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W M Drake

Publications and source records attributed to W M Drake.

At least 19 recordsLinked to original sources
PubMed2007

The endocrine system and ageing.

Complex changes occur within the endocrine system of ageing individuals. This article explores the changes that occur in the metabolism and production of various hormones and discusses the resulting clinical consequences. As individuals age there is a decline in the peripheral levels of oestrogen and testosterone, with an increase in luteinizing hormone, follicle-stimulating hormone and sex hormone-binding globulin. Additionally there is a decline in serum concentrations of growth hormone, insulin-like growth factor-I and dehydroepiandrosterone and its sulphate-bound form. Even though there are complex changes within the hypothalmo-pituitary-adrenal/thyroid axis, there is minimal change in adrenal and thyroid function with ageing. The clinical significance of these deficiencies with age are variable and include reduced protein synthesis, decrease in lean body mass and bone mass, increased fat mass, insulin resistance, higher cardiovascular disease risk, increase in vasomotor symptoms, fatigue, depression, anaemia, poor libido, erectile deficiency and a decline in immune function. For each endocrine system, studies have been carried out in an attempt to reverse the effects of ageing by altering the serum hormonal levels of older individuals. However, the real benefits of hormonal treatment in older individuals are still being evaluated.

Aging↗
PubMed2006

Cosegregation of a novel homozygous CYP11B1 mutation with the phenotype of non-classical congenital adrenal hyperplasia in a consanguineous family.

We report a novel missense mutation of CYP11B1 causing non-classical 11beta-hydroxylase deficiency in 3 members of a consanguineous Turkish family. Two siblings presented with clinical evidence of precocious pseudopubarche. Biochemistry suggested 11beta-hydroxylase deficiency and genetic analysis revealed that they were homozygous for the missense mutation L489S within exon 9 of the CYP11B1 gene. The unaffected parents were heterozygotes for the same mutation. In addition, a paternal aunt of the affected siblings presenting with primary infertility and mild hirsutism was found to have the same homozygous mutation. This is the first report of a homozygous mutation in non-classical congenital adrenal hyperplasia that cosegregates with clinical phenotype. The significance of the missense mutation L489S in CYP11B1 is further supported by the conservation of leucine at position 489 in CYP11 genes in eleven other species. Molecular modelling of the enzyme suggests that the mutation L489S in CYP11B1 may alter the enzyme's substrate-binding affinity. These findings suggest that this homozygous mutation affects 11beta-hydroxylase function, resulting in the clinical features of non-classical adrenal hyperplasia in this family.

Adrenal Hyperplasia, Congenital↗
PubMed2006

Reductions of circulating matrix metalloproteinase 2 and vascular endothelial growth factor levels after treatment with pegvisomant in subjects with acromegaly.

BACKGROUND: Vascular endothelial growth factor (VEGF) is involved in activation of the matrix metalloproteinase (MMP) system; the latter is implicated in atherosclerosis and cardiovascular disease. Patients with acromegaly have reduced life expectancy primarily due to cardiac disease. AIM: This study assessed plasma MMPs and VEGF levels in patients with active acromegaly (IGF-I > 130% upper limit of normal), and on treatment with pegvisomant. SUBJECTS AND METHODS: Twenty patients [nine female, mean age 56.1 +/- 13.8 yr (mean +/- sd)] were studied at baseline and on pegvisomant therapy and compared with data from 25 healthy volunteers (12 female; 56.6 +/- 14.2 yr). Plasma MMP-2, MMP-9, and VEGF levels were measured. RESULTS: Serum IGF-I fell from a baseline (mean +/- sd) level of 620.1 +/- 209.3 ng/ml to 237.5 +/- 118.5 ng/ml on pegvisomant (doses 10-60 mg; P < 0.001). MMP-2 levels at baseline were significantly higher in patients compared with healthy controls (380.7 +/- 204.8 vs. 207.4 +/- 62.6 ng/ml; P < 0.001), but with treatment a significant reduction in MMP-2 [380.7 +/- 204.8 vs. 203.0 +/- 77.4 ng/ml; P < 0.001] and VEGF (283.4 +/- 233.6 vs. 229.1 +/- 157.4 pg/ml; P = 0.008) was noted. There was no significant difference in MMP-9 levels between patients and controls at baseline (797.5 +/- 142.1 vs. 788.3 +/- 218.0 ng/ml; P = 0.87) or between baseline and posttreatment levels (797.5 +/- 142.1 vs. 780.0 +/- 214 ng/ml; P = 0.76). CONCLUSIONS: Our novel data demonstrate that treatment of acromegaly with pegvisomant leads to reductions in MMP-2 and VEGF concentrations. Further studies are required to determine the significance of these findings with relation to cardiac disease.

