Effects of one-year low-dose growth hormone (GH) therapy on body composition, lipid profile and carbohydrate metabolism in young adults with childhood-onset severe GH deficiency confirmed after completion of growth promotion

Wstęp: Niedobór hormonu wzrostu (GHD) u dorosłych charakteryzuje się między innymi: nieprawidłowym składem ciała, zaburzeniami profilu lipidowego, wczesną miażdżycą oraz pogorszeniem jakości życia. Celem badania było wyodrębnienie pacjentów z ciężkim przetrwałym GHD, spośród grupy pacjentów z rozpoznanym w dzieciństwie, leczonym GHD, oraz ocena korzystnego wpływu kontynuacji terapii GH w życiu dorosłym, a także ustalenie optymalnej dawki GH u młodych dorosłych osób z ciężkim GHD. Materiał i metody: Badaniem objęto 54 osoby (38 mężczyzn), w wieku 17,6 ± 1,5 roku z rozpoznanym w dzieciństwie GHD, które uzyskały wzrost ostateczny. U wszystkich pacjentów po okresie - co najmniej - 1 miesiąca od zaprzestania leczenia promującego wzrastanie, przeprowadzono kolejną ocenę wydzielania GH. Ciężką przetrwałą postać GHD stwierdzono u 13 (24%) pacjentów, ale do ponownego leczenia GH włączono tylko 9 osób (4 mężczyzn). Wyniki: Obserwowano korzystny wpływ ponownego włączenia terapii GH na skład ciała (znamienny wzrost beztłuszczowej masy ciała i zmniejszenie tłuszczowej masy ciała), profil lipidowy (znamienne obniżenie stężenia cholesterolu frakcji LDL, jednakże z towarzyszącym nieznamiennym obniżeniem stężenia cholesterolu frakcji HDL) oraz poprawę wyników testów oceniających jakość życia (QoL). Podczas terapii obserwowano nieznamienny wzrost stężenia insuliny na czczo, bez zmian dotyczących stężenia glukozy na czczo oraz z jedynie nieznacznym wzrostem odsetka HbA1c. Obserwowano również zmniejszenie insulinowrażliwości, chociaż stężenie insuliny na czczo i wskaźniki insulinooporności pozostawały w zakresie wartości referencyjnych. Wniosek: Korzystne zmiany dotyczące składu ciała i profilu lipidów oraz QoL przy braku powikłań wskazują na potrzebę leczenia hormonem wzrostu młodych osób dorosłych z ciężkim GHD.Introduction: The symptoms of GH deficiency (GHD) in adults include: abnormalities in body composition, unfavourable lipid profile, early atherosclerosis and impaired quality of life. The aim of the study was the selection of patients with confirmed severe GHD from among all the children treated due to GHD, who could benefit from GH therapy continuation in adulthood and the optimization of GH dosage in young adults with severe GHD. Material and methods: The study group consisted of 54 young adults (38 male), age 17.6 ± 1.5 years, with childhood-onset GHD, who had reached final height. At least 1 month after the GH therapy withdrawal, the second evaluation of GH secretion was performed in all the patients. In 24% of patients, permanent severe GHD (PSGHD) was confirmed, but a group of 9 patients (4 male) was involved in renewed GH therapy. Results: The renewed GH therapy gave positive effects, including a significant increase in fat-free mass and a decrease in fat mass, and a significant decrease in LDL-cholesterol, but connected with an insignificant decrease of HDL-cholesterol serum concentration and improved results of quality of life (QoL) assessment. During the therapy, an insignificant increase of fasting insulin was observed, with no change in fasting glucose and only a slight increase in HbA1c percentage. A decrease of insulin sensitivity was also observed, but both insulin secretion and the values of insulin resistance indices still remained within the reference range. Conclusions: The observed positive effects on body composition, lipid metabolism and QoL, together with the absence of adverse events, confirm the indications for GH therapy in young adults with severe GHD

Incidence and predictors of persistent growth hormone deficiency (GHD) in patients with isolated, childhood-onset GHD

