An exploratory study of positive and incongruent communication in young children with type 1 diabetes and their mothers.

BACKGROUND: The incidence of type 1 diabetes is increasing in young children. However, they are overlooked in treatment adherence and intervention research despite evidence that parents often experience difficulty securing their treatment cooperation, especially with the diet. We investigated positive and incongruent (i.e. the co-occurrence of contradictory verbal and non-verbal messages) communication in the mother-child dyad and their association with child adjustment and dietary adherence outcomes. METHODS: Participants were 23 6- to 8-year-old children with type 1 diabetes and their mothers. We conducted dietary adherence interviews with mothers and performed nutritional analyses to assess children's consumption of extrinsic sugars (e.g. confectionary). Mothers completed a standardized assessment of child psychological adjustment. Mothers and children engaged in a videotaped problem-solving task related to the dietary regimen, with maternal and child utterances and non-verbal behaviours analysed for positive dyadic and incongruent communication. RESULTS: Positive dyadic communication correlated with lower levels of child incongruent communication, fewer behavioural problems and better overall adjustment. Higher levels of maternal and child incongruent communication correlated with more behavioural and emotional problems and poorer overall adjustment. Higher levels of maternal incongruent communication correlated with poorer dietary adherence. CONCLUSIONS: Results converged to form a conceptually and empirically coherent pattern in that behavioural indices of poorer communication in both mother and child consistently correlated with poorer child adjustment outcomes. This study shows that specific features of dyadic, child and maternal communication could be targeted in developmentally sensitive interventions to promote positive communication in the home management of type 1 diabetes care for young children.

Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen.

BACKGROUND: Premature ovarian failure (POF) is currently managed by non-physiological sex steroid regimens which are inadequate at optimizing uterine characteristics. Previous short-term studies have demonstrated some benefits of a sex steroid replacement (SSR) regimen devised to replicate the physiological cycle. This study aimed to directly compare the effects of longer-term administration of physiological SSR (pSSR) and standard SSR (sSSR) regimens on the uterine volume, blood flow and endometrial thickness (ET) in women with POF. METHODS: In a controlled crossover trial, 34 women with POF were randomized to receive 12 months of 4-week cycles of transdermal estradiol and vaginal progesterone (pSSR) followed by 12 months of 4-week cycles of oral ethinylestradiol and norethisterone (sSSR), or vice versa. Each treatment period was preceded by a 2-month washout period. At 0, 3, 6 and 12 months of each treatment period, transvaginal ultrasound examined the uterine volume and ET, as primary end-points, and uterine artery resistance (UARI) and pulsatility indices (UAPI), as secondary end-points. Serum estradiol, progesterone and gonadotrophins were also measured. RESULTS: Of the 29 women eligible for the uterine analysis, 17 completed the entire study protocol, but 25 women contributed data to statistical analysis of treatment effect. There was a greater estimated mean ET with the use of pSSR (4.8 mm) compared to that with standard therapy (3.0 mm), with an estimated difference of 1.8 mm [95% confidence interval (CI), 0.7 to 2.8, P=0.002]. The estimated mean uterine volume was also greater during physiological treatment (24.8 cm(3)) than during standard treatment (20.6 cm(3)), but the estimated difference of 4.2 cm(3) (95% CI -0.4 to 8.7) was not statitsically significant, P=0.070. The small differences between the two treatments in the mean UARI and mean UAPI were not statistically significant. The estimated treatment differences were fairly constant across the treatment periods, suggesting that prolonged treatment does not increase response. CONCLUSIONS: pSSR has a greater beneficial effect upon ET in women with POF in comparison with standard therapy. A similar trend was seen for uterine volume. Further studies are required to optimize treatment and to assess pregnancy rate and outcome. Trial Registration www.ClinicalTrials.gov, NCR00732693.

Macrovascular angiopathy in children and adolescents with type 1 diabetes.