Acromegaly↗
PubMed2006

Growth hormone deficiency and replacement in patients with treated Cushing's Disease, prolactinomas and non-functioning pituitary adenomas: effects on body composition, glucose metabolism, lipid status and bone mineral density.

BACKGROUND/AIMS: This study was designed to determine whether previous Cushing's disease (CD) or prolactinoma (PRL) could exert adverse effects additional to those of growth hormone (GH) deficiency as a consequence of variable degrees of prior hypogonadism or hypercatabolism. We report the effects of 5 years GH treatment in 124 GH deficiency adults; 42 patients with non-functioning pituitary adenomas (NFPA), 43 with treated PRL and 39 with treated CD. METHODS: Fasting plasma glucose, HbA(1c), lipoprotein profile, anthropometry and bone mineral density (BMD) were measured at baseline, 6 months and annually up to 5 years. RESULTS: Mean body mass index remained unchanged in the PRL group and tended to increase in the NFPA group. In contrast, body mass index decreased in the CD group. Decreases in waist and waist/hip ratio were seen in all groups at 6 months. Decreases in total cholesterol and low-density lipoprotein cholesterol were seen in all groups and remained sustained at 5 years. Plasma glucose and HbA(1c) increased at 6 months. Subsequently, plasma glucose returned to baseline values at 5 years; in contrast, HbA(1c )remained unchanged at the end of the study. Baseline lumbar spine and hip BMD were lower in the PRL and CD groups than in the NFPA group, decreased over 1 year in all groups and subsequently increased by 2 years in NFPA with a subsequent increase in lumbar spine BMD in PRL and CD groups delayed to 3-5 years. CONCLUSIONS: Baseline characteristics and response to GH replacement are qualitatively similar in NFPA, PRL and CD patients. Because improvements in BMD occur later in PRL and CD patients, an extended trial of GH therapy may be indicated in those patients who were commenced on GH therapy as an additional treatment for reduced BMD.

Adenoma↗
PubMed2006

Benefits of screening in von Hippel-Lindau disease--comparison of morbidity associated with initial tumours in affected parents and children.

Von Hippel-Lindau (VHL) is a rare autosomal dominant syndrome characterised by the association of retinal and CNS haemangioblastomas, phaeochromocytoma and renal cell carcinoma. If a child of an affected parent has inherited a VHL mutation or the parent's mutation cannot be identified, then clinical screening is recommended. We report the clinical features in three parent-offspring pairs where the parents have presented clinically with renal cell carcinoma, phaeochromocytoma, cerebellar haemangioblastoma and retinal haemangioma, and the children have undergone pre-symptomatic screening. During the first screening a 13-year-old boy was diagnosed with bilateral phaeochromocytoma and later developed an endolymphatic sac tumour at 19 years. A right phaeochromocytoma was found in a 12-year-old girl who was screened from the age of 4 years and in a 13-year-old boy screened from 5 years of age. All children were asymptomatic at the time of diagnosis. These families demonstrate that clinical screening of children at risk of VHL can detect tumours before the first symptoms arise with a consequent reduction in morbidity. These observations strongly support the recommendation to undertake screening of the children of VHL patients.

