ENDOCRINE. THYROID. GROWTH HORMONE

1960 Ruben BL, Crigler JF Jr, Berenberg W, Shwachman H. Hypothyroidism: a complication of iodide therapy in children with chronic respiratory involvement of cystic fibrosis. Am J Dis Child 1960; 100:721-722.
This report is of two children with CF who developed hypothyroidism whilst taking iodide therapy to improve sputum clearance – in these two patients there was no thyroid enlargement. Later Dolan TF & Gibson LE (J Pediatr 1971; 79:684-687) reported 55 patients on long term iodide therapy of whom a remarkable 85% developed goitres and also 24% had evidence of hypothyroidism. Their thyroid glands were enlarged, sometimes markedly so, usually after three years or so of iodide therapy. There was discussion as to the possibility of an intrinsic defect of thyroid function but people with CF not taking iodides were all euthyroid.

1971 Dolan TF, Gibson LE. Complications of iodide therapy in patients with cystic fibrosis. J Pediatr 1971; 79:684-687. [PubMed]
Iodides had been used for asthma from the 19th century and were reported to have the effect in asthmatics that the “morning cough was of much shorter duration, say 5 minutes instead of 60 minutes, and that the phlegm was now loose” (Bernecker C Acta Allergologica 1969; XXIV:216-225). In the present study from Yale 47 of 55 patients with CF who were on long term iodides to aid expectoration developed goitres usually within two to three years; also 14 had laboratory evidence of hypothyroidism. Two patients with CF had goitres but were not taking iodides. The rather limited evidence for the efficacy of iodides was reviewed – there were no studies showing improvement in respiratory function.
The authors indicated their intention to discontinue iodide therapy and they planned to evaluate the effect of iodides in a future study (also Ruben et al, 1960 above; Vagenakis et al, 1975 below).

1975 Vagenakis, A G. Braverman, L E. Adverse effects of iodides on thyroid function. Med Clin N Am 1975; 59:1075-1088. [PubMed]
The administration of pharmacologic quantities of iodine as iodides for the treatment of pulmonary disease may result in goitre, hypothyroidism, or hyperthyroidism, especially in patients with underlying thyroid disease. The aetiology of iodide-induced goiter and hypothyroidism in patients with cystic fibrosis treated with iodides was unclear.
The use of iodides to reduce sputum viscosity was common practice and is mentioned by a number of authors including Shwachman who mentioned their use as helpful in a number of his review articles. In a subsequent report from Shwachman and colleagues (Segall-Blank, M et al, Thyroid gland function and pituitary TSH reserve in patients with cystic fibrosis. J Pediatr 1981; 98:218-222) they state that, n view of the reported enhanced sensitivity to iodide-induced hypothyroidism in patients with cystic fibrosis, studies were carried out to determine the possible mechanism of this abnormality. But their findings did not delineate the mechanism whereby patients with CF develop iodide-induced hypothyroidism (also Ruben et al, 1960 above; Dolan & Gibson, 1971 above).

2001 Hardin DS, Ellis KJ, Dyson M, Rice J, McConnell R, Seilheimer DK. Growth hormone improves clinical status in prepubertal children with cystic fibrosis: results of a randomized controlled trial. J Pediatr 2001; 139:636-642. [PubMed]
Nine children with CF treated with growth hormone had significantly greater height, height velocity, weight, weight velocity and change in lean tissue mass. Also the treated group had significant improvement in forced vital capacity compared with the year before the study, and respiratory muscle strength improved. The number of hospitalizations and outpatient intravenous antibiotic courses significantly decreased in the treated group but did not change in the control group. Results of this before and after study of GH treatment in cystic fibrosis suggested that GH improves growth and clinical status.

There was a later controlled trial by Hardin HS et al. 2006 (below). Also Schnabel D et al. 2007 (below) from Germany. However, most centres do not use and would be unlikely to use growth hormone to treat children with CF; its role is still not entirely clear particularly as the nutritional state of children with CF improves with better treatment.

