bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of insulin‐like growth factor‐I on growth hormone and prolactin secretion and cell proliferation of human somatotrophinomas and prolactinomas in vitro
Authors: Atkin S. L. , Landolt A. M. , Fay P. , Jeffreys R. V. , Hipkin L. , White M. C.
Published: March 2008

OBJECTIVE IGF‐I inhibits GH secretion from normal and some tumorous pituitary tissue, and has been shown to be mitogenic for gonadotrophinoma cells in vitro. It is not known whether IGF‐l affects somatotrophinoma cellular proliferation or the secretion of other hormones, such as PRL and α‐subunit, which are often co‐secreted by these tumours. We have therefore examined the effects of IGF‐l on proliferation and hormonal secretion of human somatotrophinomas and prolactinomas in vitro.

DESIGN Pituitary adenoma tissue was dispersed to single cells in monolayer culture. The effects of 100 nw IGF‐I on GH, PRL and α‐subunit secretion were determined over 4‐hour and over 4‐day periods, and a 4‐day dose‐response study using 1–100 nM IGF‐I was performed on two tumours. Adenoma cell S‐phase proliferation was determined after bromodeoxyuridine Incorporation for 1 hour after 4 days, using a double immunostaining method.

RESULTS Over 4 hours, 100 nw IGF‐I had no effect on GH, PRL or α‐subunit secretion in 7 tumours. Over 4 days, 100 nw IGF‐I reduced GH secretion In 518 somatotrophinomas (range 17–84%, P < 0·05) compared to controls, with tumours responding to IGF‐I having lower basal serum and in‐vitro GH levels than tumours unaffected by IGF‐I (P < 0·05). There was no effect on α‐subunit secretion in any of the three tumours studied. PRL co‐secretion was increased In 315 somatotrophinomas compared to control (20, 30 and 37%, P < 0·05), with tumours responding to IGF‐I being associated with lower basal serum and in‐vitro PRL levels than those tumours unaffected by IGF‐I. IGF‐I also increased PRL secretion in 2/2 prolactinomas (27 and 32%, P < 0·05) compared with control. GH was inhibited and PRL secretion was stimulated by 1 and 10 nw IGF‐I in the two dose‐response studies. The proliferative labelling index did not exceed 1·9% in any tumour and no proliferative effect was found with 100 nw IGF‐I in any somatotrophinoma.

CONCLUSION IGF‐I inhibited tumorous GH in 62% and stimulated PRL secretion in 71 % of tumours over 4 days, without affecting α‐subunit secretion or being mitogenic for somatotrophinoma cells in vitro. No hormonal effects were observed over short (4‐hour) incubations. IGF‐I may be a newly recognized factor directly stimulating tumorous PRL secretion.
The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism
Authors: Toogood Andrew A. , Beardwell Colin G. , Shalet Stephen M.
Published: March 2008

OBJECTIVE A number of studies of the effect of GH replacement therapy in adult patients with GH deficlency have been published, but the definition of GH deficiency has varied considerably. In order to define severe GH deficiency more critically we have determined GH status in the context of gonadotrophin, ACTH and TSH secretion in adult patients with pituitary disease.

DESIGN Analysis of peak GH response to an insulin tolerance test performed during comprehensive assessment of pituitary function.

PATIENTS One hundred and ninety non‐acromegalic patients (96 male) with pituitary disease whose ages ranged from 16 to 72 (mean 39·4) years.

MEASUREMENTS The patients were divided into four groups according to the number of anterior pituitary hormone deficiencies demonstrated; isolated GH deficiency (GHD0), or GH deficiency plus an additional one, two or three pituitary hormone deficits (GHD1, GHD2, GHD3).

RESULTS The four groups were matched for age and blood glucose nadir during the ITT. The median (interquartile range) GH peaks were GHD0, 10·0 (5·4–16); GHD1, 4·0 (2·7–7·7); GHD2, 2·0 (1–2·9); GHDB, 1·8 (1–3·2) mU/l. There was a Significant downward trend in the medians (P < 0·0001). The differences between GHD0 and GHD1, and GHD1 and GHD2, were highly significant (P < 0·0001); however, there was no difference between GHD2 and GHD3. Ninety‐one per cent of patients in combined groups GHD2 and GHD3, 55% in GHD1 and 24% in GHD0 had a peak GH < 5 mU/l.

