Does ifosfamide affect gonadal function?

BACKGROUND: Gonadal dysfunction and infertility are potential late effects of cancer therapy. Ifosfamide, an alkylating agent structurally related to cyclophosphamide, is thought to cause gonadal dysfunction, though there is little published evidence. PROCEDURE: Patients treated on sarcoma protocols containing ifosfamide as the only potential gonadotoxic agent, were evaluated, assessing pubertal development, menstrual history in the females and semen analysis in males. Biochemical evaluation included measurement of gonadotrophins, inhibin B and anti-mullerian hormone (AMH). RESULTS: All 32 males progressed normally through puberty. No gonadal dysfunction was seen at a total ifosfamide dose of <60 g/m(2). In those with a dose >60 g/m(2), two-thirds of those who underwent semen analysis were subfertile, 31% had elevated FSH and 50% showed decreased inhibin B supporting evidence of germ cell failure. All 13 females progressed through puberty normally and had regular menses. Biochemical results were in line with published data except for AMH levels, which were lower compared with an age-matched reference group. Nine patients not recruited into the study were known to have had 11 live births. CONCLUSIONS: Males appear more susceptible than females to ifosfamide gonadotoxicity. There may be a dose in males below which the risk of subfertility is low. In females there is preliminary evidence of reduction in ovarian reserve as measured by AMH levels, which may potentially lead to an early menopause and a reduction in the window of fertility.

Macroorchidism in two unrelated prepubertal boys with a normal FSH receptor.

BACKGROUND: Macroorchidism in prepuberty is an uncommon condition which we hypothesised might reflect constitutive activation of the FSH receptor (FSHR). PATIENTS AND METHODS: Patient 1 was found to have macroorchidism (15 ml testicular volume) at the time of orchidopexy when 3.7 years of age. A gonadal biopsy was obtained at the time of surgery. Patient 2 developed macroorchidism (5 ml) when 8.8 years old. Despite a testicular volume >4 ml, morning testosterone levels were unrecordable with no measurable gonadotrophin production in either patient. Patient 2 had prepubertal gonadotrophin levels 3 years later despite a testicular volume that was 8 ml bilaterally. Inhibin B was measured and the FSHR sequenced in both patients. RESULTS: Inhibin B levels were age and pubertal stage appropriate. Gonadal biopsy (patient 1) demonstrated areas of Sertoli cell hyperplasia. Sequence analysis of all 10 exons of the FSHR was normal. There was significant, presumed gonadotrophin-dependent testosterone production in both boys by 15 years of age. CONCLUSIONS: The cause of prepubertal macroorchidism in our patients is unclear but the pronounced difference in phenotype suggests that there may be more than one underlying mechanism. This mechanism was not constitutive activation of a mutated FSHR.

Diagnostic utility of a low-dose gonadotropin-releasing hormone test in the context of puberty disorders.

OBJECTIVES: The 10-microg gonadotropin-releasing hormone (GnRH) test assesses pituitary gonadotroph responsiveness, whereas the 100-microg dose assesses maximal secretory capacity. Our aims were to establish normative data for the low-dose test in children and to evaluate the test in diagnosing common pubertal disorders. METHODS: We retrospectively classified 107 children who underwent 10-microg GnRH tests into normal prepubertal (20 boys, 10 girls), normal early pubertal (10 boys, 16 girls), constitutional delay of puberty (CDP, 13 prepubertal boys >12 years), hypogonadotropic hypogonadism (HH, 5 prepubertal boys >12 years), central precocious puberty (CPP, 19 girls) or premature thelarche/variant (13 girls). RESULTS: Peak LH response was higher in prepubertal boys >12 years compared with younger boys (p < 0.01) but showed no further change in early puberty. CDP boys had LH responses similar to prepubertal boys >12 years. HH boys showed an absent LH response which diagnosed HH with 100% sensitivity and 96% specificity. Thelarche girls had LH:FSH peak ratios lower than normal prepubertal (p = 0.001), pubertal (p < 0.05) or CPP (p = 0.001) girls. CONCLUSIONS: We have established normative values for the low-dose GnRH test in children. The test successfully differentiated HH from CDP in boys, and contributed to the differential diagnosis of CPP and premature thelarche in girls.

