Biomarkers of Acromegaly and Growth Hormone Action

: Biological markers (biomarkers) play a key role in drug development, regulatory approval and clinical care of patients and are linked to clinical and surrogate outcomes. : Both acromegaly and Growth Hormone Deficiency (GHD) are pathological conditions related to important comorbidities that, in addition to having stringent diagnostic criteria, require valid markers for the definition of treatment, treatment monitoring and follow-up. GH and insulin-like growth factor-I (IGF-I) are the main biomarkers of GH action in children and adults while, in acromegaly, both GH and IGF-I are established biomarkers of disease activity. : However, although GH and IGF-I are widely validated biomarkers of GHD and acromegaly, their role is not completely exhaustive or suitable for clinical classification and follow-up. Therefore, new biological markers for acromegaly and GH replacement therapy are strongly needed. : The aim of this paper is to review and summarize the current state in the field pointing out new potential biomarkers for acromegaly and GH use/abuse.

MON-283 IGF-1 Levels During Normal Pregnancy

Pregnancy is associated with a physiological GH excess, where maternal pituitary GH is suppressed by effect of placental GH on the hepatic receptor, increasing IGF-1 serum levels1. However, it is also described that estrogens and progesterone are responsible for reduction in IGF-1 by direct hepatic action through the inhibition of the JAK-STAT pathway that results in GH resistance, being more clear at the beginning of pregnancy.2 Acromegaly is a rare disorder in which GH axis is deregulated and IGF-1 is the most reliable biochemical marker for diagnosis and monitoring. It is know that secondary hypogonadism associated with these pathology decreases fertility rates. Nonetheless, improvement of acromegaly treatment and greater access to assisted reproductive technology increase pregnancy rates in this population. The follow-up of pregnant acromegalic women acquires relevance for the comorbidities of this association and depends on the adequate interpretation of the IGF-1 values. Then, due to changes in concentration and action of IGF-1 during pregnancy3, it is important that each laboratory establish their specific reference values. For that reason we analyzed serum samples from 80 healthy pregnant women living in the Metropolitan Area of Buenos Aires (AMBA): 22 were in the 1st trimester (1T), 29 in the 2nd (2T) and 29 in the 3rd (3T). All women were between 30 and 40 years old, had no endocrinopathies or metabolic diseases. Serum IGF-1 was measured by Immulite 2000 Siemens, and Prism8 GraphPad was used for statistical analysis, calculating ranges for each trimester defined as 2,5 and 97,5 percentiles. Ranges obtained were: 64,5-165,0 ng/ml, 78,9-201,0 ng/ml and 96,1-344,0 ng/ml for 1T, 2T and 3T, respectively. Significant differences were observed between 3T and the other trimesters (1T and 2T). We also compared these ranges with our reference values from healthy non-pregnant women in the same age, and found that 3T has significantly higher values ​​of IGF-1 (55,8-188,4 ng/ml vs. 96,1-344,0 ng/ml respectively). In conclusion, IGF-1 levels during the first two trimesters of pregnancy remain within the normal range, and there is a significant increase during the third trimester. Given that IGF-1 plays an essential role during pregnancy, it is important to report ranges in healthy pregnant women to contribute in the follow-up of patients with acromegaly who get pregnant. Although our results are in agree with the available literature, it is necessary to increase the number of healthy pregnant women to establish reference values of IGF-1. 1Frankenne et al (1988). The physiology of growth hormones in pregnant women and partial characterization of the placental GH variant. Journal of Clinical Endocrinology and Metabolism 66:1171-1180 2Leung et al (2004). Estrogen regulation of growth hormone action. Endocrine Reviews 25:693-72 3Muhammad et al (2017). Pregnancy and acromegaly. Pituitary 20:179-184

Central growth hormone action regulates metabolism during pregnancy

The maternal organism undergoes numerous metabolic adaptations to become prepared for the demands associated with the coming offspring. These metabolic adaptations involve changes induced by several hormones that act at multiple levels, ultimately influencing energy and glucose homeostasis during pregnancy and lactation. Previous studies have shown that central growth hormone (GH) action modulates glucose and energy homeostasis. However, whether central GH action regulates metabolism during pregnancy and lactation is still unknown. In the present study, we generated mice carrying ablation of GH receptor (GHR) in agouti-related protein (AgRP)–expressing neurons, in leptin receptor (LepR)–expressing cells or in the entire brain to investigate the role played by central GH action during pregnancy and lactation. AgRP-specific GHR ablation led to minor metabolic changes during pregnancy and lactation. However, while brain-specific GHR ablation reduced food intake and body adiposity during gestation, LepR GHR knockout (KO) mice exhibited increased leptin responsiveness in the ventromedial nucleus of the hypothalamus during late pregnancy, although their offspring showed reduced growth rate. Additionally, both Brain GHR KO and LepR GHR KO mice had lower glucose tolerance and glucose-stimulated insulin secretion during pregnancy, despite presenting increased insulin sensitivity, compared with control pregnant animals. Our findings revealed that during pregnancy central GH action regulates food intake, fat retention, as well as the sensitivity to insulin and leptin in a cell-specific manner. Together, the results suggest that GH acts in concert with other “gestational hormones” to prepare the maternal organism for the metabolic demands of the offspring.

Bovine STAT5A gene polymorphism and its influence on growth traits in Podolica breed

Signal transducers and activators of transcription (STAT) are latent cytoplasmic transcription factors that mediate the actions of a variety of peptide hormones and cytokines within target cells. STAT5A is the main mediator of growth hormone action on target genes and plays a key role as intracellular mediator of prolactin signalling. In this study, the T→C nucleotide polymorphism at position 12 743 in exon 16 of the bovine STAT5A gene was investigated with polymerase chain reaction-restriction fragment length polymorphism in a sample of Podolica young bulls. The Podolica breed derives from Bos primigenius podolicus (forebears of the modern Bos taurus), it has been present in Italy for a very long time and represents yet another example of successful biological adaptation to a hostile environment. The aims of this study were to estimate the allele and genotype frequencies in Podolica breed and to investigate a possible relationship between this polymorphism and some growth performance traits. The observed frequencies of C and T alleles were 0.344 and 0.656, respectively. The TT genotype was the most frequent in the studied population followed by TC and CC ones. Moreover, the animals carrying TT genotypes seem to show an initial faster growth, which determined higher bodyweight at 90 and 270 days of age; conversely, CC individuals exhibit a faster growth in the post-weaning period achieving the higher bodyweight at 450 days of age.

Growth failure associated with early neglect: pilot comparison of neglected US children and international adoptees

The long-lasting impact of different neglectful environments on growth in children is not well studied. Three groups of children, 3–10 years old, were recruited (n=60): previously institutionalized international adoptees living in stable home environments for at least 2 years (IA; n=15), children with a history of neglect born in the USA (USN; n=17), and controls (n=28). Children underwent physical examination, anthropometry, and collection of serum for growth parameters. Mean height standard deviation scores (SDS) were different (p<0.05). Age-adjusted head circumference (HC) was significantly smaller (p<0.05) in IAs. Insulin growth factor (IGF-1), a marker of growth hormone action, was higher in US neglected children. IGF-1 adjusted for age and weight SDS were different (p<0.05) between control and US neglect groups. The degree of growth failure in height and HC in IAs was more severe than neglected US children. These findings may reflect differences between the impact of chronic and intermittent deprivation on the growth hormone system.