Re-evaluation of GH secretion during the transition age in patients with childhood-onset isolated GH deficiency (IGHD) after GH therapy (GHRx)

GH deficiency (GHD) in adults is associated with considerable morbidity and mortality. The diagnosis of GHD is generally straightforward in children as growth retardation is present; however, in adults, diagnosis of GHD is often challenging. Other markers are therefore needed to identify adults who have GHD and could potentially benefit from GH replacement therapy. Consensus guidelines for the diagnosis and treatment of adult GHD recommend provocative testing of GH secretion for patients who have evidence of hypothalamic-pituitary disease, patients with childhood-onset GHD, and patients who have undergone cranial irradiation or have a history of head trauma. Suspicion of GHD is also heightened in the presence of other pituitary hormone deficits. Tests for GHD include measurement of the hormone in urine or serum or measurement of stimulated GH levels after administration of various provocative agents. The results of several studies indicate that non-stimulated serum or urine measurements of GH levels cannot reliably predict deficiency in adults. Although glucagon and arginine tests produce a pronounced GH response with few false positives, the insulin tolerance test (ITT) is currently considered to be the gold standard of the GH stimulation tests available. Unfortunately, the ITT has some disadvantages and questionable reproducibility, which have prompted the development of several new tests for GHD that are based on pharmacological stimuli. Of these, GH-releasing hormone (GHRH) plus arginine and GHRH plus GH-releasing peptide (GHRP) appear to be reliable and practical. Thus, in cases where ITT is contraindicated or inconclusive, the combination of arginine and GHRH is an effective alternative. As experience with this test as well as with GHRH/GHRP-6 accumulates, they may supplant ITT as the diagnostic test of choice.

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Short and Long-Term Effects of Growth Hormone in Children and Adolescents With GH Deficiency

Frontiers in Endocrinology ◽

10.3389/fendo.2021.720419 ◽

2021 ◽

Vol 12 ◽

Author(s):

Michael B. Ranke

Keyword(s):

Gh Deficiency ◽

Child Growth ◽

Treatment Modalities ◽

Diagnostic Process ◽

Childhood And Adolescence ◽

Long Term Effects ◽

Childhood Onset ◽

Gh Secretion ◽

Number Of Patients

The syndrome of impaired GH secretion (GH deficiency) in childhood and adolescence had been identified at the end of the 19th century. Its non-acquired variant (naGHD) is, at childhood onset, a rare syndrome of multiple etiologies, predominantly characterized by severe and permanent growth failure culminating in short stature. It is still difficult to diagnose GHD and, in particular, to ascertain impaired GH secretion in comparison to levels in normally-growing children. The debate on what constitutes an optimal diagnostic process continues. Treatment of the GH deficit via replacement with cadaveric pituitary human GH (pit-hGH) had first been demonstrated in 1958, and opened an era of therapeutic possibilities, albeit for a limited number of patients. In 1985, the era of recombinant hGH (r-hGH) began: unlimited supply meant that substantial long-term experience could be gained, with greater focus on efficacy, safety and costs. However, even today, the results of current treatment regimes indicate that there is still a substantial fraction of children who do not achieve adult height within the normal range. Renewed evaluation of height outcomes in childhood-onset naGHD is required for a better understanding of the underlying causes, whereby the role of various factors - diagnostics, treatment modalities, mode of treatment evaluation - during the important phases of child growth - infancy, childhood and puberty - are further explored.

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Subnormal Serum Insulin-Like Growth Factor-I Levels in Young Adults with Childhood-Onset Nonacquired Growth Hormone (GH) Deficiency Who Recover Normal GH Secretion May Indicate Less Severe but Persistent Pituitary Failure

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-1003 ◽

2007 ◽

Vol 92 (10) ◽

pp. 3788-3795 ◽

Cited By ~ 15

Author(s):

Georges Gelwane ◽

Catherine Garel ◽

Didier Chevenne ◽

Priscilla Armoogum ◽

Dominique Simon ◽

...

Keyword(s):