Cortisol and growth hormone responses to spontaneous hypoglycaemia in infants and children.

AIMS: To evaluate responses of cortisol and growth hormone (GH) to spontaneous hypoglycaemia in infants and children. METHODS: Retrospective review of laboratory and clinical data in paediatric patients investigated for suspected hypoglycaemia over a five year period. Thirty patients (16 aged <3 months) had hypoglycaemia confirmed by laboratory analysis (glucose <2.5 mmol/l) and were compared with 26 patients (11 aged <3 months) with glucose > or =2.5 mmol/l. RESULTS: The commonest causes of hypoglycaemia were transient hyperinsulinism in infants <3 months and intercurrent infection in those >6 months of age. In both hypo- and non-hypoglycaemic patients, cortisol was positively (r(s) +0.66 and +0.68) and GH inversely (r(s) -0.65 and -0.75) correlated with age. Hypo- and non-hypoglycaemic infants <3 months had median cortisol concentrations of 205 and 116 nmol/l respectively compared with 1370 and 736 nmol/l in hypo- and non-hypoglycaemic children >6 months. Conversely, median GH was 46.5 and 51.2 mU/l in hypo- and non-hypoglycaemic infants compared with 14.3 and 12.1 mU/l in older hypo- and non-hypoglycaemic patients. Older non-hypoglycaemic patients with glucose levels below the glycaemic thresholds established for cortisol and GH secretion in adults had higher cortisol and GH concentrations than patients whose glucose levels exceeded these thresholds. CONCLUSIONS: Cortisol and GH responses to spontaneous hypoglycaemia in children are highly age dependent. Young infants mount a poor cortisol response compared with older infants and children. Children older than 6 months may have glycaemic thresholds for cortisol and GH similar to those established for adults.

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.

Cortisol responses to the insulin hypoglycaemia test in children.

AIM: To determine the timing of the peak cortisol response to the insulin hypoglycaemia (IH) test in children and to establish paediatric reference data. METHODS: We retrospectively reviewed all IH tests in a tertiary paediatric endocrine referral centre over a 6-year period. Inclusion criteria were age <16 years and adequate hypoglycaemia (glucose < or =2.0 mmol/l). Patients with an impaired hypothalamic-pituitary-adrenal axis or receiving glucocorticoid medication were excluded. Fifty-four subjects (35 males) met the criteria. Blood samples were collected at -30, 0, 20, 30, 60, 90, 120, and 150 min in relation to insulin bolus injection (0.15 U/kg) at 0 min. Glucose, cortisol, and growth hormone (GH) were measured in all samples. RESULTS: Peak cortisol and GH responses occurred by 90 min in all subjects. Peak cortisol was inversely correlated with age (rs -0.65, p<0.0001). The median (5th centile) peak cortisol value was 689 nmol/l (547 nmol/l) in children younger than 10 years as compared with 555 nmol/l (468 nmol/l) in those older than 10 years (p<0.0001). Peak cortisol was not related to peak GH (rs -0.20, p=0.15). CONCLUSIONS: Blood sampling in the IH test may be curtailed 90 min after injection. The peak cortisol response to IH is age related.

Is inhibin B a potential marker of gonadotoxicity in prepubertal children treated for cancer?

