bluuebunny/crossref_metadata_2025 huggingface dataset:
Response of sex hormone binding globulin and insulin‐like growth factor binding protein‐1 to an oral glucose tolerance test in obese women with polycystic ovary syndrome before and after calorie restriction
Authors: Hamilton‐Fairley D. , Kiddy D. , Anyaoku V. , Koistinen R. , Seppälä M. , Franks S.
Published: March 2008

OBJECTIVE We determined the relationship of short‐term changes in circulating insulin concentrations, resulting from an oral glucose load, to those in both sex hormone binding globulin (SHBG) and insulin‐like growth factor binding protein 1 (IGFBP‐1) and assessed the effect of a short‐term low calorie diet on the levels of SHBG and IGFBP‐1 during an oral glucose tolerance test.

DESIGN A within‐group comparison of biochemical indices during an oral glucose tolerance test before and after calorie restriction.

PATIENTS AND METHODS Six obese women with polycystic ovary syndrome with mean (SD) BMI 34 2 (3 4) kg/m2 were studied before and after one month on a very low calorie diet (350 kcal/day; Cambridge diet). Each subject was given a 75‐g oral glucose load after an overnight fast and blood samples were taken every 30 minutes for 3 hours. These were analysed for glucose, insulin, SHBG, and IGFBP‐1.

RESULTS All the women lost weight (range 1.7–9.5 kg). The SHBG concentrations did not change significantly during the oral glucose tolerance test but there was a highly significant decline in IGFBP‐1 levels both before (0 min, mean (SD) 27 3 (10 6); 180 min, 8.9 (4.2) μg/l) and after (0 min, 28 4 (12 1); 180 min, 6 2 (2 1) μg/l, P< 0 001) dieting. The sum of the SHBG concentrations during the test, however, was significantly lower prior (129 9 (405) nmol/l) to calorie restriction than after (164 3 (70 6) nmol/l), whereas there was no significant effect of dieting on the IGFBP‐1 response to glucose.

CONCLUSIONS The changes in insulin and SHBG concentrations found after dieting have been confirmed. SHBG levels, in contrast to IGFBP‐1, do not change in response to a short‐term increase in insulin or glucose concentrations. The difference in the response of the two binding proteins may be explained by differences in their half‐lives in the circulation or the regulation of mRNA for the peptides by insulin. This study confirms that insulin regulates both SHBG and IGFBP‐1 but that there is a difference in the time course of the response of the two proteins to insulin.
Short and long‐term effects of growth hormone treatment on bone turnover and bone mineral content in adult growth hormone‐deficient males*
Authors: Vandeweghe Mark , Taelman Paul , Kaufman Jean‐Marc
Published: March 2008

OBJECTIVE In view of the fact that GH‐deficient adults present with pronounced osteopaenia and can be considered at risk for osteoporotic fractures, we wanted to investigate the effects of biosynthetic GH replacement therapy (0.25 IU/kg/week) on biochemical indices of bone turnover and on bone mineral content (BMC) in a group of GH‐deficient adult males.

DESIGN We performed a 6‐month randomized, double‐blind, placebo‐controlled study, followed by 12–24 months of GH treatment in all patients.

PATIENTS Twenty adult males with GH deficiency of childhood onset were studied.

MEASUREMENTS We measured serum IGF‐I, serum phosphate, biochemical indices of bone turnover (serum alkaline phosphatase activity, serum osteocalcin, serum carboxyterminal propeptide of type‐I procollagen, fasting urinary hydroxyproline/creatinine and calcium/creatinine ratios) and bone mineral content, measured at the forearm and the lumbar spine by single and dual‐photon absorptiometry respectively.

RESULTS After 3 and 6 months of GH administration, the serum levels of alkaline phosphatase, osteocalcin and carboxyterminal propeptide of type‐I procollagen, and the fasting urinary hydroxyproline/creatinine ratio were significantly increased compared to placebo‐treated patients (P<0.01 to P<0.001). During the open study phase, the values for these indices of bone turnover remained elevated above pretreatment levels (P<0 01 to P<0 001 at 12 months), a downward trend becoming apparent after about one year of GH treatment. BMC values showed an initial decline after 3 months of GH treatment (most likely due to an expansion of the remodelling space), followed by a significant and progressive increase above pretreatment values, reaching 7–8% for total BMC at the lumbar spine (L2‐L4) and 9–9% for total BMC at the forearm, after 30 months of GH administration.

CONCLUSIONS The data of our study show that administration of substitutive doses of growth hormone to GH‐deficient adult males activates bone turnover for a period of at least one year and suggests that this may have a beneficial effect on bone mass in these patients.
Plasma IGFBP‐3 and its relationship with quantitative growth hormone secretion in short children*
Authors: Phillip Moshe , Chalew Stuart A. , Kowarski A. Avinoam , Stene Mark A.
Published: March 2008

OBJECTIVE We assessed the relationship between serum IGFBP‐3 levels with IGF‐I and quantitative GH secretory status in poorly growing children.

DESIGN We studied the relationship between 24‐hour integrated concentration of GH, peak GH to paired sequential stimulation tests, IGF‐I and the IGFBP‐3 serum levels. PATIENTS One hundred and two children (82 males, 20 females, age 11.7±2.7 years) with short stature (height 2.6±0.7 SDS) were studied.

