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S M Shalet

Publications and source records attributed to S M Shalet.

At least 37 records · Page 2Linked to original sources
PubMed2002

Dexamethasone inhibits and thyroid hormone promotes differentiation of mouse chondrogenic ATDC5 cells.

The effects of glucocorticoid (GC) excess, thyrotoxicosis, and hypothyroidism on linear growth indicate that growth plate chondrocytes are exquisitely sensitive to GC and thyroid hormone (T(3)). Murine ATDC5 cells undergo chondrogenesis in vitro and were used to evaluate the effects of dexamethasone (Dex) and T(3) on cell proliferation and differentiation. Immature and differentiated ATDC5 cells expressed glucocorticoid and T(3)-receptor mRNAs. Cells proliferated and organized into cartilage-like nodules after 7 days. Chondrocyte maturation progressed over 9-40 days, with increasing alkaline phosphatase (ALP) activity, secretion of an Alcian blue-positive matrix, and mineralization of cartilage-like nodules. Dex reduced cell number over the 40 day period, causing inhibition of ALP activity and matrix production with failure of mineralization. Following withdrawal of Dex, chondrocytes proliferated and re-entered the differentiation and mineralization program, indicating that GC inhibition of chondrogenesis is reversible. In contrast, T(3) reduced cell proliferation, but induced ALP activity and increased matrix secretion earlier than in control cultures. Thus, GCs and T(3) regulate growth plate chondrocyte differentiation by distinct mechanisms. GCs arrest cell proliferation, differentiation, and cartilage mineralization and maintain chondrocyte precursors in a state of quiescence with the capacity to re-enter chondrogenesis. T(3) inhibits cell proliferation but accelerates differentiation to stimulate chondrogenesis.

Animals↗
PubMed2002

Spinal irradiation impairs the osteo-anabolic effects of low-dose GH replacement in adults with childhood-onset GH deficiency.

BACKGROUND AND OBJECTIVE: Both adult- and childhood-onset GH-deficient adults are prone to osteopenia. Studies of GH replacement have, for the most part, demonstrated increases in bone mineral density (BMD). Previous studies have, however, used GH doses in excess of those currently used in low-dose titration regimens aimed at normalizing the serum IGF-I level. Furthermore, the effect of GH on the lumbar spine that has been irradiated during treatment of childhood cancer is unknown. PATIENTS: Thirty-two adult patients with childhood-onset GH deficiency were subdivided according to whether or not they had received spinal irradiation in childhood. The cohort in whom the spine had not been irradiated was comprised of 17 patients (seven male, 10 female), median age 29.8 years (range 20.6--40.8), the median age at primary pathological diagnosis being 9 years (range 4--16). The cohort who received spinal irradiation was composed of 15 patients (seven male, eight female), median age 22.9 years (range 16.5--40.3), with a median age at craniospinal irradiation of 9 years (range 2--16). MEASUREMENTS: At baseline, BMD was assessed at the lumbar spine and femoral neck by DXA, and at the ultradistal and distal radius by SXA. The patients were then commenced on GH replacement, titrating the dose at 4--6-weekly intervals to normalize the serum IGF-I level. BMD scans were reassessed following at least 1 year of GH replacement therapy. The mean duration of GH therapy was 1.68 plus minus 0.52 years. RESULTS: BMD was significantly reduced, compared to the reference data, at all four sites measured in both the spinally irradiated and unirradiated groups. No significant difference was observed between the subgroups with respect to lumbar spine BMD (P = 0.64). In the cohort who did not receive spinal irradiation, an increase in BMD of 3.5% above baseline was observed at the lumbar spine (P = 0.018), 13/17 patients showing a positive increment in lumbar spine BMD. No significant changes in BMD were observed at any other site within this cohort, or at any site in the patients who received spinal irradiation. A significantly greater change in lumbar spine BMD was observed in the unirradiated spine cohort compared with the spinally irradiated cohort (P = 0.018). No differences in response were demonstrated at the other sites studied between the two subgroups. CONCLUSIONS: We have demonstrated an increase in lumbar spine BMD with long-term (mean 1.78 +/- 0.55 years) GH therapy in adults with childhood-onset GH deficiency, who have not received spinal irradiation, when GH was administered by a titration regimen aimed at normalizing the serum IGF-I level. No improvements were observed at the femoral neck, ultradistal or distal radius. Patients who had received spinal irradiation during childhood did not present with a reduction in spinal BMD in excess of that observed in the nonirradiated cohort. The spinally irradiated group were, however, resistant to the osteo-anabolic effects of GH, which we propose reflects the capacity of radiation-induced damage to suppress the skeletal response.