BACKGROUND AND OBJECTIVE: Chemotherapy treatment of childhood cancer may impair gonadal function, which may be manifested only in adulthood as permanent sterility. Detection of gonadal dysfunction in prepubertal children has been hampered by the absence of a sensitive marker. Inhibin B is secreted by small antral follicles and Sertoli cells in females and males, respectively, and may be a marker of gonadal function in prepubertal children. The aim of this pilot study was to evaluate inhibin B in relation to sensitive measurements of gonadotrophins as markers of the early gonadotoxic effects of chemotherapy in prepubertal children treated for cancer. STUDY DESIGN AND SUBJECTS: Twenty-five prepubertal children (9 females), median age 4.5 years (range 1.2-12.8 years) with cancer (16 solid tumours, nine acute lymphoblastic leukaemia, ALL) were studied longitudinally. Blood samples were collected before and during chemotherapy (solid tumours) or immediately following induction and first intensification (ALL). Post-treatment (1-6 months) samples were collected in 12 of the patients (5 females). MEASUREMENTS: Dimeric inhibin B was measured by double antibody enzyme-linked immunosorbent assay (ELISA). FSH and LH were measured by sensitive time-resolved immunofluorescence. RESULTS: Girls: Pretreatment inhibin B was slightly high in one girl but normal for age and sex in all others: median 16.1 (range 9.4-186.2) ng/l, median SD score +0.2 (-1.3 to +2.6). Inhibin B decreased to undetectable levels (< 8 ng/l) in 8/9 girls during treatment (P = 0.03), with no accompanying rise in FSH or LH. Post-treatment recovery of inhibin B was variable: median 16.1 (range < 8.0-44.2) ng/l, median SD score +0.1 (range < -2.4 to +1.8). Sustained undetectable inhibin B levels were observed in 2/5 girls with correspondingly elevated FSH concentrations (11.8 and 10.9 U/l). Boys: Inhibin B was normal for age and sex in all boys before treatment with no significant change during or after treatment (medians 93 ng/l, 85 ng/l and 94 ng/l, SD scores -0.3, -0.6 and -0.2, respectively). Inhibin B decreased to undetectable levels in one boy post-treatment with no accompanying increase in FSH or LH. CONCLUSIONS: In prepubertal girls with cancer, chemotherapy is associated with suppression of inhibin B, usually transient, which may indicate arrest of follicle development. Sustained suppression of inhibin B following treatment may be indicative of permanent ovarian damage. In prepubertal boys, chemotherapy had little immediate effect on Sertoli cell production of inhibin B, although one boy showed a delayed effect. Inhibin B, together with sensitive measurements of FSH, may be a potential marker of the gonadotoxic effects of chemotherapy in prepubertal children with cancer.

Malnutrition, zinc supplementation and catch-up growth: changes in insulin-like growth factor I, its binding proteins, bone formation and collagen turnover.

OBJECTIVE: Zinc may be a limiting factor in restricting catch-up growth in severely malnourished children. This study had two aims: (i) to examine the effect of different zinc supplementation regimens on IGF-I, its binding proteins and on markers of bone and collagen turnover in severely malnourished children and (ii) to investigate mechanisms underlying catch-up growth by examining changes in these markers during nutritional rehabilitation, their inter-relationships and their relationships with ponderal and linear growth. DESIGN: Double-blind randomized intervention study of three regimens of oral zinc supplementation. PATIENTS: One hundred and forty-one children, aged 6-36 months, mean (SD) age 15.4 (8.7) months, with day 1 weight-for-height SD score (whz) -2.6 (0.93) and height-for-age SD score (haz) -3.79 (1.29). MEASUREMENTS: Weight, height, lower leg length (by knemometry) at 15-day intervals from day 1 to day 90 of nutritional rehabilitation. Blood collection on days 1, 15 and 30 for IGF-I, IGFBP3, IGFBP2, bone alkaline phosphatase (BAP, osteoblast marker), procollagen type I C-terminal propeptide (PICP, marker of type I collagen synthesis), procollagen type III N-terminal propeptide (P3NP, marker of soft tissue type III collagen synthesis) and type I collagen telopeptide (ICTP, marker of type I collagen breakdown). RESULTS: There was early rapid weight gain during refeeding, whereas height gain occurred later in the trial. IGF-I, IGFBP3, BAP, PICP and P3NP were low or very low on day 1 compared to well-nourished age-matched European children, and all increased within 15 days (P < 0.001), with PICP and P3NP reaching levels higher than European norms. IGFBP2 and ICTP were high on day 1 and decreased over the same period (P < 0.001). There were no differences in anthropometric outcome or marker responses among zinc regimens. Day 1 whz was correlated with BAP, PICP and P3NP (P < 0.001). Changes in IGF-I, IGFBP3, BAP, PICP and P3NP over 30 days correlated with ponderal growth (whz change) over the same period (all P < 0.01). However, changes in these markers over 30 days correlated better with lower leg growth (all P < 0.01) and linear growth (haz change, P < 0.01 for PICP and P3NP, P < 0.05 for IGFBP3) measured over 90 compared with 30 days. At most time points, there were strong positive correlations (i) among IGF-I, IGFBP3, BAP, PICP and P3NP (P < 0.01) and (ii) between IGFBP2 and ICTP (P < 0.01). Conversely, IGFBP2 was negatively correlated with IGF-I, IGFBP3, BAP, PICP and P3NP at most time points (P < 0.01). CONCLUSIONS: We found no difference among zinc regimens in growth, IGF-I and its binding proteins or markers of bone and collagen turnover. Severe malnutrition was associated with low rates of bone and collagen synthesis and high rates of collagen degradation, and nutritional rehabilitation was associated with full or partial 'normalization' of the markers studied. Early weight gain and subsequent linear growth were associated with early increments in IGF-I, IGFBP3 and markers of bone and collagen formation. The study of these markers has provided additional insights into the mechanisms of the effects of malnutrition and refeeding on growth.