MEASUREMENTS Quantitative GH secretory status was assessed by the 24‐hour integrated GH and by response to arginine and insulin stimulation. GH, IGFBP‐3 and IGF‐I were measured by radioimmunoassay. To adjust for age and gender, IGFBP‐3 levels were converted to SD score. RESULTS IGFBP‐3 SDS was strongly correlated with IGF‐I SDS (r= 0 64, P<0.0001), and weakly with peak GH (r= 0.28, P<0 0004), but not with the integrated GH concentration (r= 0 07, P<0 46). IGFBP‐3 SDS increased with pubertal maturation (P< 0 0001). There was no difference in mean IGFBP‐3 SDS in subgroupings of the patients based on the results of their quantitative GH tests. CONCLUSION In short children, IGFBP‐3 levels increase with puberty, are strongly correlated with IGF‐I levels, weakly correlated with peak response to GH stimulation tests, but not correlated with integrated GH. Consequently, diagnostic classifications of patients based on quantitative measurements of GH secretion and IGFBP‐3 differ.
Direct in‐vivo detection of atypical hormonal expression of a Sertoli‐Leydig cell tumour following stimulation with human chorionic gonadotrophin
Authors: Cohen Ilan , Shapira Menahem , Cuperman Solomon , Goldberger Shmuel , Siegal Annette , Altaras Marco , Beyth Yoram
Published: March 2008

A 60‐year‐old woman presented with progressive hirsutism and elevated serum testosterone levels. Selective bilateral ovarian and adrenal vein catheterization demonstrated mild elevated testosterone and androstenedione levels in the right ovarian vein, which increased considerably 15 minutes following intravenous injection of 5000 IU human chorionic gonadotrophin. Androgen levels decreased remarkably after administration of gonadotrophin hormone releasing hormone‐agonist (GnRH‐a). On histological examination, diffuse stromal hyperplasia of both ovaries was noted, with a small Sertoli‐Leydig cell tumour in the right ovary. This is the first report of preoperative, direct selective diagnosis of a small Sertoli‐Leydig cell tumour with such a hormonal expression.

Ovarian Sertoli‐Leydig cell tumours are rare sex cord stromal tumours that exhibit testicular‐like structure and differentiation. These tumours are potentially malignant, can cause progressive virilization (Young & Scully, 1985), and are often clinically manifested as palpable pelvic masses and virilization (Meldrum & Abraham, 1979; Friedman et al., 1985). We describe a patient with postmenopausal virilization due to Sertoli‐Leydig cell tumour, in whom a remarkable increase in androgens was detected following intravenous human chorionic gonadotrophin injection, during adrenal and ovarian selective vein blood sampling. A remarkable decrease in the serum androgen level was noticed following an injection of gonadotrophin hormone releasing hormone‐agonist (GnRH‐a).
Suppressed TSH levels secondary to thyroxine replacement therapy are not associated with osteoporosis
Authors: Grant David J. , McMurdo Marion E.T. , Mole Patricia A. , Paterson Colin R. , Davies Robert R.
Published: March 2008

OBJECTIVE Recent studies have suggested that patients receiving thyroxine are at increased risk of osteoporosis. We set out to measure bone mineral densities in two groups of post‐menopausal women receiving thyroxine replacement therapy (those with serum TSH levels persistently suppressed or non‐suppressed) and to compare the results in both groups with those of the local control population.

DESIGN Cross‐sectional study.

PATIENTS Seventy‐eight post‐menopausal women who had been treated with thyroxine for primary autoimmune or idiopathic hypothyroidism for a minimum of 5 years, 44 with TSH persistently suppressed and 34 non‐suppressed. One hundred and two control subjects.

MEASUREMENTS Forearm bone mineral density at proximal and distal sites as measured by single‐photon absorptiometry.

RESULTS Results were expressed as Z‐scores, i.e. number of standard deviations from the mean of a 5‐year age‐band from the local control population. Mean Z‐scores at proximal and distal sites for the non‐suppressed patients were ‐003 and ‐007 and for the suppressed patients were 0 20 and ‐0 25, representing a decrease in bone mineral density of at most 5% in the suppressed patients. The differences between the three groups were not statistically significant.

CONCLUSION In this patient population, the reduction in bone mineral density due to thyroxine is small. It is unlikely to be of clinical significance and should not on its own be an indication for reduction of thyroxine dose in patients who are clinically euthyroid.
Effects of different oral oestrogen formulations on insulin‐like growth factor‐I, growth hormone and growth hormone binding protein in post‐menopausal women
Authors: Kelly John J. , Rajkovic Ivan A. , O'Sullivan Anthony J. , Sernia Conrad , Ho Ken K. Y.
Published: March 2008

OBJECTIVE Insulin like growth factor‐I (IGF‐I) levels in post‐menopausal women are reduced by oral administration of the synthetic oestrogen ethinyl oestradiol but increased by transdermal delivery of 17 β‐oestradiol. Since these oestrogen types are different, the aim of this study was to clarify whether reduction in IGF‐I is a specific effect of ethinyl oestradiol or common to other oral oestrogen formulations.

DESIGN Randomized cross‐over study comparing one month of treatment with ethinyl oestradiol (20 μ g), conjugated equine oestrogen (1 25 mg Premarin) and oestradiol valerate (2 mg).

SUBJECTS Six healthy post‐menopausal women, age 60 3 ± 5 6 years.

MEASUREMENTS Mean 24 hour GH (from hourly sampling), IGF‐I, GH binding protein (GHBP), pituitary (LH, FSH) and hepatic function (SHBG and angiotensinogen) were measured.

RESULTS All three oestrogen formulations resulted in a significant reduction in IGF‐I levels compared to baseline and significant elevations of GH and GHBP (P & lt; 0 05). The percentage increase in GH during oestrogen treatment was significantly related to the percentage decrease in IGF‐I levels (P= 0 04). All three oestrogen formulations resulted in significant suppression of LH and FSH and induction of the hepatic proteins, SHBG and angiotensinogen (P <0 05). GHBP increased in parallel with other hepatic proteins.

