Radioiodine for hyperthyroidism.
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Humans↗
Biomedical subjects
S M Shalet
Publications and source records attributed to S M Shalet.
Growth hormone and tumour recurrence.
OBJECTIVE: To determine whether using growth hormone to treat radiation induced growth hormone deficiency causes tumour recurrence. DESIGN: Comparison of tumour recurrence rates in children treated with growth hormone for radiation induced deficiency and an untreated population. Computed tomograms from children with brain tumours were reviewed when starting growth hormone and subsequently. SETTING: North West region. PATIENTS: 207 children treated for brain tumour, 47 of whom received growth hormone and 161 children with acute lymphoblastic leukaemia 15 of whom received growth hormone. MAIN OUTCOME MEASURES: Tumour recurrence and changes in appearances on computed tomography. RESULTS: Among children with brain tumour, five (11%) who received growth hormone had recurrences compared with 42 (26%) who did not receive growth hormone. Also adjusting for other variables that might affect tumour recurrence the estimated relative risk of recurrence was 0.82 (95% confidence interval 0.28 to 2.37). The only child with acute lymphoblastic leukaemia who relapsed while taking growth hormone had relapsed previously before starting treatment. Two of the five children with brain tumours who relapsed had abnormal appearances on computed tomography when growth hormone was started. 14 other children who remained relapse free and had follow up computed tomography showed no deterioration in radiological appearance during treatment. CONCLUSIONS: In this population growth hormone did not increase the risk of tumour recurrence but continued surveillance is essential. Abnormal results on computed tomography are not a contraindication to treatment with growth hormone.
Adolescent↗
Chemotherapy with actinomycin D influences the growth of the spine following abdominal irradiation.
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Age Factors↗
Irradiation-induced growth failure.
GH deficiency, skeletal disproportion and early or precocious puberty may complicate irradiation to the head or axial skeleton in childhood. Certain cohorts of children are at particular risk, including those irradiated for brain tumours and various haematological malignancies. Both GH deficiency and impaired spinal growth may result in short stature, whereas the occurrence of early puberty in association with GH deficiency reduces the time available for GH therapy. The age of the child at irradiation is critical in that, in younger children, the central nervous system is more radiosensitive, the severity of the subsequent skeletal disproportion is greatest and the onset of puberty earliest. It is the very young craniospinally-irradiated child who is most at risk of extreme short stature.
Age Factors↗
Point mutations detected in the androgen receptor gene of three men with partial androgen insensitivity syndrome.
OBJECTIVE: Determine the sequence of the androgen receptor gene in men with impaired responsiveness to androgens in order to identify the molecular basis of their under-virilization. DESIGN: Blood samples were used as the source of genomic DNA. Portions of the androgen receptor gene were amplified by polymerase chain reaction and sequenced. PATIENTS: Samples were obtained from three patients and five normal fertile controls. Patients were all 46 XY and were undervirilized with ambiguous external genitalia, gynaecomastia and infertility. MEASUREMENTS: Total cellular DNA was purified from peripheral blood leucocytes. Pairs of oligonucleotide primers designed to flank the individual exons of the androgen receptor gene were synthesized. The specific regions of the androgen receptor were amplified from the samples of cellular DNA by polymerase chain reaction. Amplified DNA was purified, sequenced and compared to the published sequence. RESULTS: In all three patients point mutations in the androgen receptor gene were detected but no defects were detected in samples from normal controls. In two of the patients, an identical single nucleotide change from G to T was detected. This nucleotide was within the codon for amino acid 866 and would change it from valine to leucine. Amino acid 866 is found within an area of the steroid binding domain thought to be involved in receptor dimerization. Within the repetitive sequence of exon I patient 1 had 21 glutamine residues and patient 2 had 25. In the third patient a single change of G to A would result in incorporation of lysine in place of a conserved arginine residue at position 607 within the second zinc finger of the DNA binding domain. The sequence of the androgen receptor gene of the mother of the third patient revealed her to be heterozygous for the same defect. CONCLUSION: Patients 1 and 2 are unrelated although they have an identical point mutation in their androgen receptor gene. A patient with complete androgen insensitivity syndrome has been reported to have a defect at the same position causing the amino acid substitution of methionine for valine. Therefore we confirm that the nature of the amino acid change in the peptide sequence of the androgen receptor as well as its location within the protein, can have a profound effect on the phenotypic severity of androgen resistance. Studies on mutated receptors from individuals with a wide range of degrees of androgen resistance may enable us to construct a map of the key amino acids in the different domains of the protein.
Adult↗
A novel variant of growth hormone (GH) insufficiency following low dose cranial irradiation.