Inhibin B in boys from birth to adulthood: relationship with age, pubertal stage, FSH and testosterone.

OBJECTIVE: Inhibin B in males is produced principally by Sertoli cells under the influence of FSH and is thought to have a role in feedback regulation of FSH. The aims of our study were to investigate how inhibin B changes from birth to late adolescence in boys, to derive reference data and to explore its relation with pubertal stage, FSH and testosterone. DESIGN AND SUBJECTS: Blood samples were collected from (i) 366 boys aged 0--18 years to obtain age-related reference data; (ii) 195 boys who had full pubertal staging; and (iii) a cohort of 15 boys studied longitudinally as they approached and entered early puberty. MEASUREMENTS: Dimeric inhibin B was measured by double antibody enzyme-linked immunosorbent assay (ELISA), FSH by immunoradiometric assay (IRA) and testosterone by an extraction radioimmunoassay. RESULTS: Inhibin B was high in infant boys, decreased gradually to a nadir at 6--10 years of age, then increased rapidly in early adolescence to reach a new plateau at 12--17 years. It was detectable in all samples. Age-related reference ranges and data for calculation of SD scores are presented. In prepubertal boys, inhibin B correlated positively with age (P < 0.001), but not with FSH. Inhibin B increased progressively from pubertal stages G1 to G3 but then decreased slightly at stages G4 to G5 (P less-than-or-equal 0.01). At stage G2, inhibin B correlated positively with testosterone (P < 0.01) but not with FSH. From stage G3 onwards, inhibin B correlated inversely with FSH (P < 0.01) but lost its relationship with testosterone. In the cohort of boys studied longitudinally, inhibin B increased progressively prior to pubertal onset and further on entry into early clinical puberty (P < 0.05). Testosterone also increased over this period (P < 0.05) but FSH showed no significant change. CONCLUSIONS: The two peaks of inhibin B during infancy and early puberty appear to reflect the two periods of Sertoli cell proliferation in normal human males. During mid-childhood, a relatively constant amount of inhibin B is secreted constitutively. The early FSH-independent increase in inhibin B that precedes clinical puberty and continues to stage G2 may be stimulated by testosterone or other factors from Leydig cells. The inverse relationship between inhibin B and FSH that subsequently develops from mid-puberty onwards is consistent with the establishment of a negative feedback loop at this time.

Dimeric inhibins in girls from birth to adulthood: relationship with age, pubertal stage, FSH and oestradiol.