CONCLUSIONS Reduction in IGF‐I levels is an intrinsic effect of oral oestrogen therapy and increased GH levels may occur as a result of reduced feedback inhibition by IGF‐I. Since GHBP activity is not changed by transdermal oestrogen, we conclude that the liver is a major source of circulating GHBP and that GHBP is an oestrogen sensitive protein.
Effect of oestrogen status on serum levels of growth hormone‐binding protein and insulin‐like growth factor‐I in non‐pregnant and pregnant women
Authors: Massa Guy , Igout Ahmed , Rombauts Luc , Frankenne Francis , Vanderschueren‐Lodeweyckx Magda
Published: March 2008

OBJECTIVE Since there appears to be a relationship between circulating oestrogens and growth hormone, we have investigated the effect of the oestrogen status of adult women on serum levels of GHBP and IGF‐I.

DESIGN AND patients The investigation was performed on serum samples of 14 spontaneously menstruating women, 10 women taking oral contraceptives containing 20–50 μ g ethinyloestradiol, and 30 pregnant women at different stages of pregnancy.

MEASUREMENTS Serum levels of GHBP were measured by HPLC gel filtration and IGF‐I levels were measured by RIA after acid‐ethanol extraction.

RESULTS In the spontaneously menstruating women the mean ± SD serum level of GHBP was 34.6 ± 6.7% and of IGF‐I 30 ± 7 nmol/l. Serum GHBP levels were negatively (r=0.67; P<0.01) and IGF‐I levels were positively related (r= 0.69; P< 0.01) to serum oestradiol concentrations. In the women taking oral contraceptives serum levels of GHBP were 470 ±7 4%. This was significantly (P<0.001) higher than in spontaneously menstruating women. In contrast, IGF‐I levels were not different from those obtained in spontaneously menstruating women. In the pregnant women, the mean ± SD serum level of GHBP was not different from that observed in non‐pregnant spontaneously menstruating women. Polynomial regression analysis, however, showed a significant (P= 0.01) second‐order relationship between the duration of pregnancy and serum GHBP levels, with increasing levels during the first half of pregnancy and decreasing levels thereafter. Serum concentrations of IGF‐I increased during the second half of pregnancy and were significantly (P<0.005) elevated in the third trimester.

CONCLUSIONS In non‐pregnant women the endogenous oestrogen status seems to modulate negatively GHBP levels and positively IGF‐I levels, whereas oral oestrogen administration, in contrast, increases serum levels of GHBP without modification of IGF‐I levels. During pregnancy serum GHBP levels increase slightly during the first half of pregnancy and decrease thereafter, whereas IGF‐I concentrations increase during the second part of pregnancy. The oestrogen status of women has a complex effect on serum concentrations of GHBP and IGF‐I and has therefore to be taken into account when evaluating serum levels of GHBP and IGF‐I.
Tissue‐specific modulation of insulin receptor mRNA levels in a patient with a phaeochromocytoma
Authors: Leal M. A. , Aller P. , Torres A. , Picardo A. , Calle C.
Published: March 2008

We have observed that the expression of the insulin‐receptor gene is regulated in a tissue‐specific manner in a patient with a phaeochromocytoma. Our results Indicate that insulin receptor mRNA levels are decreased in adipose tissue and increased in both liver and skeletal muscle as compared with the corresponding values in the same tissues of a control patient. These findings provide the first evidence that insulin receptor mRNA levels may be modulated in vivo by high levels of catecholamines.
Differences in testosterone metabolism by beard and scalp hair follicle dermal papilla cells
Authors: Thornton M. J. , Laing I. , Hamada K. , Messenger A. G. , Randall V. A.
Published: March 2008

OBJECTIVE Androgens have paradoxically different effects on hair follicles depending on body site, stimulating beard growth while inducing regression in some areas of the scalp. The mesenchyme derived dermal papilla at the base of the hair follicle regulates many aspects of the growth of follicular epithelium, and is probably the site of androgen action. Since 5α‐dihydrotes‐tosterone is considered to be the active intracellular androgen in many target tissues and is required for some androgen‐mediated hair growth, such androgen‐sensitive cells should contain 5α‐reductase. This study was designed to investigate whether cultured human dermal papilla cells contain 5α‐reductase and whether the metabolic capacity varies with the body site of the follicle in line with the clinical picture.

DESIGN Testosterone metabolism in cultured dermal papilla cells from androgen sensitive beard follicles was compared with less androgen dependent non‐balding scalp follicles. Primary cell cultures were established from follicles of 11 patients with normal hair growth. The cells were grown to confluence in 10‐cm Petri dishes and incubated with 5 nM 3H‐testosterone in serum‐free medium for 2 hours. The cells and the culture medium were collected separately for individual analysis.

MEASUREMENTS Unlabelled carrier and 14C‐marker steroids were added to both the cell and medium extracts before separation by thin‐layer chromatography. The individual steroid identities were confirmed by recrystal‐lizing up to five times to a constant 3H/14C ratio.

RESULTS Testosterone was taken up by both cell types; significant amounts of 5α‐dihydrotestosterone were recovered inside beard cells, but not in scalp cells, whereas androstenedione was identified in both. An unidentified compound was present intracellularly in both cell types, but was not present in the culture medium. 5α‐Dihydrotes‐tosterone was present only in the culture medium of beard cells but androstenedione was present in a similar amount in the medium from both cell types. The presence of other steroids could not be confirmed in either the cell extracts or the culture medium.

CONCLUSIONS The production of 5α‐dihydrotestosterone by beard cells concurs with the poor beard growth in men with 5α‐reductase deficiency, supporting our hypothesis that androgens mediate their effects on the hair follicle via the mesenchyme‐derived dermal papilla.
Identification of olfactory dysfunction in carriers of X‐linked Kallmann's syndrome
Authors: Kirk J. M. W. , Grant D. B. , Savage M. O. , Besser G. M. , Bouloux P.‐M. G.
Published: March 2008

OBJECTIVE The aim of the study was to test the hypothesis that clinically unaffected female carriers of X‐linked Kallmann's syndrome have an olfactory defect.

DESIGN Assessment of the olfactory threshold to seven standard odorants, each at a concentration of 1‐10‐8mol/1.