Adolescent↗
PubMed2002

Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome.

OBJECTIVE: Adult growth hormone deficiency (AGHD) is associated with an adverse lipid profile. The majority of previous studies of GH replacement have used supraphysiological doses and reported favourable changes in the lipid profile. Whether this beneficial effect is the result of pharmacological GH therapy, or occurs in response to low-dose GH replacement aimed at normalization of the serum IGF-I, has not been fully elucidated. STUDY DESIGN: We studied 67 patients with GH deficiency using a low-dose individualized GH replacement regimen. GH was commenced at a dose of 0.27 mg/day and the GH dose titrated until the serum IGF-I was normalized. Serum lipids were assessed at baseline, 12 and 24 months. RESULTS: A reduction in total cholesterol (TC) was observed at 12 (6.01 vs. 5.77 mmol, P = 0.04) and 24 months (6.01 vs. 5.56, P = 0.09). The reduction in LDLC failed to reach significance at 12 months (3.97 vs. 3.8, P = 0.09), but was significant at 24 months (3.97 vs. 3.50, P = 0.02). Levels of HDLC did not change significantly at 12 or 24 months. Significant improvements in the TC/HDLC ratio were observed at both 12 (5.68 vs. 5.29, P = 0.01) and 24 months (5.68 vs. 4.86, P = 0.007). A significant fall in triglycerides (TG) was present at 12 months (2.07 vs. 1.83, P = 0.01), and was maintained at 24 months, but was no longer significant (2.07 vs. 1.89, P = 0.28). At 12 months there was no correlation between improvements in lipid parameters and either the change in IGF-I SD score or the GH dose. Using multivariate analysis the change in TC, LDLC and the TC/HDLC ratio with 12 months GH replacement were determined by the baseline TC, LDLC and TC/HDLC levels (R2 = 0.18, P = 0.004; R2 = 0.20, P = 0.006; and R2 = 0.33, P < 0.0001), respectively. CONCLUSIONS: Low-dose individualized GH replacement aimed at normalization of the serum IGF-I is associated with significant improvements in TC, LDLC, TGs and the TC/HDLC ratio. The greatest improvements are observed in patients with the most adverse lipid profiles at baseline. Improvements are independent of changes in the IGF-I SDS and GH dose.

Adult↗
PubMed2002

Timing of onset of growth hormone deficiency is a major influence on insulin-like growth factor I status in adult life.

