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The effects of oxandrolone or biosynthetic human growth hormone (r-hGH) on the growth of 26 boys with constitutional delay of growth and puberty were studied. Both regimens increased growth rate twofold, oxandrolone to a greater extent than r-hGH. We conclude that oxandrolone is a more effective method of increasing growth rate in such children.
OBJECTIVES: Constitutional delay of growth and puberty (CDGP) is a variant of normal pubertal timing and progress, often with dominant inheritance. It is likely that one or more genes will be associated with CDGP. Possible candidates are the leptin (L) and the leptin receptor (LR) genes, as the leptin axis links nutritional status to pubertal development. This study has assessed whether a) L or LR gene polymorphisms were associated with CDGP and b) the CDGP phenotype was influenced by these polymorphisms. DESIGN: Case-control and transmission disequilibrium tests were used to test genetic association of L and LR polymorphisms with CDGP. METHODS: We genotyped L (3'CTTT repeat) and LR polymorphisms (Gln > Arg substitution, exon 6) in 81 CDGP children and 94 controls in the UK and 88 CDGP children from the US and assessed the effect of genotype on their anthropometric characteristics. RESULTS: There was no association of these L or LR gene polymorphisms with CDGP. There was no difference in height or bone age delay within L or LR genotypes. However, UK CDGP children homozygous for the L short allele were heavier than heterozygotes and long allele homozygotes, with a similar trend in the US cohort. UK CDGP children with severe pubertal delay, who were thin, had significantly greater bone age delay and an increased frequency of parental pubertal delay than other groups and were less likely to be L short allele homozygotes. CONCLUSIONS: There was no association of specific L or LR polymorphisms with CDGP, but L short allele carriage influenced the phenotype within CDGP.
Although it has been well established that GH treatment increases final height (FH) in girls with Turner syndrome (TS), the optimal ages to start GH therapy and introduce estrogens for pubertal induction have not been defined. We evaluated retrospectively the influence of the age at onset of GH treatment and age at onset of puberty on FH of 186 adult TS women treated during childhood with GH. Puberty started spontaneously in 38 patients, and it was induced in 148 girls with ethinyl estradiol (mean +/- SD starting dose, 66 +/- 32 ng/kg.d). Patients with spontaneous or induced puberty were divided into quartiles on the basis of age at initiation of GH treatment (3-10, 10-12, 12-14, and 14-19 yr). FH was 151.7 +/- 6.0 cm; there were no FH differences between patients with induced or spontaneous puberty, nor were there differences between the age quartiles. Puberty started earlier in the girls with spontaneous puberty than in those with induced puberty (12.4 +/- 1.3 yr vs. 14.5 +/- 1.9 yr; P < 0.0001). The age at onset of puberty was not related to FH. Pubertal growth was 15.4 +/- 4.6 cm in the girls with spontaneous puberty and 8.6 +/- 4.3 cm in the girls with induced puberty (P < 0.0001). We conclude that GH treatment results in a significant increase in FH in most TS girls. Under the conditions of GH treatment and induction of puberty that we have used, the age at start of GH treatment was not related to FH; in addition, late or delayed induced or spontaneous puberty did not affect FH.
This study reports on the endocrine abnormalities associated with delayed growth and puberty, observed in 10 children presenting with thalassemia major. Hormonal changes were followed up during treatment with regular transfusions and efficient chelating agents. Recovery of growth and onset of puberty were observed in most cases. When puberty was delayed, an associated substitutive treatment with sexual hormones was useful. In one case only, an isolated gonadotropic deficiency could be proven. In all cases STH, TSH and PRL secretions were normal. Without efficient and early treatment, the main consequence of the disease with respects to growth seems to be the risk of delayed puberty, mainly functional, or rarely hypogonadotropic due to definite LH and FSH deficiency.
Late puberty is defined as the lack of pubertal development at two standard deviations above the mean age for the general population of the geographical area. In practical terms, this is a chronological age of 14 years for males (testicular volume <4 ml) and 13 years for girls (lack of thelarche). The goal of the assessment is to determine whether the delay or lack of development is due to a lag in normal pubertal maturation or represents an abnormality that must be investigated. Etiologies of pubertal delay and pubertal failure include: a) Constitutional delay of puberty (healthy patients with a clinical history of delayed growth and development; b) Hypogonadotropic states (congenital abnormalities, tumours, endocrinopathies); c) Hypergonadotropic states (chromosomal alterations, syndromes, genetic disorders, radiotherapy/chemotherapy); d) Secondary to chronic illness (organic abnormalities, oncological diseases, malnutrition, eating disorders and endocrinopathies). Diagnostic evaluation must include: a detailed physical examination, including auxological parameters (height and bone maturation), personal and familial antecedents, measurements of general hematological and biochemical parameters, gonadotropins, prolactin, thyroid hormones, sex steroids, growth hormone and growth factors. When necessary, an MRI must be performed. A karyotype is indicated in girls with delayed puberty and short stature and in boys who have small testes and hypergonadotropism.