Adolescent↗
PubMed2006

Selective parathyroid venous sampling in patients with complicated hyperparathyroidism.

OBJECTIVE: The role of preoperative localisation of abnormal parathyroid glands remains controversial but is particularly relevant to the management of patients with recurrent or persistent hyperparathyroidism and familial syndromes. We report our experience of the use of selective parathyroid venous sampling (PVS) in the localisation of parathyroid disease in such patients. DESIGN: We report a retrospective 10-year experience (n = 27) of the use of PVS in complicated primary hyperparathyroidism and contrast the use of PVS with neck ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) and sestamibi imaging modalities. RESULTS: In 14 out of 25 patients who underwent surgery PVS results were completely concordant with surgical and histological findings and 88% of patients achieved post-operative cure. Out of 13 patients referred after previous failed surgery, 12 underwent further surgery which was curative in 9. In total PVS yielded useful positive (n = 13) and/or negative information (n = 6) in 19 out of 25 patients undergoing surgery. Using histology as the gold standard, 59% of PVS studies were entirely consistent with histology, as compared with 39% of ultrasound scans, 36% of sestamibi scans and 17% of MRI/CT scans. CONCLUSIONS: PVS is a valuable adjunct to MRI/CT and sestamibi scanning in selected patients with complicated hyperparathyroidism when performed in an experienced unit.

Adult↗
PubMed2005

Tumour surveillance imaging in patients with extrapituitary tumours receiving growth hormone replacement.

OBJECTIVE: GH replacement is widely used in the management of patients with adult-onset (AO)-GH deficiency (GHD). In most cases, AO-GHD arises as a result of pituitary/peripituitary tumours and/or their treatment, but the effect of GH replacement on recurrence/regrowth of these tumours is unknown. The aim of this study was to examine the effect of GH replacement in a group of patients with primary tumours of the parasellar region, many of which (e.g. craniopharyngioma, glioma or germ cell tumours) might be anticipated to have a higher recurrence rate than secretory and nonsecretory anterior pituitary tumours. PATIENTS AND DESIGN: We report here our experience of prospective imaging in 50 consecutive patients (21 males; mean age 45.9 years) with nonanterior pituitary parasellar tumours treated with GH. All had severe GHD (peak serum GH 9 mU/l or less on dynamic testing) and were treated with an identical dose-titration regimen to maintain serum IGF-I concentrations between the median and upper end of the age-adjusted normal range. The primary diagnoses were: craniopharyngioma (28), germ cell tumour (8), arachnoid cyst (4), meningioma (4), glioma (4) and mensenchymal tumour (2). External pituitary irradiation had been given to 37 (74%) of patients. Measurements Surveillance imaging (magnetic resonance imaging (MRI) 70%, computed tomography (CT) 16%, both 14%) was performed at baseline (prior to GH), at 6--12 months, and then again yearly or as clinically indicated. Median follow-up was 36 months (range 7--129 months). All images were reviewed by the same radiologist. RESULTS: Four patients had an apparent increase in tumour volume but in only one patient was it considered necessary to abandon GH replacement. In two of the four cases marginal increases in cystic parasellar tumours were not progressive; and in the fourth case apparent recurrence of a suprasellar germ cell tumour was shown to be acellular fibrous tissue only on biopsy. In all other cases either the appearances were unchanged or the amount of tissue was reduced during long-term follow-up on GH. CONCLUSIONS: Overall, GH appears safe with respect to tumour recurrence over this time period in this patient group. Comparison with similar prospective series in patients not receiving GH replacement is desirable.

Adult↗
PubMed2005

Disease activity in acromegaly may be assessed 6 weeks after discontinuation of pegvisomant.