PATIENTS Five families with X‐linked Kallmann's syndrome (KS) were tested, containing 19 males with KS, and 9 female carriers. Related but unaffected males (n= 8) were used as a control group, and in addition seven patients with Turner's syndrome (XO) were assessed.

MEASUREMENTS The olfactory threshold was taken as the lowest concentration at which each odorant was clearly distinguished from control (liquid paraffin). The threshold for each odorant was compared between the subject groups using the non‐parametric Mann‐Whitney test.

RESULTS All patients with KS were anosmic to all odorants. The female carriers had hyposmla, with a significant reduction in the olfactory threshold to putrid, peppermint, floral and pungent odorants compared to control subjects, and to peppermint, floral and pungent odorants compared to subjects with Turner's syndrome. The latter had olfactory thresholds which were statistically identical with the control group.

CONCLUSIONS Obligate female carriers of X‐linked Kallmann's syndrome are hyposmic compared to control subjects. The overlap between the two groups, however, makes olfactory testing unreliable as a diagnostic test.
Optimal frequency of administration of pamidronate in patients with hypercalcaemia of malignancy
Authors: Wimalawansa* Sunil J.
Published: March 2008

OBJECTIVE Hypercaicaemia of malignancy (HM) is a common metabolic complication associated with cancer. The hypocaicaemic effects of medications used to reduce serum calcium levels in HM are short lived and relapse in hypercaicaemia is not uncommon. Pamidronate is one of the most commonly used bisphosphonates in the treatment of HIM but there are no specific guidelines for the frequency of use of this drug in recurrent hypercalcaemia. This study was conducted to assess the optimum frequency of pamidronate therapy necessary to maintain normocalcaemia in patients with HM.

DESIGN AND PATIENTS Thirty‐four patients With HM were randomly allocated into two groups and treated with intravenous pamidronate administered every 14th or 21st day for 16 weeks (n= 17 each group). Serum calcium and urinary hydroxyproline creatinine ratio were measured at weekly intervals.

RESULTS The calcium‐lowering effect of pamidronate was apparent by 48 hours and normocalcaemia was maintained for an average of 15 days. When the drug was administered every 3 weeks, hypercalcaemia and associated symptoms developed in 50% of patients (22 separate episodes) during the 3rd week, before the next dose of pamidronate. The incidence of symptomatic hypercalcaemia was significantly decreased (10%, 8 separate episodes, P < 0·01) and survival was improved (P< 0·05) in patients who received pamidronate every 2nd week, thereby minimizing the unpleasant and potentially dangerous effects of hypercalcaemia.

CONCLUSIONS Intravenous pamidronate 60 mg/dose, administered every two weeks, can maintain normocalcaemia in the vast malority of patients with hypercalcaemia of malignancy.
Serum lipoproteins in acromegaly before and 6‐15 months after transsphenoidal adenomectomy
Authors: Oscarsson Jan , Wiklund Olov , Jakobsson Karl‐Erlk , Petruson Björn , Bengtsson Bengt‐Åke
Published: March 2008

OBJECTIVES Acromegaly is a rare disorder characterized by over‐secretion of GH, most often because of a pituitary adenoma. The disease is associated with disturbances in lipoprotein metabolism and an increased cardiovascular mortality. The aim of the present study was to investigate whether treatment of acromegaly results in changes in serum concentrations of lipids and apolipoproteins, Including lipoprotein(a) (Lp(a)).

DESIGN Fourteen patients with clinical features of acromegaly and Increased GH secretion were studied 1‐10 months before and 6‐15 months after transsphenoidal adenomectomy in an open study.

PATIENTS Three patients had diabetes mellitus before surgery and two of these patients had normalized serum glucose levels post‐operatively. Mean and baseline plasma GH levels were determined from 24‐hour GH profiles. Serum samples were taken in the morning after an overnight fast. All patients were normocholesterolaemic, and four patients were hypertriglyceridaemic before treatment.

RESULTS Mean plasma GH levels decreased from 34·5 ±7·4 to 2·1 ±0·4 μ/l (mean ±SEM). Serum IGF‐I, insulin and free T3 levels decreased and serum SHBG concentrations Increased post‐operatively. There was no effect of treatment on serum cholesterol concentrations, but serum triglyceride concentrations decreased. Serum apollpoprotein (apo) B and apoE levels were unaffected by treatment. Serum apoA‐I levels increased and Lp(a) levels decreased post‐operatively.

CONCLUSIONS Successful treatment of acromegaly, resulting in normal mean GH values (< 5mU/l) and/or normal responsiveness to TRH, have beneficial effects on serum lipoproteins with increased serum apoA‐I levels and decreased serum levels of triglycerides and Lp(a). These effects seem to be independent of improvement In glucose tolerance, since patients with diabetes mellitus before surgery and normal fasting blood glucose levels post‐operatively had similar lipoprotein responses to treatment as those with normal fasting blood glucose levels before surgery.
Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose‐dependent manner and suppresses circadian thyrotrophin levels: studies in GH‐deficient adults
Authors: Jørgensen J. O. L. , Møller J. , Laursen T. , Ørskov H. , Christiansen J. S. , Weeke J.
Published: March 2008

OBJECTIVE The impact of exogenous GH on thyroid function remains controversial although most data add support to a stimulation of peripheral T4 to T3 conversion. For further elucidation we evaluated iodothyronine and circadian TSH levels in GH‐deficient patients as part of a GH dose‐response study.

PATIENTS Eight GH‐deficient adults, who received stable T4 substitution due to central hypothyroidism; two patients, who were euthyroid without T4 supplementation were studied separately.

DESIGN All patients were initially studied after at least 4 weeks without GH followed by 3 consecutive 4‐week periods in fixed order during which they received daily doses of 1, 2 and 41U of GH/m2 body surface area. The patients were hospitalized for 24 hours at the end of each period.