OBJECTIVE: Inhibin B is produced by granulosa cells in small antral follicles under the influence of FSH, whilst inhibin A is produced by larger follicles and the corpus luteum. The aims of our study were to investigate how these inhibins change from birth to late adolescence in girls, to derive reference data and to explore their relation with pubertal stage, FSH, oestradiol and each other. STUDY DESIGN AND SUBJECTS: Blood samples were collected from: (a) 345 girls aged 0--18 years to obtain age-related reference data, and (b) 80 pre-menarcheal girls with full pubertal staging, of whom 40 were on GH treatment at the time of sampling. MEASUREMENTS: Dimeric inhibins A and B were measured by double antibody enzyme-linked immunosorbent assay (ELISA), FSH by immunoradiometric assay (IRMA) and oestradiol by radioimmunoassay. RESULTS: Median inhibin B was low until age 6 years, slightly higher from 6 to 10 years, then increased from 10 to 12 years to reach a plateau from 12 to 18 years. Inhibin A was usually detectable in girls younger than 3 months but thereafter became undetectable in most samples until after age 10 years, when median levels rose progressively to 14 years, then stabilized from 14 to 18 years. Both inhibins displayed considerable scatter about the median throughout infancy, childhood and adolescence. Girls aged 0--10 years showed a positive correlation between inhibins A and B (P < 0.0001), whereas those aged 14--18 years showed an inverse relationship (P < 0.001), indicating the onset of ovulatory cycles. Age-related reference ranges and data for calculation of SD scores are presented. GH-treated girls at pubertal stage B2 (but not at B1 or B3--5) had higher inhibin B and FSH levels than untreated girls and were excluded from further analysis. Both inhibins A and B increased during puberty (P < 0.0001) and were positively correlated with each other (P < 0.01). Both inhibins were also positively correlated with FSH in pre-pubertal girls (P < 0.05) but not at pubertal stages B3--5. CONCLUSIONS: Although median levels of inhibins A and B remained low until after age 10 years in girls, the increased levels of both inhibins in individual samples, together with their positive relationship with FSH, provide further evidence of sporadic follicular development throughout infancy and childhood under the influence of FSH. The increase in both inhibins during puberty and their changing relationship with FSH are in keeping with the concept of follicular growth being dependent on the duration of FSH elevation above a critical threshold rather than the degree of elevation per se.

Bone turnover and growth during and after continuing chemotherapy in children with acute lymphoblastic leukemia.

Children treated for acute lymphoblastic leukemia may develop reduced bone mineral density during treatment, but there is little information on the mechanisms involved. In a prospective, longitudinal study on 15 children with ALL, we undertook serial measurements of markers of bone and collagen turnover, insulin-like growth factor (IGF)-I and its binding proteins (IGFBPs)-3 and -2 during the second year of continuing chemotherapy. In eight patients we also measured lower leg length by knemometry. Height SD scores, lower leg length velocity, IGF-I, and markers of bone collagen turnover did not differ significantly from healthy children. However, bone alkaline phosphatase, a marker of the differentiated osteoblast, was lower (mean SD score, -0.64; p < 0.0001), whereas procollagen type III N-terminal propeptide (P3NP, a marker of soft tissue collagen turnover; mean SD score, +0.93, p < 0.05), IGFBP-3 (mean SD score, +0.76; p < 0.01), and IGFBP-2 (mean SD score, +1.24, p = 0.01) were all higher than in healthy children. IGFBP-3 decreased during episodes of afebrile neutropenia (p < 0.05). Within 3 mo after completion of treatment, bone ALP increased in all eight patients, but collagen markers showed little change. IGFBP-2 returned to normal posttreatment, but P3NP and IGFBP-3 remained significantly elevated compared with healthy children (mean SD scores, +1.51 and +1.36, respectively; p < 0.01). We conclude that continuing chemotherapy was associated with normal growth and bone collagen turnover but enhanced soft tissue collagen turnover. Bone bone alkaline phosphatase was low throughout treatment, which suggests impaired osteoblast differentiation resulting from a direct effect of chemotherapy on bone. Although the effect was reversible, the long-term implications for bone health in survivors remain uncertain.

Effects of dexamethasone treatment on bone and collagen turnover in preterm infants with chronic lung disease.

Dexamethasone is used commonly in the treatment of chronic lung disease of prematurity, but there are concerns about possible deleterious effects on growth and bone. Our aim in this study was to examine the effects of dexamethasone treatment on bone and collagen turnover in preterm infants. Bone-specific alkaline phosphatase, the C-terminal propeptide of type I collagen (PICP, reflecting whole-body type I collagen synthesis), and the N-terminal propeptide of type III procollagen (P3NP, reflecting soft tissue collagen turnover), together with the C-terminal telopeptide of type I collagen (ICTP), urinary pyridinoline (Pyd), and deoxypyridinoline (all markers of collagen breakdown) were measured at weekly intervals over the first 12 wk of life in 14 preterm infants with chronic lung disease treated with dexamethasone. Results were expressed as SD scores relative to preterm control infants not treated with dexamethasone. PICP, P3NP, ICTP, and Pyd all showed marked decreases (-2.1 to -3.7 SD scores) during the first week of treatment (p < 0.001), returning to pretreatment levels after stopping dexamethasone. In the group as a whole, these collagen markers were negatively correlated with dexamethasone dose (p < 0.0001); negative correlations were also seen in most individual babies, although the slopes of individual regression lines varied by a factor of 2. Weight gain at 12 wk was correlated with PICP, expressed as the mean SD score over 12 wk for each baby, (r = 0.69, p < 0.01) but not with other markers or cumulative dose of dexamethasone. We conclude that dexamethasone markedly suppressed collagen turnover in preterm infants in a dose-dependent fashion, although some babies were more affected than others. The degree of suppression of type I collagen synthesis was a strong independent predictor of overall weight gain over the first 12 wk of life.

