Response to growth hormone treatment in very young patients with growth hormone deficiencies and mini-puberty.

BACKGROUND: The aim of the study was to assess the response to growth hormone (GH) treatment in very young patients with GH deficiency (GHD) through a national, multi-center study. Possible factors affecting growth response were assessed (especially mini-puberty). METHODS: Medical reports of GHD patients in whom treatment was initiated between 0 and 3 years of age were retrospectively evaluated. RESULTS: The cohort numbered 67. The diagnosis age was 12.4±8.6 months, peak GH stimulation test response (at diagnosis) as 1.0±1.4 ng/mL. The first and second years length gain was 15.0±4.3 and 10.4±3.4 cm. Weight gain had the largest effect on first year growth response; whereas weight gain and GH dose were both important factors affecting second year growth response. In the multiple pituitary hormone deficiency (MPHD) group (n=50), first year GH response was significantly greater than in the isolated GH deficiency (IGHD) group (n=17) (p=0.030). In addition first year growth response of infants starting GH between 0 and 12 months of age (n=24) was significantly greater than those who started treatment between 12 and 36 months of age (n=43) (p<0.001). These differences were not seen in the second year. Δ Length/height standard deviation score (SDS), Δ body weight SDS, length/height SDS, weight SDS in MPHD without hypogonadism for the first year of the GH treatment were found as significantly better than MPHD with hypogonadism. CONCLUSIONS: Early onsets of GH treatment, good weight gain in the first year of the treatment and good weight gain-GH dose in the second year of the treatment are the factors that have the greatest effect on length gain in early onset GHD. The presence of the sex steroid hormones during minipubertal period influence growth pattern positively under GH treatment (closer to the normal percentage according to age and gender).

A unique case of growth hormone and human chorionic gonadotropin treatment in a 45,X male with Y: autosome translocation and literature review.

Maleness associated with a 45,X karyotype is a rare condition in childhood. It is usually diagnosed in adult age because of infertility. We report a unique case of an unbalanced translocation t(Y;21) in a 14-year-old boy with 45,X karyotype referred because of short stature, thin habitus and puberty delay. Hormone analysis showed low serum levels of basal testosterone, insulin-like growth factor (IGF-I) and gonadotrophins. Diagnosis of GH deficiency and puberty delay were made. He was treated with human chorionic gonadotropin (hCG) and GH therapy, respectively, for 6 and 24 months.

Growth and the Growth Hormone-Insulin Like Growth Factor 1 Axis in Children With Chronic Inflammation: Current Evidence, Gaps in Knowledge, and Future Directions.

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt are often seen during adolescence. The underlying inflammatory state mediated by proinflammatory cytokines, prolonged use of glucocorticoid, and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the GH-IGF axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biological therapy may lead to improvement of growth in some of these children, but approximately one-third continue to grow slowly. There is increasing evidence that the use of relatively high-dose recombinant human GH may lead to partial catch-up growth in chronic inflammatory conditions, although long-term follow-up data are currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis, systemic abnormalities of the GH-IGF axis, and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human GH in these conditions and discussed the role of recombinant human IGF-1.

GH therapy in transition age: state of the art and future perspectives.

Growth hormone (GH) has been recently approved by the Italian Health Authorities for use in transition patients with childhood onset-growth hormone deficiency (CO-GHD). GH in addition to promote linear growth influences several key metabolic processes. In particular, in the transition period, from late adolescent to early adulthood, GH plays an important role in the achievement of a complete somatic development including body composition, muscle mass maturation, full skeletal mineralization and reproductive maturation, as well as in the prevention of metabolic and cardiovascular risk. Therefore, GH replacement should be restarted if a GH stimulation test at the re-evaluation fulfills established criteria. Endocrinologists experienced in the care of GHD adolescent patients held a workshop in Rome, Italy in July 2012 to review in detail the literature data and compare experiences of five Italian endocrinological centers on the negative consequences of interrupting GH treatment and the positive effects of continued GH replacement on intermediary metabolism, heart, muscle, pubertal development, and bone. The aim of the meeting was to delineate the state of the art on GH therapy in transition age and provide suggestions to pediatric and adult endocrinologists for a smooth transition care.

Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with ß-thalassemia major.

Iron overload in ß-thalassemia major (TM) typically results in iron-induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long-term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion-dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P = 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n = 5) and hypoparathyroidism (n = 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P < 0.001) and the number of patients with lumbar spine osteoporosis significantly decreased (P = 0.022) irrespective of bisphosphonate therapy, hormonal replacement therapy, and calcium or vitamin D supplementation. There were no significant differences in the number of pediatric patients below the 5th centile for height between baseline and study completion. Six pregnancies occurred successfully, and four of them were spontaneous without ovarian stimulation. This is the first study evaluating endocrine function during the newest oral chelation therapy with deferasirox. A low rate of new endocrine disorders and a stabilization of those pre-exisisting was observed in a real clinical practice setting.