MEASUREMENTS Circulating total and free concentrations of T4 and T3, total rT3 and TSH were measured once at the end of each study period. Circadian TSH levels were recorded during the period without GH and during GH treatment with 2 IU GH.

RESULTS Highly significant GH dose‐dependent increases in total and free T3 and a reduction in rT3 were observed. The T3/T4 ratio also increased with increasing GH dosages (P < 0·001). In seven patients subnormal T3 levels were recorded in the period off GH, despite T4 levels well within the normal range. Resting energy expenditure also increased and correlated with free T3 levels (r= 0·47, P < 0·05). The Circadian TSH levels exhibited a significant nocturnal increase during the period without GH, whereas GH therapy significantly suppressed the TSH levels and blunted the circadian rhythm (mean TSH levels (mU/I) 0·546 ± 0·246 (no GH) vs 0·066 ± 0·031 (21U GH) (P < 0·05)). The two euthyroid non‐T4 substituted patients exhibited qualitatively similar changes in ail parameters.

CONCLUSIONS GH adminstration stimulated peripheral T4 to T3 conversion in a dose‐dependent manner. Serum T3 levels were subnormal despite T4 substitution when the patients were off GH but normalized with GH therapy. Energy expenditure increased with GH and correlated with free T3 levels. GH caused a significant blunting of serum TSH. These findings suggest that GH plays a distinct role in the physiological regulation of thyroid function in general, and of peripheral T4 metabolism in particular.
The effect of oestradiol implants on regional and total bone mass: a three‐year longitudinal study
Authors: Ryde S. J. S. , Bowen‐Simpkins K. , Bowen‐Simpkins P. , Evans W. D. , Morgan W. D. , Compstont J. E.
Published: March 2008

OBJECTIVE Although there is evidence from cross‐sectional studies that percutaneous oestrogen administration protects against menopausal bone loss, few longitudinal data are available. We have examined the effect of 3 years' treatment with percutaneous oestradiol on total body calcium, spinal trabecular bone mineral density and radial bone mineral content in post‐menopausal women.

DESIGN and PATIENTS Twenty‐nine post‐menopausal women, aged 37–55 years, who had undergone hysterectomy and had experienced the onset of menopausal symptoms within the previous 2 years, were studied before and for 3 years during hormone replacement with oestradiol implants, given at approximately 6‐monthly intervals.

MEASUREMENTS Total body calcium was measured by prompt gamma neutron activation analysis, spinal trabecular bone mineral density by quantitative computed tomography and radial bone mineral content by single‐photon absorptiometry.

RESULTS There was a significant increase in the mean total body calcium, spinal trabecular bone mineral density and radial bone mineral content over the 3 years of the study. The mean (± SEM) percentage change per annum was +2 4% (±0.8) for total body calcium (P <0 01), + 3.3% (±0.6) for spinal trabecular bone mineral density (P < 0.001) and +12% (± 0.6) for radial bone mineral content (P < 0 05).

CONCLUSIONS Percutaneous oestradiol replacement therapy prevents menopausal bone loss and is associated with a sustained and significant increase in total body calcium, spinal trabecular bone mineral density and radial bone mineral content over a 3‐year treatment period. Oestradiol implants thus have skeletal effects comparable to those of oral or transdermal oestrogens.
Impaired glucose tolerance and insulin insensitivity in primary hyperparathyroidism
Authors: Kumar S. , Olukoga A. O. , Gordon C. , Mawer E. B. , France M. , Hosker J. P. , Davies M. , Boulton A. J. M.
Published: March 2008

OBJECTIVE A high prevalence of diabetes mellitus has been shown in patients with primary hyperparathyroidism (PHPT). However, it is unclear whether this is related to the metabolic abnormalities in PHPT or to the presence of other risk factors for glucose intolerance in these patients. The aim of our study was to determine whether glucose intolerance and insulin insensitivity occur in subjects with PHPT who do not have other risk factors for diabetes mellitus.

DESIGN Cross‐sectional study of glucose metabolism in PHPT patients without other risk factors for diabetes mellitus, compared to age and body mass index (BMI) matched healthy subjects.

SUBJECTS Nineteen non‐obese, non‐diabetic, normotensive patients with PHPT and 11 age and BMI matched healthy subjects.

MEASUREMENTS The continuous infusion of glucose test was used to assess glucose tolerance. Plasma glucose and insulin were measured during a 1‐hour continuous infusion of glucose (5 mg/kg ideal body weight/min); insulin sensitivity and beta‐cell function were derived from the glucose and insulin data by mathematical modelling. Fasting serum concentrations of parathyroid hormone, ionized calcium and 1,25‐dihydroxyvitamin D (1,25(OH)2D) were measured in all subjects.

RESULTS PHPT patients attained higher plasma glucose levels at the end of the glucose infusion (median 9.0 (interquartile range 8.1–9.8) mmol/l) than did controls (7.9 (7.1–8.9) mmol/l, P<0.05), and 8 (42%) PHPT patients had impaired glucose tolerance. Insulin sensitivity was lower in PHPT (60.3% (49.8–85.4)) than in controls (113.7% (89.3–149.2), P<0.001); beta‐cell function was not different in PHPT subjects. PHPT subjects with impaired glucose tolerance had reduced beta‐cell function compared to PHPT subjects with normal glucose tolerance (89.9% (70.5–106.4) vs 120% (98.8–156.6) respectively, P<0.05). No significant correlations were found between insulin sensitivity and PTH (rs=−0.21), 1,25(OH)2D (rs=−0.14), ionized calcium (rs=–0.11) and inorganic phosphate (rs= 0.34). Beta‐cell function did not correlate with PTH (rs= 0.15), 1,25(OH)2D (rs= 0.04), ionized calcium (rs= 0.23) or inorganic phosphate (r,=− 0.35).