Wstęp: U znacznej części pacjentów z rozpoznaną w dzieciństwie somatotropinową niedoczynnością przysadki (SNP) stwierdza się normalizację wydzielania hormonu wzrostu (GH) po osiągnięciu wzrostu końcowego (FH). Celem pracy była ocena częstości i czynników prognostycznych trwałego i przemijającego niedoboru GH u dzieci z rozpoznaną w dzieciństwie izolowaną, nienabytą SNP.Materiał i metody: Analizą objęto 150 dzieci (117 chłopców) z niedoborem wzrostu, z rozpoznaną w dzieciństwie izolowaną, nienabytą SNP, którzy zakończyli terapię GH i uzyskali FH. Przed leczeniem i po osiągnięciu FH oceniono wybrane wskaźniki auksologiczne oraz wydzielanie GH i IGF-I; przed leczeniem zmierzono ponadto wysokość przysadki (PHt).Wyniki: Częstość trwałego niedoboru GH wynosiła 12,0%. Pacjenci z trwałym niedoborem GH mieli przed leczeniem znamiennie niższe wydzielanie GH i niższe stężenia IGF-I, a także uzyskali większy przyrost SDS wysokości ciała (DHSDS) podczas terapii GH niż pacjenci z przemijającym niedoborem GH. Stwierdzono ujemną korelację pomiędzy DHSDS i wydzielaniem IGF-I, przy braku korelacji między DHSDS a wydzielaniem GH. Częstość występowania hipoplazji przysadki u pacjentów z trwałym i przejściowym niedoborem GH nie różniła się znamiennie.Wnioski: Częstość trwałego niedoboru GH u pacjentów z rozpoznaną w dzieciństwie izolowaną, nienabytą SNP jest względnie niska. Pomimo istnienia czynników warunkujących trwały niedobór GH w tej grupie pacjentów, możliwych do zidentyfikowania w momencie rozpoznania SNP w dzieciństwie, u wszystkich pacjentów z tej grupy rozpoznanie niedoboru GH wymaga weryfikacji podczas ponownej diagnostyki przeprowadzonej po uzyskaniu FH. (Endokrynol Pol 2014; 65 (5): 334–341)Introduction: In a considerable proportion of patients with childhood-onset growth hormone (GH) deficiency (GHD), a normalisation of GH secretion at the attainment of final height (FH) is observed. The aim of the present study was to assess the incidence of, and to find out the predictors of, persistent and transient GHD, available in the pre-treatment period, in patients with childhood-onset isolated, non-acquired GHD.Material and methods: The analysis comprised 150 short children (117 boys), with childhood-onset isolated, non-acquired GHD who completed GH therapy and attained FH. Before treatment and at FH (in retesting), auxological parameters were measured, GH peak in stimulation tests and IGF-I concentration were assessed, and pituitary height (PHt) was measured before treatment.Results: The incidence of persistent GHD was 12.0%. The patients with persistent GHD had before treatment significantly lower GH and IGF-I secretion, as well as significantly better increase of height SDS (DHSDS) during GH therapy than those with transient GHD. A negative correlation was observed between DHSDS and IGF-I concentration, but not between DHSDS and GH peak. There was no significant difference in the incidence of pituitary hypoplasia between the patients with persistent and transient GHD.Conclusions: The incidence of persistent GHD in patients with childhood-onset, isolated, non-acquired GHD is relatively low. Despite the fact that the predictors of persistent and transient GHD may be identified in childhood, a diagnosis of GHD should be verified in retesting after the attainment of FH in each case. (Endokrynol Pol 2014; 65 (5): 334–341

Do IGF-I concentrations better reflect growth hormone (GH) action in children with short stature than the results of GH stimulating tests? Evidence from the simultaneous assessment of thyroid function

