the salinity tolerance of sea trout parr at a developmental stage where FW life is obligatory.     

Glycated haemoglobin predicts progression to diabetes mellitus in Pima Indians with impaired glucose tolerance

Summary Glycated haemoglobin could offer several practical advantages over the OGTT for assessing glucose metabolism. Initial cross-sectional studies (1983–1985) on 381 subjects (mostly Pima Indians) described the relationship between HbA_1c (a specific glycated Hb) and the OGTT. We performed follow-up OGTTs and HbA_1c measurements on 257 of these same subjects 1.6–6.1 years later. Subjects were again grouped according to both the result of the OGTT (normal, IGT or diabetes, by WHO criteria) and HbA_1c result (normal or elevated based on mean ± 1.96 SD of normal). Of 66 subjects with IGT at baseline, 47 (71%) had normal HbA_1c and 19 (29%) had elevated HbA_1c. Twentysix (39%) of these subjects had diabetes at follow-up. Of these subjects with IGT, a significantly greater percentage of subjects with elevated HbA_1c at baseline (68%) showed worsening to diabetes than those with a normal HbA_1c (28%); (chi-square=7.8, df=1, p<0.01). Thus, in subjects with IGT, glycated Hb may be a useful predictor of progression to diabetes.Abbreviations OGTT Oral glucose tolerance test - WHO World Health Organisation - IGT impaired glucose tolerance