OBJECTIVE: Pegvisomant, a modified growth hormone (GH) molecule, is a novel medical therapy for acromegaly that functions as a GH receptor antagonist. Serum GH cannot be used as a marker of disease activity in patients taking this form of therapy, partly because GH levels rise on pegvisomant and partly because the drug cross-reacts with many routine GH assays. The purpose of this study was to assess the time for which it is necessary to discontinue pegvisomant prior to biochemical reassessment of acromegaly. DESIGN AND METHODS: This was a retrospective study of 13 patients (seven male, median age 61 years, range 43-77) enrolled in two separate, open-label studies of the efficacy and tolerability of pegvisomant in the treatment of acromegaly. All had been taking a stable dose of pegvisomant (median dose 15 mg daily, range 10-30) as monotherapy for at least 3 months before discontinuing the drug. After discontinuation of pegvisomant, serum IGF-I was measured at 0, 2, 4, 6 and 8 weeks in all patients. Serum GH (single sample) was measured in nine patients at 2, 4, 6 and 8 weeks, but not at baseline on account of the cross-reactivity of pegvisomant with the GH assay. RESULTS: Mean serum IGF-I rose from 210+/-105 ng/ml (S.D.) at baseline to 392+/-175 ng/ml at 2 weeks after discontinuation of pegvisomant (P < 0.0001). Although there was no statistically significant change in mean serum IGF-I beyond 2 weeks (412+/-181, 392+/-152 and 399+/-150ng/ml at 4, 6 and 8 weeks respectively; P = 0.13 (2 vs 4 weeks), 0.31 (4 vs 6 weeks) and 0.46 (6 vs 8 weeks), serum IGF-I rose by more than twice the interassay coefficient of variation (CV) in two of the 13 patients between weeks 2 and 4. The standard deviation of the difference in serum IGF-I between time points was calculated. The values declined from 118% (weeks 0-2) 17%, 19.7% and 10% (weeks 2-4, 4-6 and 6-8 respectively). The expected measure if there was no systematic change in base would be 15% (1.4 x interassay CV). Mean serum GH was virtually unchanged at 2-8 weeks after cessation of pegvisomant therapy. CONCLUSIONS: These results suggest that the activity of acromegaly may be assessed by serum IGF-I levels 6 weeks after the discontinuation of pegvisomant.

Acromegaly↗
PubMed2005

Markers of cell proliferation in a GH-producing adenoma of a patient treated with pegvisomant.

We report our findings on markers of cell proliferation (Ki-67 labelling index and topoisomerase-alpha expression) in a somatotroph pituitary tumour before and after exposure to pegvisomant, a GH receptor antagonist developed for the treatment of acromegaly. Specimens from two separate pituitary operations, separated by a period of 17 years that included 4 years of pegvisomant treatment, were stained for markers of cellular proliferation. Ki-67 labelling index and topoisomerase-alpha expression were both markedly greater (1-3% compared with 0-0.5% and 15-80% compared with 2-10% respectively) in the pegvisomant-exposed tumour compared with the earlier specimen. Clearly, caution must be exercised when interpreting findings from a single case, particularly one sufficiently refractory to conventional therapies to require treatment with pegvisomant. However, our data reinforce the requirement for careful radiological surveillance of the pituitary in the context of a drug that does not target the tumour responsible and where serum GH cannot serve as a marker of disease activity or tumour size.

Acromegaly↗
PubMed2004

Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth.

