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A A Toogood

Publications and source records attributed to A A Toogood.

31 records · Page 2Linked to original sources
PubMed1997

Relationship between growth hormone (GH) status, serum leptin and body composition in healthy and GH deficient elderly subjects.

OBJECTIVE: Growth hormone (GH) secretion declines with age and is affected by body composition. The signal that mediates the latter relationship remains III-defined. Leptin, the protein product of the adipocyte specific ob gene, is thought to accurately reflect fat mass and could therefore be a candidate to influence GH secretion. We have therefore investigated the relationship between GH status, leptin and body composition in normal and GH-deficient elderly subjects. DESIGN: GH Secretion was assessed by 20-minute sampling over 24 hours and serum leptin concentrations were measured in a single morning, fasted sample. PATIENTS: Twenty-one GH deficient elderly patients (61-83 years) and 22 gender- and BMI-matched controls (61-88 years). MEASUREMENTS: Body composition was assessed by dual-energy X-ray absorptiometry (DEXA). GH was measured in an ultrasensitive chemiluminescent assay and serum leptin was determined by radio-immunoassay. RESULTS: Leptin was correlated with percentage body fat in both sexes (male r = 0.75, female r = 0.89, both P < 0.001). Male patients had increased fat mass (FM) (P < 0.01) and leptin concentrations (P < 0.05) but similar lean mass (LM) compared with controls. However, leptin concentration per unit FM was identical in both groups (P = 0.3). In contrast, female patients had lower LM (P < 0.05) but similar FM to controls, yet their leptin concentration per unit FM was twice that of the controls (P < 0.05). In multiple linear regression (MLR) leptin was determined positively by FM and negatively by LM (controls r2 = 76%; patients r2 = 73%, both P < 0.0001). When controlled for gender, GH secretion in the controls was correlated negatively with leptin (r = -0.68, P < 0.01) and negatively with percentage body fat (r = -0.73, P < 0.01). In MLR, using leptin as a marker of body composition, 66% of the variability in GH secretion in the controls could be explained by gender (38%) and by leptin (28%). CONCLUSIONS: Both decreased lean mass and increased fat mass raise serum leptin concentrations in normal and growth hormone-deficient elderly subjects. Leptin is therefore a marker of body composition rather than fat mass alone. The influence of body composition on growth hormone secretion in the elderly may be mediated through leptin, acting as a peripheral signal from adipose tissue to decrease GH secretion.

Absorptiometry, Photon↗
PubMed1997

Diagnosis of severe growth hormone (GH) deficiency in young adults who received GH replacement therapy during childhood.

Between 20% and 87% of young adults who had completed growth hormone (GH) therapy in childhood for a putative diagnosis of GH deficiency (GHD) had normal GH responses to provocative tests when they were retested. Patients with isolated idiopathic GHD were more likely to exhibit normal GH responses at retest in young adult life than were patients with multiple pituitary hormone deficits. When determining which patients should receive GH therapy in adult life, those who have isolated GHD should undergo two tests of GH status, while those with multiple anterior pituitary hormone deficits require only one test. Most information is available for the insulin tolerance test, the arginine stimulation test and the glucagon stimulation test, but more recent methods, such as GH-releasing hormone in combination with pyridostigmine, are showing promise in the investigation of GHD. In young adults with childhood-onset GHD, the serum concentration of insulin-like growth factor I is a useful marker of GH status, and can be used in conjunction with a GH provocative test. The choice of GH provocative test should ultimately depend on the experience and policy developed at the centre performing the assessment. Whichever tests are chosen, each should be validated in subjects known to have hypothalamic-pituitary disease as well as in normal individuals.

Adult↗
PubMed1997

Elderly patients with adult-onset growth hormone deficiency are not osteopenic.