<p>Abstract</p> <p>Background</p> <p>The diagnosis of growth hormone (GH) deficiency (GHD) in short children seems unquestionable when both GH peak in stimulating tests (GHST) and IGF-I concentration are decreased. However, the discrepancies between the results of GHST and IGF-I secretion are observed. It seems purposeful to determine the significance of GHST and IGF-I assessment in diagnosing GHD. The relationship between GH secretion and thyroid function, as well as GH influence on the peripheral thyroxine (T₄) to triiodothyronine (T₃) deiodination, mediated by IGF-I, were identified. Thus, clear differences in thyroid function between GH-deficient and non-GH-deficient subjects should exist.</p> <p>Methods</p> <p>Analysis comprised 800 children (541 boys), age 11.6 ± 3.1 years (mean ± SD), with short stature, in whom two (2) standard GHST (with clonidine and with glucagon) were performed and IGF-I, free T₄(FT₄), free T₃(FT₃) and TSH serum concentrations were assessed. The patients were qualified to the following groups: GHD - decreased GH peak in GHST and IGF-I SDS (n = 81), ISS - normal GH peak and IGF-I SDS (n = 347), low GH - normal IGF-I SDS, and decreased GH peak (n = 212), low IGF - decreased IGF-I SDS, and normal GH peak (n = 160). The relationships among the results of particular tests were evaluated.</p> <p>Results</p> <p>In the groups with decreased IGF-I concentrations (GHD Group and low IGF Group), the more severe deficit of height was observed, together with higher TSH and FT₄but lower FT₃levels than in groups with normal IGF-I concentrations (ISS Group and low GH Group), independently of the results of GHST. TSH, FT₄and FT₃concentrations were - respectively - similar in two groups with decreased IGF-I secretion, as well as in two groups with normal IGF-I levels. Significant correlations were found between patients' height SDS and IGF-I SDS, between FT₃and IGF-I SDS (positive), and between FT₄and IGF-I SDS (negative), with no correlation between GH peak and any of the parameters analyzed.</p> <p>Conclusion</p> <p>The assessment of thyroid function in children with short stature provides the evidence that measurement of IGF-I concentration may be a procedure reliable at least to the some degree in diagnosing GHD as the results of GHST.</p

Limited usefulness of the test of spontaneous growth hormone (GH) nocturnal secretion as a screening procedure in diagnosing GH deficiency in children with short stature

[b]introduction and objective[/b]. In Poland, the assessment of nocturnal GH secretion has gained the status of screening test; however, this procedure is not included in international recommendations. The aim of the study was to assess the accuracy and predictive value of the test of nocturnal GH secretion as a screening procedure in diagnosing GHD, and to check the adequacy of the cut-off value for GH peak in this test on the level of 10 ng/ml. [b]materials and methods. [/b]The analysis comprised the data of 1,000 children with short stature. In all the patients, GH secretion was assessed in a screening test (after falling asleep) and in 2 stimulating tests (reference tests), with simultaneous assessment of IGF-I secretion before stimulating tests. The indices of screening test accuracy, likelihood ratios and predictive values were assessed. The cut-off level of GH peak after falling asleep, ensuring its 95% sensitivity, was calculated in ROC curve analysis. [b]results[/b]. Sensitivity of the screening test was 70.4%, while the specificity – 61.2%, positive likelihood ratio – 1.842, negative likelihood ratio – 0.482, positive predictive value – 0.462, negative predictive value – 0.812. The sensitivity of the test of GH secretion after falling asleep is too low with respect to the requirements for screening test. The ROC curve analysis showed 95% sensitivity for the screening test on the level of 19.0 ng/ml; however, with a very low specificity – below 25%, thus making this test completely useless as a screening procedure. [b]conclusions.[/b] The obtained results strongly contradict the opinion that the assessment of GH secretion after falling asleep should be a screening test in diagnosing GHD in children with short stature

Częściowy niedobór hormonu wzrostu (GHD) u dzieci - więcej podobieństw do idiopatycznej niskorosłości niż do ciężkiego GHD