Diabetes represents one of the most common diseases globally. Worryingly, the worldwide incidence of type 1 diabetes (T1D) is rising by 3% per year. Despite the rapid increase in diabetes incidence, recent advances in diabetes treatment have been successful in decreasing morbidity and mortality from diabetes-related retinopathy, nephropathy, and neuropathy. In contrast, there is clear evidence for the lack of improvement in mortality for cardiovascular diseases (CVDs). This emphasizes the importance of focusing childhood diabetes care strategies for the prevention of CVD in adulthood. Furthermore, although most work on diabetes and macrovascular disease relates to type 2 diabetes, it has been shown that the age-adjusted relative risk of CVD in T1D far exceeds that in type 2 diabetes. As T1D appears predominantly during childhood, those with T1D are at greater risk for coronary events early in life and require lifelong medical attention. Because of the important health effects of CVDs in children and adolescents with T1D, patients, family members, and care providers should understand the interaction of T1D and cardiovascular risk. In addition, optimal cardiac care for the patient with diabetes should focus on aggressive management of traditional cardiovascular risk factors to optimize those well-recognized as well as new specific risk factors which are becoming available. Therefore, a complete characterization of the molecular mechanisms involved in the development and progression of macrovascular angiopathy is needed. Furthermore, as vascular abnormalities begin as early as in childhood, potentially modifiable risk factors should be identified at an early stage of vascular disease development.

Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry.

OBJECTIVE: To investigate the reported association between exaggerated adrenarche (EA) and reduced foetal growth and to identify possible risk factors for future morbidity in Scottish children with clinical features of EA. DESIGN: Three-year prospective study. MEASUREMENTS: Auxology, blood pressure (BP), biochemical analysis of blood and urine, pelvic ultrasound in girls. RESULTS: Fifty-two patients were recruited of whom one girl had nonclassical congenital adrenal hyperplasia (17-OHP 17 nmol/l) and one had insufficient blood for analysis. The final cohort comprised 42 girls of mean (SD) age 7.7 (0.99) and eight boys of 8.8 (0.67) years. Mean (SD) birth weight was 3.27 (0.49) and 3.10 (0.76) kg in girls and boys respectively. Height/weight SDS were 1.13/1.69 in girls and 1.69/1.88 in boys. Mean systolic/diastolic BP was 107.8/60.4 (50th-75th centile) in girls and 115.5/63.9 (75th-91st centile) in boys. Uterine and ovarian development was prepubertal. Median serum dehydroepiandrosterone sulphate (DHEAS) was 2.1 and 4.1 mumol/l, androstenedione 3.1 and 3.8 nmol/l in girls and boys respectively, with DHEAS within the reference range/undetectable in 18/2 and androstenedione in 12/6 patients. Fasting insulin was 9.0 and 15.0 mU/l in girls and boys respectively, with concomitant low normal SHBG. Anti-Mullerian hormone (AMH) was 15.7 pmol/l in 27 girls, compared with 5.0 pmol/l in normal girls aged 5-8 years. CONCLUSIONS: Our Scottish EA cohort showed female predominance, no evidence of reduced foetal growth, a tendency to overweight with commensurate mild hyperinsulinaemia and modest elevation of serum androgens in some patients. We have found raised AMH levels in the girls, indicating advanced ovarian follicular development.

Male fertility and strategies for fertility preservation following childhood cancer treatment.

Infertility in the male is a potential complication of childhood cancer treatment for long-term survivors. The risk is dependent primarily on the treatment used, but also on the underlying disease. Chemotherapy (especially alkylating agents) and radiotherapy, even in low doses, may damage the seminiferous epithelium and impair spermatogenesis in both children and adults. Leydig cell function and testosterone production are generally preserved after chemotherapy and low dose radiotherapy, whilst larger doses of radiotherapy may result in hypogonadism. Patients treated with potentially gonadotoxic treatments require regular multidisciplinary follow-up including assessment of puberty and gonadal function. Currently the only option available for fertility preservation in young males treated for cancer is semen cryopreservation. For pre-pubertal patients, techniques for fertility preservation remain theoretical and as yet unproven. These include hormonal manipulation of the gonadal environment before treatment, germ cell transplantation and testis xenografting, which have all shown promise in a variety of animal studies. Refinement of these techniques requires investigations in relevant animal models. In the present chapter we include data which suggest that the common marmoset (Callithrix jacchus) monkey, a New World primate, exhibits important parallels with human testicular development and may help us to understand why the pre-pubertal testis is vulnerable to effects of cytotoxic therapy on future fertility.

Germ cell differentiation in the marmoset (Callithrix jacchus) during fetal and neonatal life closely parallels that in the human.