The age-related decline in GH secretion has been implicated in the development of osteoporosis. GH-deficient adults show a significant reduction in bone mineral density (BMD), which is greater in those with childhood-onset GH deficiency than in those with GH deficiency occurring in adult life. To determine whether GH deficiency in late adult life causes a reduction in BMD beyond the decline observed with increasing age, we studied 21 patients over the age of 60 yr with GH deficiency caused by organic pituitary disease and 23 controls of similar age and sex distribution and BMI. Dual energy x-ray absorptiometry was used to determine total bone mass and BMD at the hip and in the lumbar spine. Serum osteocalcin was determined in all subjects and urinary deoxypyridinoline/creatinine ratio in 19 patients and 21 controls. The median (range) known duration of GH deficiency in the patients was 8 yr (range, 4-41 yr). The median (range) total bone mass was 2774 g (range, 1534-3734) in the patients and 2717 g (range, 1235-3549) in the controls (P = 0.42). Specific measurements of BMD made at L2-L4, the right femoral neck, the right femoral trochanter, and Ward's triangle were 1.234 (range, 0.778-1.507) vs. 1.144 g/cm2 (range, 0.809-1.466; P = 0.48), 0.921 (range, 0.605-1.372) vs. 0.96 g/cm2 (range, 0.534-1.315; P = 0.62), 0.92 (range, 0.523-1.229) vs. 0.915 g/cm2 (range, 0.353-1.313; P = 0.68), and 0.773 (range, 0.408-1.289) vs. 0.806 g/cm2 (range, 0.353-1.154; P = 0.81) in the patients and controls, respectively. The median (range) serum osteocalcin was 11.5 (range, 3.6-23.0) vs. 15.1 ng/mL (range, 0.7-40.5; P = 0.019) in the patients and controls, respectively. The median (range) deoxypyridinoline cross-links/creatinine ratio was 3.5 micromol/mol (range, 0.8-8.3) in the patients and 4.9 micromol/mol (range, 3.0-9.7) in the controls (P 0.038). There was a significant correlation between serum insulin-like growth factor I and total bone mass in the controls, but not in the patients. These data demonstrate that BMD is not significantly altered in GH-deficient adults over the age of 60 yr. Markers of bone formation and resorption are decreased, however, suggesting that bone turnover is reduced. Further studies are required to determine whether the reduction in bone turnover in these patients is of benefit.

Absorptiometry, Photon↗
PubMed1997

Preservation of growth hormone pulsatility despite pituitary pathology, surgery, and irradiation.

Detailed assessment of physiological and pathophysiological GH secretion has, until recently, been limited by the poor sensitivity of the available assays. We have used an ultrasensitive chemiluminescence GH assay (sensitivity, 0.002 microgram/L) to study 24-h GH profiles (20-min sampling) from 24 patients who had been treated for hypothalamic-pituitary disease with surgery and irradiation and from 24 healthy control subjects matched for age, sex, and body mass index. Twenty-three of the 24 patients demonstrated pulsatile GH secretion, determined by Cluster. The median (range) area under the curve for GH, mean pulse area, mean pulse height, average valley mean level, and mean interpeak nadir were lower in the patients than in the controls [119.25 (7.273-843.600) vs. 968.539 (227.200-4625.000) min/microgram.L (P < 0.00001); 3.777 (0.288-30.850) vs. 61.390 (12.880-224.210) min/microgram.L (P < 0.00001), 0.107 (0.010-0.958) vs. 1.408 (0.368-5.050) micrograms/L (P < 0.00001), 0.074 (0.006-0.415) vs. 0.348 (0.048-2.350) microgram/L (P < 0.00001), and 0.066 (0.003-0.270) vs. 0.205 (0.021-1.838) microgram/L (P = 0.0004), respectively]. The median (range) number of pulses, mean pulse duration, and mean interval between pulses did not differ between the patients and controls [10 (4-15) vs. 10 (7-15; P = 0.36), 96.4 (68.0-220.0) vs. 104.0 (72.0-151.4) min (P = 0.65) and 128.0 (92.8-255.0) vs. 126.2 (90.0-180.0) min (P = 0.73), respectively]. The diurnal rhythm of GH secretion was present in the controls, but there was only limited evidence of residual diurnal rhythm in the patients. This study has demonstrated that GH secretion remains pulsatile in GH-deficient patients despite the mass effect of hypothalamic-pituitary pathology, pituitary surgery, and radiotherapy. With the development of potent GH secretagogues that are active orally, our findings may have important implications for the future management of GH-deficient subjects.

