The landscape of retesting in childhood-onset idiopathic growth hormone deficiency and its reversibility: a systematic review and meta-analysis

Abstract

Objective Children diagnosed with idiopathic, isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH deficient at a later stage of growth as a result of “GHD reversal”. Reevaluation of GH status by stimulation test is currently incorporated into management guidelines at attainment of final height (FH). Over the past three decades, numerous studies have evaluated reversal rates using different methodologies including crucial parameters like GHD etiology, GH cut-off and retesting time point, with heterogeneous results. We aimed to systematically analyze the reversibility of childhood-onset IGHD dependent on retesting GH cut-offs and retesting time points. Methods PubMed, Cochrane Library, TRIP database and NHS Evidence were searched for publications investigating reversibility of IGHD from database initiation to 30 June 2020 following PRISMA recommendations. Study cohorts were pooled according to retesting GH cut-off and time point. Reversal rates were calculated using random-effects models. Results Of 29 studies initially identified, 25 provided sufficient detail for IGHD-analysis, resulting in 2030 IGHD patient data. Reversal rates decreased significantly as the retesting GH cut-off increased (p = 0•0013). Pooled (95% CI) reversal rates were 80% (59-92%, n = 227), 73% (62-81%, n = 516) and 55% (41-68%, n = 1287) for cohorts using retesting GH cut-offs of 3-4 ng/ml, 5-6 ng/ml and 7•7-10 ng/ml, respectively. Individuals retested at FH (n = 674) showed a pooled reversal rate of 74% (64-82%) compared to 48% (25-71%) when retested before FH (n = 653). Conclusion Provided evidence supports reevaluation of current IGHD management guidelines. The high reversal rates should instigate consideration of early retesting.

Diagnosis and testing for growth hormone deficiency across the ages: a global view of the accuracy, caveats, and cut-offs for diagnosis

“…GH stimulation testing during the transition period typically utilizes provocative agents and diagnostic thresholds that are used in adults. A substantial proportion of patients (25–100%) with CO-GHD, especially children with isolated GHD and normal or small pituitary on MRI, have normalization of GH secretion following re-testing ( 2 ). Professional societies recommend at least 4 weeks after discontinuation of childhood GH replacement for re-testing ( 4 , 5 ).…”

“…Childhood-onset GHD (CO-GHD) is often idiopathic but may also be triggered by organic causes. To distinguish between transient and persistent GHD in the adolescent patient transitioning into adulthood requires re-testing in the transition phase after the completion of linear growth ( 1 , 2 , 3 ). The exceptions when re-testing is generally not required are in patients with genetic/congenital defects, irreversible hypothalamic–pituitary lesions, and in those with panhypopituitarism and low serum insulin-like growth factor 1 (IGF1) levels ( 4 , 5 ).…”

New developments and therapies in pediatric endocrinology

“…Diagnostics of short stature have improved with genetic advances too. GH deficiency may be overdiagnosed, and there is a move to re-testing of GH deficiency in puberty [25]. Genetic variants or deletions in the GH signalling pathway such as those in GHR (growth hormone receptor) [26], STAT5B (signalling transducer and activator of transcription 5B) [27], IGF1 (insulin-like growth factor 1) [28] and IGF1R (IGF1 receptor) [29] may be more common than initially thought, but seem to be still far rarer than variants in genes involved in bone or cartilage development as a cause for short stature.…”

Sex steroid priming in short stature children unresponsive to GH stimulation tests: Why, who, when and how

“…28 out of 33 GHD patients of an Italian cohort with normal pituitary morphology at brain MRI normalized GH secretion even before commencement of GH treatment ( 10 ). Recently published data suggested patients with isolated GHD without a hypothalamic-pituitary abnormality on MR scanning (including small anterior pituitary) can also be considered for early retesting of the GH axis once they are established in puberty (Tanner stages B2/3 in girls & 6-12 ml testes in boys) ( 53 ). In addition, GH treatment seems to have little effect on final height in adolescents with transient GHD ( 54 ).…”