OBJECTIVE: We aimed to investigate the effect of low dose (1800 cGy) prophylactic cranial irradiation on physiological growth hormone secretion. DESIGN: We performed an analysis of 24-hour serum GH profiles using 20-minute sampling. PATIENTS: Forty-four children were studied, of whom 21 were long-term survivors of acute lymphoblastic leukaemia and 23 were normal children. They were further subdivided into prepubertal, pubertal and post-pubertal groups. MEASUREMENTS: GH profiles were analysed by autocorrelation, Fourier transformation and spectral analysis of stationarized data, and peak detection using the Pulsar peak detection program. RESULTS In the normal children, there was a significant increase in the median (range) area under the curve (AUC) of the GH profile between the prepubertal and pubertal groups (62 (11-124) and 137 (142-158) IU/I/h respectively, (P less than 0.01)). There was also a change in the spectral analysis through puberty. The dominant frequencies were spread widely in the prepubertal and post-pubertal groups but sharply focused in the pubertal group. In the cranially irradiated children there was no significant increase in AUC between the prepubertal (62(13-110) IU/I/h) and pubertal groups (92 (14-163) IU/I/h). The wide range of dominant frequencies persisted in the pubertal cranially irradiated group due to the presence of additional high frequency pulses. The impression of a disturbance of the periodicity of GH secretion in the cranially irradiated pubertal group was further supported by the finding that the autocorrelation function in this group alone was not significantly different from that which would arise from random data. CONCLUSIONS: A novel form of GH insufficiency has been observed after low dose irradiation in childhood in which an abnormality of periodicity and a quantitative reduction in GH secretion appears restricted to puberty.
Adolescent↗
Abdominal irradiation in childhood; the potential for pregnancy.
OBJECTIVE: To investigate the impact of premature ovarian failure due to whole abdominal radiotherapy (DXT) in childhood on uterine physical characteristics and blood flow and measuring the uterine response to exogenous sex steroid replacement. DESIGN: A comparative observational study SUBJECTS: 10 women with premature ovarian failure due to treatment with whole abdominal irradiation in childhood. A comparison group of 22 women with premature ovarian failure who had not received whole abdominal DXT. MAIN OUTCOME MEASURES: Uterine length and uterine blood flow measurement plus serial assessment of endometrial thickness during a cycle of exogenous sex steroid replacement. RESULTS: Uterine length was significantly less (P less than 0.01) in women who had been exposed to whole abdominal DXT in childhood (mean 4.1 cm, 2SE 0.8) compared with a mean of 7.3 cm (2SE 0.6) in the comparison group. The three women in the DXT group who were studied serially had no increase in endometrial thickness in response to physiological sex steroid replacement therapy and most of the 10 irradiated women had no detectable uterine blood flow with Doppler ultrasound. CONCLUSIONS: Uterine musculature and blood flow are irreversibly affected by high dose irradiation in childhood. Non-invasive assessment of this nature may predict potential for pregnancy following ovum donation and embryo transfer.
Adult↗
Relationship between urinary and serum growth hormone and pubertal status.
Urinary growth hormone (uGH) excretion and serum growth hormone concentrations have been compared in three groups of children. Group 1 consisted of 21 children who had had cranial irradiation as part of their treatment for acute lymphoblastic leukaemia; group 2, 18 normal children; and group 3, 12 boys with constitutional delay in growth and puberty who were in early puberty. Children in groups 1 and 2 each had a 24 hour serum growth hormone profile (sampling every 20 minutes) and concurrent urine collection. The 12 boys in group 3 had a total of 21 profiles (sampling every 15 minutes for 12 hours) and concurrent urine collections. In the prepubertal children (n = 17), in both groups 1 and 2, there was a significant correlation between mean serum growth hormone and total uGHng/g creatinine. There were also significant correlations between total uGHng/g creatinine and both peak serum growth hormone and mean amplitude of the pulses in the growth hormone profile. In the pubertal children (n = 22), in groups 1 and 2, whether combined or in separate groups, there was no significant correlation between total uGHng/g creatinine and mean serum growth hormone, peak serum growth hormone, or mean amplitude of the pulses in the growth hormone profile. In group 3 there were significant correlations between total uGHng/g creatinine and both the mean serum growth hormone and mean amplitude of the pulses in the profile. Therefore uGH estimations appear to correlate well with serum growth hormone profiles in children who are prepubertal or in early puberty, but not in those further advanced in pubertal development. These results may reflect a variation in the renal handling of growth hormone during pubertal development. uGH estimation may be an unreliable screening investigation for growth hormone sufficiency in mid to late puberty.
Adolescent↗
Does growth hormone treatment improve final height attainment of children with intrauterine growth retardation?
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Body Height↗
Endocrine deficit after fractionated total body irradiation.