Age Factors↗
PubMed1996

The assessment of growth hormone status in normal young adult males using a variety of provocative agents.

OBJECTIVE: In adults, there are few data regarding GH responses to provocative stimuli other than insulin-induced hypoglycaemia. We have compared the GH response to four different growth hormone secretagogues and placebo in normal healthy adult males. DESIGN: This was a prospective, randomized, placebo-controlled study in 18 normal male subjects. After an overnight last, an intravenous cannula was inserted into the arm of each subject and a blood sample was taken for GH at -30, -15, and 0 minutes. Four provocative agents (intravenous insulin 0.2 IU/kg; intravenous arginine 20 g/m2 as an infusion over 30 minutes; oral clonidine, either 100 or 200 micrograms; intramuscular glucagon 1 mg) and placebo were administered to each subject in a randomized manner on different days. Further blood samples were taken at 15-minute intervals for 180 minutes for GH estimation. RESULTS: The median (range) GH peak response for each agent was insulin 107.7 (28.1-200) mU/l; arginine 22.3 (3.1-72.9) mU/l; glucagon 42 (11.8-200) mU/l; 100 micrograms clonidine 7.2 (< 1-22.2) mU/l; 200 micrograms clonidine 8.2 (1.1- 88) mU/l and placebo 2.4 (< 1-30.2) mU/l. The peak GH response to insulin-induced hypoglycaemia (ITT) was significantly greater than for any other agent (P < 0.0001). The peak GH response to glucagon was significantly greater than for arginine (P < 0.05), clonidine at 100 and 200 micrograms (P < 0.01) and placebo (P < 0.01). The peak GH response following administration of arginine was significantly greater than for clonidine 100 and 200 micrograms (P < 0.05), and placebo (P < 0.01). The peak GH response following clonidine 200 micrograms was not significantly greater than following clonidine 100 micrograms (P = 0.38) or placebo. On an individual basis two, six and 15 of 18 subjects failed to achieve a peak GH level of > 20 mU/l to glucagon, arginine and clonidine respectively. In complete contrast only one subject achieved a peak response of less than 40 mU/l (28.1 mU/l) to ITT. CONCLUSIONS: The most profound GH release is seen after insulin-induced hypoglycaemia. Glucagon appears to be more effective at inducing GH release than arginine. Clonidine at a dose of 100 or 200 micrograms is no more effective than placebo.

Adult↗
PubMed1996

The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood [see comment].