The effects of chronic phencyclidine (PCP) treatment on sexual maturation and seizure-susceptibility in the developing female rat were studied. Postnatal female rats were injected once daily with 5 mg/kg PCP from Day 5 till Day 15 and were observed for sexual maturation--vaginal opening and estrus cyclicity were used as indices of sexual maturation. PCP-treated rats showed a delay in both vaginal opening and in estrus cyclicity compared to saline-treated pair-fed controls. On postnatal Day 21, PCP-treated rats and saline-treated controls were tested for seizure-susceptibility using the pentylenetetrazol (PTZ)-induced seizure paradigm. PCP-treated female rats did not differ from saline-treated controls in their susceptibility to PTZ-induced seizures. In conclusion, chronic PCP administration during development in female rats disrupts sexual maturation but has no short-term effect on seizure susceptibility.
BACKGROUND: Constitutional delay of growth and puberty (CDGP) is a frequent cause of short stature in childhood. Controversial results have been reported on the full achievement of these patients of their target height. PATIENTS AND METHODS: The final adult height of 20 patients with CDGP (11 male and 9 female), who did not received hormonal treatment, was compared with their target height and with the predicted adult height, by the Bayley-Pinneau method obtained before the onset of puberty. RESULTS: A spontaneous improvement of the stature from pre-puberty to adulthood was observed in all patients (from -2.9 +/- 0.7 SDS to -1.3 +/- 0.6 SDS in male and from -2.6 +/- 0.6 SDS to -0.9 +/- 0.3 SDS in female; P < 0.001). Adult height in male (166.4 +/- 4.1 cm) at the mean age of 21 years was very close to the target height (165.7 +/- 3.9 cm) and to the predicted adult height (167.3 +/- 3.1 cm). Also in female, final height (156.6 +/- 2.0 cm) did not differ from target height (153.3 +/- 4.2 cm) and from predicted adult height (155.6 +/- 2.3 cm). CONCLUSIONS: In our experience, patients with CDGP reach their predicted adult height and achieve their genetic potential without medical treatment.
OBJECTIVE: To investigate the effect of low dose oxandrolone and testosterone on the pituitary-testicular and GH-IGF-I axes. DESIGN: Prospective double-blind placebo-controlled trial. PATIENTS: Sixteen boys with constitutional delay of growth and puberty (CDGP) with testicular volumes 4-6 ml were randomized to 3 months treatment: Group 1 (n = 5), daily placebo: Group 2 (n = 5), 2.5 mg oxandrolone daily or Group 3 (n = 6), 50 mg testosterone monthly intramuscular injections with assessment (growth, pubertal development and overnight hormone profiles) at 0, 3, 6 and 12 months. MAIN OUTCOME MEASURES: LH and GH profiles (15-minute samples) were analysed by peak detection (Pulsar), Fourier transformation and autocorrelation. Testosterone levels were measured hourly and insulin, SHBG, IGF-I, and IGFBP-3 levels at 0800 h. Statistical analysis was by multivariate analysis of variance for repeated measures. RESULTS: LH and testosterone parameters increased significantly with time in all 16 (LH AUC, P < 0.001; peak amplitude, P = 0.02; number of peaks, P = 0.02; testosterone AUC, P = 0.02; morning testosterone, P = 0.002). In Group 2, however, LH and testosterone parameters decreased at 3 months followed by a rebound increase at 6 and 12 months. SHBG levels were markedly reduced at 3 months (P = 0.006) and a wider range of dominant GH frequencies was present although GH AUC was not increased until 6 months, with an increase in GH pulse frequency but not amplitude. IGF-I levels were increased at both 3 and 12 months. In Group 3, pituitary-testicular suppression was not apparent, but GH levels increased with an increase in GH amplitude at 3 and 12 months. CONCLUSION: Oxandrolone transiently suppressed the pituitary-testicular axis and altered GH pulsatility. Testosterone increased GH via amplitude modulation.
