Influence of biochemical diagnosis of growth hormone deficiency on replacement therapy response and retesting results at adult height

AbstractIsolated growth hormone deficiency (IGHD) is the most frequent endocrinological disorder in children with short stature, however the diagnosis is still controversial due to the scarcity of reliable diagnostic criteria and pre-treatment predictive factors of long term-response. To evaluate recombinant growth hormone (rGH) long-term response and retesting results in three different groups of children divided in accordance with the biochemical criteria of initial diagnosis. Height gain (∆HT) at adult height (AH) and retesting results were evaluated in 57 rGH treated children (M = 34, 59.6%) divided into 3 groups according to initial diagnosis: Group A (n = 25) with max GH peak at stimulation test < 8 µg/L, Group B (n = 19) between 8 and 10 µg/L and Group C (n = 13) with mean overnight GH < 3 µg/L (neurosecretory dysfunction, NSD). Retesting was carried out in all patients after at least one month off therapy upon reaching the AH. 40/57 (70.2%) patients were pre-pubertal at diagnosis and showed ∆HT of 1.37 ± 1.00 SDS, with no significant differences between groups (P = 0.08). Nonetheless, 46% patients in Group B showed ∆HT < 1SDS (vs 13% and 12% in Group A and C, respectively) and 25% children failed to reach mid-parental height (vs 6% and 0% in Group A and C, respectively). At AH attainment, IGHD was reconfirmed in 28% (7/25) and 10% (2/19) in Group A and B, respectively. A reduction of diagnostic cut-off at GH stimulation tests could better discriminate between “good” and “poor responders” and predict the persistence of IGHD through transition. Group C response and the predictive value of baseline IGF-I SDS bring back to light NSD: should we consider an underlying hypothalamic derangement when the clinical presentation is strongly consistent with IGHD but pharmacological stimulation test is normal?

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Transient impairment or delay of urinary trihydroxypregnanone (THS) response to metyrapone in boys with delayed adolescence and in patients with isolated growth hormone deficiency

Acta Endocrinologica ◽

10.1530/acta.0.0990166 ◽

1982 ◽

Vol 99 (2) ◽

pp. 166-173 ◽

Cited By ~ 1

Author(s):

M. Zachmann ◽

D. Tassinari ◽

W. Sorgo ◽

G. U. Exner ◽

B. Kempken ◽

...

Keyword(s):

Growth Hormone ◽

Single Dose ◽

Growth Hormone Deficiency ◽

Bone Age ◽

Urine Samples ◽

Hormone Deficiency ◽

Cortisol Response ◽

Transient Impairment ◽

Group A ◽

Group B

Abstract. Twentythree boys with delayed adolescence (age 15.7 ± 2.0, bone age 12.4 ± 2.1 years) were studied. Their cortisol response to insulin was normal. After oral metyrapone (500 mg/m2 by mouth) one to three consecutive 12 h urine samples were collected for analysis of THS. Thirtyseven tests with 37 first, 21 second, and 11 third samples were carried out. The results could be divided into two main groups: 25 tests (group A) were subnormal in the first sample, 12 of them with a very weak (40 ± 8 μg/m2/12 h) and 13 with an insufficient (191 ± 16 μg/m2/12 h) THS response. Values in the second and third sample were higher, indicating a dealyed response. In 12 tests (group B), the results were normal (1016 ± 143 μg/m2/12 h) in the first and lower in the second and third samples. In three patients with repeated tests, there was improvement with increasing bone age. The THS-responses to metyrapone did not correlate with those of growth hormone, gonadotrophins, and TSH to stimuli. It is concluded that the THS-response to a single dose of metyrapone may be temporarily insufficient or delayed in delayed adolescence. We interpret this finding as showing transiently reduced or slow hypothalamic responsiveness.