BACKGROUND: Testicular germ cell tumours (TGCT) are thought to originate from fetal germ cells that fail to differentiate normally, but no animal model for these events has been described. We evaluated the marmoset (Callithrix jacchus) as a model by comparing perinatal germ cell differentiation with that in humans. METHODS: Immunohistochemical profiling was used to investigate germ cell differentiation (OCT4, NANOG, AP-2gamma, MAGE-A4, VASA, NANOS-1) and proliferation (Ki67) in fetal and neonatal marmoset testes in comparison with the human and, to a lesser extent, the rat. RESULTS: In marmosets and humans, differentiation of gonocytes into spermatogonia is associated with the gradual loss of pluripotency markers such as OCT4 and NANOG, and the expression of germ cell-specific proteins such as VASA. This differentiation occurs asynchronously within individual cords during fetal and early postnatal life. This contrasts with rapid and synchronous germ cell differentiation within and between cords in the rat. Similarly, germ cell proliferation in the marmoset and human occurs throughout perinatal life, in contrast to rats in which proliferation ceases during this period. CONCLUSIONS: The marmoset provides a good model for normal human germ cell differentiation and proliferation. The perinatal marmoset may be a useful model in which to establish factors that lead to failure of normal germ cell differentiation and the origins of TGCT.

Growth and skeletal development in families with NOGGIN gene mutations.

INTRODUCTION: There is a scarcity of data on height as well as bone densitometry in humans with NOGGIN mutations. METHODS: In 2 families with symphalangism, anthropometry, bone densitometry and genetic analysis of the NOGGIN gene were performed. RESULTS: In family A, the height standard deviation scores of the affected father and son were -0.4 and 3.5, respectively. In family B, the height standard deviation scores of the affected father, twin daughters and another daughter were 1.7, 1.8, 2.4 and 1.8, respectively. In the children, percentage predicted bone mineral content (BMC) for height at the appendicular sites (total femur, femoral neck) was lower than at an axial site lumbar spine. In the 2 fathers, median bone mineral density at total femur and femoral neck was -0.3 standard deviation scores (-0.7, 0.2) and at lumbar spine the scores were -0.4 and 0.9. The children had median tibial and radial speed of sound velocities of -2.1 (-0.9 to -6.4) and -1.4 (-0.2 to -4.9), respectively. DNA analysis revealed a novel missense mutation in family A and family B, resulting in a Met190Val substitution and a Pro42Arg substitution, respectively. CONCLUSION: Heterozygous gene mutations in NOGGIN are associated with tall stature in children but not necessarily in adults. The appendicular BMC and speed of sound may be low in affected children but normalises by adulthood. However, axial BMC seems normal in childhood and is high in adulthood.

Evidence-based child health: SIGN and NICE.

Clinical medicine is a holistic attempt to provide the best care for patients. What is the relevance of evidence-based child health and guidelines in informing clinical practice? In this review, examples drawn from paediatric endocrinology practice and an outline of the (sometimes contrasting) methodologies of the National Institute for Health and Clinical Effectiveness (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN) are used to inform what needs to be a continuing debate. There is regular contact and cooperation between guideline-producing bodies both nationally and internationally, but there are still many impediments to avoiding duplication. Policies and practice do not inevitably flow from research evidence and guidelines. There is an urgent need to produce evidence of the impact of guidelines, not only on changing clinical practice where appropriate, but also on improving child health.

Symptoms of hypoglycemia in children with IDDM.

OBJECTIVE: To examine the symptoms of hypoglycemia in children with insulin-dependent diabetes, from the perspective both of the child and of the child's parents, and to compare the symptom reporting of the diabetic children with that of adult diabetic patients. RESEARCH DESIGN AND METHODS: Interviews were conducted with 100 parents and 43 of their children. The frequency and intensity of symptoms of hypoglycemia were documented using a structured interview and classified into groups using Principal Components Analysis (PCA). RESULTS: Diabetic children and their parents showed close agreement concerning the relative frequency and the intensity of symptoms reported. PCA of the symptom reports showed that diabetic children and their parents identified the same distinct subgroups of hypoglycemia-related symptoms: behavioral disturbance and autonomic-neuroglycopenic subgroups. CONCLUSIONS: Hypoglycemic symptoms in children with diabetes clearly differ from those experienced by insulin-treated adults and, in particular, include behavioral changes as primary features of a low blood glucose. These observations have important implications for parental education on hypoglycemia.

Patterns of pulsatile luteinizing hormone secretion before and during the onset of puberty in boys: a study using an immunoradiometric assay.