Endocrine function was assessed in 31 children (17 boys) after fractionated total body irradiation used in the preparative regimen for bone marrow transplantation. Endocrine dysfunction was present in 25 children. Fifteen of 29 had growth hormone insufficiency 0.9-4.9 years after total body irradiation, yet only three of the 15 had received previous cranial irradiation. Five of 30 had thyroid dysfunction: two with a low thyroxine and raised thyroid stimulating hormone (TSH) concentration and three with a raised TSH and normal thyroxine concentration. Thus the incidence of thyroid dysfunction (16%) is much lower than that reported after single fraction total body irradiation (39-59%). In only two children were abnormalities of the hypothalamic-pituitary-adrenal axis demonstrated. The majority of pubertal children assessed (n = 15) showed evidence of gonadal damage. All the pubertal girls (n = 5) had ovarian failure, although there was evidence of recovery of ovarian function in one girl. All seven boys in late puberty showed evidence of damage to the germinal epithelium, and two of three in early puberty had raised follicle stimulating hormone concentrations. Despite the use of a fractionated total body irradiation regimen, endocrine morbidity is substantial and children undergoing such procedures will require long term endocrine review and management.
Adolescent↗
Tumour occurrence and recurrence.
There is growing concern about the oncogenic potential of growth hormone (GH) used therapeutically. In rat experiments, a variety of malignant tumours have been induced following administration of supraphysiological doses of GH, whilst in other studies in hypophysectomized animals a lower than normal incidence of carcinogen-induced neoplasms was reported. In acromegaly, in which there is a pathologically sustained high GH level, there is a significantly increased incidence of cancer in general and specifically of colonic neoplasia. To determine whether the use of GH in the treatment of radiation-induced GH deficiency causes tumour recurrence, a comparison was made of tumour recurrence rates between 47 children treated with GH for radiation-induced GH deficiency after treatment for a brain tumour and a control population from the North West Children's Cancer Registry who did not receive GH (n = 160). All cases of acute lymphoblastic leukaemia (ALL), including those that were (n = 15) and were not (n = 146) treated with GH were reviewed. The computerized tomography (CT) scans in the children with brain tumours were reviewed at the time of GH commencement and subsequently. There were 5 brain tumour recurrences after GH therapy: 1 astrocytoma, 2 ependymomas and 2 medulloblastomas. Adjusting for variables other than GH which might affect tumour recurrence, the estimated relative risk of tumour recurrence was 0.82 (95% confidence interval: 0.28-2.37). In each tumour category there was no association between the use of GH and subsequent tumour recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Growth hormone and puberty.
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Adolescent↗
Final height in girls with untreated constitutional delay in growth and puberty.
During a 10-year period, 23 girls compared to 118 boys presented with constitutional delay in growth and puberty. Of these girls, 15 were followed to final height to determine the outcome of the untreated condition in terms of both growth and psychological well-being. At presentation chronological age was 13.2 (1.7) years [mean (S.D.)], bone age delay 2.7 (0.9) years, standing height standard deviation score (SDS) -3.4 (0.9), and predicted adult height (PAH) SDS -1.3 (0.7) (Tanner-Whitehouse II method). Final height SDS was -1.5 (0.8) measured at 18.9 (2.6) years of age. Mean age at menarche was 15.6 (0.9) years. There was no significant difference between final adult height (FH) and PAH but there was a significant difference between FH and target height (P less than 0.001). Psychological questionnaires revealed no significant difference in self-esteem, marital or employment status between the patient and control groups. There was no significant correlation between self-esteem and FH but 80% felt their growth delay had affected success either at school, work or socially. Of the patients, 50% would have preferred treatment to advance their growth spurt. This study demonstrates that girls with constitutional delay in growth and puberty reached their PAH, although this was lower than the midparental heights. The girls also experienced significant distress due to delayed growth and puberty and treatment to advance growth should be considered more frequently.
Adolescent↗
Thyroid function after treatment of brain tumors in children.
In 134 children who had been treated for a brain tumor not involving the hypothalamic-pituitary axis, thyroid function was assessed up to 24 years after treatment with cranial or craniospinal irradiation. In addition, 78 children received up to 2 years of cytotoxic chemotherapy. Of 85 children who received craniospinal irradiation, 30 (35%) had abnormalities of thyroid function, and 10 (20%) of 49 who received cranial irradiation had such abnormalities. Frank hypothyroidism developed in three children and thyrotoxicosis in one. Thirty-six children had an elevated thyroid-stimulating hormone level in the presence of a normal thyroxine level; in 16 of them the thyroid-stimulating hormone level subsequently returned to normal. Twenty-eight children who were treated between 1960 and 1970 were excluded from the analysis. Of 34 children who received cranial irradiation, five had thyroid dysfunction and 24 of 72 who received craniospinal irradiation had such dysfunction (p = 0.013). Thyroid dysfunction was present in 4 of 35 children who received no chemotherapy and in 25 of 71 who received chemotherapy (p = 0.014). Direct irradiation plus chemotherapy was more damaging than irradiation alone. These data confirm the high incidence of thyroid dysfunction when the thyroid gland is included in the radiation field. However, in a high proportion, the thyroid abnormalities are minor and revert to normal with time; life-long replacement therapy with thyroxine may be unnecessary.