Bone and collagen markers in preterm infants: relationship with growth and bone mineral content over the first 10 weeks of life.

In a longitudinal study of 25 preterm infants, we have examined the relationship of bone-specific alkaline phosphatase (ALP), C-terminal propeptide of type I collagen (PICP), N-terminal propeptide of type III procollagen (P3NP), C-terminal telopeptide of type I collagen, urinary pyridinoline (Pyd) and deoxypyridinoline (Dpd), with rates of gain in weight, length, and lower leg length and with bone mineral content (BMC), all measured at weekly intervals over the first 10 wk of life. Concentrations of all collagen markers were 10-fold higher than in older children. Each marker showed a distinctive pattern of postnatal change, with early increases in PICP and P3NP and decreases in ICTP reflecting postnatal growth. Once markers had reached a plateau during weeks 4-10, P3NP was positively correlated, whereas Pyd and Dpd were negatively correlated with rate of weight gain (r = +0.44, -0.46, and -0.40, respectively, p < 0.05). P3NP was also positively correlated with overall linear growth (r = +0.44, p < 0.05). PICP was strongly correlated with mean BMC (r = +0.63,p < 0.01) and with total BMC attained by the end of the study period (r = +0.81, p < 0.001). Bone ALP was positively correlated with the rate of bone mineral accretion (r = +0.55, p = 0.01). We conclude that the marker of soft-tissue collagen formation, P3NP, is a good marker for overall ponderal and linear growth in preterm infants, whereas the markers of collagen breakdown, Pyd and Dpd, have inverse relationships with weight gain. The osteoblast markers, PICP and bone ALP, seem to be good surrogate markers for bone mineralization in preterm infants. Markers may provide information on whole-body turnover of bone and collagen that is complementary to traditional physical measures of growth and bone mineralization.

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.

Short-term changes in lower leg length in children treated for acute lymphoblastic leukaemia.

The lower leg length velocity (LLLV) of 14 children with a median age of 4.5 yr who were undergoing chemotherapy (CT) for acute lymphoblastic leukaemia (ALL) was studied for a median duration of 56 weeks (range 14-112). Nine children were studied over the first 6 months, six over the first year, four over the full 2-year course and nine children over the 3 months before and after the end of CT. Over the first month of CT, during induction, median LLLV was 0 mm/wk (P5, P95: -1.6, 0.11); during the fourth month of CT, at the end of CNS-directed therapy, there was a significant rise to 0.38 mm/wk (P5, P95: -0.04, 0.81; p = 0.01, WSR). In the children measured following the end of CT, median LLLV rose from 0.46 mm/wk (P5, P95: -0.02, 0.79) in month 23 to 0.84 mm/wk (P5, P95: 0.72, 1.12) (p = 0.03). There was a positive relationship between neutrophil count and LLLV during continuation chemotherapy (r = 0.4, p = 0.0002); median LLLV was 0.2 mm/ wk (P5, P95: -0.15, 0.5) when the neutrophil count was less than 1 x 10(9)/l and 0.65 mm/wk (P5, P95: 0.1, 1.0) (p = 0.01) when the count was above 1 x 10(9)/l. No significant differences in LLLV were observed between children randomised to different UKALLXI regimens. Intensive chemotherapy for ALL adversely affects lower leg growth. Growth was subnormal during the first few weeks of chemotherapy, but was comparable to healthy children during CNS directed and continuation therapy. There was a significant relationship between growth velocity and neutrophil count during continuation chemotherapy. On discontinuation of chemotherapy there was a further acceleration in lower leg length velocity to supranormal levels ("catch-up" growth).

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.

Bone and collagen markers in paediatric practice.