OBJECTIVE: Several reports have suggested that IGF-I levels in patients with childhood-onset (CO) GH deficiency are lower than those observed in patients with adult-onset (AO) GH deficiency. However, these reports are unsatisfactory as there are several differences between the cohorts studied other than the timing of onset of GH deficiency; in particular, the patients were not matched for equal severity of GH deficiency. We have pursued this question further by examining the IGF-I standard deviation score (SDS) in patients with CO and AO GH deficiency, with equal degrees of severity of GH deficiency, as defined by the peak GH response to the insulin tolerance test (ITT). PATIENTS AND MEASUREMENTS: IGF-I SDS were compared in 146 non acromegalic patients (69 male), aged 15.7-76.6 years (median 33.4 years), bone mass index (BMI) 27.8 +/- 5.8 kg/m2, with severe GH deficiency (peak GH response < 9 mU/l to insulin-induced hypoglycaemia). Patients were subdivided by timing of onset of GH deficiency and the peak GH response to the ITT (GH response < or = 1 mU/l, group 1; > 1-3 mU/l, group 2; > 3-6 mU/l, group 3; > 6-8.9 mU/l, group 4). RESULTS: The IGF-I SDS (mean value +/- SD) in the CO group (n = 63) as a whole was significantly lower than that found in the AO group (n = 83) (-3.7 +/- 2.8 vs.-1.55 +/- 2.2, respectively; P < 0.0001). Despite this, there was no significant difference in the peak GH response to an ITT between the two cohorts (2.8 +/- 2.3 mU/l in the AO cohort and 2.6 +/- 2.2 mU/l in the CO cohort; P = 0.5). When the cohorts were subdivided by severity of GH deficiency, there remained a significant difference in IGF-I SDS in groups 1 (P < 0.0001), 2 (P = 0.05) and 3 (P < 0.05), but there was no significant difference between the AO and CO cohorts in group 4. The peak GH response to an ITT was similar in the AO and CO cohorts in all groups (P = 0.8, 0.8, 0.9 and 0.3 in groups 1-4, respectively). Although increasing severity of hypopituitarism was associated with a decline in IGF-I SDS in the CO cohort (P < 0.01), this was not the case in the AO cohort (P = 0.3). CONCLUSION: These data support the hypothesis that there is an innate difference between adult patients with either CO or AO GH deficiency that cannot be explained solely by variation in the severity of GH deficiency. A possible explanation is that childhood GH deficiency programmes the subsequent relationship between GH and IGF-I in adult life or that the body composition changes, which are more severe in AO GH deficiency, influence IGF-I status.

Adolescent↗
PubMed2002

Gender and age influence the relationship between serum GH and IGF-I in patients with acromegaly.

BACKGROUND: In patients with acromegaly serum IGF-I is increasingly used as a marker of disease activity. As a result, the relationship between serum GH and IGF-I is of profound interest. Healthy females secrete three times more GH than males but have broadly similar serum IGF-I levels, and women with GH deficiency require 30-50% more exogenous GH to maintain the same serum IGF-I as GH-deficient men. In a selected cohort of patients with active acromegaly, studied off medical therapy using a single fasting serum GH and IGF-I measurement, we have reported previously that, for a given GH level, women have significantly lower circulating IGF-I. OBJECTIVE: To evaluate the influence of age and gender on the relationship between serum GH and IGF-I in an unselected cohort of patients with acromegaly independent of disease control and medical therapy. METHODS: Sixty (34 male) unselected patients with acromegaly (median age 51 years (range 24-81 years) attending a colonoscopy screening programme were studied. Forty-five had previously received pituitary radiotherapy. Patients had varying degrees of disease control and received medical therapy where appropriate. Mean serum GH was calculated from an eight-point day profile (n = 45) and values obtained during a 75-g oral glucose tolerance test (n = 15). Serum IGF-I, IGFBP-3 and acid-labile subunit were measured and the dependency of these factors on covariates such as log10 mean serum GH, sex, age and prior radiotherapy was assessed using regression techniques. RESULTS: The median calculated GH value was 4.7 mU/l (range 1-104). A significant linear association was observed between serum IGF-I and log10 mean serum GH for the cohort (R = 0.5, P < 0.0001). After simultaneous adjustment of the above covariates a significant difference in the relationship between mean serum GH and IGF-I was observed for males and females. On average, women had serum IGF-I levels 11.44 nmol/l lower than men with the same mean serum GH (P = 0.03, 95% CI 1.33-21.4 nmol/l). Age significantly influenced the relationship and for a given serum GH, IGF-I was estimated to fall by 0.37 nmol/l per year (P = 0.04, 95% CI 0.015-0.72). CONCLUSIONS: In keeping with previous observations of relative GH resistance in normal and GH-deficient females we have observed lower serum IGF-I levels for equivalent mean serum GH levels in females patients with acromegaly. This gender-dependent difference is independent of disease activity and the use of concomitant medical therapy. Additionally, we have demonstrated that for a given serum GH level, age significantly influences IGF-I concentrations in patients with acromegaly. These data have important implications for the use of serum IGF-I and GH as markers of disease activity in acromegaly.

Acromegaly↗
PubMed2002

The effect of long-term untreated growth hormone deficiency (GHD) and 9 years of GH replacement on the quality of life (QoL) of GH-deficient adults.

