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New evidence for pediatric endocrinologists

New evidence for pediatric endocrinologists
  • Endocrinology and metabolism
  • Growth disorder

A number of interesting papers have been published during 2017, some of which will directly impact daily clinical practice for pediatric endocrinologists, and others will contribute to improving the current knowledge of the physiology of human growth regulating mechanisms.

This article aims to highlight the key papers of the year, to make them easily accessible to anyone involved in the care of growth-related disorders. Four articles have been selected which between them cover new insights on the mechanisms involved in the GH-IGF1 axis, information on new genes involved in pituitary organogenesis and a new potential field of treatment for recombinant human growth hormone (rhGH).

Although it is not possible to provide a complete overview of all the outstanding literature produced and presented in 2017, these articles are those that provide depth to the field and may significantly change everyday practice.
 


 

NEW MECHANISM

This article is selected because it demonstrates a direct connection between programming during prenatal life and pituitary function during adulthood. Other articles have previously reported on how much maternal environment is important for metabolism regulation in progeny. This article is the first to show a direct impact of the maternal environment on the GH-IGF1 axis in progeny in an animal model.

 

Maternal obesity programs reduced leptin signaling in the pituitary and altered GH/IGF1 axis function leading to increased adiposity in adult sheep offspring.

Tuersunjiang N, Odhiambo JF, Shasa DR, et al.

PLoS One 2017 Aug 3;12(8):e0181795.

 

Abstract

Studies in rodents highlight a role for leptin in stimulation of pituitary growth hormone (GH) secretion, with an impact on body composition regulation. Authors previously reported that maternal obesity (MO) during ovine pregnancy results in hyperphagia, glucose-insulin dysregulation, increased adiposity, hypercortisolemia and hyperleptinemia in mature offspring subjected to a bout of ad libitum feeding. Maternal obesity has been postulated reducing leptin signaling in the pituitary and down regulating the GH/IGF1 axis, with an increase in circulating cortisol leading to increased adiposity in their adult offspring. Male lambs born to MO (n = 6) or control (CON, n = 6) ewes were fed only to requirements until placed on a 12-week ad libitum feeding trial at maturity. The pituitary, hypothalamic arcuate nucleus, and liver were collected at necropsy and mRNA and protein expression determined. Plasma cortisol concentrations were increased (P<0.05) in MO vs. CON offspring at the end of the feeding trial. Further, serum concentrations of IGF1 decreased (P<0.01) and GH tended to decrease (P<0.08) in MO vs. CON offspring. Pituitary mRNA and leptin receptor protein expression were decreased in MO vs. CON offspring in association with decreased GH mRNA expression, and decreased IGF1 mRNA and protein expression in liver. Liver 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) expression was increased (P<0.01) and its cofactor hexose-6-phosphate dehydrogenase tended to increase (P<0.06) in MO vs. CON offspring. 11βHSD2 expression remained unchanged. These data indicate that MO induced an increase in liver conversion of cortisone to cortisol in adult offspring and support a role for leptin signaling in the pituitary in mediating offspring adiposity.

Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542597/

 

NEW GENES

Genetics play a crucial role in the management of many patients with hypopituitarism and Clinicians need to be regularly up-dated to drive the genetic analysis according to the patient’s phenotype. However, finding the genetic cause of hypopituitarism is not straightforward. Indeed, only a small percentage of congenital hypopituitarism cases can be associated with a specific gene mutation, while the majority remain unexplained. The following article is recommended as it is an excellent example of how modern genetic investigation may improve our knowledge of the genetic causes underling congenital abnormalities of hypothalamic-pituitary organogenesis and its function.

 

Mutations in the human ROBO1 gene in pituitary stalk interruption syndrome.

Bashamboo A, Bignon-Topalovic J, Moussi N, et al.

J Clin Endocrinol Metab 2017 Jul 1;102(7):2401-6.

 

Abstract

Pituitary stalk interruption syndrome (PSIS) is characterized by a thin or absent pituitary stalk, usually in association with an ectopic posterior pituitary and hypoplasia/aplasia of the anterior pituitary. Associated phenotypes include varied ocular anomalies, hypoglycemia, micropenis/cryptorchidism, growth failure, or combined pituitary hormone deficiencies. Although genetic causes have been identified, they explain only around 5% of PSIS cases. This study aims to identify genetic causes of PSIS by exome sequencing.