CONCLUSIONS Our study has shown that GH deficiency is variable according to the degree of hypopltuitarism present and that the greater the number of pituituary hormone deficits the more severe the GH deficiency. These observations will help to clarify the diagnosis of GH deficiency In adult life.
Acute changes in thyroid volume and function following 131I therapy of multinodular goitre
Authors: Nygaard Birte , Faber Jens , Hegedüs Laszlo
Published: March 2008

OBJECTIVE Many textbooks claim that radioIodine (131I) treatment should be given with care to a goitre with substernal extension, for fear of acute swelling of the gland and thus respiratory problems. Since 131I Is used increasingly in the treatment of non‐toxic as well as toxic goitre we have evaluated the acute changes in thyroid volume following 131I therapy.

DESIGN Evaluation of potential acute changes in thyroid volume and function after 131I treatment in patients with non‐toxic goitre treated because of compression symptoms or for cosmetic reasons, as well as In patients with toxic goitre.

PATIENTS Out‐patients with multinodular goitre, either non‐toxic (n= 20) or toxic (n= 10). Excluded were patients with a substernal goitre.

MEASUREMENTS Ultrasonically determined thyroid volume and standard thyroid function variables were Investigated before and 2, 7, 14, 21, 28 and 35 days after treatment.

RESULTS In non‐toxic goitres the thyroid volume did not increase significantly, the maximum increase in the median volume being 4% on day 7. Serum levels of free T3 and free T4 Indices increased by 20% (day 7) and 13% (day 14) (P= 0·002), respectively.

Likewise thyroid volume in toxic nodular goitre did not change significantly after 131I treatment (maximum median increase was 2%). None of the patients presented symptoms of tracheal compression.

CONCLUSIONS 131I treatment of non‐toxic as well as toxic multinodular goitre does not seem to increase thyroid volume.
Variability of serum thyroglobulin levels is determined by a major gene
Authors: Premawardhana L. D. K. E. , Lo S. S. S. , Phillips D. I. W. , Prentice L. M. , Smith B. Rees
Published: March 2008

OBJECTIVE There are large variations in the circulating concentrations of thyroglobulin. The purpose of this study was to explore the possibility of a genetic basis for the variability of serum concentration of thyroglobulin (Tg) in euthyroid individuals.

DESIGN The serum concentration of thyroglobulin (Tg) varies several‐fold in euthyroid individuals. Other circulating proteins also show wide normal ranges of concentration and these variations have been shown to have a genetic as well as an environmental basis. To explore the possibility of a genetic bash for variability in serum Tg levels, an analysis was made of serum Tg levels in 44 pairs of identical twins and 66 nuclear families who were euthyroid and thyroid autoantibody negative (thereby eliminating subclinical autoimmune thyroid disease and Tg autoantibody Interference with the Tg assay).

RESULTS Each pair of identical twins tended to have a similar Tg level and the overall correlation was highly significant (r= 0·734, P < 0·001). There was no relation between Tg and TSH levels In the twins (r= 0·119; P= 0·366). Segregation analysis of the 66 families showed that where both parents had Tg levels above the overall median for the subjects (males, 19 μg/l; females, 33 μg/l), 73% of the offspring also had concentrations above these levels, compared with 30% of the offspring when one parent had a high Tg level and only 16% in families where neither parent had a high Tg level.

CONCLUSIONS Complex segregation analysis using the computer program Pointer suggested that variability in Tg levels was the result of a major dominant‐like gene effect (accounting for 80% of the variability) combined with a multifactorial component. Thyroglobulin, a template for thyroid hormone production, is also a major thyroid autoantigen and inherited variations in serum Tg levels may have implications for the pathogenesis of auto‐Immune thyroid disease.
Bone mineral density and metabolism in premenopausal women taking l‐thyroxine replacement therapy
Authors: Garton Mark , Reid Ivan , Loveridge Nigel , Robins Simon , Murchison Lilian , Beckett Geoffrey , Reid David
Published: March 2008

BACKGROUND AND OBJECTIVE Excess endogenous thyroxine causes bone loss, but the effects of exogenous thyroxine are disputed. We report on bone mass and metabolism in women taking l‐thyroxine therapy.

DESIGN Cross‐sectional and longitudinal studies.

PATIENTS Cross‐sectional study: 40 healthy premenopausal women with autoimmune thyroiditis taking either physiological (serum TSH usually normal, 0·35–3·3 mU/l) or suppressive (serum TSH usually < 0·35 mu/l) doses of l‐thyroxine; patients were also compared with previously acquired age and weight matched premenopausal volunteers with no history of thyroid dysfunction. Longitudinal study: 28 patients were followed‐up ≥ 1 year later.