Partial normalization of pubertal timing in female mice with DSS colitis treated with anti-TNF-α antibody.

BACKGROUND: Inflammatory bowel disease (IBD) and resultant colitis occurring prior to puberty are frequently associated with delayed puberty and losses of growth and bone mineralization. Some of this delay may be due to colonic inflammation and associated systemic inflammation. To date no treatments for IBD have been shown to normalize the timing of puberty. Our objective in this study was to determine whether there is a normalization of the timing of puberty during treatment of colitis using monoclonal antibodies (abs) to tumor necrosis factor (TNF)-α. METHODS: We induced colitis in 23-day-old C57Bl6 female mice using 3% dextran sodium sulfate (DSS) for 7 days, followed by removal of DSS for an additional 3 days, resulting in 10 days of worsening colitis. DSS-treated mice received either TNF-α ab or Control ab on days 4 and 8 of colitis, while non-colitic Control mice received injections of TNF-α ab (Control + TNF-α ab). All groups were followed for the timing of vaginal opening until day of life 33, when they were euthanized for serum and colon collection. RESULTS: The DSS + TNF-α ab group had lower levels of systemic interleukin (IL)-6 and a partial normalization of the timing of vaginal opening compared to the DSS + Control ab group. There were no differences in weight gain, growth, or colon histological inflammatory scores between the DSS + TNFα ab and DSS + Control ab groups over the course of the experiment. CONCLUSIONS: We conclude that anti-TNF-α ab treatment causes a partial normalization of pubertal timing coincident with decreased systemic inflammation in DSS colitis. These data may have implications regarding growth and bone mineralization outcomes in pediatric IBD.

Anosmia predicts hypogonadotropic hypogonadism in CHARGE syndrome.

OBJECTIVE: To test the hypothesis that a smell test could predict the occurrence of hypogonadotropic hypogonadism (HH) in patients with CHARGE syndrome, which is a variable combination of ocular coloboma, heart defects, choanal atresia, retardation of growth/development, genital hypoplasia, and ear anomalies or hearing loss caused by mutations in the CHD7 (chromodomain helicase DNA binding protein 7) gene. STUDY DESIGN: We performed endocrine studies and smell testing (University of Pennsylvania Smell Identification Test) in 35 adolescent patients with molecularly confirmed CHARGE syndrome. RESULTS: Complete data on smell and puberty were available for 15 patients; 11 patients had both anosmia and HH, whereas 4 patients had normosmia/hyposmia and spontaneous puberty. In addition, 7 boys were highly suspected of having HH (they were too young for definite HH diagnosis, but all had cryptorchidism, micropenis, or both) and had anosmia. The type of CHD7 mutation could not predict HH because a father and daughter with the same CHD7 mutation were discordant for HH and anosmia. CONCLUSION: Anosmia and HH were highly correlated in our cohort, and therefore smell testing seems to be an attractive method for predicting the occurrence of HH in patients with CHARGE syndrome. The use of this test could prevent delay of hormonal pubertal induction, resulting in an age-appropriate puberty.

Comparison of oral and subcutaneous iron chelation therapies in the prevention of major endocrinopathies in beta-thalassemia major patients.

While hypertransfusion and subcutaneous iron chelation therapy have increased longevity of patients with beta-thalassemia (thal) major, endocrinopathies have become more common and impair the quality of their lives. Additionally, subcutaneous iron chelation therapy is an uncomfortable experience and can prevent patients from regular compliance with iron chelation therapy. We compared the efficacy of oral deferiprone (L1) to subcutaneous desferrioxamine (DFO) chelation therapy for the prevention of major endocrinopathies (growth hormone insufficiency, diabetes mellitus and gonadal dysfunction) among patients with beta-thal major to see if we could offer these patients an easier and more painless way to reduce their body iron load and related endocrine complications.

Impact of long-term iron chelation therapy on growth and endocrine functions in thalassaemia.

A large number of children treated from the time of diagnosis with modern transfusion and chelation therapy are now entering early adolescence or early adulthood, and only now can we evaluate how many complications, secondary to iron overload, can be prevented by daily s.c. desferrioxamine (DFX) therapy. In 1989, we planned a multi-centre study on growth and endocrine complications in patients who started chelation therapy with DFX early in life. Height, weight, endocrine complications, haematological variables and compliance with DFX were evaluated in a study group of 238 patients aged 2-17 years with beta-thalassaemia major regularly followed in 13 paediatric and haematological Italian centres. The LMS method by Cole and Green and the Mann-Whitney test were applied for statistical analysis. Twenty-six patients with thalassaemia (12.4%) had growth hormone insufficiency, five patients (2.1%) had primary hypothyroidism and four patients (1.7%) had hypoparathyroidism. Delayed puberty was present in 18.4% of boys and 17.7% of girls. At the beginning of chelation, standing height was in the normal range when compared to Swiss standards, while in the following years a progressive decline of growth was observed in both sexes. In conclusion, our study noted a positive effect of DFX therapy on sexual maturation and endocrine complications. Nevertheless, short stature has persisted despite major advances in treatment.