CONCLUSION Insulin insensitivity is present in PHPT even in the absence of hypertension and obesity, and may be the cause of glucose intolerance and diabetes. PHPT subjects with reduced beta‐cell function are more likely to develop glucose intolerance.
The HLA association with Graves' disease is sex‐specific in Hong Kong Chinese subjects
Authors: Cavan D. A. , Penny M. A. , Jacobs K. H. , Kelly M. A. , Jenkins D. , Mijovic C. , Chow C. , Cockram C. S. , Hawkins B. R. , Barnett A. H.
Published: March 2008

OBJECTIVE Graves' disease is associated with different HLA genes in Caucasians and the Chinese, in whom the HLA associations may be stronger in males than females. Common HLA‐associated susceptibility in both races may occur at the HLA‐DQ loci. The aims of this study were to examine the HLA‐A, B, DR and DQ associations with Graves' disease in a Hong Kong Chinese population and to determine whether the HLA associations differ between the sexes and between subjects with and without thyrotoxic periodic paralysis.

DESIGN HLA‐A, B and DR types were determined by serological typing and DQA1 and DQB1 alleles by oligonucleotide probing of the respective enzymatically amplified gene.

PATIENTS Ninety‐seven Chinese patients with Graves' disease (31 males with, 35 males without and 31 females without thyrotoxic periodic paralysis) and 105 racially matched healthy controls.

MEASUREMENTS Frequencies of HLA types/alleles at each locus were compared between patients and controls and between the Graves' subgroups using the χ2 test.

RESULTS HLA‐B46, DR9 and DQB1*0303 were associated with Graves' disease in males only; these associations were weaker in males with thyrotoxic periodic paralysis. DR12, DQA1*0401 and DQB1*0301 were protective, regardless of sex or the presence of thyrotoxic periodic paralysis. The positive HLA associations in the Hong Kong Chinese were distinct from those in Caucasians whereas the protective haplotype was similar to that described in Caucasians.

CONCLUSIONS These findings call in question the role of HLA genes in disease susceptibility but suggest a role for HLA in protection from Graves' disease.
Stimulation of extraocular muscle fibroblasts by cytokines and hypoxia: possible role in thyroid‐associated ophthalmopathy
Authors: Metcalfe R. A. , Weetman A. P.
Published: March 2008

OBJECTIVE Smoking is a risk factor for the development of thyroid‐associated ophthalmopathy, an inflammatory process primarily affecting the fibroblasts in extraocular muscles. We wished to determine whether the extraocular muscle fibroblasts are more sensitive than dermal fibroblasts to T‐cell derived cytokines, as a reason for this anatomical localization, and whether hypoxia alters fibroblast function, as one explanation for the susceptibility conferred by smoking.

DESIGN Fibroblasts derived from the skin or extraocular muscles of healthy subjects were cultured with cytokines under normal (5% CO2:95% air) and hypoxic (5% C02:95% N2) conditions.

MEASUREMENTS Glycosaminoglycan, protein and DNA synthesis were measured by assessing incorporation of d‐6‐3H‐glucosamine, 3H‐amino acids, and 3H‐thymidine respectively.

RESULTS α‐lnterferon and interleukin‐6 had no effect on fibroblasts, γ‐Interferon, tumour necrosis factor and inter‐leukin‐1 stimulated glycosaminoglycan synthesis; this effect was greater in orbital than in dermal fibroblasts with γ‐interferon and interleukin‐1 (P<0.05). The same cytokines stimulated total protein with a greater response in orbital fibroblasts with γ‐interferon. Interleukin‐1 inhibited DNA synthesis in orbital fibroblasts but stimulated DNA synthesis in dermal fibroblasts (P< 0.01); tumour necrosis factor also displayed a differential effect (P<0.01). Hypoxia caused a significant increase in glycosaminoglycan, protein and DNA synthesis in both types of fibroblasts, under both basal and cytokine‐treated conditions (P < 0.05).

CONCLUSIONS Extraocular muscle fibroblasts respond differently from dermal fibroblasts following cytokine stimulation, which may explain in part the anatomical localization of ophthalmopathy. Hypoxia stimulates fibroblasts and this could contribute, as an enhancing factor, to the adverse effects of smoking on thyroid eye disease.
Growth hormone releasing hormone 1‐44 NH2 and 1‐40 OH levels in normal subjects during growth hormone stimulation tests
Authors: Page M. D. , Dieguez C. , Valcavi R. , Koppeschaar H. P. F. , Scanlon M. F.
Published: March 2008

OBJECTIVE Little is known about the relative circulating concentrations of growth hormone releasing hormone (GHRH) 1‐44 NH2 and 1‐40 OH in response to dynamic GH stimulation. We therefore studied the concentrations of growth hormone‐releasing hormone (GHRH) 1‐44 NH2 and 1‐40 OH in the peripheral plasma of normal male subjects during GH stimulation tests.

DESIGN Tests were performed at 0900 h after an overnight fast. Stimulation tests, commenced at 0 minutes, included α‐adrenergic activation with adrenaline (10 μg/min from 0 to 30 minutes) following β‐blockade with propranolol (1.5 mg/min from ‐10 to 0 minutes), α2‐adrenergic activation with clonidine 150 μg i.v., insulin hypoglycaemia (0.15 U/kg soluble insulin), l‐arginine infusion (30 g from 0 to 30 minutes), l‐dopa (500 mg orally) and oral glucose (100 g). SUBJECTS Groups of healthy male volunteers aged 20‐42 years, all within 10% of ideal body weight. MEASUREMENTS Serum GH and plasma GHRH 1‐44 NH2 and 1‐40 OH were measured at intervals for between 60 and 390 minutes, depending on the stimulation test. RESULTS There were no significant changes in either GHRH 1‐44 or 1‐40 following a‐adrenergic activation with propranolol/adrenaline infusion, a2‐adrenergic activation with i.v. clonidine, insulin‐induced hypoglycaemia or arginine infusion despite the expected rise in GH levels.