Exon enrichment was performed using the Agilent SureSelect Human All Exon V4. Paired-end sequencing was performed on the Illumina HiSeq2000 platform with an average sequencing coverage of ×50. Patients with unexplained PSIS were included in the study. In five cases of unexplained PSIS including two familial cases, authors identified a novel heterozygous frameshift and nonsense and missense mutations in the ROBO1 gene (p.Ala977Glnfs*40, two affected sibs; p.Tyr1114Ter, sporadic case, and p.Cys240Ser, affected child and paternal aunt) that controls embryonic axon guidance, and branching in the nervous system. Interestingly, four of the five cases of PSIS also presented with ocular anomalies, including hypermetropia with strabismus as well as ptosis. These data suggest that mutations in ROBO1 contribute to PSIS and associated ocular anomalies.

Available from: https://academic.oup.com/jcem/article-abstract/102/7/2401/3574895

 

NEW THERAPEUTIC OPTIONS

rhGH has been used in several conditions affecting human growth, and not only those GH-related. Other conditions affecting stature do not yet have any specific treatments. Here, two articles are highlighted describing the effects of rhGH treatment for two diseases affecting adult height, which may represent potential new indications for rhGH treatment.

Growth hormone with aromatase inhibitor may improve height in CYP11B1 congenital adrenal hyperplasia. Hawton K, Walton-Betancourth S, Rumsby G, et al.                                                                                       Pediatrics. 2017 Feb;139(2).

Abstract

With an estimated prevalence of 1 in 100 000 births, 11β-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in CYP11B1. Clinical features include virilization, early gonadotropin-independent precocious puberty, hypertension, and reduced stature. The current mainstay of management is with glucocorticoids to replace deficient steroids and to minimize adrenal sex hormone overproduction, thus preventing virilization and optimizing growth. Authors report a patient with CAH who had been suboptimally treated and presented at 6 years of age with precocious puberty, hypertension, tall stature, advanced bone age, and a predicted final height of 150 cm. Hormonal profiles and genetic analysis confirmed a diagnosis of 11β-hydroxylase deficiency. In addition to glucocorticoid replacement, the patient was commenced on growth hormone and a third-generation aromatase inhibitor, anastrozole, in an attempt to optimize his growth. After the initiation of this treatment, the patient's growth rate improved significantly and bone age advancement slowed. The patient reached a final height of 177.5 cm (0.81 SD score), 11.5 cm above his mid-parental height. This patient is only the second reported case of the use of an aromatase inhibitor in combination with growth hormone to optimize height in 11β-hydroxylase-deficient CAH. This novel treatment proved to be highly efficacious, with no adverse effects. It may therefore provide a promising option to promote growth in exceptional circumstances in individuals with 11β-hydroxylase deficiency presenting late with advanced skeletal maturation and consequent short stature.

Available from: http://pediatrics.aappublications.org/content/139/2/e20160730

 

Randomized trial of aromatase inhibitors, growth hormone, or combination in pubertal boys with idiopathic short stature.                                                                                                                                                                        Mauras N, Ross JL, Gagliardi P, et al.                                                                                                                                J Clin Endocrinol Metab. 2016 Dec;101(12):4984-4993.

Abstract

Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion. This study aimed to compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups. This study was designed as a randomized, three-arm, open-label comparator trial, organized as an outpatient clinical research. Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)] were enrolled. Patients were divided into three groups for treatment: 1) daily AIs (anastrozole or letrozole), 2) GH, or 3) AI/GH for 24-36 months. The following outcomes were assessed: anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs.

Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8) cm (P < .0006, analysis of covariance). Height SDS was: AI, -1.73 (0.12); GH, -1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, ∼97.6%] was: AI, -1.4 (0.1); GH, -1.4 (0.2); AI/GH, -1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, +22.5 (1.4) cm (P = .01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole.

Authors concluded that combination therapy with AI/GH for 24-36 months increases height potential in pubertal boys with ISS more than GH and AI alone, with a strong safety profile.

Available from: https://academic.oup.com/jcem/article-abstract/101/12/4984/2765085?redirectedFrom=fulltext

 

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