Young Adults ◽

Anterior Pituitary ◽

Gh Deficiency ◽

Childhood Onset ◽

Mri Findings ◽

Gh Secretion ◽

Structural Abnormalities ◽

Igf I ◽

Ectopic Neurohypophysis

Abstract Context: The unexpected observation of a normal GH peak in 22% of young adults with childhood-onset GH deficiency (GHD) and ectopic neurohypophysis has raised questions about the criteria defining GHD in young adults and whether patients with subsequent increases in GH secretion nonetheless have a subtle form of GHD. Objective: Our objective was to determine the characteristics of patients with childhood-onset nonacquired GHD who recover normal peak GH secretion when adult height has been achieved. Design and Setting: We conducted a university hospital-based observational follow-up study. Participants: Sixty-two patients with ectopic neurohypophysis (n = 24), isolated hypoplastic anterior pituitary (n = 14), or normal hypothalamic pituitary area (n = 24) on magnetic resonance imaging (MRI) at the time of GHD diagnosis underwent reevaluation of the GH-IGF-I axis at a mean age of 16.8 ± 1.6 yr. Main Outcome Measures: Outcome measures included clinical and MRI findings and serum IGF-I and peak GH levels. Results: On retesting, peak GH exceeded 10 μg/liter in 31 patients (50%): six (20%) patients with ectopic neurohypophysis, 10 (32%) patients with initially isolated hypoplastic anterior pituitary, and 15 (48%) patients with normal MRI findings. Among these patients, serum IGF-I levels were significantly lower in patients with ectopic neurohypophysis than in those without structural abnormalities of the hypothalamic pituitary axis (n = 25), but patients without structural abnormalities also had significantly lower serum IGF-I levels than control subjects, after controlling for age, sex, and body mass index (mean serum IGF-I levels of 374 ± 83 vs. 446 ± 108 μg/liter; β-coefficient = −72; P = 0.003). Conclusions: The severity of the disease seems to have decreased over time in these patients, who may nonetheless present persistent pituitary failure. The natural history and clinical implications of these findings remain to be clarified. The possibility of a deterioration in the secretion of GH and other pituitary hormones later in life in a subset of these patients warrants the careful long-term follow-up of this population.

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Transitional care of GH deficiency: when to stop GH therapy

Acta Endocrinologica ◽

10.1530/eje.0.151s061 ◽

2004 ◽

pp. S61-S65 ◽

Cited By ~ 20

Author(s):

MO Savage ◽

WM Drake ◽

PV Carroll ◽

JP Monson

Keyword(s):

Transitional Care ◽

Gh Deficiency ◽

Final Height ◽

Drop Out ◽

Smooth Transition ◽

Pituitary Hormone ◽

Gh Therapy ◽

Gh Treatment ◽

Somatic Development ◽

Gh Secretion

While the benefits of growth hormone (GH) therapy in adult hypopituitary patients with GH deficiency (GHD) are established, the role of continued GH therapy after final height in adolescent GH-deficient patients remains unclear. Preliminary data suggest that cessation of GH on completion of linear growth may be associated with impairment of somatic development and adverse changes in body composition. For the present time, the decision whether to continue GH treatment in adolescent patients with GHD is best made on an individual basis. For such patients, continuity of care is crucial. Children and adults with GHD are usually managed by physicians in separate departments, who may focus on different aspects of treatment and care. Close collaboration between paediatric and adult physicians is essential to ensure smooth transition and to minimize the drop-out rate from follow-up. Given the previous period of treatment during childhood, paediatric physicians should be best placed to discuss the potential benefits of continuing GH therapy and instigate retesting of GH secretion. Many children with isolated idiopathic GHD will produce normal GH responses if retested at adult height. Patients with multiple pituitary hormone deficits are more likely to have ongoing GHD, as are patients who have received CNS irradiation. Quality of life does not appear to be decreased in adolescents with GHD who stop treatment, so achievement of satisfactory bone mass is a major determinant of the decision whether to continue therapy.

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Inclusion and Withdrawal Criteria for Growth Hormone (GH) Therapy in Children with Idiopathic GH Deficiency—Towards Following the Evidence but Still with Unresolved Problems

10.20944/preprints202201.0017.v1 ◽

2022 ◽

Author(s):

Joanna Smyczyńska

Keyword(s):

Growth Hormone ◽

Gh Deficiency ◽

Final Height ◽

Threshold Value ◽

Reference Ranges ◽

Gh Therapy ◽

Gh Secretion ◽

Accelerate Growth ◽

Stimulation Tests ◽

Definition Of

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most of children diagnosed with isolated GHD presents with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature.

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Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition

Acta Endocrinologica ◽

10.1530/eje-13-0572 ◽

2013 ◽

Vol 169 (5) ◽

pp. 587-596 ◽

Cited By ~ 7

Author(s):

Carine Courtillot ◽

Roselyne Baudoin ◽

Tatiana Du Souich ◽

Lucile Saatdjian ◽

Isabelle Tejedor ◽

...