OBJECTIVE: The few previous studies in which reassessment of GH status has been carried out in young adults treated with GH therapy for childhood GH deficiency concentrated on determining the incidence of 'transient GH deficiency'. As the benefits of GH replacement therapy in adults become increasingly appreciated, it is likely that GH therapy started in childhood for GH deficiency will be continued into adult life in many of those with severe GH deficiency. The aim of this study is to determine how many patients who received GH replacement therapy in childhood until completion of growth have GH deficiency severe enough to be considered for GH replacement therapy in adult life. DESIGN: Retrospective analysis of the peak GH responses to provocative stimuli performed at the time of diagnosis of GH deficiency in childhood and at the completion of growth after GH replacement therapy had been stopped. PATIENTS: Eighty-eight adults (49 male, 39 female) who had received GH therapy in childhood for a diagnosis of GH deficiency. The aetiology of the GH deficiency included craniopharyngioma, radiation induced associated with either a cerebral tumour or acute lymphoblastic leukaemia, histiocytosis-X and idiopathic. MEASUREMENTS: In childhood the original diagnosis of GH deficiency was based biochemically on the failure of the peak GH response to reach 20 mU/l during two provocative tests in 59 of the 88 patients and to a single test in the remaining 29. A total of 147 tests were performed, the most common being an insulin tolerance test (ITT, n = 72) and an arginine stimulation test (AST, n = 53). At reassessment in young adult life 146 tests were performed (74 ITT, 64 AST). Severe GH deficiency was defined arbitrarily as a peak GH response of less than 9 mU/l to a single (n = 33) or to two (n = 55) pharmacological stimuli. RESULTS: By definition all patients were considered GH deficient at the time of initial diagnosis. A peak GH response of less than 9 mU/l was seen in 64.8% at initial assessment and 60.2% at reassessment. Analysis in aetiological terms, however, showed that between assessments the incidence of severe GH deficiency increased in the group of radiation induced (48.8 vs. 55.8%) but decreased in the idiopathic group (78.1 vs. 53.1%). Out of the 55 patients who underwent two tests at reassessment, 47.3% of those with a GH peak less than 9 mU/l at one test had a GH peak greater than 9 mU/l at the second test. Fifteen of the 55 patients had additional pituitary hormone deficiencies and all 15 had a GH peak below 9 mU/l in both tests. CONCLUSIONS: Our study suggests that all children who have received GH replacement therapy in childhood should undergo reassessment of GH status in young adult life. Between 40 and 60% of such patients merit consideration for GH therapy in adult life depending on the definition of severe GH deficiency in use. Patients with isolated GH deficiency should undergo two provocative tests of GH secretion, but those with additional anterior pituitary hormone deficiencies require only one test at reassessment.

Adolescent↗
PubMed1996

Body composition in growth hormone deficient adults over the age of 60 years.

OBJECTIVE: Elderly patients with hypothalamic-pituitary disease exhibit a reduction in GH secretion distinct from the decline in GH secretion related to age. GH deficiency in young adults causes a change in body composition, with increased fat mass (FM) and reduced fat free mass (FFM), similar to that seen as a result of the normal ageing process. The aim of this study was to determine whether organic GH deficiency in elderly patients may cause changes in body composition beyond those due to ageing. SUBJECTS: Twenty-one patients (15 male) with documented pituitary disease and 24 controls (17 male) matched for age, height, weight and BMI, all over the age of 60, in whom GH status had been defined by a 24-hour GH profile and an arginine stimulation test. MEASUREMENTS: Serum was taken for fasting IGF-l and IGFBP-1 estimations. Total and regional FM and FFM were determined using dual-energy X-ray absorptiometry. RESULTS: FM (median (range)) was increased in the patients, 27.76 (19.25-50.24) vs 21.23 (8.81-49.15) kg in the controls (P < 0.005). FM was significantly increased in the arms, legs and trunk in the patients compared with the controls. The proportion of fat deposited centrally did not differ significantly between the two groups (57.0% (47.6-65.1) in the patients vs 55.3% (44.1-63.8) in the controls, P = 0.25). There was an inverse relation between total FM and serum IGFBP-1 present in the patients, p = -0.632, P < 0.005, and in the controls p = -0.467, P < 0.05, but the relation between total FM and area under the GH profile was significant only in the controls (p = -0.651, P < 0.001) and not in the patients. FFM (51.19 (26.96-69.18) kg in the patients vs 51.55 (32.35-60.53) kg in the controls, P = 0.99) and serum IGFBP-1 levels did not differ significantly between the two groups. CONCLUSION: Organic growth hormone deficiency causes changes in body composition beyond the changes associated with the ageing process. These changes differ from those seen in younger GH deficient adults in that they are limited to an increase in FM with no change in FFM. These findings indicate that even in the elderly, in whom GH secretion is normally very low, the additional imposition of GH deficiency due to organic disease has significant biological impact.

Absorptiometry, Photon↗
PubMed1996

Beyond the somatopause: growth hormone deficiency in adults over the age of 60 years.