Although GH replacement improves the features of GH deficiency (GHD) in adults, it has yet to be established whether cessation of GH at completion of childhood growth results in adverse consequences for the adolescent with GHD. Effects of continuation or cessation of GH on body composition, insulin sensitivity, and lipid levels were studied in 24 adolescents (13 males, 11 females, aged 17.0 +/- 0.3, yr, mean +/- se, puberty stage 4 or 5) in whom height velocity was less than 2 cm/yr. Provocative testing confirmed severe GHD [peak GH < 9 mU/liter (3 microg/liter)] in all cases and was followed by a lead-in period of 3 months during which the pediatric dose of GH continued unchanged. Baseline investigations were then performed using dual-energy x-ray absorptiometry (body composition), lipid measurements, and assessment of insulin sensitivity by both homeostasis model assessment and a short insulin tolerance test. Twelve patients remained on GH (0.35 U/kg.wk), and 12 patients ceased GH treatment. The groups were followed up in parallel with repeat observations made after 6 and 12 months. No endocrine differences were evident between the groups at baseline. GH cessation resulted in a reduction of serum IGF-I Z score [-1.62 +/- 0.29, baseline vs. -2.52 +/- 0.12, 6 months (P < 0.05) vs. -2.52 +/- 0.10, 12 months (P < 0.01)] but values remained unchanged in those continuing GH replacement. Lean body mass increased by 2.5 +/- 0.5 kg ( approximately 6%) over 12 months in those receiving GH but was unchanged after GH discontinuation. Cessation of GH resulted in increased insulin sensitivity [short insulin tolerance test, 153 +/- 22 micromol/liter.min, baseline vs. 187 +/- 20, 6 months (P < 0.05) vs. 204 +/- 14, 12 months (P = 0.05)], but no significant change was seen during 12 months of GH continuation. Lipid levels remained unaltered in both groups. Continuation of GH at completion of linear growth resulted in ongoing accrual of lean body mass (LBM), whereas skeletal muscle mass remained static after GH cessation in these adolescents with GHD. This divergence of gain in LBM is of potential importance because increases in LBM occur as a feature of healthy late adolescent development. GH is a major mediator of insulin sensitivity, independent of body composition in adolescents. Further studies are required to determine whether discontinuation of GH in the adolescent with severe GHD once linear growth is complete results in long-term irreversible adverse physical and metabolic consequences and to determine conclusively the benefits of continuing GH therapy.

Adolescent↗
PubMed2004

Transitional care of GH deficiency: when to stop GH therapy.

While the benefits of growth hormone (GH) therapy in adult hypopituitary patients with GH deficiency (GHD) are established, the role of continued GH therapy after final height in adolescent GH-deficient patients remains unclear. Preliminary data suggest that cessation of GH on completion of linear growth may be associated with impairment of somatic development and adverse changes in body composition. For the present time, the decision whether to continue GH treatment in adolescent patients with GHD is best made on an individual basis. For such patients, continuity of care is crucial. Children and adults with GHD are usually managed by physicians in separate departments, who may focus on different aspects of treatment and care. Close collaboration between paediatric and adult physicians is essential to ensure smooth transition and to minimize the drop-out rate from follow-up. Given the previous period of treatment during childhood, paediatric physicians should be best placed to discuss the potential benefits of continuing GH therapy and instigate retesting of GH secretion. Many children with isolated idiopathic GHD will produce normal GH responses if retested at adult height. Patients with multiple pituitary hormone deficits are more likely to have ongoing GHD, as are patients who have received CNS irradiation. Quality of life does not appear to be decreased in adolescents with GHD who stop treatment, so achievement of satisfactory bone mass is a major determinant of the decision whether to continue therapy.

Adolescent↗
PubMed2003

The effect of pegvisomant-induced serum IGF-I normalization on serum leptin levels in patients with acromegaly.