Introduction: Assessment of growth hormone (GH) secretion is based on stimulation tests. Low GH peaks in stimulation tests, together with decreased insulin-like growth factor-I (IGF-I) secretion, confirm a diagnosis of GH deficiency (GHD). However, limitations in interpreting the test results and discrepancies between GH and IGF-I secretion in particular patients have both been reported. GH therapy should improve the prognosis of adult height (PAH). The aim of the study was to compare the deficit of height at diagnosis, IGF-I secretion and PAH in children with either decreased (in varying degrees of severity) or normal GH secretion in stimulation tests. Material and methods: The analysis comprised 540 short children (373 boys, 167 girls), aged 11.7 &plusmn; 3.2 years. In all the patients two GH stimulation tests were performed, IGF-I serum concentration was measured, bone age was assessed and PAH was calculated. According to the GH peak in the two stimulation tests, the patients were classified into the following groups: severe GHD (sGHD) - GH peak < 5 ng/mL (n = 44), partial GHD (pGHD) - GH peak 5&#8211;10 ng/mL (n = 190), idiopathic short stature (ISS) - GH peak at least 10 ng/mL (n = 306). Results: A significantly greater deficit of height, lower IGF-I secretion and worse PAH were observed in sGHD than in both remaining groups, while all the differences between pGHD and ISS in the parameters analysed were insignificant. Conclusion: The results obtained indicate the necessity of applying another methods of qualifying short children for GH therapy other than GH stimulation tests with a cut-off value at a level of 10 ng/mL. (Pol J Endocrinol 2007; 58 (3): 182-187)Wstęp: Podstawową metodą oceny wydzielania hormonu wzrostu (GH) są testy stymulacyjne. Stwierdzenie obniżonego maksymalnego wydzielania GH (maxGH) w testach stymulacyjnych oraz obniżonego stężenia insulinopodobnego czynnika wzrostowego-I (IGF-I) w surowicy stanowi podstawę rozpoznania niedoboru GH (GHD). Istnieje jednak szereg ograniczeń w interpretacji wyników testów stymulacyjnych, jak również rozbieżności pomiędzy wynikami testów a wydzielaniem IGF-I u poszczególnych pacjentów. Terapia preparatem GH powinna prowadzić do poprawy prognozy wzrostowej pacjentów. Celem pracy było porównanie ciężkości niedoboru wzrostu, stężenia IGF-I i prognozy wzrostowej u pacjentów z prawidłowym i w różnym stopniu obniżonym wydzielaniem GH. Materiał i metody: Analizą objęto dane 540 dzieci (373 chłopców, 167 dziewcząt) z niedoborem wzrostu, w wieku 11,7 &#177; 3,2 lat, u których wykonano 2 testy stymulacyjne na wydzielanie GH i oznaczono stężenie IGF-I w surowicy oraz oceniono wiek kostny i obliczono prognozę wzrostową. W zależności od maksymalnego wydzielania GH w testach stymulacyjnych, pacjentów podzielono na grupy: ciężki GHD (sGHD) - maxGH < 5 ng/ml (n = 44), częściowy GHD - maxGH 5-10 ng/ml (n = 190), idiopatyczny niski wzrost (ISS) &#8212; maxGH &#8805; 10 ng/ml (n = 306). Wyniki: Stwierdzono znamiennie cięższy niedobór wzrostu, znamiennie niższe wydzielanie IGF-I oraz znamiennie gorszą prognozę wzrostową u pacjentów z sGHD niż w obu pozostałych grupach przy braku znamiennych różnic w zakresie wszystkich analizowanych parametrów pomiędzy pacjentami z pGHD i ISS. Wniosek: Uzyskane wyniki wskazują na celowość stosowania w praktyce klinicznej innych metod diagnostycznych i kryteriów kwalifikacji dzieci z niedoborem wzrostu do terapii GH niż wartość progowa maxGH w testach stymulacyjnych na poziomie 10 ng/mL. (Endokrynol Pol 2007; 58 (3): 182-187

Ocena wydzielania prolaktyny u dzieci: profil dobowego wydzielania prolaktyny i zasady jego interpretacji