Delayed growth and puberty in patients with Gaucher disease type 1: natural history and effect of splenectomy and/or enzyme replacement therapy.

BACKGROUND: Growth retardation in childhood was only recently recognized as a prominent feature of Gaucher disease type 1, but there are few data on both the pubertal development and the final outcome of growth and sexual maturation. OBJECTIVE: To investigate the natural pattern of growth and puberty in patients with Gaucher disease type 1 and the effect of splenectomy and enzyme replacement therapy. METHODS: We retrospectively analyzed growth and puberty in 57 patients with Gaucher disease type 1; 52 were followed since childhood and/or prepuberty and 42 have reached sexual maturity and final height. In the analysis we considered severity of disease, time of splenectomy, and start of enzyme replacement therapy. RESULTS: Deceleration of growth at age 3-5 years was observed in 30 of 57 patients followed since early childhood while untreated: height-SDS decreased from -0.34 +/- 0.42 at age 0-3 years to -1.93 +/- 0.95 (P < 0.01) at age 7-10 years and was more pronounced with severe disease. A high prevalence (59.6%) of delayed puberty, which was more frequent with severe disease, was observed in 47 patients followed before and throughout puberty. No primary endocrine pathology was found. All patients, untreated as well as treated, with growth and pubertal delay had a spontaneous catch-up, achieved full sexual maturation, and most (83.3%) reached a final height within the range of parental height-standard deviation score. Splenectomy (partial and/or total) performed in 20 patients while still growing had a beneficial effect on growth, which was temporary in some and did not affect puberty. ERT improved growth in 11 patients who started therapy before puberty, as evidenced by a progressive increase in the height-SDS, and seemed to normalize the onset of puberty. CONCLUSIONS: Growth retardation in childhood and delay of puberty are characteristic of Gaucher disease type 1 and are more frequent with severe disease. There is a spontaneous catch-up later in life and most patients reach a final height within their genetic growth potential. Enzyme replacement therapy apparently normalizes growth and possibly also the onset of puberty.

Exercise and female adolescents: effects on the reproductive and skeletal systems.

It is generally accepted that exercise is beneficial for young women, since it increases cardiovascular fitness and reduces adiposity. Too much exercise can have negative effects on the reproductive and skeletal systems, however, including primary and secondary amenorrhea thought to be caused by several factors including low body weight and improper nutrition. Primary and secondary amenorrhea present similar patterns of luteinizing hormone and follicle stimulating hormone suppression, probably involving the hypothalamic-pituitary-gonadal axis and possibly also the hypothalamic-pituitary-adrenal axis. Recent research has also suggested that leptin (a hormone made by the fat cell) is a possible link between menstrual cycles and fat and energy levels. The female athletic triad consists of three interrelated problems: eating disorders, amenorrhea, and osteopenia. The most serious aspect of hypoestrogenism is its effect on bone growth of elite athletes; those with delayed menarche show a higher incidence of scoliosis, stress fractures, and osteopenia than do girls with normal menarche. The higher incidence of bone problems may be linked to a lower rate of bone accretion, which may lead to lower peak bone mass. Unfortunately, the loss may be irreversible. In addition to decreasing training and gaining weight, treatment for menarcheal delay may include oral contraceptive therapy.

A cross-sectional study of growth, puberty and endocrine function in patients with thalassaemia major in Hong Kong.

METHODOLOGY: A cross-sectional study of growth, puberty and endocrine function was performed on 35 girls and 33 boys with thalassaemia major. RESULTS: Despite regular transfusion and chelation therapy, 75% of the girls and 62% of the boys over the age of 12 years were below the third percentile for height. Hypogonadotropic hypogonadism was found in a similar percentage of patients. Moderate to marked zinc deficiency secondary to chelation therapy was considered unlikely because normal serum zinc levels were found in all but three of our patients, but we could not exclude the possibility of a marginal status of zinc nutrition causing growth failure. Growth hormone deficiency and diabetes mellitus were sometimes encountered but hypothyroidism, hypoparathyroidism and adrenal insufficiency were rare among our patients. Most of the patients with growth failure had normal growth hormone (GH) response to insulin induced hypoglycaemia. The serum insulin-like growth factor-1 (IGF-1) levels were low in our patients and no significant difference in the serum IGF-1 levels was found between prepubertal children with or without growth failure (0.4 +/- 0.1 mU/mL vs 0.37 +/- 0.11 mU/mL, P = 0.39). Similarly, no difference in the serum IGF-1 levels was found between pubertal children with or without growth failure (0.48 +/- 0.2 U/mL vs 0.56 +/- 0.14 U/mL, P = 0.26). CONCLUSIONS: Delayed sexual maturation and a possible defect in growth unrelated to the GH-IGF-1 axis may be responsible for the growth failure in adolescent children with thalassaemia major.