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Long-term response to human growth hormone in 36 children with idiopathic growth hormone deficiency

European Journal of Pediatrics ◽

10.1007/bf00496846 ◽

1979 ◽

Vol 132 (4) ◽

pp. 221-238 ◽

Cited By ~ 51

Author(s):

M. Ranke ◽

B. Weber ◽

J. R. Bierich

Keyword(s):

Growth Hormone ◽

Growth Hormone Deficiency ◽

Human Growth Hormone ◽

Human Growth ◽

Hormone Deficiency ◽

Idiopathic Growth Hormone Deficiency ◽

Term Response

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SAT-LB16 Maintenance of Favorable Treatment Effect of Once-Weekly TransCon hGH for Children With Growth Hormone Deficiency: Interim Analysis From the Enlighten Long-Term Extension Trial

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2102 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Aristides K Maniatis ◽

Samuel J Casella ◽

Ulhas M Nadgir ◽

Gail J Mick ◽

Paul Hofman ◽

...

Keyword(s):

Growth Hormone ◽

Treatment Effect ◽

Interim Analysis ◽

Hormone Deficiency ◽

First Year ◽

Treatment Naïve ◽

Group A ◽

Group B ◽

Extension Trial

Abstract Background Once-weekly TransCon hGH is an investigational long-acting prodrug for growth hormone deficiency (GHD) that consists of 3 components: unmodified growth hormone (hGH; somatropin), an inert carrier that protects it, and a linker that temporarily binds the two. In the randomized phase 3 heiGHt Trial evaluating treatment-naïve children with GHD, TransCon hGH demonstrated superior annualized height velocity and ∆ height standard deviation score (SDS) compared to Genotropin and had a similar safety and tolerability profile. Methods Results are reported from an interim analysis of subjects from heiGHt who continued in the ongoing enliGHten long-term extension trial for 26 weeks. In the 52-week heiGHt Trial, treatment-naïve, prepubertal subjects with GHD were randomized 2:1 to receive once-weekly TransCon hGH 0.24 mg hGH/kg/week or an equivalent weekly dose of daily Genotropin. Subjects completing heiGHt could enroll in enliGHten, where all subjects received TransCon hGH. Two groups were analyzed: Group A (TransCon hGH in both heiGHt and enliGHten) and Group B (Genotropin in heiGHt, followed by TransCon hGH in enliGHten). Safety and growth outcomes were evaluated approximately every 13 weeks in heiGHt and enliGHten. IGF-1 was sampled on postdose Day 5 (±1 day) in enliGHten. A by-visit ANCOVA model was used to analyze numeric efficacy endpoints.ResultsAll but one subject who completed heiGHt continued into enliGHten (A: N=103, B: N=55). Baseline characteristics at the start of heiGHt were balanced between groups. The statistically significant treatment difference in ∆ height SDS (Group A vs B) at the end of heiGHt (Week 52, N=159; 1.10 vs 0.96, P=0.0149) was sustained through Week 78 (N=154; 1.39 vs 1.24, P=0.0436), demonstrating persistence of catch-up growth for both groups and maintenance of superior treatment effect for subjects treated with TransCon hGH in the first year of therapy. At Week 78, least-squares mean (SE) IGF-1 SDS on postdose Day 5 (N=153) was 0.52 (0.15) for Group A and 0.59 (0.19) for Group B. Adverse events (AEs) were comparable between groups during heiGHt. During enliGHten, 48.7% (76/156) and 1.9% (3/156) of subjects experienced AEs and serious AEs, respectively; the AE profile was consistent with what was previously observed in heiGHt. A low titer of anti-hGH binding antibodies were detected in 10/156 (6.4%) subjects during treatment with TransCon hGH in heiGHt and enliGHten; no neutralizing antibodies were detected. Lab parameters (HbA1c, cortisol, free thyroxine) were stable and generally remained within the normal range throughout the trials. Mean (SD) BMI SDS was 0.0 (0.8) for Group A and 0.1 (0.9) for Group B at Week 78.Conclusions Children treated with TransCon hGH showed continued improvement of height SDS beyond the first year. Treatment with TransCon hGH through 78 weeks demonstrated an AE and immunogenicity profile comparable to that of a daily hGH therapy.

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