To study spontaneous pulsatile LHRH/LH secretion around the onset of puberty, nocturnal plasma LH was measured by means of a highly sensitive immunoradiometric assay in 30 boys (aged 5.6-16.8 yr) investigated for potential problems with growth and/or development. Blood was withdrawn at 10- to 20-min intervals from 2000-0800 h. Pulse analysis was accomplished by a computerized peak detection algorithm. Pituitary and gonadal responsiveness was assessed by a standard exogenous LHRH challenge and testosterone. Subsequent clinical progress was monitored for a mean duration of 2.08 +/- 0.16 yr and used as the basis for classifying patients retrospectively into three groups: 1) prepubertal (n = 14), 2) peripubertal (n = 11), and 3) pubertal (n = 5). LH pulses were undetectable in 9 and present in 5 prepubertal subjects, the youngest of whom was aged 7.3 yr. In peripubertal and pubertal individuals, 2-7 LH pulses/12 h were detectable. LH pulses were detectable before sleep by midpuberty (Tanner stage 3). There was a highly significant (P less than 0.0001) increase in LH/LHRH pulse frequency from 0.93 +/- 0.38 to 4.55 +/- 0.43/12 h (mean +/- SEM) between the prepubertal and peripubertal groups and a further increase to 6.20 +/- 0.37/12 h in the pubertal group. LH pulse amplitude remained under 1.0 U/L in both the prepubertal and peripubertal groups and only increased significantly to 2.02 +/- 0.17 U/L in pubertal boys. Response to LHRH increased significantly between the prepubertal (2.47 +/- 0.49 U/L) and peripubertal (6.53 +/- 2.02 U/L) patients. T increased significantly at each stage, with the greatest rise between the peripubertal and pubertal stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of pulsatile luteinizing hormone and follicle-stimulating hormone secretion in prepubertal (midchildhood) boys and girls and patients with idiopathic hypogonadotropic hypogonadism (Kallmann's syndrome): a study using an ultrasensitive time-resolved immunofluorometric assay.

To study the ontogeny of spontaneous pulsatile LH and FSH secretion before the onset of puberty, plasma LH and FSH were measured by an ultrasensitive time-resolved immunoflurometric assay in 16 boys and 6 girls, aged 6.5 +/- 0.2 yr (+/- SEM; range, 4.4-8.0) with short stature. Eight male patients with idiopathic hypogonadotropic hypogonadism (Kallmann's syndrome), aged 24.1 +/- 3.4 yr, were also investigated. Blood samples were withdrawn at 10- to 20-min intervals for 12 h from 2000-0800 h. Pituitary responsiveness was assessed by a standard iv LHRH challenge test. LH and/or FSH pulses were detectable in all but two prepubertal subjects. In boys, low amplitude LH (0.16 +/- 0.06 U/L) and FSH (0.19 +/- 0.03 U/L) pulses were detectable at mean frequencies of 2.19 +/- 0.37 and 2.13 +/- 0.46 pulses/12 h, respectively. In girls, low amplitude LH (0.29 +/- 0.18 U/L) pulses, but higher (P less than 0.05 compared to boys) amplitude FSH (1.62 +/- 1.05 U/L) pulses were observed at frequencies of 1.71 +/- 0.56 and 1.67 +/- 0.53 pulses/12 h, respectively. Mean FSH in prepubertal girls (1.95 +/- 0.88 U/L) was significantly (P less than 0.05) higher than that in boys (0.46 +/- 0.07 U/L), but mean LH was not different at 0.17 +/- 0.07 and 0.10 +/- 0.03 U/L, respectively. Patients with Kallmann's syndrome had mean LH and FSH levels indistinguishable from those of prepubertal boys. Nocturnal augmentation of pulsatile LH or FSH secretion was observed in 74% of children (71% in girls and 75% in boys), but in none of the eight patients with Kallmann's syndrome. A close temporal association was observed between sleep onset and the appearance of nocturnal pulsatile gonadotropin secretion. The FSH response to exogenous LHRH in prepubertal girls was significantly greater than that in patients with Kallmann's syndrome and prepubertal boys, but LH responses were not different. Our results show that pulsatile LH and FSH secretion occurs in the majority of boys and girls in midchildhood, with a robust association with nocturnal sleep onset. Between the ages of 4-8 yr, these low amplitude and low frequency pulses are unable to activate gonadal function. The regulation of FSH secretion in prepubertal girls appears to be different from that in prepubertal boys.(ABSTRACT TRUNCATED AT 400 WORDS)

Ontogeny of pulsatile gonadotropin releasing hormone secretion from midchildhood, through puberty, to adulthood in the human male: a study using deconvolution analysis and an ultrasensitive immunofluorometric assay.