BACKGROUND: In humans, serum leptin correlates positively with fat mass. GH is lipolytic and patients with active acromegaly have lowered serum leptin compared to age, sex and body mass index (BMI)-matched controls, but a direct influence of GH on serum leptin remains unclear. In patients with acromegaly, total leptin increases following successful pituitary surgery and during somatostatin (SMS) analogue therapy (despite no change in BMI) but whether this represents changes in soluble leptin receptor, bound or free leptin is unclear. Pegvisomant, a GH receptor antagonist capable of normalizing serum IGF-I in over 97% of patients, represents a novel treatment strategy in acromegaly and its effect on leptin has not previously been reported. PATIENTS: Sixteen patients (nine male (M), seven female (F), median age 52 years, range 27-78 years) with active acromegaly (serum IGF-I at least 30% above the upper limit of an age-related reference range) were studied. Serum IGF-I was normalized in all subjects with pegvisomant [mean duration 7 months (range 3-11 months), median dose 20 mg/day (range 10-40 mg/day)]. A single batch measurement of leptin, bound leptin (BL), soluble leptin receptor (SLR), insulin and glucose were performed on samples from baseline and first occurrence of serum IGF-I normalization. RESULTS: As in normal subjects, females with acromegaly had higher baseline serum leptin [median M = 6.1 (range 1.6-58.7), F = 25.9 (range 3.19-54.1) ng/ml; P = 0.04], which correlated positively with BMI (R = 0.78, P = 0.0004). Forward step-wise regression analysis demonstrated that BMI and gender accounted for 90% of the variance in mean serum log10 leptin. Pegvisomant-induced serum IGF-I normalization was associated with a rise in serum leptin [8.9 (range 1.6-58.3) to 12.7 (range 2.3-90.8) ng/ml, P < 0.0001]. Although the absolute increase was not significantly different, mean percentage increase was greater in men (M = 66.6 +/- 51%, F = 11.8 +/- 16%, P = 0.017) despite similar serum IGF-I and BMI in male and female subjects at baseline. No change in BL or SLR accompanied serum IGF-I normalization [0.27 (range 0.15-1.26) to 0.27 (range 0.14-1.2) nmol/l, P = 0.27 and 3.2 (range 1.2-6.8) to 2.7 (range 1-7.4) nmol/l, P = 0.5, respectively]. After normalization of serum IGF-I, a correlation between BMI and leptin remained (R = 0.86, P < 0.0001) and together BMI and gender accounted for 87% of the variance in mean log10 serum leptin (P = 0.0002). CONCLUSION: Pegvisomant-induced serum IGF-I normalization in patients with active acromegaly is associated with a significant increase in total, and by implication, free leptin.

Acromegaly↗
PubMed2003

The effect of cessation of growth hormone (GH) therapy on bone mineral accretion in GH-deficient adolescents at the completion of linear growth.

In many countries, treatment of childhood-onset GH deficiency (GHD) with GH ceases when linear growth is complete. Peak bone mass occurs several years after the completion of linear growth. Given that GH has important anabolic actions on bone, discontinuation of GH therapy at the completion of linear growth may have adverse consequences for the attainment of peak bone mass in adolescent GHD patients. In this United Kingdom multicenter study, 24 adolescents (13 males, mean age 17.0 +/- 1.4 yr, SD) with severe GHD were randomized to discontinue or continue GH (0.35 IU/kg x wk) at the completion of linear growth. Whole body bone mineral content (BMC) and lumbar spine bone mineral density were assessed by dual-energy x-ray absorptiometry at baseline and then at 6-month intervals for 1 yr. Markers of bone remodeling (serum bone-specific alkaline phosphatase and urinary deoxypyridinoline) were measured at the same time points. In patients who continued GH (GH+), median BMC increased by 3.8% (interquartile range, 2.6, 5.9, P < 0.001) at 6 months; and by 6.0% (3.7-9.1, P < 0.001) at 12 months. In patients who discontinued GH (GH-) median BMC was unchanged at 6 and 12 months (+1.9%, -0.4-4.2, P = 0.9; and +2.4%, 0.4-4.9, P = 0.5, respectively, median, interquartile range). The differences in median change in BMC between the two groups at 6 and 12 months was marginally significant (P = 0.085 and 0.074, respectively). Mean lumbar spine bone mineral density increased by 4.7 (95% confidence interval, 1.0, 8.2) at 12 months in patients continuing GH (P = 0.01), but the mean change was not statistically significant change in patients who discontinued GH [+2.7% (95% confidence interval, -0.8, +6.2)]. These preliminary data suggest that, in adolescent patients with severe GHD, discontinuation of GH at completion of growth may limit the attainment of peak bone mass in this patient group. This may predispose to clinically significant osteopenia in later adult life.