BACKGROUND: Quality of life (QoL) is reduced in GH-deficient adults compared with the normal population. Further support for the role of GH in the maintenance of QoL is derived from short-term studies of GH replacement in severely GH-deficient adults; these have predominantly reported beneficial effects, although the degree of improvement has often been modest. To date, however, there are few data to demonstrate whether this beneficial effect on QoL is maintained in the long term. PATIENTS AND METHODS: This study consisted of the follow-up of 85 GH-deficient adults who completed the Nottingham Health Profile (NHP) and the Psychological General Well-Being Schedule (PGWB) self-rating questionnaires in 1992, as part of a 12-month double-blind randomized study of GH replacement. In 2001 we attempted to contact all 85 patients and asked them to complete the two questionnaires again. Follow-up data were obtained in 61 patients. The findings were analysed according to whether the individual had received GH continuously since completion of the initial study, received no further GH replacement, or received GH replacement for only part of the intervening time. Both the NHP and the PGWB give a total score and subsection scores for six specific areas of QoL. A high score correlates with increased morbidity in the NHP, and with reduced morbidity in the PGWB. RESULTS: Fifty-nine patients completed the NHP at both time points. The patients who continued GH (n = 17) had significantly greater morbidity at baseline than patients who opted to discontinue therapy (n = 27), as reflected by the higher scores overall (5.7 +/- 4.0 vs. 2.8 +/- 3.5; P = 0.01) and in the energy subsection (47.0 +/- 34.7 vs. 13.2 +/- 28.6; P < 0.001). Over the study period energy levels improved in the patients who remained on GH therapy (47.0 +/- 34.7 vs. 25.7 +/- 31.0; P = 0.04). By contrast, a deterioration in the physical mobility subsection (2.4 +/- 5.4 vs. 8.2 +/- 16.7; P = 0.04) occurred in the patients who did not continue GH therapy, and no change occurred in the energy subsection. In the 36 patients who completed the PGWB significant differences were observed at baseline between patients who received GH replacement continuously (n = 10) and those who discontinued therapy (n = 21) in the overall score (67.2 +/- 14.1 vs. 86.8 +/- 14.7; P = 0.001); and in the subsections for anxiety (P = 0.04), depression (P = 0.04), well-being (P = 0.001), self-control (P = 0.04) and vitality (P < 0.001); the greater morbidity at baseline being observed in the patients who continued GH replacement. In the patients receiving GH continuously for 9 years the vitality subsection score improved significantly (7.7 +/- 2.4 vs. 12.5 +/- 3.2; P = 0.003), whereas no change in vitality score occurred in patients who did not continue GH therapy. The change in the energy subsection of the NHP and vitality subsection of the PGWB over the 9 years of the study were significantly different between the patients who opted to continue GH replacement and those who discontinued therapy (P = 0.008 and P < 0.001, respectively). CONCLUSION: During this 9-year study, small but significant declines in health were observed in GH-deficient adults who remained untreated. By contrast, the patients who received GH continuously experienced improvements in energy levels while all other areas of QoL were maintained. The beneficial effects of GH on QoL are therefore maintained with long-term GH replacement and obviate the reduction in QoL seen over time in untreated GH-deficient adults.

Adult↗
PubMed2002

Effect of cancer therapy on pituitary-testicular axis.

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men. Alkylating agents, such as cyclophosphamide and procarbazine, are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas are rendered permanently infertile. Treatment with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) appears to have a significant advantage in terms of testicular function, with a return to normal fertility in the vast majority of patients. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men with a recovery of spermatogenesis in about 50% after 2 years and 80% after 5 years. There is also evidence of chemotherapy-induced Leydig cell impairment in a proportion of these men, although this appears to be of no clinical significance in the majority of patients. The germinal epithelium is very sensitive to radiation-induced damage with changes to spermatogonia following as little as 0.1 Gy, and permanent infertility after fractionated doses of 2 Gy and above, whereas clinically significant Leydig cell impairment occurs rarely with doses of less than 20 Gy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Growth and growth hormone status after a bone marrow transplant.