The ontogeny of gonadotropin releasing hormone pulse generator activity underlying pubertal development in the human male is incompletely defined because of the limitations of assay sensitivity in measurements and the inaccuracies attendant upon the analyses of pulsatile secretion of circulating gonadotropins. Using an ultrasensitive immunofluorometric assay (DELFIA) to measure plasma LH and deconvolution analysis to depict LH secretory characteristics, we compared nocturnal (2000-0800 h) pulsatile LH secretion cross-sectionally in 16 boys in midchildhood (mean +/- SD age 6.6 +/- 0.3 yr), 8 prepubertal boys (12.0 +/- 0.3 yr), 8 early pubertal boys (14.3 +/- 0.4 yr), and in 8 young fertile adult men (32.6 +/- 1.6 yr) as an indirect in vivo assessment of hypothalamic GnRH pulse generator activity over the entire span of pubertal development in the human male. We confirmed that sleep-entrained GnRH/LH burst secretory activity was present in midchildhood. The first increase in sleep-entrained GnRH/LH secretion occurred some 2 yr before the clinical onset of puberty. From midchildhood to sexual maturity, LH production rate increased 39-fold. However, GnRH/LH pulse frequency showed only a relatively small (1.8-fold) increment from midchildhood to the clinical onset of puberty, with no subsequent changes to continuing development towards adulthood. Thus 91.7% of the increment in LH plasma concentration from childhood to sexual maturity could be accounted for by an amplification of a pre-existing ultradian rhythm of secretion with a steadily and markedly increasing mass of LH secreted per burst. The duration of secretory burst and apparent half-life of plasma LH disappearance remained constant from midchildhood, through puberty, to adulthood. The nyctohemeral rhythm-and sleep-associated LH/GnRH secretion was eventually lost in young adulthood. We conclude that the onset of puberty in man is heralded by the reawakening of a partially quiescent GnRH pulse generator. This predominantly involves an amplification of a pre-existing pattern of hypothalamic GnRH secretion leading to a major augmentation of the total quantity of LH molecules released per burst. The almost two-fold increment in GnRH pulse frequency contributed synergistically to the pubertal process, before the clinical onset of puberty, possibly by enhancing gonadotropic sensitivity to increase the mass of LH produced per burst. The relative constancy of GnRH pulse frequency in the gonad-intact hypothalamic-pituitary-testicular axis from pubertal onset to adulthood implies that testicular steroidal feedback plays a role in restraining the burst frequency of the GnRH pulse generator during pubertal development and adulthood.

Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys.

In the management of constitutional delayed growth and/or puberty, there is a need for simple tests which can assess the overall developmental maturity of the hypothalamic-pituitary-testicular axis in clinically prepubertal patients. This would enable the physician to predict the likelihood or otherwise of an individual entering puberty spontaneously within subsequent months. Based on our previous physiological data on the sequential pattern of peripubertal pituitary-testicular activation by hypothalamic GnRH, we hypothesized that the nocturnal secretion of testosterone, in response to sleep-entrained LH secretion, may provide a basis for an in vivo bioassay of neuroendocrine sexual maturity. Overnight testosterone secretion by the testis in clinically prepubertal boys was assessed with respect to their subsequent clinical progress, the target being the attainment of testicular volumes of greater than or equal to 4 mL (a clinical landmark when puberty has assuredly begun and virilization will soon follow). Forty-five prepubertal (Tanner stage G1PH1 testicular volume < or = 2 mL) boys aged 10.0-15.3 yr (mean +/- SEM 11.8 +/- 0.2) with short stature had paired plasma T concentration measured at 2000 h and 0800 h the following morning. After the initial assessment, all patients were reviewed clinically at 3-month intervals for a minimum of 21 months (mean 26.0 +/- 1.1, range 21-50 months). During this period, 38 (84.4%) patients received treatment in the form of sc human GH 2-4 IU daily or oxandrolone 2.5 mg daily by mouth to improve short-term growth although this did not have any significant effect on the subsequent timing of pubertal onset. The patients were divided according to whether 1) there was a demonstrable increase in plasma T between 2000 and 0800 h and 2) morning plasma T concentration was less than or greater than or equal to 0.7 nmol/L at their initial assessment. In those with a significant overnight T increment, 58% and 89% achieved testicular volume of greater than or equal to 4 mL after 12 and 21 months, respectively. In contrast, only 12% and 56% of patients who had not shown a T increase went into puberty by these times. In patients who had morning plasma testosterone concentrations greater than or equal to 0.7 nmol/L, 77% entered puberty within 12 months and 100% within 15 months. However, in those with a morning testosterone of less than 0.7 nmol/L, only 12.5% and 25% entered puberty within 12 and 15 months, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia.