This prospective study was designed to assess growth response, side effects, other possible long-term effects, and final adult height in boys treated with the oral androgen, fluoxymesterone. From 1973 to 1984, eighty-two short boys (71 with constitutional delay of growth and puberty [CDGP] and 11 with genetic short stature [GSS]) were treated with daily oral doses of 2.5 mg of fluoxymesterone from 6 to 60 months. Final height assessment was made from 1989 to 1991. A group of 34 untreated boys (26 with CDGP and 8 with GSS) were also followed to assess the accuracy of the Greulich-Pyle and Bayley-Pinneau (GP-BP) and sexual maturity index height prediction methods. During treatment, each patient had a 1.7- to 2.5-fold increase in linear growth velocity. Accelerated velocity (over baseline) continued as long as the bone age was less than 14 years. No adverse androgenic effects (or undue acceleration of puberty) were observed. Final height exceeded pretreatment predictions for CDGP + GSS by 6.1 +/- 3.5 (SD) cm (GP-BP) and 5.4 +/- 3.2 cm (sexual maturity index). It is concluded that a daily oral dose of 2.5 mg of fluoxymesterone can be used to accelerate linear growth in boys with CDGP and GSS when needed to alleviate emotional problems secondary to slow growth and short stature without fear of compromising final adult height.
The aim of this study was to evaluate bone mineral density and some markers of bone metabolism (alkaline phosphatase activity, osteocalcin concentration, deoxypirydinoline excretion), as well as the influence of physical activity and dietary calcium supplementation on bone density and bone metabolism in boys with a constitutional delay of growth and puberty (CDGP), in relation to calendar age, bone age and pubertal stage. The study was done in 41 boys aged 8-18 years with CDGP diagnosed on the basis of family history and typical pattern of growth, with prior exclusion of hormonal and non-hormonal causes of height deficiency. According to Tanner's criteria, boys were assigned to 4 groups corresponding to 4 stages of puberty (Tab. 1). Total body (total BMD) and lumbar spine (L2L4 BMD) bone mineral density were obtained using DEXA densitometry. The activity of alkaline phosphatase (AP) and serum osteocalcin (OC) concentration served as markers of bone formation. 24-h urinary deoxypirydinoline (DPD) excretion was a marker of bone resorption. Using a questionnaire, daily dietary calcium intake and physical activity were established. A positive correlation between calendar age, total BMD and L2L4 BMD was found (R = 0.70 and R2 = 0.49; R = 0.72 and R2 = 0.51; p < 0.001, respectively). Bone age was positively correlated with total BMD and L2L4 BMD (for both correlations R = 0.68, R2 = 0.47; p < 0.001). Total BMD adjusted for calendar age revealed osteoporosis in 4 cases (9.7%), osteopenia in 19 cases (46.3%) and normal bone density in 18 cases (43.9%). After adjustment of BMD to bone age, 2 boys (4.9%) were diagnosed with osteoporosis, 9 (21.9%) with osteopenia, and 30 (73.2%) with normal bone density. L2L4 BMD adjusted for calendar age showed osteoporosis in 6 cases (14.6%), osteopenia in 21 cases (51.2%) and normal density in 14 cases (34.2%). After adjustment of BMD to bone age, 3 boys (7.3%) were diagnosed with osteoporosis, 10 (24.4%) with osteopenia, and 28 (68.3%) with normal bone density. A significant correlation between stage of puberty, total BMD (p < 0.045) and L2L4 BMD (p < 0.001) was found. Values for total BMD and L2L4 BMD in boys with CDGP in relation to pubertal stage are presented in Table 2. Mean AP activity, serum OC concentration, DPD excretion, dietary calcium intake and physical activity in boys at consecutive stages of puberty are presented in Table 3. No significant correlation between pubertal stage, markers of bone metabolism, daily dietary calcium intake or physical activity was found. The boys were next grouped according to level of physical activity: low (< 10 h/week) or high (> 10 h/week). Table 4 summarizes the results for both groups. No significant differences between the groups were found concerning the parameters studied. Two groups with a low (< 1.2 g) and high (> 1.2 g) dietary calcium intake were also formed. The results for both groups are presented in Table 5. A significant correlation between dietary calcium intake and total BMD (R = 0.34 and R2 = 0.11; p < 0.03) was revealed. On the basis of these results it can be concluded that BMD values in boys with CDGP should be adjusted for bone age, thus significantly limiting the diagnosis of osteoporosis and osteopenia. BMD values for these boys increase with consecutive pubertal stage, while markers of bone metabolism do not reveal significant abnormalities (markers of bone formation increase until stage IV, markers of bone resorption show fluctuating values).