The three most common clinical situations which have given rise to diagnostic and therapeutic issues involve the child treated for: (1) a brain tumour or extracranial tumour with radiotherapy (XRT) which includes an XRT dose of > or =30 Gy to the hypothalamic-pituitary axis; (2) acute lymphoblastic leukaemia with a cranial XRT dose of 18-24 Gy, and (3) haematological malignancy or solid tumour requiring total body irradiation (dose 10-14 Gy) and BMT. The decision about the intent to treat and the timing of GH replacement needs to be taken in collaboration with the paediatric oncologist who will provide guidance about overall prognosis and the risk of relapse. After a dose of > or =30 Gy to the hypothalamic pituitary axis the risk of GH deficiency (GHD) 2 years later is very high (>50%) and therefore there is 'solid' epidemiological evidence, which predicts outcome. Therapeutically the choice is whether or not to offer GH replacement at 2 years in the presence of biochemical evidence of GHD but independent of auxology, or wait until the growth rate declines. Diagnostically the IGF-1 SDS is more useful than previously thought, particularly if XRT-induced GHD is severe; there may, however, be systematic discordancy between the GH responses to different pharmacological stimuli (ITT vs. arginine). For irradiated children in categories 2 and 3, greater emphasis is placed on auxology in determining the need for assessment of GH status. Early rather than very precocious puberty is a real issue and needs to be actively treated with a GnRH analogue if final height appears to be significantly compromised.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Effects of chemotherapy on bone metabolism and skeletal growth.

In recent years there has been a significant increase in both acute and chronic toxicity associated with the more successful but now highly intensive chemotherapy (CT) regimens used to treat childhood cancers. The incidence of childhood cancers coincides with periods of rapid skeletal development. Consequently, short stature and osteoporosis are important long-term effects in adult survivors. Clinical data indicate that the effects of CT, including glucocorticoids, on final height are due to direct effects of these drugs on the skeleton. The multiple modes of action of CT drugs suggest a complex and diverse influence on chondrocytes, extracellular matrix and bone cells. However, only limited data demonstrate these direct effects on the proliferative capacity of growth plate chondrocytes and on key steps of endochondral ossification, the multistep process that determines rate and extent of long bone growth. Endochondral ossification requires coordinated maturation, proliferation and differentiation of growth plate chondrocytes leading to hypertrophic cells which eventually undergo apoptosis to leave a cartilaginous scaffold that is mineralized prior to the laying down of new bone. Disruption of the physiological cellular activity of growth plate chondrocytes and/or bone cells result in skeletal growth disturbances. Thus, CT drugs which disrupt normal cell division may manifest their effects on the growth plate as either a reduction in cell number and/or the loss of functional integrity of extracellular matrix. Histological and cell kinetic studies, using in vivo and in vitro models of long bone growth, are essential to increase our understanding of the cellular mechanisms involved and to finally determine how the individual growth potential might be maintained during treatment for childhood cancers.

Antineoplastic Agents↗
PubMed2002

GH-deficient survivors of childhood cancer: GH replacement during adult life.