To investigate the effects of disease and intensive chemotherapy on bone turnover and growth in children with acute lymphoblastic leukemia (ALL), a longitudinal prospective study was carried out in 22 children, aged 1.2-13.5 yr, enrolled in the Medical Research Council-funded randomized trial of childhood ALL treatment in the UK. We measured lower leg length and markers of bone formation [bone alkaline phosphatase (ALP) and procollagen type I C-terminal propeptide (PICP)], bone resorption [pyridinoline, deoxypyridinoline, and carboxyl-terminal telopeptide of type I collagen (ICTP)], soft tissue turnover [procollagen type III N-terminal propeptide (P3NP)], and the GH axis [IGF-I, IGF-binding protein-3 (IGFBP-3), IGFBP-2, and urinary GH] at 1- to 4-week intervals from diagnosis to week 27 of treatment. In addition, GH-binding protein was measured at diagnosis. At diagnosis, mean SD scores were: bone ALP, -1.84; PICP -1.77; pyridinoline, -1.42; deoxypyridinoline, -1.66; ICTP, -0.42; P3NP, +1.45; GH, +24.4; IGF-I, -1.70; IGFBP-3, -0.88; IGFBP-2, +2.42; and GH-binding protein, -0.69. Bone ALP, PICP, and IGFBP-3 were all correlated (P < or = 0.03). During induction and intensification, there was shrinkage of the lower leg, with decreases in PICP, pyridinoline, ICTP, and P3NP (P < 0.05), whereas IGF-I and IGFBP-3 increased (P < 0.05). After prednisolone was discontinued, bone ALP and collagen markers increased markedly (P < 0.01), but there was no significant change in IGF-I and IGFBP-3. In 12 children who received high dose i.v. methotrexate, postglucocorticoid increases in bone ALP and PICP were less, whereas those in ICTP and P3NP were greater, compared to levels in children who did not receive methotrexate (P < 0.05). We conclude that ALL itself caused GH resistance and low bone turnover. During early intensive chemotherapy, further suppression of osteoblast proliferation and osteoclast activity occurred, not mediated through the systemic GH axis, probably by the direct action of prednisolone on bone. The postglucocorticoid increase in bone turnover was also independent of the GH axis and was modulated by high dose i.v. methotrexate, which depressed osteoblast recovery and enhanced osteoclast activity.

Growth hormone therapy and growth in children with Noonan's syndrome: results of 3 years' follow-up.

Growth data from the first 3 yr of a multicenter study examining the efficacy and safety of recombinant human GH [rhGH; 4 IU (1.3 mg)/m(2).day, sc] in children with Noonan's syndrome (NS) are reported for 23 subjects. Sixteen male and seven female patients (age, 9.3 +/- 2.6 yr at onset of GH therapy, mean +/- SD; range, 4.8-13.7) were each assessed at 1, 2, and 3 yr after starting treatment. Comparisons were made with a group of eight subjects (six males and two females, age, 9.0 +/- 4.1 yr; range, 4.1-14.8) with NS, not treated with rhGH, measured over the same period. All treated subjects underwent annual cardiac assessment. Height SD score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/- 0.9 3 yr later (P < 0.001, two-tailed t test). This corresponded to an increase in height from 116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4 +/- 1.7 cm/yr in the year before treatment to 8.4 +/- 1.7 (P < 0.001), 6.2 +/- 1.7 (P < 0.001), and 5.8 +/- 1.8 (P = 0.01, two-tailed t test compared with baseline) during the first, second, and third years of GH treatment, respectively. Height acceleration was not significant during the second or third years when pubertal subjects were excluded. The comparison group showed an increase in height from 116.0 +/- 19.8 to 131.9 +/- 21.1 cm over the 3 yr (height SD score, -2.7 +/- 0.6 to -2.4 +/- 0.7, P = 0.3). None of the 23 children developed hypertrophic cardiomyopathy during GH treatment. The increase in growth rate in NS resulting from 1 yr of GH therapy seems to be maintained during the second year, although height velocity shows a less significant increase over pretherapy values. Possible abnormal anabolic effects of rhGH on myocardial thickness were not confirmed, and no treated patient developed features of hypertrophic cardiomyopathy.