Fifty-six prepubertal Hereford cross Friesian heifers were assigned to seven treatment groups: (1) primary (day 0) and booster (day 41) using 10 mg human serum albumin (HSA) (control); (2) primary and booster (day 41) immunizations using 3.3 mg prostaglandin F2 alpha PGF-HSA conjugate; (3) primary and booster (day 83) using 3.3 mg PGF-HSA; (4) primary and booster (day 210) using 3.3 mg PGF-HSA; (5-7) as in treatments 2-4 except 10 mg PGF-HSA were used. Plasma progesterone concentrations were used to determine the onset of puberty and the presence of a corpus luteum (CL); plasma PGF antibody titres were determined at 28-day intervals. There was no effect (P > 0.05) of conjugate dose or booster interval on mean antibody titres and there was no interaction between them. However, heifers in the 83- and 210-day booster treatments had higher (P < 0.05) peak antibody titres than heifers in the 42-day booster treatments. Puberty was delayed in 40% (16/40) of PGF-immunized heifers and 40% (16/40) of heifers formed persistent CL after puberty. Overall, eight of the heifers with delayed puberty also formed a persistent CL. There was a positive correlation between mean titre and onset of puberty but not with duration of persistent CL.
Helicobacter pylori is a gastroduodenal pathogen strongly associated with chronic gastritis and duodenal ulceration. It is thought that H. pylori infection might be one of the causes of growth retardation in children. The aim of this study was to evaluate the seroprevalence of H. pylori in children with constitutional delay of growth and puberty (CDGP). H. pylori seropositivity was studied in 24 children with CDGP (22 M, 2 F) and 32 healthy age-matched children with normal pubertal development. Mean age of the children with CDGP was 14.53 +/- 1.12 yr and all of them had been diagnosed as CDGP after physical and laboratory assessment. H. pylori IgG positivity was detected in 16 of the 24 children with CDGP (66.6%) and 12 of 32 controls (37.5%) (p <0.05). This finding is consistent with the hypothesis that H. pylori infection could be one of the environmental factors causing CDGP.
BACKGROUND/AIMS: According to FDA-approved guidelines, boys whose height predictions fall to 160 cm or less are considered for treatment with recombinant growth hormone (rGH). The aim of this study was to analyze the value of different height prediction methods by accurately identifying those boys with constitutional delay of growth and puberty (CDGP) in whom final height (FH) prognosis was poor (<or=160 cm) and who might therefore be candidates for this treatment modality. METHODS: In 69 boys with CDGP diagnosed at a mean age of 14.9 +/-1.2 years, FH prediction was calculated by means of Bayley-Pinneau (BP), Roche-Wainer-Tissen (RWT), Tanner-Whitehouse II (TWII) and target height (TH) methods. At the age of 22.6 +/- 3.5 years their height was remeasured and the accuracy of height prediction was analyzed. RESULTS: In 6 men (8.7%) measured FH was <or=160 cm. Depending on the prediction method, different individual patients within the 14- to 16-year age range would have been candidates for rGH treatment. The BP method would have recruited 8 subjects of whom only 3 had FH <or=160 cm (sensitivity 50%, specificity 92%). The RWT and TW II methods identified only one recruit, and this patient did achieve FH <or=160 cm (sensitivity 17%, specificity 100%). None of the 8 subjects with FH <or=160 cm would have qualified for GH treatment using the TH method. In three boys none of the four methods predicted their final height <or=160 cm. CONCLUSION: Although some boys with CDGP may be considered the candidates for rGH treatment according to FDA recommendations, none of the available methods of prediction are sufficiently sensitive to reliably recruit 14- to 16-year-old boys whose final height will fall at or below 160 cm.
Serotonin and norepinephrine levels in the hypothalamus and blood of albino female rats with a normal and abnormal course of puberty were studied to find a solution to the problem of the role of monoamines in the pathogenesis of pubertal disorders. Intense physical exercise the 21- and 40-day animals were subjected to, was used to simulate a delay in puberty. It was established that the nature and intensity of disorders of the sexual system were determined, to a certain extent, by changes in the monoamine content in the hypothalamus over time. A significant rise of the serotonin level and a simultaneous decrease in the epinephrine level were revealed in the rats with delayed puberty. Possible mechanisms of the role of monoamines in the pathogenesis of pubertal disorders, function of the female sexual system in the period of puberty are discussed.