MEASUREMENTS In all subjects bone mineral density (BMD) was measured at the anteroposterior lumbar spine and left hip (femoral neck, greater trochanter and Ward's area) using dual‐energy X‐ray absorptiometry, and physical activity assessed using the Framingham physical activity index. Serum osteocalcin (OC), PTH and vitamin D, and urinary pyridinoline and deoxypyridinoline excretion were measured in patients.

RESULTS Cross‐sectional study: The patient groups were well matched for disease duration and physical activity although the suppressed group were slightly younger (mean 3·1 (SD 7·5) vs 43·3 (3·9) years, P < 0·05). BMD, serum OC, PTH and vitamin D, and urinary cross‐link excretion did not differ significantly between the two groups. Multivariate analysis of the whole group suggested that BMD at the femoral neck and greater trochanter was related positively to weight and physical activity and negatively to thyroxine dose (μg/kg/day) and patient age. At the lumbar spine BMD was reduced non‐specifically in the presence of thyroid disease and treatment, but this effect appeared to decline with increasing duration of therapy. A similar analysis of the patient group suggested that urinary cross‐link excretion correlated positively with thyroxine dose, and negatively with duration of treatment. Longitudinal study: Annualized changes in BMD were inversely related to thyroxine dose (μg/kg/day) at all sites but achieved statistical significance only at the femoral neck and Ward's area.

CONCLUSION We did not find any effect of persistent historical TSH suppression on current bone mass, and this might relate to the relative insensitivity of older TSH assays. However, the cross‐sectional and longitudinal data suggest that high daily doses of thyroxine In relation to patient body weight might adversely affect bone mass, particularly at the hip. These findings support the contention that excess exogenous thyroxine might predominantly deplete skeletal sites, such as the femoral neck, rich in cortical bone.
Amplification of nocturnal melatonin secretion in women with functional secondary amenorrhoea: relation to endogenous oestrogen concentration
Authors: Okatani Yujl , Sagara Yusuke
Published: March 2008

BACKGROUND AND OBJECTIVE Although there is extensive evidence that melatonin inhibits gonadotrophin secretion in animals, there is a parity of data on the relation between melatonin and ovarian function in humans. The purpose of this study was to evaluate the relation between endogenous oestrogen concentrations and nocturnal melatonin secretion occurring in patients with secondary amenorrhoea (SA).

DESIGN AND PATIENTS Nocturnal serum melatonin concentrations were determined in 20 women with SA, 5 women with endometriosis showing normal menstrual cycles and 11 volunteers with normal menstrual cycles.

MEASUREMENT Serum melatonin concentrations were determined by high performance liquid chromatography with electrochemical detection. Differences in melatonin concentrations were examined by analysis of variance.

RESULTS Nocturnal melatonin concentrations in patients with SA were significantly higher than in normal women (P < 0·01 vs women with normal menstrual cycles). There were significant negative correlations between cummulative melatonin levels (between 2000 and 0800 h) and serum 17β‐oestradiol (r= ‐0·561, p < 0·01) and between peak serum melatonin values and the serum 17β‐oestradiol (r= ‐0·608, P < 0·01) in SA. Intravenous administration of a conjugated oestrogen (Premarin 20 mg) significantly suppressed nocturnal melatonin secretion (P < 0·05). A low oestrogen state, induced by long‐term (3·5 months) GnRH agonist treatment (900 μg/day of buserelin acetate) of the women with endometriosis produced an increase in nocturnal melatonin secretion comparable to that found in SA women.

CONCLUSION Our findings suggest that elevated nocturnal melatonin secretion in women with secondary amenorrhoea may be related to their low oestrogen concentrations.
Effects of follicular phase exercise on luteinizing hormone pulse characteristics in sedentary eumenorrhoeic women
Authors: Williams Nancy I. , McArthur Janet W. , Turnbull Barry A. , Bullen Beverly A. , Skrinar Gary S. , Beltins Inese Z. , Besser G. Michael , Rees Lesley H. , Gilbert Ian , Cramer Derek , Perry Leslle , Tunstall Pedoe Dan S.
Published: March 2008

OBJECTIVE Current studies reveal little regarding the Inception of exercise‐induced LH changes during physical training. This study aimed to assess the susceptibility of the hypothalamic–pituitary axis to the acute physical stress of exercise in untrained, physically inactive women. The acute effects of submaximal endurance exercise upon the pulsatile LH secretion in the follicular phase were compared with those accompanying leisurely strolling for a similar time period.

SUBJECTS All subjects were eumenorrhoelc, as determined by biphasic temperature patterns, detection of the urinary LH surge, and mid‐luteal serum progesterone levels. Subjects were not physically active and had little history of strenuous exercise (V o2max = 38·0 ± 1·8) (mean ± SEM) ml/kg/min).