Adolescent↗
Dose dependency of time of onset of radiation-induced growth hormone deficiency.
Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response, greater than 15 mU/L) within the first 5 years, in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showed that dose (p = 0.007) and time from irradiation (p = 0.03), but not age at therapy, had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years), but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis.
Adolescent↗
The evolution of spinal growth after irradiation.
Spinal growth has been monitored in 13 children treated with craniospinal irradiation for brain tumours. Six were irradiated prepubertally and seven peripubertally, all with 30 Gy to the whole spine over four weeks. The change in (subischial leg length (SILL)--sitting height (SH)) standard deviation score (SDS) was used as an index of disproportionate segmental growth, which allowed the influence of growth hormone deficiency on growth to be discounted. Spinal growth over the prepubertal years was relatively normal: annual change in (SILL-SH) SDS was +0.07 SD 0.2. However, over puberty, annual change in (SILL-SH) SDS had increased significantly to +0.41 SD 0.14 (P = 0.03). If irradiated peripubertally, annual change in (SILL-SH) SDS to final height was +0.22 SD 0.23, not significantly different from the change over puberty in the prepubertal group. Relatively normal spinal growth after irradiation in the prepubertal child should be interpreted with caution, as it is during puberty that skeletal disproportion manifests itself.
Adolescent↗
The effect of external pituitary irradiation on elevated serum prolactin levels in patients with pituitary macroadenomas.
The response of serum prolactin to external radiotherapy was studied in 58 patients (32 women) with pituitary tumours, aged between 16 and 75 years. Forty-four patients underwent pituitary surgery before radiotherapy. Six patients were irradiated with a regimen of 20 Gy in eight fractions over 10-11 days and the remainder received 35-42.5 Gy in 15 fractions over 20-22 days. Following radiotherapy, 44 patients received additional treatment with dopaminergic agonists. Prolactin levels ranged from 1078 to 491,000 mU/l (median 11,750 mU/l) before radiotherapy and all but three patients showed a fall in serum prolactin (measured 4 weeks after stopping bromocriptine in those on dopamine agonist therapy) during observation over periods of up to 154 months. All patients had evidence of pituitary fossa erosion or expansion at presentation and large tumours (Hardy-Vezina Grade 3-4) were more common in male patients (chi 2 = 10.08, p less than 0.01). The rate of fall of serum prolactin levels was greater in patients with true prolactin-secreting tumours when compared with those who had stalk or hypothalamic damage (p less than 0.005). The rate of decline of serum prolactin was also significantly related to the pre-radiotherapy value (rho = 0.519, p less than 0.01). A serum prolactin level less than 500 mU/l was achieved in 31 out of 44 patients treated with radiotherapy and dopaminergic agonist but only nine remained normoprolactinaemic when medication was discontinued for 4 weeks or more. The serum prolactin level fell permanently to less than 500 mU/l in two of 14 patients treated with radiotherapy only. Actuarial analysis of data from all patients indicated a 50 per cent probability that prolactin would be reduced to less than 500 mU/l by 10 years; this increased to 58 per cent for patients with smaller tumours (Hardy-Vezina grade 2).(ABSTRACT TRUNCATED AT 250 WORDS)
Adenoma↗
Episodic ACTH and cortisol secretion in normal children.
The aim of this study was to determine the normal relationship between ACTH and cortisol secretion in children. Fourteen children (nine male, five female; median age 11.3 years) were hospitalized and blood samples were taken every 20 min for 24 h. A circadian rhythm was observed with median 0900 h and midnight ACTH values of 1.80 and less than 0.97 pmol/l, and for cortisol 296 and 62 nmol/l respectively. The median (range) areas under the curve for ACTH and cortisol were 29.7 (9.0-53.8) pmol/l/h and 5114 (3562-8630) nmol/l/h respectively. There were no significant differences detected for ACTH and cortisol secretion between males and females, or between prepubertal (n = 9) and pubertal subjects (n = 5). Using a novel form of time series analysis we have shown that both ACTH and cortisol are secreted with a dominant periodicity of 0.7-1.0 h, representing 24-34 secretory episodes of ACTH and cortisol in 24 h. For cortisol, but not ACTH, there is a significant secondary periodicity of 2-3.2 h. To look for shared periodicities we have used the technique of coherency. This reveals that for six of the children ACTH and cortisol are secreted with a significant shared periodicity of 0.8-1.0 h, and for a further five children a similar secondary shared periodicity is present. Therefore in normal children ACTH and cortisol secretion are interdependent and episodic but are not influenced by either pubertal status or gender.
Adolescent↗