Keyword(s):

Gh Deficiency ◽

Mineral Density ◽

Childhood Onset ◽

Gh Therapy ◽

Bone Status ◽

Long Term Follow Up ◽

And Function ◽

Design And Methods

ObjectivesOur aim was to analyze a large cohort of childhood onset GH deficiency (CO-GHD) adults from a unique adult center, in order to analyze their clinical management and to study the metabolic and bone status in relation to GHD and to the other pituitary deficits, and to evaluate these parameters during the long-term follow-up.Design and methodsObservational retrospective cohort study on 112 consecutive CO-GHD adults transferred to our unit from 1st January 1994 to 1st March 2012. Evaluation of GHD in pediatrics and after transition was conducted following consensus guidelines. Data recorded from pediatric and adult files were GH doses, pituitary magnetic resonance imaging and function, and metabolic and bone status.ResultsMost patients presented with severe CO-GHD (64%) associated with other pituitary deficits (66%). CO-GHD was acquired in 56%, congenital in 33%, and idiopathic in 11% cases. Most patients (83%) stopped GH before transfer, at 16.3 years (median), despite persistence of GHD. Median age at transfer was 19.4 years. After transfer, GHD persisted in 101 patients and four of the 11 resolutive GHD were non idiopathic. IGF1 level was <−2 SDS in 70% of treated patients at transfer and in 34% of them after 3 years of treatment. Follow-up showed improvement in lipid profile and bone mineral density in severely persistent GHD patients under GH therapy. In multivariate analysis, the associated pituitary deficits seemed stronger determinant factors of metabolic and bone status than GHD.ConclusionsThis study raises concern about discontinuation of GH replacement therapy in pediatrics in severely persistent GHD patients and about the often insufficient dose of GH in the treatment of adult patients.

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Do All Patients with Childhood-Onset Growth Hormone Deficiency (GHD) and Ectopic Neurohypophysis Have Persistent GHD in Adulthood?

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-1274 ◽

2005 ◽

Vol 90 (2) ◽

pp. 650-656 ◽

Cited By ~ 53

Author(s):

Juliane Léger ◽

Stéphanie Danner ◽

Dominique Simon ◽

Catherine Garel ◽

Paul Czernichow

Keyword(s):

Anterior Pituitary ◽

Adult Height ◽

Pituitary Stalk ◽

Childhood Onset ◽

Gh Therapy ◽

Group Iii ◽

Gh Secretion ◽

Group I ◽

Height Gain ◽

Ectopic Neurohypophysis

Cerebral magnetic resonance imaging findings are of great value for the diagnosis of nonacquired GH deficiency (GHD), and ectopic posterior pituitary hyperintense signal (EPPHS) is a sensitive and specific indicator of hypopituitarism. It has been suggested that patients with childhood-onset GHD and EPPHS do not require additional investigation of GH secretion and should not be retested when adult height is achieved. This recommendation has never been validated through a systematic study. This study aimed to characterize the anterior pituitary function status of patients with EPPHS treated for GHD during childhood after completion of GH therapy when adult height had been achieved. Patients (n = 18; 15 males and three females) with childhood-onset GHD associated with ectopic neurohypophysis were treated with hGH (0.20 ± 0.05 mg/kg·wk) for 9.9 ± 4.0 yr (from 6.8 ± 4.7 to 17.7 ± 1.3 yr of age) with a mean height gain of 2.6 ± 1.4 sd score. GH secretion was reevaluated by arginine insulin (n = 15) or propanolol glucagon (n = 3) test after 0.5 ± 0.6 yr of GH withdrawal. At reevaluation, peak GH was more than 10 μg/liter in four patients (22%; range, 11.7–19.5 μg/liter; group I), between 5 and 10 μg/liter in three patients (17%; range, 7.3–9 μg/liter; group II), and less than 5 μg/liter in 11 patients (61%; range, 0–4.7 μg/liter; group III). A positive correlation was found between serum IGF-I and peak GH levels after attainment of adult height (P = 0.007). Only one of the seven patients who showed increased GH secretion ability in adulthood (groups I and II) demonstrated other hormonal deficiencies (gonadotropin and adrenal insufficiencies). Among the 11 patients with persistent severe GHD (group III), 10 (91%) of the 11 subjects were shown to have multiple pituitary hormone deficits after attainment of adult height. The structure of the hypothalamo-pituitary axis differs among groups [i.e. patients who showed increased GH secretion ability in adulthood (groups I and II) vs. those who remained severely GHD (group III)]. The location of the EPPHS was significantly different among groups (P < 0.003). The EPPHS was found at the median eminence in all but one of group III patients and along the pituitary stalk (proximal stalk) in all but one of group I and II patients. The pituitary stalk was visible and described as normal (n = 1) or thin (n = 6) in all group I and II patients, whereas the pituitary stalk was not visible even after enhancement in seven of the 11 group III patients (P < 0.02). The prevalence of anterior pituitary hypoplasia and the mean height gain sd score were similar in each group. In conclusion, only 61% of patients with childhood-onset GHD and EPPHS remained severely GHD, and thus suitable for GH therapy, in adulthood. Although the pathogenesis of anterior pituitary dysfunction remains unclear in patients with ectopic neurohypophysis, isolated GHD, location of EPPHS along the stalk, and visibility of the pituitary stalk on magnetic resonance imaging findings clearly represent important markers to predict a less severe form of the disease.

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