2004 Hardin DS. GH improves growth and clinical status in children with cystic fibrosis -- a review of published studies. [Review] Eur J Endocrinol 2004; 151 Suppl 1:S81-85. [PubMed]
The purpose of this article is to summarize studies evaluating GH use in children with CF. All published studies of GH use in children with CF have demonstrated significant improvement in height velocity and height Z score. All studies but one, in which subjects were treated only three times per week with GH, have demonstrated improvement in weight as reported by weight velocity and/or weight Z score, and one trial has demonstrated a substantial improvement when GH was used to augment nutritional therapy. Several reports suggest that GH treatment results in improved forced vital capacity, and multiple studies have found improved clinical status as measured by decreased hospitalizations and courses of intravenous antibiotics. Furthermore studies to date also suggest that GH results in improvement in exercise tolerance and bone accumulation. To date significant side effects, including glucose intolerance, have not been reported. Thus mounting evidence suggests that human recombinant GH provides safe and effective therapy in children with CF.

Hardin has published a previous study on human growth hormone in CF (Hardin et al. 2001) [PubMed] and also a more recent study). [PubMed]

2005 Hardin DS. Ferkol T. Ahn C. Dreimane D. Dyson M. Morse M. Prestidge C. Rice J. Seilheimer DK. A retrospective study of growth hormone use in adolescents with cystic fibrosis. Clin Endocrinol 2005; 62:560-566. [PubMed]
The results of this study suggest that growth hormone use in pubertal adolescents with CF safely improves height, body weight, bone mineralization and clinical status. hardin and colleagues have published a number of previous studies on the use of growth hormone in CF.

2006 Hardin DS, Adams-Huet B, Brown D, Chatfield B, Dyson M, Ferkol T, Howenstine M, Prestidge C, Royce F, Rice J, Seilheimer DK, Steelman J, Shepherds R. Growth hormone treatment improves growth and clinical status in prepubertal children with cystic fibrosis: results of a multicenter randomized controlled trial. J Clin Endocrin Metab 2006; 91:4925-9. [PubMed]
Sixty one prepubertal children were either treated with growth hormone or were controls. After 1 yr, growth hormone treated children had significantly greater gain in height, weight, lean body mass, and bone mineral content. They had fewer hospitalizations and an improvement in CF quality of life but there was no difference in pulmonary function between groups. After cessation of GH treatment, there was a sustained effect for increased height and weight velocity, as well as accrual of bone mineral.
Although there was a significant favourable effect for the growth hormone treatment there are few children who receive or indeed now require this treatment (also Hardin et al, 2001 above). [PubMed]

2007 Schnabel D, Grasemann C, Staab D, Wollmann H, Ratjen F. German Cystic Fibrosis Growth Hormone Study Group. A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the metabolic and respiratory effects of growth hormone in children with cystic fibrosis. Pediatrics 2007; 119:e1230-1238. [PubMed]
Another multicenter, randomized, placebo-controlled, double-blind study to assess the efficacy and safety of 2 dosages of growth hormone in cystic fibrosis. Sixty-three dystrophic patients with cystic fibrosis were randomly assigned for 24 weeks to 1 of 3 treatment arms followed by an open treatment period of 24 weeks. Height, growth velocity, and growth factors increased significantly in both treatment groups, whereas weight gain did not differ between the growth hormone groups and placebo. Maximal oxygen uptake during peak exercise increased significantly in treated patients. The authors concluded that these data suggest that in the group investigated, growth hormone therapy was well tolerated and had positive metabolic effects but did not result in short-term improvement of lung function in patients with cystic fibrosis

It is unlikely that many CF clinicians would advise growth hormone therapy except perhaps in exceptional circumstances; also it is hoped that with present day treatment there will be fewer “dystrophic” children who would benefit from this form of treatment which involves daily subcutaneous injections and costs up to £15K per year (also Hardin et al, 2001 above; Hardin et al, 2006 above).

2009 Switzer M. Rice J. Rice M. Hardin DS. Insulin-like growth factor-I levels predict weight, height and protein catabolism in children and adolescents with cystic fibrosis. J Pediatr Endocrinol 2009; 22:417-424. [PubMed]
There was also a strong relationship between leucine rate of appearance (a measure of protein catabolism) and IGF-I. These results suggest a strong correlation between IGF-I and height, weight and protein catabolism and emphasize the need to normalize IGF-I levels in children with cystic fibrosis.
Hardin has written a number of papers on the use of growth hormone. Here they analyze the IGF-1 levels in the patients studied previously studied. It is interesting that in recent animal studies involving CF pigs there seems to be a relationship between IGF-1 and the growth potential of the animals (Rogan MP et al. 2010. [PubMed]