Oral testosterone undecanoate in the management of delayed puberty in boys: pharmacokinetics and effects on sexual maturation and growth.

Therapeutic induction of puberty using oral testosterone (T) undecanoate (TU) 40 mg daily was performed in 4 pubertal boys aged 12.7-17.1 yr with constitutional delayed puberty and/or short stature. Single-dose pharmacokinetics study was performed on matched plasma and saliva samples obtained half-hourly for 10 h after the first dose and then repeated 3 and 6 months later. Treatment was continued for 15-21 months. Peak plasma total T concentration was achieved at 255 +/- 51 (SEM) min after the first 40 mg dose of TU, 300 +/- 76 min at 3 months, and 293 +/- 103 min at 6 months, the levels remaining elevated above baseline for at least 8 h after a single oral dose. Total T levels were initially high (mean 13.0 +/- 2.5; peak 38.7 +/- 4.2 nmol/L) but dropped significantly at 3 months (mean 8.3 +/- 1.8; peak 23.6 +/- 5.6 nmol/L) and at 6 months (mean 9.2 +/- 1.6; peak 24.8 +/- 3.5 nmol/L) paralleled by a dramatic fall in sex hormone binding globulin (73.9 +/- 18.0 to 35.1 +/- 9.7 at 3 month and 29.2 +/- 6.0 nmol/L at 6 month). Mean concentrations of unbound and free T (non-sex hormone binding globulin-bound T, free T, and salivary T) were below the normal adult range and remained unchanged over the same period. Plasma dihydrotestosterone concentrations were elevated after the first dose (mean 5.4 +/- 1.3; peak 11.0 +/- 2.5 nmol/L), the extent of this rise being less after 6 months (mean 4.1 +/- 0.8; peak 7.1 +/- 1.1 nmol/L) as was the case with mean estradiol (51.5 +/- 8.9 to 38.1 +/- 3.7 pmol/L). Signs of virilization progressed to Tanner stage G3 PH2-3 with testicular volumes increasing to 3-4 mL at 12 months, and G4 PH4-5 with further testicular growth to 6-10 mL at 24 months. Height velocity rose from 3.2 +/- 0.3 cm/yr (pretreatment) to 7.2 +/- 1.0 cm/yr in the first year and was maintained at 7.3 +/- 0.4 cm/yr despite cessation of therapy during the second year. Bone age advanced by 1.1 +/- 0.1 yr at 12 months and a further 0.8 +/- 0.3 yr at 24 months. Predicted adult height remained unchanged. No side effects were observed. Our preliminary data suggest that oral TU is a well accepted, effective, and safe treatment for the initiation of male puberty without disproportionate skeletal maturation. Continued pubertal advance was evident after cessation of treatment in all patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Nocturnal secretory dynamics of inhibin B and testosterone in pre- and peripubertal boys.

To investigate the secretory dynamics of testosterone and inhibin B, we collected samples every 20 min from 2000 h to 0800 h in 20 boys. Boys in group 1 (n = 5) were aged less than 8 yr, group 2 (n = 5) were aged more than 8 yr but 1.5 yr or more before pubertal onset, group 3 (n = 5) were studied 1.0 yr or less before pubertal onset, and group 4 (n = 5) were in early puberty. Testosterone increased after midnight in peripubertal boys, coinciding with the onset of LH pulsatility, and showed a pulsatile pattern in 6 of 10 of these boys. Cross-correlation analysis indicated significant temporal coupling between LH and testosterone. Inhibin B was higher in groups 3 and 4, compared with groups 1 and 2 (P < 0.01) and showed a downward trend overnight with no evidence of pulsatility and no evidence of short-term interactions with LH, FSH, or testosterone. Inhibin B and LH nocturnal means were both inversely correlated with time before pubertal onset (r(s) > or = -0.85, P < 0.01). Only LH nocturnal mean and amplitude, respectively, contributed independently to prediction of testosterone and inhibin B nocturnal means, explaining 71 and 65% of their variability. We conclude that both testosterone and inhibin B are related to nocturnal LH release in peripubertal boys but over different time scales.