Childhood survivors of cancer are prone to a number of adverse sequelae related to the therapeutic interventions undertaken to achieve remission. The endocrine system is frequently affected; hypothalamo-pituitary dysfunction, in particular GH deficiency, is common after cranial irradiation. It is unclear to what extent GH deficiency contributes to the abnormalities observed in adult survivors of childhood cancer, and whether GH replacement reverses these anomalies. We compared 27 GH-deficient survivors of childhood cancer with 27 adult age- and sex-matched controls and went on to replace GH in the patient group to determine whether GH resulted in improvements of the baseline abnormalities. The GH-deficient survivors of childhood cancer had an adverse lipid profile (total cholesterol, 5.4 vs. 4.6 mM, P = 0.004; high-density lipoprotein cholesterol, 1.05 vs. 1.6 mM, P < 0.001; and triglycerides, 1.3 vs. 1.0 mM, P < 0.001) and were osteopenic (lumbar spine z-score, -1.53 vs. -0.31 SD score, P < 0.001; femoral neck z-score, -1.23 vs. -0.27 SD score, P = 0.02); additionally, the female subgroup had an increased percentage body fat (43.6 vs. 32.8%, P = 0.016). In keeping with the selection criterion, quality of life in the patient cohort, relative to the healthy controls, was severely impaired [adult GH-deficiency assessment (AGHDA), 15.5 (range, 8-25) vs. 1 (range, 0-19), P < 0.0001; psychological general well-being schedule, 67.5 (range, 18-86) vs. 89.0 (range, 51-104), P < 0.0001]. After 12 months of GH replacement, small (but significant) improvements were observed in body composition in the male subgroup (waist-hip ratio, 0.871 vs. 0.863, P < 0.05); and in the female cohort, total cholesterol (6.0 vs. 5.2 mM, P = 0.01) and triglyceride (2.1 vs. 1.4 mM, P = 0.01) levels fell. Bone mineral density improved in only one of the four sites studied (ultradistal radius, -1.21 vs. -1.09, P = 0.048) after a median duration of GH therapy of 18 months. Quality of life improved dramatically by 3 months (AGHDA, 15.5 vs. 10.0, P < 0.001), and the improvement was maintained at 12 months (AGHDA, 15.5 vs. 9.0, P < 0.001). Importantly, there was no clinical suggestion of tumor recurrence during the 12 months of GH replacement. The minor improvements observed in body composition, the lipid profile, and bone mineral density in GH-deficient adult survivors of childhood cancer after 12-18 months of physiological GH replacement suggest that GH deficiency may not be the major etiological factor in their pathogenesis; the converse seems to be true for the quality of life status of these individuals. We propose that, as in patients with hypopituitarism caused by pituitary disease, the main indication for GH replacement in GH-deficient survivors of childhood cancer should be severe impairment of quality of life.

Adolescent↗
PubMed2001

Orthotopic reimplantation of cryopreserved ovarian cortical strips after high-dose chemotherapy for Hodgkin's lymphoma.

BACKGROUND: Infertility is a common late effect of chemotherapy and radiotherapy, and has a substantial effect on the quality of life for young survivors of cancer. For men, semen cryopreservation is a simple way of preserving reproductive potential but for women, storage of mature eggs rarely proves successful, and the alternative-immediate in vitro fertilisation with cryopreservation of embryos-is not always appropriate. Reimplantation of cryopreserved ovarian tissue has been shown to restore natural fertility in animals. We applied this technique in a woman who had received sterilising chemotherapy for lymphoma. METHODS: A 36-year-old woman underwent a right oophorectomy with cryopreservation of ovarian cortical strips before receiving high-dose CBV chemotherapy for a third recurrence of Hodgkin's lymphoma. 19 months later, when serum sex steroid analysis confimed a postmenopausal state, two ovarian cortical strips were thawed and reimplanted-one onto the left ovary and another at the site of the right ovary. FINDINGS: 7 months after reimplantation of ovarian cortical strips, the patient reported resolution of hot flashes and, for the first time, oestradiol was detected in the serum. This finding was associated with a decrease in the concentrations of follicle-stimulating hormone and luteinising hormone, and ultrasonography revealed a 10 mm thick endometrium, a poorly visualised left ovary, and a 2 cm diameter follicular structure to the right of the midline. The patient had one menstrual period, but by 9 months after the implantation, her sex steroid concentrations had returned to those seen with ovarian failure. INTERPRETATION: Orthotopic reimplantation of frozen/thawed ovarian cortical strips is a well tolerated technique for restoring ovarian function in women treated with sterilising chemotherapy for cancer.

Adult↗
PubMed2001

Isolation of germ cells from human testicular tissue for low temperature storage and autotransplantation.