GH secretion declines by 14% decade of adult life, leading to the suggestion that people over the age of 60 yr are functionally GH deficient. If this is the case, one might not be able to detect a difference in GH secretion between the elderly with documented hypothalamic-pituitary disease and an age-matched control group. We studied GH secretion in 24 patients with hypothalamic-pituitary disease and 24 controls matched for body mass index and age using 24-h GH profiles, arginine stimulation tests, and serum insulin-like growth factor I (IGF-I) levels. The median (range) area under the curve of the GH profile [< 9.6 (< 9.6-20) vs. 18.5 (10.7-74.4) micrograms/L.24 h; P < 0.0001], the median stimulated peak GH response to arginine [< 0.4 (< 0.4-7.7) vs. 8.0 (1.6-37.0) micrograms/L; P < 0.0001], and the median serum IGF-I concentration [102 (< 14-162) vs. 147 (65-255) ng/mL; P = 0.0002] were significantly lower in the patients than in the controls. Fifteen patients showed no evidence of spontaneous or stimulated GH secretion, whereas all controls had evidence of both. The area under the GH curve in the 33 subjects with demonstrable GH secretion correlated significantly with the peak GH response to arginine (r = 0.71; P < 0.0001), but not with serum IGF-I concentration. This study suggests that organic GH deficiency in the elderly is distinct from the decline in GH secretion associated with the aging process. These patients may benefit from GH replacement therapy.

Aged↗
PubMed1995

No mutation at codon 918 of the RET gene in a family with multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare cancer syndrome which is inherited in an autosomal dominant manner. The molecular basis of this condition has recently been defined as a mutation of codon 918 of exon 16 of the RET proto-oncogene. The mutation in codon 918 has been described in 69 out of 72 families with MEN 2B. We have studied a brother and sister who undoubtedly have the features of MEN 2B as evidenced by medullary thyroid carcinoma, phaeochromocytoma, mucosal neuromas and skeletal abnormalities. Neither of these patients has the classic gene mutation at codon 918 of exon 16 of the RET proto-oncogene, and although exons 2-20 have also been sequenced, no abnormality has been found. DNA analysis is a sensitive method of screening families for the MEN 2 syndromes. The absence of the mutation at codon 918 in a phenotypically normal individual would refute the diagnosis of MEN 2B, but in an individual with some of the features of MEN 2B would make the clinician reconsider the diagnosis. This family demonstrates that, although it is rare, the absence of the mutation in codon 918 of exon 16 of the RET proto-oncogene does not always exclude the diagnosis of MEN 2B. In such families routine biochemical screening for medullary thyroid carcinoma and phaeochromocytoma must be maintained for all individuals at genetic risk.

Adolescent↗
PubMed1995

The evolution of radiation-induced growth hormone deficiency in adults is determined by the baseline growth hormone status.

OBJECTIVE: Recent studies of GH replacement have suggested several beneficial effects for GH deficient adults. It would therefore be helpful to predict the time of onset of GH deficiency after external pituitary irradiation. We have studied the evolution of GH deficiency with time in patients irradiated for pituitary adenomas and other hypothalamic pituitary tumours. DESIGN: Analysis of serial peak GH responses to insulin hypoglycaemia following external irradiation to the hypothalamic-pituitary axis using statistical models which allowed for age, sex, previous surgery and the pre-radiotherapy GH peak response. PATIENTS: Eighty-five non-acromegalic adults (48 male), 75 of whom had either a pituitary adenoma or a craniopharyngioma and 10 who had other tumours in the hypothalamic-pituitary region. All the patients had received a radiation dose between 37.5 and 45 Gy divided into 15 fractions given over 21 days. MEASUREMENTS: The GH responses to an insulin tolerance test (ITT) performed as part of the regular endocrine follow-up in patients who received irradiation to the hypothalamic-pituitary region. RESULTS: Three hundred and forty-five ITTs were performed over a period of 10 years following radiotherapy. There was a decline in the modelled mean peak GH response to an ITT over the first 5 years which then appeared to plateau. Using an extended model, women had higher GH peak responses than men and this difference was maintained throughout the ten-year period. The magnitude of the post-radiotherapy peak GH response at any given time was dependent on the baseline peak GH response, but the rate of the decrease was not affected (P = 0.66). To develop severe GH deficiency (peak GH response less than 5 mU/l) after radiotherapy it took patients with baseline GH peaks of 30, 20 and 10 mU/l approximately 4 years, 3 years and 1 year respectively. Those patients with a baseline GH peak of greater than 50 mU/l are unlikely to develop severe GH deficiency within the first 5 years following radiotherapy. CONCLUSION: These results provide an insight into the pattern of the decline in GH secretion following radiotherapy in patients with pituitary disease and the factors affecting it. This information will help the clinician predict the frequency and timing of GH deficiency in patients irradiated for pituitary disease and the potential need for GH replacement therapy.