Adolescent↗
PubMed2003

An investigation of the predictors of bone mineral density and response to therapy with alendronate in osteoporotic men.

Male osteoporosis is an important disease, with 25-30% of all hip fractures occurring in men. In a recent randomized, placebo-controlled study of osteoporotic males, alendronate 10 mg daily for 2 yr led to significant increments in bone mineral density (BMD), of a similar magnitude to those observed in postmenopausal women. In this study, specimens collected at intervals during the recent trial of alendronate in male osteoporosis, from 197 of the original 241 participants, were assayed for testosterone, estradiol, IGF-I, IGF binding protein 3 (IGFBP-3), bone-specific alkaline phosphatase [BSAP (serum)], and N-telopeptide of type I collagen corrected for creatinine [NTx (urine)]. Together with fracture and densitometry data from the original study, relationships were examined between BMD and serum IGF-I, IGFBP-3, testosterone, estradiol, BSAP, and urine NTx, both at baseline and during treatment with alendronate, to gain possible insights into the pathogenesis of male osteoporosis. Statistically significant (P <or= 0.05) associations were documented, at baseline, between the presence of vertebral fracture and each of serum IGF-I, serum IGFBP-3, serum free testosterone, total spine BMD, and total body BMD. No statistically significant correlations were observed between any of the baseline variables (IGF-I, IGFBP-3, estradiol, testosterone, and presence of vertebral fracture) and the BMD response to alendronate at any site. In a multivariate analysis, used to identify possible combinations of factors capable of predicting baseline BMD or response to alendronate, statistically significant (P <or= 0.01) relationships were seen, at baseline, between BMD and body mass index, age, and prior fracture. However, no statistically significant relationships were seen between any of the baseline variables (age, body mass index, testosterone, estradiol, IGF-I, IGFBP-3, and prior fracture) and change in BMD at any site. These data suggest that among men with osteoporosis it is not possible to identify patients who would be particularly good candidates for therapy with alendronate on the basis of biochemical or hormonal markers. Alendronate therapy appears to benefit osteoporotic males equally, irrespective of baseline serum testosterone, estradiol, IGF-I, or markers of bone turnover.

Adult↗
PubMed2003

Hadju-Cheney syndrome: response to therapy with bisphosphonates in two patients.

Hadju-Cheney syndrome is characterized by short stature, distinctive facies, and a slowly progressive skeletal dysplasia including acro-osteolysis. Autosomal dominant inheritance is typical, but the genetic defect and molecular pathogenesis of the syndrome are unknown. Osteoporosis with atraumatic fracture is a frequent finding, and previous studies have documented biochemical and morphometric evidence of high bone turnover. Here, we report the clinical details and response to therapy with bisphosphonates in two patients (mother and son) with Hadju-Cheney syndrome and postulate that osteoclast-mediated bone resorption is important in the generalized osteoporosis commonly associated with this condition.

Acro-Osteolysis↗
PubMed2003

Insulin sensitivity and glucose tolerance improve in patients with acromegaly converted from depot octreotide to pegvisomant.