The short-term effects of growth hormone therapy on height velocity and cardiac ventricular wall thickness in children with Noonan's syndrome.

Noonan's syndrome (NS) is associated with short stature and cardiac defects. Small studies reported linear growth increases with recombinant human GH (rhGH) therapy, but also raised concerns related to the anabolic effects of rhGH and the possible progression of ventricular hypertrophy. We report a multicenter study examining the efficacy and safety of rhGH (4 IU/m2.day, sc) in children with NS. Entry criteria were: NS confirmed by single observer, height SD score less than -2(UK Height Standards 1990), prepubertal, and normal maximal left ventricular (LV) wall thickness less than 1 cm by 2-dimensional echocardiography. Thirty subjects were recruited (19 males and 11 females), aged 8.9 +/- 0.5 yr (range, 4.8-13.7 yr). Growth was monitored for 12 months before and at 3-month intervals during therapy. Measurements of maximal LV wall thickness were taken at 0 and 12 months. Serum insulin-like growth factor I(IGF-I), IGF-II, and IGF-binding protein-3 levels were determined at 0, 3, 6, 9, and 12 months. Ten subjects with NS (4 females and 6 males), aged 8.8 +/- 0.7 yr (range, 6.3-11.8 yr), were monitored over the same period as a comparison group. In the treatment group, 27 subjects completed 12 months of therapy. Height SD score increased from -3.01 +/- 0.10 to -2.36 +/- 0.10 (P < 0.0001) after 12 months; height velocity (HV) increased from 4.9 +/- 0.2 to 8.9 +/- 0.3 cm/yr at 6 months and 8.1 +/- 0.4 cm/yr (P < 0.0001) from 6-12 months. The HV SD score increased from -0.7 +/- 0.15 to +2.42 +/- 0.32 over 12 months (P < 0.0001). The increase in HV was more than 2 cm/yr in 24 patients. IGF-I increased from 121 +/- 13 to 240 +/- 22 micrograms/L at 12 months (P < 0.0001), and IGF-binding protein-3 increased from 2.65 +/- 0.20 to 4.01 +/- 0.42 mg/L at 12 months (P = 0.0009). In the comparison group, there was no change in height SD score (-2.03 +/- 0.19), HV (4.4 +/- 0.24 CM/yr), or HV SD score (- 1.08 +/- 0.21). There was no increase in mean maximal LV wall thickness during the study in either the treatment group (12 month values were 0.63 +/- 0.02 cm at the mitral valve level and 0.66 +/- 0.02 cm at the papillary muscle level) or in the comparison group (0.63 +/- 0.04 cm at the mitral valve level and 0.61 +/- 0.03 cm at the papillary muscle level). In conclusion, rhGH was effective in 24 of the treated patients; these subjects achieved a significant increase in height SD score and HV over 1 yr. Abnormal anabolic effects of rhGH on myocardial thickness were not confirmed, and no patient developed features of hypertrophic cardiomyopathy.

Effects of a third intensification block of chemotherapy on bone and collagen turnover, insulin-like growth factor I, its binding proteins and short-term growth in children with acute lymphoblastic leukaemia.

Children with acute lymphoblastic leukaemia (ALL) have reduced bone turnover caused by the disease itself and early intensive chemotherapy, but the effects of later chemotherapy using different drug combinations are uncertain. We report here a longitudinal study on 9 children with ALL randomised to receive an additional third intensification block of chemotherapy, compared with 9 children receiving continuing chemotherapy over the same period. During third intensification, bone alkaline phosphatase, procollagen type I C-terminal propeptide, the carboxyterminal propeptide of type I collagen, procollagen type III N-terminal propeptide and lower leg length all decreased in response to dexamethasone, then returned to (but not beyond) baseline levels after dexamethasone was stopped and other drugs started. These changes were unrelated to circulating insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 or IGFBP-2. In all children, bone alkaline phosphatase remained below the population mean throughout. We conclude that dexamethasone decreased bone and soft tissue turnover, probably through direct effects on target tissues. The postdexamethasone phase of third intensification and continuing chemotherapy had no major deleterious effect on collagen turnover, but there was evidence of continuing suboptimal bone mineralisation.