Adolescent↗
PubMed1994

Detection of antibodies to ovarian antigens in women with premature ovarian failure.

Premature ovarian failure is a common condition of uncertain aetiology in most cases, although autoimmunity is thought to play a role in a proportion of cases. The frequency of ovarian antibodies, which may be markers for an autoimmune aetiology in this condition, remains unclear. To define this further, we have examined the sera of 45 women with premature ovarian failure (five with iatrogenic ovarian failure, nine with an associated autoimmune disease, and 27 with idiopathic ovarian failure), as well as four women with infertility due to Turner's syndrome and 41 pre- and post-menopausal controls. Using two human ovarian antigen preparations, 24% and 60% of the ovarian failure patients reacted in an ELISA (P < 0.05 and P < 0.001 compared with controls), but frequent cross-reactivity was found with fallopian tube antigens. The apparent aetiology of ovarian failure did not correlate with the presence of ovarian antibodies. Using bovine ovary as an antigen, there was a significant overall increase in binding by the ovarian failure patients, but this was almost identical to binding in an ELISA with bovine fallopian tube. In contrast to a previous report, there was no significant increase of binding to soluble or Triton-extracted membrane fractions of bovine corpora lutea containing the LH/hCG receptor by the patients with ovarian failure. These results suggest that ovarian antibodies are common in premature ovarian failure, but their specificity and pathogenic role are questionable.

Amenorrhea↗
PubMed1994

The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism.

OBJECTIVE: A number of studies of the effect of GH replacement therapy in adult patients with GH deficiency have been published, but the definition of GH deficiency has varied considerably. In order to define severe GH deficiency more critically we have determined GH status in the context of gonadotrophin, ACTH and TSH secretion in adult patients with pituitary disease. DESIGN: Analysis of peak GH response to an insulin tolerance test performed during comprehensive assessment of pituitary function. PATIENTS: One hundred and ninety non-acromegalic patients (96 male) with pituitary disease whose ages ranged from 16 to 72 (mean 39.4) years. MEASUREMENTS: The patients were divided into four groups according to the number of anterior pituitary hormone deficiencies demonstrated; isolated GH deficiency (GHD0), or GH deficiency plus an additional one, two or three pituitary hormone deficits (GHD1, GHD2, GHD3). RESULTS: The four groups were matched for age and blood glucose nadir during the ITT. The median (interquartile range) GH peaks were GHD0, 10.0 (5.4-16); GHD1, 4.0 (2.7-7.7); GHD2, 2.0 (1-2.9); GHD3, 1.8 (1-3.2) mU/l. There was a significant downward trend in the medians (P < 0.0001). The differences between GHD0 and GHD1, and GHD1 and GHD2, were highly significant (P < 0.0001); however, there was no difference between GHD2 and GHD3. Ninety-one per cent of patients in combined groups GHD2 and GHD3, 55% in GHD1 and 24% in GHD0 had a peak GH < 5 mU/l. CONCLUSIONS: Our study has shown that GH deficiency is variable according to the degree of hypopituitarism present and that the greater the number of pituitary hormone deficits the more severe the GH deficiency. These observations will help to clarify the diagnosis of GH deficiency in adult life.

Adolescent↗