Introduction: Prolactin (Prl) is secreted in a circadian pattern, although no method of interpreting it has yet been established. The aim of the study was to assess Prl secretion in children on the basis of the Prl circadian profile and to establish principles for the interpretation of the results obtained by this method. Material and methods: The analysis comprised 41 healthy short children (25 boys); aged 5.2-16.3 years, in whom hormonal disorders and chronic diseases had been excluded. The children were divided into prepubertal or pubertal subgroups. Serum Prl concentrations were measured every 3 hours for 24 hours. To assess the rhythm the parameters of macroscopic analysis were calculated and receiver operating characteristic (ROC) analysis was performed. The group for comparison consisted of 30 children aged 8.9-17.2 years with hyperprolactinaemia. Results: In each subgroup significantly higher Prl concentrations were observed at night than by day. No statistical differences were noticed between the groups regarding Prl concentrations at particular time points or parameter values during circadian Prl rhythm evaluation. In the group analysed weak correlations were found between age and Prl peak and trough levels. On the basis of ROC analysis criteria for the existence of normal circadian Prl rhythm in children were established. Conclusions: 1. The presence of normal circadian Prl rhythm is observed if at least one of the following three criteria is fulfilled: amplitude >1.8779; Xn/Xd ratio >1.685; regression indexWstęp: Prolaktyna (Prl) jest wydzielana w rytmie dobowym, jednak dotychczas nie ustalono metody jego interpretacji. Celem pracy była ocena wydzielania Prl u dzieci na podstawie badania dobowego profilu Prl i ustalenie zasad interpretacji uzyskanych wyników badania. Materiały i metody: Do badań zakwalifikowano 41 zdrowych niskich dzieci (25 chłopców); w wieku 5,2-16,3 lat, u których wykluczono zaburzenia hormonalne i choroby przewlekłe. Dzieci zostały podzielone na podgrupy ze względu na stadium dojrzewania płciowego. Stężenie Prl oznaczano w surowicy, co 3 godziny przez 24 godziny. W celu oceny istnienia prawidłowego rytmu Prl obliczono parametry analizy makroskopowej oraz przeprowadzono analizę receiver operating characteristic (ROC). Grupę porównawczą stanowiło 30 dzieci w wieku 8,9-17,2 lat z hiperprolaktynemią. Wyniki: W każdej podgrupie stwierdzono znamiennie wyższe stężenie Prl w nocy niż w ciągu dnia. Pomiędzy podgrupami nie zaobserwowano żadnych znamiennych różnic w odniesieniu do stężenia Prl w tych samych punktach czasowych oraz wartości parametrów opisujących dobowy profil Prl. Ustalono istnienie słabej, znamiennej korelacji pomiędzy wiekiem kalendarzowym dzieci a maksymalnym i minimalnym stężeniem Prl w ciągu doby. Opierając się na analizie ROC, ustalono kryteria świadczące o istnieniu prawidłowego rytmu dobowego Prl u dzieci. Wnioski: 1. Za istnieniem prawidłowego rytmu dobowego wydzielania Prl przemawia spełnienie przynajmniej jednego z 3 kryteriów: amplituda > 1,8779; współczynnik Xn/Xd > 1,685; współczynnik regresji < -0,4107. 2. U dzieci nie ma potrzeby stosowania innej, niż wymieniona, interpretacji wyników badania dobowego profilu Prl w zależności od wieku, płci czy stadium dojrzewania płciowego badanego dziecka

Relationship between IGF-I Concentration and Metabolic Profile in Children with Growth Hormone Deficiency: The Influence of Children’s Nutritional State as well as the Ghrelin, Leptin, Adiponectin, and Resistin Serum Concentrations

Background. Some, however not all, children with growth hormone deficiency (GHD) reveal a tendency towards metabolic disorders. Insulin-like growth factor I (IGF-I) is the main mediator of GH anabolic effects. Objective. The aim of the study was to compare ghrelin, adiponectin, leptin, resistin, lipid, glucose, and insulin concentrations in GHD children, depending on the IGF-I bioavailability. Methods. The analysis comprised 26 children with GHD, aged 5.7–15.3 yrs. Fasting serum concentrations of IGF-I, IGFBP-3, ghrelin, leptin, adiponectin, resistin, lipids, glucose, and insulin were measured. The GHD children were divided into two subgroups: (1) with lower IGF-I/IGFBP-3 molar ratio and (2) with higher IGF-I/IGFBP-3 molar ratio. The control group consisted of 39 healthy children, aged 5.1–16.6 yrs, of normal height and body mass. Results. GHD children with lower IGF-I/IGFBP-3 molar ratio were found to have a significantly lower body mass and insulin and triglyceride concentrations, as well as significantly higher ghrelin and adiponectin concentrations than GHD children with higher IGF-I/IGFBP-3. Conclusions. A better metabolic profile characterised GHD children with low IGF-I bioavailability. This phenomenon may be the result of high adiponectin and ghrelin concentrations in those children and their influence on adipose tissue, glucose uptake, and orexigenic axis

Ogólnopolski Program Leczenia Ciężkiego Niedoboru Hormonu Wzrostu u Osób Dorosłych oraz u Młodzieży po Zakończeniu Terapii Promującej Wzrastanie