After oral glucose, GH was initially suppressed with a late rise. There were no changes in GHRH 1‐44 or 1‐40 levels during either phase of this response. After l‐dopa GH levels peaked at 90 minutes, 24.5 ± 11.0 mU/l (mean ± SEM). At 0 minutes GHRH 1‐44 and 1‐40 levels were 3.25 ± 0.89 and 4.93 ± 1.28 pmol/l respectively and rose in both cases, peaking at 60 minutes at 4.23 ± 1.01 and 7.55 ± 1.80 pmol/l (P < 0.05). At no time was there any evidence of differential secretion of GHRH 1‐44 or 1‐40.

CONCLUSIONS We have confirmed previous studies demonstrating a small rise in GHRH before the GH response to l‐dopa. However, in all other situations of pharmacological stimulation of GH release we were unable to detect any significant changes in GHRH 1‐44 or 1‐40 levels. It seems most likely that peripheral GHRH does not reflect hypothalamic secretion. As yet there is no evidence for differential release of GHRH 1‐44 and 1‐40.
Energy expenditure and body composition in growth hormone deficient adults on exogenous growth hormone
Authors: Chong P. K. K. , Jung R. T. , Scrimgeour C. M. , Rennie M. J. , Paterson C. R.
Published: March 2008

OBJECTIVES We assessed whether the obesity observed in growth hormone deficient adults is maintained by a reduction in energy expenditure. We studied the effects of exogenous growth hormone on energy expenditure and body composition.

DESIGN We performed an open study with growth hormone administered at 0 5 units per kilogram ideal body weight per week for 3 months.

PATIENTS Seven growth hormone deficient adults were studied. Thirty‐eight healthy volunteers had their resting metabolic rate measured, with seven of them proceeding to have their total energy expenditure assessed.

MEASUREMENTS Total energy expenditure was measured by the doubly labelled water method (D2018), resting metabolic rate by ventilated hood indirect calorimetry, and fat free mass from the dilution volume of oxygen‐18. Body composition and components of energy expenditure were assessed before, at 2 weeks and at the end of the 3‐month treatment period on exogenous growth hormone.

RESULTS Growth hormone deficient adults did not have a low total energy expenditure compared to healthy controls (13 12 vs 12 75 MJ/24 h) with only one patient expending less than 10 MJ/24 h. None had a resting metabolic rate lower than the 95% confidence limits of normality. The amount of energy expended on physical activity and thermogenesis was significant (6 54 MJ/24 h) and was similar to healthy controls (6 47 MJ/24 h).

Resting metabolic rate increased by 15 9% after 14 days on exogenous growth hormone and was elevated 12‐1% after 3 months treatment but the ratio to fat‐free mass remained unaltered. Total energy expenditure increased by 13 4% after 14 days therapy. Fat‐free mass increased significantly after 3 months treatment by (mean) 4 5 kg with no change in fat mass and no loss in body weight.

CONCLUSIONS Obesity maintenance in growth hormone deficient adults is not a consequence of reduced total energy expenditure or a reduced exercise energy output. There was also no evidence for an energy sparing mechanism. Energy expenditure was increased by exogenous growth hormone but was not associated with a loss in fat mass or body weight suggesting the need for dietetic advice for those already obese at the outset of therapy.
Pituitary stone: two cases of densely calcified thyrotrophin‐secreting pituitary adenomas
Authors: Webster Jonathan , Peters John R. , John Rhys , Smith Jeanne , Chan Vivien , Hall Reg , Scanlon Maurice F.
Published: March 2008

Calcification is a well recognized but relatively uncommon feature of prolactin‐secreting, growth hormone‐secreting and non‐functional pituitary tumours. It varies in extent, but rarely exceeds a tiny amount histologically or radiologicatly. Thyrotroph adenomas are the rarest of the secretory pituitary tumours, accounting for less than 1% of cases, and partial calcification of such lesions has been reported in only three cases. We describe two patients in whom the clinical and biochemical features indicated the presence of a TSH‐secreting adenoma and radiology demonstrated a large ‘pituitary stone’. One patient, a 59‐year‐old female, initially presented with hyperthyroidism, aged 18, and was rendered euthyroid by two subtotal thyroidectomies before a pituitary lesion was suspected, over 20 years later. Autonomous secretion of thyrotropin was demonstrated by dynamic tests, and the failure of exogenous T3 to reduce the serum TSH. In the absence of tumour expansion and compressive symptoms, pituitary surgery was not undertaken. At the age of 56, she developed symptoms of intermittent ataxia and diplopia, culminating in a focal seizure, and was found on CT scan to have, in addition to the pituitary lesion, a parasagittal meningioma. This was successfully removed at craniotomy.

In the second patient, a 42‐year‐old male, the finding of hyperthyroidism in association with an elevated TSH concentration led to the discovery of a pituitary stone which was removed transethmoidally, together with surrounding adenomatous tissue which stained positively for TSH on immunocytochemistry.

We suggest that calcific changes may be at least as common in TSH‐secreting tumours as in other pituitary adenoma subtypes and may occur to the extent of ‘pituitary stone’ formation. The possible association between meningiomas and pituitary adenomas is discussed.
Detection of vasopressin cell antibodies in some patients with autoimmune endocrine diseases without overt diabetes insipidus
Authors: De Bellis A. , Bizzarro A. , Paglionico V. Amoresano , Di Martino S. , Criscuolo T. , Sinisi A. A. , Lombardi G. , Bellastella A.
Published: March 2008

OBJECTIVE Cytoplasmic autoantibodies to vasopressin cells (AVP) have been detected in patients with idiopathic central diabetes insipidus and only in one patient with endocrine autoimmune diseases without clinical diabetes insipidus. The aim of this study was to look for AVP cell antibodies (AVP‐cell‐Ab) in human sera of a large population of autoimmune endocrine disease patients without diabetes insipidus and to test whether an occurrence of these antibodies in some patients can be associated with partial impairment of posterior pituitary function.