Biochemical markers of bone and collagen turnover have been found to be a valuable adjunct to measurements of bone mineral density in post-menopausal women in whom they appear to be independent predictors of osteoporosis and fracture risk. In children, they have been less extensively studied but have begun to find a similar complementary role in a number of disorders affecting bone turnover and growth. Although they may give helpful information in their reflection of recent bone turnover and growth in various disorders, their principal value appears to be in giving an early and sensitive indication of response to treatment, before changes in either height velocity or bone mineral density can be accurately determined. This review discusses the use and limitations of these markers in children, the clinical conditions in which they have been studied and their potential value in monitoring either beneficial or adverse effects of treatment on bone turnover and growth.

Serum concentrations of carboxyl-terminal propeptide of type I procollagen, amino-terminal propeptide of type III procollagen, cross-linked carboxyl-terminal telopeptide of type I collagen, and their interrelationships in schoolchildren.

We report pediatric age- and sex-specific 95% reference intervals for procollagen type I C-terminal propeptide (PICP), the cross-linked C-terminal telopeptide of type I collagen (ICTP), and procollagen type III N-terminal propeptide (P3NP), measured in plasma from 302 schoolchildren (156 boys, 146 girls) ages 4-19 years. All three markers displayed a significant variation with age (ANOVA P < or = 0.0015). PICP showed no detectable increase during adolescence for either sex, but decreased towards adult concentrations after the age of puberty, with an earlier decrease for girls than for boys (P < 0.01). ICTP and P3NP both increased in pubertal-aged children (P < 0.05), with an earlier increase in girls than in boys (P < 0.05), before decreasing towards adult concentrations (P < 0.01). All three collagen markers were highly correlated with one another (P < 0.001). The patterns observed mirrored the childhood growth curve and reflected the high turnover of bone and soft tissue during childhood growth.

Changes in dimeric inhibin A and B during normal early puberty in boys and girls.

OBJECTIVE: Although recently developed specific and sensitive assays of bioactive dimeric inhibin A and B have given new insights into the pituitary-gonadal axis in adult men and during the adult female menstrual cycle, there have been no reports on circulating inhibin A and B during normal human puberty. The aim of this study was to assess the relationship of dimeric inhibin A and B to pubertal stage, FSH and testosterone or oestradiol in late prepuberty and in early puberty. STUDY DESIGN AND SUBJECTS: Serial samples were collected during a prospective longitudinal trial of GH treatment in short normal children. Seven boys were studied from late prepuberty to genital stage 3, and six pre-menarche girls from late prepuberty to breast stage 4. MEASUREMENTS: Dimeric inhibin A (girls only) and inhibin B (boys and girls) were measured by highly specific and sensitive two-site ELISAs, FSH by IRMA, testosterone and oestradiol by RIA. RESULTS: In boys, inhibin B increased progressively from pubertal stages 1 to 3 (ANOVA P < 0.0001) and correlated strongly with mean testicular volume (r = 0.72, P = 0.0005). Prepubertal boys showed a positive correlation between inhibin B and FSH (r = 0.65, P = 0.056), whereas pubertal boys gave a strong negative correlation (r = 0.75, P = 0.012). In both prepubertal and pubertal boys positive correlations were observed between inhibin B (y) and testosterone (x) (r = 0.81, P = 0.008 and r = 0.62, P = 0.054 respectively), but the slope of the regression line between the two was much steeper before than after the onset of clinical puberty. In girls, both inhibin A and B increased through pubertal stages 1-4 (ANOVA P = 0.01 and P = 0.047 respectively). Both showed strong positive correlations with oestradiol (r = 0.80 and 0.79, P = 0.001) and with FSH (r = 0.83, P = 0.0004 and r = 0.80, P = 0.001). Inhibin A and B were also strongly correlated with each other (r = 0.92, P = 0.0001). CONCLUSIONS: In boys, testicular production of inhibin B increases as puberty progresses. Our results show for the first time that the initiation of puberty is accompanied by a dramatic switch from a positive to a negative relation between inhibin B and FSH as inhibin B begins to exert the expected negative feedback on FSH. The results in girls suggest that, prior to menarche, the ovarian follicles produce inhibin A and B in strict proportion, and in progressively greater amounts as puberty proceeds. Measurement of dimeric inhibin A and B may provide a sensitive new tool for determining gonadal maturity in late prepuberty and early puberty.