AIM AND METHOD: Insulin resistance leading, in some cases, to glucose intolerance is an important contributory factor to the cardiovascular morbidity and mortality associated with acromegaly. The aim of this study was to document changes in insulin sensitivity (IS) in a group of seven patients with acromegaly (three male, four female, mean+/-s.d. age 59+/-13 Years) treated initially with a stable dose of depot octreotide (OT; median dose 30 mg four times weekly, range 10-30 mg) for a median of 18 Months (range 16-19 Months) and who were then transferred to treatment with pegvisomant (median dose 15 mg daily, range 10-20 mg) for a median of 8 Months (range 7-9 Months). IS was assessed by homeostatic model assessment (HOMA) using fasting glucose and insulin concentrations and by a short insulin tolerance test (sITT). Body composition was assessed by dual energy X-ray absorptiometry. RESULTS: Mean+/-s.d. serum IGF-I concentrations during therapy with OT and with pegvisomant were not statistically different (283+/-119 ng/ml on OT vs 191+/-39 ng/ml on pegvisomant (P=0.4)). However, mean+/-s.d. fasting plasma glucose fell from 6.2+/-1.0 mmol/l on OT to 5.2+/-0.6 mmol/l on pegvisomant (P=0.017) and was lower on pegvisomant in all seven patients. In four patients, fasting plasma glucose fell from values diagnostic of diabetes mellitus or impaired fasting glucose on OT to within the normal range on pegvisomant. Mean+/-s.d. peripheral IS (by sITT) increased from 139+/-39 micromol/l per min on OT to 169+/-59 micromol/l per min on pegvisomant (P=0.037). Mean+/-s.d. IS (by HOMA %S) was unchanged over the course of the study (149.1+/-43.7% on OT vs 139.9+/-76.6% on pegvisomant, P=0.28). Mean+/-s.d. pancreatic beta-cell secretory function (HOMA %B) improved significantly on pegvisomant compared with OT (49.4+/-19.2% vs 82.4+/-43.5%, P=0.01). No statistically significant change in total fat (P=0.3), % fat (P=0.28) or circulating non-esterified fatty acids (P=0.35) was observed. CONCLUSIONS: IS and glucose tolerance improved in patients converted from OT therapy to pegvisomant, without a change in body composition and even when serum IGF-I concentrations remained equally well controlled. This may be an important factor in the choice of medical therapy for patients with acromegaly.

Acromegaly↗
PubMed2002

Use of phalangeal bone mineral density and multi-site speed of sound conduction to monitor therapy with alendronate in postmenopausal women.

In women with postmenopausal osteoporosis (PMO), response to therapy with bisphosphonates is conventionally monitored using central-site (hip and spine) bone mineral density (BMD), but more convenient alternatives are desirable. During a randomized parallel-group study of the efficacy of once-weekly (80 mg vs 160 mg) oral alendronate in the treatment of PMO, 81 women (mean age 70.2 years +/- 4.6 SD) had BMD measurements of total hip (TH) and lumbar spine (LS) (L1-L4, Hologic); and of the middle phalanx of the middle digit of the non-dominant hand (accuDXA) at baseline and after 6 and 12 months of therapy with alendronate. At the same timepoints, subjects also had measurements of speed of sound (SOS) through bone at four sites (distal 1/3 radius, proximal phalanx of the third finger, midshaft of the tibia and fifth metatarsal) using the Sunlight Omnisense Ultrasound Bone Sonometer. Data from both patient groups were pooled for this analysis. Mean TH BMD at baseline was 0.705 g/cm2 +/- 0.093 (SD) and increased by 1.7% +/- 2.3% and 2.5% +/- 2.3% at 6 and 12 months respectively (p = 0.09 and p<0.0001). Mean LS BMD at baseline was 0.718 +/- 0.076 g/cm2 and increased by 3.9% +/- 3.6% and 6.1% +/- 3.5% at 6 and 12 months respectively (both p<0.0001). There was no statistically significant change from baseline in mean BMD by accuDXA at either 6 or 12 months. The only statistically significant changes in SOS were at the radius (decrease in SOS at 12 months, p= 0.04) and tibia (increase at 6 months, p<0.01, but no change between baseline and 12 months). Baseline correlation coefficients between accuDXA and LS and TH DXA were 0.22 (p = 0.05) and 0.27 (p = 0.02) respectively. Correlation coefficients between SOS and LS DXA ranged from 0.05 to 0.22; and between SOS and TH DXA ranged from -0.08 to 0.10 (all p = NS). These data suggest that the response to alendronate therapy over this time period cannot be measured by accuDXA or Sunlight SOS at the sites studied.

Administration, Oral↗