OBJECTIVE: To develop a new protocol for conserving fertile potential in men undergoing sterilizing chemotherapy by low temperature banking of germ cells which can be returned to the patient's testes after thawing. DESIGN: Isolation of human and murine germ cells for comparing cellular viability after cooling to liquid nitrogen temperatures by the use of different cryoprotective agents and for infusion into the testis. SETTING: Laboratory research environment. PATIENT(S): Men undergoing routine surgery in a urology department. INTERVENTION(S): Testicular biopsy. MAIN OUTCOME MEASURE(S): Cellular viability and infusion of seminiferous tubules. RESULT(S): After isolation using a two-step enzymatic disaggregation protocol, 66% to 87% of germ cells from human and murine specimens, respectively, were still viable. Cell survival was similar in four commonly used cryoprotective agents after cooling to liquid nitrogen temperatures. Seminiferous tubules infused by back flow with dye solution via the rete testis were filled with an efficiency of 55%. CONCLUSION(S): Judging from the high viability of unfractionated germ cells, it is feasible to isolate germ cells from testicular biopsies for low temperature banking with the aim of attempting to restore fertility after iatrogenic sterilization.

Animals↗
PubMed2001

High-risk colorectal adenomas and serum insulin-like growth factors.

BACKGROUND: This study investigated the hypothesis that circulating levels of insulin-like growth factor (IGF) I and its main binding protein (IGFBP-3) predict for the presence of colorectal adenomas, surrogate markers of colorectal cancer risk. METHODS: Within the Flexi-Scope Trial (healthy volunteers aged 55-64 years), at one study centre, IGF-I and IGFBP-3 levels in serum samples collected prospectively from 442 attendants were measured. Of these, 100 individuals underwent a complete screening colonoscopy. There were 47 normal examinations, while in 11 examinations low-risk adenomas and in 42 examinations high-risk adenomas were identified. Estimates of relative risk (RR) for the adenomatous stages were calculated by means of unconditional logistic regression, adjusting for known risk factors. RESULTS: Mean serum IGF-I and IGFBP-3 levels were similar in individuals with a normal colonoscopy finding and in those with low-risk adenomas. By contrast, the mean(s.d.) serum IGF-I level was increased (190(53) versus 169(54) microg/l; P = 0.06) and the serum IGFBP-3 concentration was significantly decreased (3.22(0.60) versus 3.47(0.62) mg/l; P = 0.05) in individuals with high-risk adenomas compared with levels in those with normal colonoscopy and low-risk adenomas combined. Levels were unaffected by removal of the adenomas. With high-risk adenoma as the dependent factor, regression models demonstrated a significant positive association with IGF-I after controlling for IGFBP-3 (RR per one standard deviation (1s.d.) change 4.39 (95 per cent confidence interval (c.i.) 1.31-14.7); P = 0.02) and, independently, an inverse association with IGFBP-3 after adjustment for IGF-I (RR per 1s.d. change 0.41 (95 per cent c.i. 0. 20-0.82); P = 0.01). CONCLUSION: These findings suggest that circulating IGF-I and IGFBP-3 levels are related to future colorectal cancer risk and, specifically, may predict adenoma progression.

Adenoma↗
PubMed2001

The diagnosis of growth hormone deficiency (GHD) in successfully treated acromegalic patients.

Due to persistent qualitative abnormalities in GH secretion following treatment, and lack of a sensitive marker of GHD in mid-adult life it is extremely difficult to diagnose GHD in treated acromegalic patients. The diagnosis of GHD in patients with pituitary disease relies on provocative tests of GH reserve. Arginine releases GH by reducing somatostatin inhibition of GH release, whereas GH secretagogues (GHS) affect GH release by direct stimulation of the GHS receptor, though an intact GH releasing hormone (GHRH) axis is a prerequisite. The peak GH response to insulin-induced hypoglycaemia and arginine in acromegalic patients, in whom basal serum GH levels of less than 5 mU/l have been achieved, is greatly diminished in those treated by hypothalamo-pituitary irradiation. We aimed to study the response of successfully treated acromegalic patients to the growth hormone secretagogue hexarelin in view of its different putative mechanism of action, and in addition, to determine whether it has any value in the diagnosis of GH deficiency in this subset of patients. Nineteen acromegalic patients, in whom mean serum GH levels below 5 mU/l have been achieved through treatment, were recruited. Eight of the patients had been treated by surgery alone (Group A) and 11 had received primary or postoperative irradiation (Group B). All patients underwent 20 min blood sampling to provide a 24-h GH profile. Serum IGF-I was measured from a sample drawn between 0900 h and 1000 h. On a second visit arginine 20 g/m2 was infused over 30 min, blood samples were taken before commencing the infusion and at 30-min intervals thereafter for 180 min. At the final visit hexarelin 1.5 mcg/kg was administered as an intravenous bolus at t = 0. Blood was drawn at 15-min intervals from - 30 to 180 min. All patients in group A showed an increment in serum GH following hexarelin (DeltaGHHEX) > 20 mU/l, a normal response to arginine, and a mean 24-h GH > 0.5 mU/l. In group B only 4/11 achieved a DeltaGHHEX > 20 mU/l, 5/11 producing a response of < 2 mU/l. Four of the five patients with a DeltaGHHEX < 2 mU/l were also demonstrated to have a mean 24-h GH of < 0.5 mU/l and serum IGF-I SDS < + 0.5. All four patients in Group B who achieved a DeltaGHHEX > 20 mU/l, were observed to show an absent or minimal GH response to arginine. Despite loss of the GH response to arginine, the DeltaGHHEX is retained in a proportion of those patients in whom "safe" GH levels were achieved following irradiation. From the putative mechanisms of action of these provocative agents a plausible explanation would be that the GHRH axis is more resilient than endogenous somatostatin-secreting neurones to radiation-induced damage. Furthermore, GH secretagogues may have a role, in combination with serum IGF-I levels, in the diagnosis of GH deficiency in treated acromegaly.