Asthma, glucocorticoids and growth.

Most asthmatic children grow normally. However, the disease itself and the treatments used, e.g. glucocorticoids (GCs) may affect growth, especially delaying puberty. Presently, the extensive use of early anti-inflammatory therapy is changing asthma to a milder disease and the effects on growth will probably further decline. Also, the use of inhaled instead of oral GCs has minimized the risk of systemic side-effects. High doses of inhaled GCs have systemic effects, and because there are individual differences in sensitivity to GCs, growth should be monitored in every child treated with GCs. The preparations with the lowest systemic bioavailability and the lowest dose to control asthma should be used.

Growth and sexual maturation in children with thalassemia major.

BACKGROUND AND METHODS. Growth and endocrine disturbances are still important problems for patients with thalassemia major, which is a major health problem in southern part of Turkey. In the present study 71 thalassemia major patients over 3 years of age were evaluated for physical and sexual maturation status. RESULTS AND CONCLUSION. Twenty-three patients (32.4%) were below the third centile for height. Growth retardation was more pronounced in patients 10 years of age and up according to height and weight standard deviation scores (SDS). Delay in bone age SDS was found in almost all patients, and 74.5% of our patients over 12 years of age had not yet entered puberty. These results show that growth and endocrine disturbances have significant negative effects in the quality of life of thalassemic patients. More detailed studies will help to solve these problems.

Parathyroid function and bone metabolism in children with beta thalassaemia major: effects of sex steroid treatment.

OBJECTIVE: Data on parathyroid function in patients with homozygous beta-thalassaemia are discordant. Moreover, there is no report on the effects of sexual steroid treatment on bone metabolism in these patients. METHODS: Serum parathyroid hormone (PTH), calcitonin (CT) and osteocalcin (GLA protein) levels were measured in 121 patients. Thirty-three prepubertal subjects were treated for six months with sexual steroids. RESULTS AND CONCLUSIONS: Primary hypoparathyroidism was present in 3.3% of the patients. Osteocalcin levels were found to be lower in thalassaemic subjects than in controls, whereas CT values were similar. No effects of sexual steroid administration on plasmatic levels of osteocalcin were observed.

Hypopituitarism and idiopathic delayed puberty: a longitudinal study in an attempt to diagnose gonadotropin deficiency before puberty.

Fifty-five hypopituitary patients (43 boys and 12 girls) treated with human GH were studied longitudinally before and during puberty, occurring either spontaneously or induced with testosterone enanthate (100 mg/month, im) in boys and ethinylestradiol (10 micrograms/day, orally) in girls. In addition, 53 boys with idiopathic delayed puberty (IDP) were studied. Gonadotropin integrated responses (IRs) during 90 min after the iv injection of 25 micrograms/m2 LRH, bone ages (BA), and plasma levels of dehydroepiandrosterone sulfate and testosterone were determined at least yearly. Prepubertal hypopituitary patients with gonadotropin deficiency were characterized by: 1) a lowered FSH IR to LRH in most boys and in all girls; 2) a low LH IR for BA; 3) adrenarche either absent or delayed BA; 4) height age close to BA; and 5) the presence of several pituitary deficiencies. In contrast, most prepubertal hypopituitary patients without gonadotropin deficiency showed: 1) a normal FSH IR to LRH; 2) a normal or intermediate (greater than or equal to 75 mIU/ml . 90 min) LH IR for BA; 3) a normal adrenarche for BA; 4) a height age below BA; and 5) isolated GH or GH plus TSH deficiencies. A significant linear correlation was found between LH IR and the logarithm of plasma testosterone. The slopes and levels were similar in controls and hypopituitary boy without gonadotropin deficiency. In IDP, the level was significantly higher. All data obtained in these patients show that the increase in plasma testosterone and the clinical onset of puberty are delayed for the observed pubertal pattern of LH responsiveness. It is concluded that the study of several clinical and biological features, especially the gonadotropin IR to LRH, are of predictive value for the diagnosis of normal or deficient gonadotropic function in prepubertal patients with IDP and hypopituitarism.