MEASUREMENT Sera from 410 patients (310 females, 100 males, age range 10–46 years) with autoimmune endocrine disorders (260 with thyroid autoimmune disease, and 150 with insulin dependent diabetes mellitus) without clinical diabetes insipidus, and from 100 normal subjects, were investigated for hypothalamic autoantibodies by an indirect immunofluorescence method. Positive sera were subsequently tested with specific rabbit anti AVP serum. RESULTS None of controls, but five out of 410 patients (1–2%) were AVP‐cell‐Ab positive. All positive and nine negative from the 410 screened patients were tested for posterior pituitary function. Two out of five AVP‐cell‐Ab positive patients showed partial diabetes Insipidus.

CONCLUSION AVP cell antibodies can be shown in some patients with endocrine autoimmune disease without diabetes insipidus and can sometimes be associated with findings of partial posterior pituitary dysfunction. This suggests that clinical diabetes insipidus could be preceded by a long subclinical period characterized only by the occurrence of AVP‐cell‐Ab in the sera associated or followed by alterations in functional tests. Longitudinal studies are needed to confirm this hypothesis.
Double blind randomized study using oral or injectable bromocriptine in patients with hyperprolactinaemia
Authors: Ciccarelli E. , Grottoli S. , Miola C. , Avataneo T. , Lancranjan I. , Camanni F.
Published: March 2008

OBJECTIVE A new long‐acting injectable form of bromocriptine has become available for long‐term treatment of hyperprolactinaemic patients. The objective of this study was to compare efficacy and tolerability of injectable and oral forms of bromocriptine.

DESIGN A double‐blind randomized study. All patients received either one injection of bromocriptine 50 mg intramuscularly and placebo tablets for 28 days (Group A) or one placebo injection and oral bromocriptine 7 5 mg daily for 28 days (Group B).

PATIENTS Twenty‐three (12 patients for Group A and 11 patients for Group B) hyperprolactinaemia patients with (19 patients) or without (4 patients) CT/MRI evidence of tumour were studied.

MEASUREMENTS Plasma PRL levels and serum bromocriptine levels were assessed during a follow‐up of 42 days. MRI and/or CT were evaluated before and 28 days after the beginning of the study.

RESULTS All patients had significant reductions of PRL levels from 1000 h and 1100 h of day 1 to 2000 h of day 35. Normoprolactinaemia was shown in eight patients of Group A and six of Group B on days 1‐28. Normal PRL levels were still present in five patients of Group A and in one patient of Group B on day 35; only three patients of Group A had normoprolactinaemia on day 42. A significantly greater decrease in Group A in comparison with Group B was shown at 1200 h on day 1 and at all times as a percentage decrease from basal levels. Significantly higher levels of bromocriptine were shown in Group A at all timepoints studied. No difference was shown in tolerability and incidence of side‐effects.

CONCLUSION Our data show that injectable bromocriptine more frequently induced a prolonged normoprolactinaemia than did the oral drug. Moreover, bromocriptine levels released during injectable bromocriptine were significantly higher than during oral bromocriptine. On the other hand no difference was shown in the tolerability of bromocriptine according to the route of administration.
ACTH precursors characterize the ectopic ACTH syndrome
Authors: Stewar P. M. , Gibson S. , Crosby S. R. , Pennt R. , Holder R. , Ferry D. , Thatcher N. , Phillips P. , London D. R. , White A.
Published: March 2008

OBJECTIVE ACTH is secreted by the pituitary following processing of larger molecular weight precursors, proopiomelanocortin and pro‐ACTH. Ectopic ACTH syndrome refers to the secretion of ACTH by non‐pituitary tumours, but the predominant circulating form of proopiomelano‐cortin‐related peptides remains unclear.

PATIENTS Fifteen patients with ectopic ACTH syndrome were compared to 20 patients with pituitary‐dependent Cushing's syndrome, 22 patients with small cell lung carcinoma but no evidence of Cushing's syndrome, and 25 controls.

DESIGN AND MEASUREMENTS Measurement of plasma ACTH and ACTH precursors using specific monoclonal‐based immunoradiometric assays at 0900 h and, in five patients with ectopic ACTH syndrome, at 15‐minute intervals for 6‐24 hours.

RESULTS ACTH precursors were grossly elevated in patients with ectopic ACTH syndrome (median 2194, range 139‐18000 pmoI/I) compared to patients with Cushing's disease (median 33, 8‐73 pmoI/I, P<0 001), patients with small cell lung carcinomas (38, 8‐117 pmoI/I, P<0 001) and controls (26, 10‐39 pmoI/I, P<0 001). ACTH levels were also elevated in ectopic ACTH syndrome (0900 h median 34, 11‐152 pmol/l) compared to patients with Cushing's disease (0900 h median 8, 3‐19 pmol/l), but not to the same degree as ACTH precursors. In contrast with Cushing's disease, ACTH was secreted in a non‐pulsatile fashion. ACTH precursors but not ACTH itself correlated wtih plasma Cortisol in patients with ectopic ACTH syndrome (r= 0‐65, P<005). Chromatographic analysis of plasma from a patient with ectopic ACTH syndrome confirmed ACTH precursors and not ACTH to be the predominant circulating form. With the cross‐reactivity of proopiomelanocortin and pro‐ACTH in the ACTH IRMA of <1 and <10% respectively, ACTH precursors could represent all the ACTH immunoreactivity in patients with ectopic ACTH syndrome.

CONCLUSIONS Ectopic ‘ACTH’ is characterized by aberrant processing of proopiomelanocortin and should be more accurately referred to as ‘ectopic ACTH precursor syndrome’.