Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts’ consensus

Abstract

Isolated growth hormone deficiency (GHD) is defined by growth failure in combination with retarded bone age, low serum insulin-like growth factor-1, and insufficient GH peaks in two independent GH stimulation tests. Congenital GHD can present at any age and can be associated with significant malformations of the pituitary-hypothalamic region or the midline of the brain. In rare instances, genetic analysis reveals germline mutations of transcription factors involved in embryogenesis of the pituitary gland and the hypothalamus. Acquired GHD is caused by radiation, inflammation, or tumor growth. In contrast to organic GHD, idiopathic forms are more frequent and remain unexplained. There is a risk of progression from isolated GHD to combined pituitary hormone deficiency (> 5% for the total group), which is clearly increased in children with organic GHD, especially with significant malformation of the pituitary gland. Therefore, it is prudent to exclude additional pituitary hormone deficiencies in the follow-up of children with isolated GHD by clinical and radiological observations and endocrine baseline tests. In contrast to primary disorders of endocrine glands, secondary deficiency is frequently milder in its clinical manifestation. The pituitary hormone deficiencies can develop over time from mild insufficiency to severe deficiency. This review summarizes the current knowledge on diagnostics and therapy of additional pituitary hormone deficits occurring during rhGH treatment in children initially diagnosed with isolated GHD. Although risk factors are known, there are no absolute criteria enabling exclusion of children without any risk of progress to combined pituitary hormone deficiency. Lifelong monitoring of the endocrine function of the pituitary gland is recommended in humans with organic GHD. This paper is the essence of a workshop of pediatric endocrinologists who screened the literature for evidence with respect to evolving pituitary deficits in initially isolated GHD, their diagnosis and treatment.

Decreased Thyroxine Levels during rhGH Therapy in Children with Growth Hormone Deficiency

“…In the pediatric population, van Iersel et al [ 26 ] showed in a large retrospective cohort study that rhGH therapy could unmask central hypothyroidism, especially in those initially classified as non-acquired apparent isolated GH-deficient children who had congenital structural pituitary abnormalities. Regardless of the cause of thyroid function alterations during rhGH therapy, most authors agree that there is a need for the regular monitoring of thyroid hormone levels in all GH-deficient children after the initiation of rhGH therapy in order to early identify and correct the possible thyroid function abnormalities that could occur during therapy [ 5 , 13 , 14 , 15 , 23 , 29 ]. Thyroid hormones directly stimulate the transcription of GH, IGF-1 and insulin-like growth factor binding protein-2 (IGFBP-2) and insulin-like growth factor binding protein-4 (IGFBP-4) genes, as well as increasing the mRNA of GH and growth hormone-releasing hormone (GHRH) receptors [ 45 , 46 ].…”

“…In those cases, levothyroxine (L-thyroxine) supplementation should be taken into account as a possible way to achieve the optimal growth effect of rhGH therapy [ 27 ]. The clinical significance of thyroid hormone changes during rhGH therapy seemed to be underappreciated despite many authors agreeing that the regular monitoring of thyroid function during rhGH therapy is needed [ 5 , 13 , 14 , 22 , 23 , 24 , 27 , 28 , 29 ].…”

Advances in differential diagnosis and management of growth hormone deficiency in children

“…MRI identification of the triad of ectopic posterior pituitary, anterior pituitary hypoplasia and pituitary stalk agenesis is of great value in recognizing patients at risk for evolving pituitary hormone deficiencies. In particular, small size and location of ectopic posterior pituitary are predictive of MPHD development 146,147 .…”

Thyroid Hormone Changes Related to Growth Hormone Therapy in Growth Hormone Deficient Patients

“…They also concluded that regular monitoring of thyroid hormone levels during rhGH therapy is not warranted in such children [34]. On the other hand, a recently published expert opinion is that "there are no absolute criteria enabling exclusion of children without any risk of progress to combined pituitary hormone deficiency" [64], and lifelong monitoring of the pituitary gland function is recommended, especially in patients with organic GHD [64].…”