Acromegaly↗
PubMed2001

Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy.

OBJECTIVE: Testosterone deficiency is associated with significant morbidity, and androgen replacement in overt hypogonadism is clearly beneficial. However, there are few data concerning the response to therapy in young men with mild testosterone deficiency. DESIGN AND PATIENTS: We have identified a cohort of 35 men, mean age 40.9 years, with mild Leydig cell dysfunction, defined by a raised LH level (LH >or= 8 IU/l) and a testosterone level in the lower half of the normal range or frankly subnormal (testosterone < 20 nmol/l), following treatment with cytotoxic chemotherapy for malignancy. Patients were assigned randomly to 12 months treatment with transdermal testosterone (n = 16) (Andropatch 2.5 mg patches, 1-2 patches per day) or placebo patches (n = 19) in a single blinded manner. MEASUREMENTS: Measurements of bone mineral density (BMD) and body composition were performed at baseline, 6 months and 12 months using single and dual energy X-ray absorptiometry (SXA, DXA). In addition, spinal BMD was assessed at baseline and 12 months by quantitative CT (QCT). Subjects were reviewed at 3-monthly intervals; at each visit blood was taken for measurement of testosterone, SHBG, LH, FSH, oestradiol, lipids and IGF-1 and patients completed three questionnaires which assessed energy levels, mood and sexual function. RESULTS: Total testosterone and calculated free testosterone increased significantly in the testosterone-treated group compared with the placebo-treated group (13.3 nmol/l and 342.9 pmol/l at baseline compared with 17.3 nmol/l and 454.8 pmol/l during the study period in the testosterone-treated group; P = 0.05 and P = 0.02, respectively). LH was suppressed into the normal range in 15 of the 16 testosterone-treated men and mean LH significantly reduced from 11.1 IU/l at baseline to 6.8 IU/l during the study. There was no significant change in BMD at the hip, spine or forearm and no change in fat or lean body mass. There was a significant reduction in physical fatigue in the testosterone-treated group compared with the placebo-treated group (P = 0.008) and a borderline improvement in activity score (P = 0.05). There were no significant effects of treatment on mood or sexual function. Neither oestradiol nor IGF-1 levels differed between the two groups during the study. There was no significant change in mean total cholesterol, HDL cholesterol or triglyceride levels, but there was a small, but significant reduction in LDL cholesterol levels in the testosterone-treated group compared with the placebo group (P = 0.02). CONCLUSIONS: These results suggest that testosterone therapy in young men with raised LH levels and low/normal testosterone levels does not result in significant changes in BMD, body composition, lipids or quality of life, apart from a reduction in physical fatigue and a small reduction in LDL cholesterol. This implies that mild hypogonadism defined on this basis is not of clinical importance in the majority of men, and that androgen replacement cannot be recommended for routine use in these patients.

Adult↗