To determine the natural history and psychological impact of the growth pattern in boys with constitutional delay in growth and puberty (CDGP), 43 boys presenting with short stature due to CDGP were followed up to final height. At presentation mean (SD) chronological age was 14.0 (1.9) years, bone age delay 2.7 (1.0) years, standing height standard deviation score (SDS) -3.4 (0.6), and predicted adult height SDS -1.3 (0.7). Final adult height SDS was -1.6 (0.9), measured at 21.2 (2.6) years. There was no significant difference between final height and predicted adult height, but there was a significant difference between final height and measured mid-parental height. Psychological questionnaires showed no significant difference in self esteem, marital, or employment state between the CDGP group and a control group. There was no correlation between self esteem and final height, but 25 felt their growth delay had affected their success either at school, work, or socially and 20 would rather have had treatment to advance their growth spurt. This study supports the more frequent use of active medical treatment to advance growth in boys with CDGP, and shows that although boys with CDGP reach their predicted heights, this is short for their families.
The aim of the study was to determine serum concentration and urinary excretion of selected parameters of bone metabolism in boys with constitutional delay of growth and puberty (CDGP) in the relation to pubertal stages. The study group consisted of 41 boys (aged 8 to 18 yrs) with CDGP. Patients were divided on the basis of Tanner's criteria into 4 groups according to the pubertal stage. Serum alkaline phosphatase (AP) activity and serum osteocalcin (OC) concentration as markers of bone growth, as well as urinary deoxypyridinoline (DPD) as a marker of bone resorption were determined. Serum AP activity in 31 (75.6%) boys was within normal age range. Mean values of serum AP activity increased insignificantly from I to IV stage of puberty. Serum OC concentrations were normal in 33 (80.5%) patients. Eight (19.5%) boys showed decreased values of serum OC concentration. Mean OC concentration insignificantly increased with the pubertal stages. DPD urinary excretion was within normal age range in all patients and was the highest in stage III of pubertal stage. No significant abnormalities of bone metabolism parameters in boys with constitutional delay of growth and puberty were found.
We report on 49 boys with constitutional growth delay (CGD) who were initially seen in our clinic at a mean chronological age of 13.3 years (range, 7.3-16.4) and a bone age of 11.1 years (range, 6.0-13.5). All were below the 5th height percentile for chronological age. A positive family history with delayed growth and puberty in one or both parents could be elicited in 75%. All 49 patients were re-examined at a mean age of 22.9 years (range, 20.4-31.2). Measured final height was 171.3 cm (range, 161.2-181.7), which was slightly, but significantly lower than mean target height of 173.0 cm. Final height expressed as standard deviation score (SDS) of a male adult population standard was -1.0 (range, -2.4 to 5), also significantly lower than initial height SDS related to bone age (SDSBA) of -0.5 (range, -1.6 to 2). If related to target height (Tanner), final height was found to correlate positively with the initial bone age deficit and the initial height SDSBA. Observed final height was also compared with the predicted adult height by the methods of Bayley-Pinneau (BP), Tanner-Whitehouse Mark II (TW II) and Roche-Wainer-Thissen. Regression equations between all three prediction methods and final height showed an excellent correlation (P < 0.0001). However, only by the BP method was predicted height very close to and no different from measured final height (paired t-test). Despite this, final height in 16 of 49 patients (32.6%) differed by more than 5.0 cm from BP predicted height.(ABSTRACT TRUNCATED AT 250 WORDS)
This paper highlights a series of studies using the male rhesus monkey that has led to a model for the control of the onset of puberty in higher primates. The model proposes that the timing of puberty in these species is governed by the duration of a central brake that, during juvenile development, holds in check the hypothalamic network of gonadotropin-releasing hormone (GnRH) neurons, which, in the adult, drive the pituitary-gonadal axis. The neurobiology of this hypothalamic brake, and the physiological mechanisms that time its application and removal, are incompletely understood. Nevertheless, the pubertal resurgence of pulsatile GnRH release, which terminates the juvenile phase of primate development and triggers the initiation of puberty in man and monkeys, is associated with structural and molecular remodeling of the hypothalamus. A major component of this developmental plasticity appears to involve neuropeptide Y (NPY). NPY inhibits GnRH release, and NPY gene expression in the hypothalamus is elevated during juvenile development when GnRH release is restrained. Since the changes in hypothalamic function and morphology that trigger primate puberty unfold in the absence of gonadal steroid feedback, the possibility is raised that, in addition to activating the pituitary-gonadal axis at this stage of development, they may also contribute directly to the causation of behaviors and affective states that emerge at adolescence.