Growth hormone (GH) has been used in the treatment of short stature in children with GH deficiency (GHD) for 60 years, and for about 30 years also in the treatment of adults with GHD, in whom such treatment is carried out due to metabolic indications. In Poland, GH treatment is reimbursed only in children with GHD, while so far it has not been refunded in adults with GHD. There are two groups of adults (or adolescents after growth completion) with GHD, who require GH therapy: patients with GHD that occurred in childhood (childhood-onset GHD — CO-GHD) and patients with GHD acquired in adulthood (adulthood-onset GHD — AO-GHD). This review presents a brief outline of the history of GH treatment in humans, the latest data on the causes and symptoms of GHD in adults, and the complications of untreated GHD. Current recommendations regarding diagnosis, treatment and monitoring of GH therapy in adults are also discussed. Moreover, the review paper presents the objectives, assumptions, and plans of implementation of the “National Treatment Program for Severe Growth Hormone Deficiency in Adults and Adolescents after Completion of the Growth Promoting Therapy”, as well as the expected health and economic effects of introduction of GH treatment in adults with GHD in Poland.Od 60 lat hormon wzrostu (ang. growth hormone – GH) znajduje zastosowanie w terapii niskorosłych dzieci z niedoborem GH (GH deficiency – GHD), zaś od około 30 lat również w terapii osób dorosłych z GHD, u których leczenie to prowadzone jest ze wskazań metabolicznych. W Polsce leczenie GH podlega refundacji jedynie u dzieci z GHD, natomiast jak dotąd nie było refundowane u osób dorosłych z GHD. Osoby dorosłe (lub młodzież po zakończeniu procesu wzrastania) z GHD, które wymagają terapii GH, kwalifikuje się do 2 grup: GHD, który wystąpił w wieku dziecięcym (childhood-onset GHD – CO-GHD) oraz GHD nabyty w wieku dorosłym (adult-onset GHD – AO-GHD). W pracy przedstawiono krótki zarys historii leczenia GH u ludzi, omówiono najnowsze dane dotyczące przyczyn i objawów GHD u osób dorosłych oraz powikłania nieleczonego GHD. Omówiono aktualne zalecenia dotyczące diagnostyki oraz leczenia i monitorowania terapii GH u osób dorosłych. W podsumowaniu zaprezentowano cele, założenia oraz schemat realizacji „Ogólnopolskiego Programu Leczenia Niedoboru Hormonu Wzrostu u Osób Dorosłych oraz Młodzieży po zakończeniu Terapii Promującej Wzrastanie”, jak również spodziewane efekty zdrowotne i ekonomiczne wprowadzenia leczenia GH u osób dorosłych z GHD w Polsce

Treatment of severe primary IGF-1 deficiency using rhIGF-1 preparation — first three years of Polish experience

Introduction: The objective of this study was to analyse the effects of the first three years of treatment with recombinant human insulinlike growth factor 1 (rhIGF-1) in patients from the Polish population. Material and methods: Twenty-seven children (22 boys and five girls) aged 2.8 to 16.0 years old were qualified for treatment with rhIGF-1 (mecasermin) in different treatment centres, according to Polish criteria: body height below –3.0 SD and IGF-1 concentration below percentile 2.5 with normal growth hormone (GH) levels. Mecasermin initial dose was 40 μg/kg bw twice a day and was subsequently increased to an average of 100 μg/kg bw twice a day. Body height, height velocity, weight, body mass index (BMI), and adverse events were measured. Results: Mecasermin treatment resulted in a statistically significant increase in body height (1.45 ± 1.06 SD; p &lt; 0.01) and height velocity in comparison with pre-treatment values. The biggest change in height velocity happened during the first year and diminished during subsequent years. Body weight and BMI also increased significantly after treatment (1.16 ± 0.76 SD and 0.86 ± 0.75 SD, respectively; p &lt; 0.01). Eight patients reported adverse events. These were mild and temporary and did not require treatment modification except in two patients. Conclusions: Treatment with rhIGF-1 was effective and safe in Polish patients with primary IGF-1 deficiency. It had a clear beneficial effect on the height of the patients and significantly accelerated the height velocity, particularly in the first year of treatment

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

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 children diagnosed with isolated GHD present 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, and 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