DESIGN All women completed a 13·5‐hour pulsatility test which included three consecutive 20‐minute runs on a treadmill at 50, 60 and 70% of the subjects’maximum oxygen uptake (n= 16). Six of these same subjects completed a separate test on another occasion in which one hour of leisurely strolling was substituted for exercise. Blood was sampled every 10 minutes via an indwelling cannula for 4·5 hours before and 8 hours after one hour of exercise and or strolling.

MEASUREMENTS A pulse algorithm (Pulsar) was used to quantify LH pulse characteristics.

RESULTS Exercise produced no significant effects upon LH pulse frequency or mean serum LH concentration. However, exercise of moderate intensity caused a significant increase in LH pulse amplitude (P < 0·05). Strolling produced no significant changes in LH secretion.

CONCLUSION Acute exercise of moderate intensity in the follicular phase of untrained women is an insufficient stimulus to inhibit the GnRH pulse generator in the post‐exercise period, yet may produce a slight stimulatory effect on the amount of LH released per pulse
p53 gene mutations in pituitary adenomas: rare events
Authors: Levy Andrew , Hall Leonard , Yeudall W. Andrew , Lightman Stafford L.
Published: March 2008

OBJECTIVE Occult pituitary adenomas are said to occur in up to 20% of random autopsy examinations, yet the only oncogene known to be associated with pituitary adenomas, gsp, is found in only 40% of somatotrophinomas, a subtype that accounts for a minority of pituitary tumours. Mutations of the p53 tumour suppressor gene are thought to be involved in the pathogenesis of as many as 50% of all human cancers, including tumours of the central nervous system. The objective of this study was to determine whether p53 gene mutations are associated with pituitary adenomas.

DESIGN AND PATIENTS Fragments of pituitary adenoma tissue from 29 patients undergoing routine hypophysectomy for pituitary tumour were coated in cryostat embedding medium and frozen at ‐80°C within 24 hours of resection. They consisted of 9 somatotroph, 4 corticotroph, 1 mammotroph and 15 endocrinologically inactive adenomas, all of the non‐invasive clinical phenotype. Sequential frozen sections were subjected to in situ hybridization analysis for anterior pituitary hormone transcripts and examined histologically to ensure that the frozen sections Used to generate DNA templates for polymerase chain reaction amplification were not contaminated with non‐tumour tissue.

MEASUREMENTS p53 exons 7 and 8, within which 98% of substitution mutations are thought to occur, and exons 4–6 in tumours immunopositive for p53, were amplified by polymerase chain reaction and ligated Into the vector pCR2. DNA from small‐wale plasmid preparations of pCR2 containing cloned p53 exons from human pituitary adenomas was sequenced using an automated fluorescence‐based system (DuPont Genesis 2000) and compared with wild‐type sequence. Apparent mutations were confirmed or refuted by sequencing a further 2–4 clones isolated from the same template.

RESULTS Although immunocytochemical staining patterns for wild‐type p53 varied markedly between different tumours, no mutations were identified in any of the exonic sequences examined.

CONCLUSIONS p53 mutations, at least within the high mutation domains of p53, occur infrequently in human pituitary adenomas. Increased steady‐state levels of p53 protein identified immunocytochemically may be a consequence of binding to other cellular proteins in these tumours.
Quinagolide efficacy and tolerability in hyperprolactinaemic patients who are resistant to or intolerant of bromocriptine
Authors: Vilar L. , Burke C. W.
Published: March 2008

OBJECTIVE To audit the efficacy of quinagoiide (CV205‐502, Norprolac, Sandoz) in lowering prolactin, and its tolerability, in patients with bromocriptine resistance (BCR) or bromocriptine intolerance (BCI), in view of the paucity of results published in patients specifically with BCR or BCI, by collating results in our own patients with the reports in the literature.

DESIGN Open prospective, uncontrolled administration of quinagolide in patients with BCR (defined for this report as failure to attain normal prolactin levels after 4 months of bromocriptine at maximum tolerated doses), or BCI (defined as a patient request to cease bromocriptine treatment because of side‐effects at doses that were required, or failed, to normalize PRL levels).

MEASUREMENTS Prolactin levels, menses or pregnancy, and side‐effects.

PATIENTS Six with BCR, and six with BCI (microprolactinoma in 7, macroprolactinoma in 5), treated with quinagolide 75 μg nightly increasing incrementally to a maximum of 450 μg. One patient who had taken part in a multicentre study of quinagolide in macroprolactinomas had BCI, and 11 further patients in the endocrine clinic who had BCR or BCI were offered quinagolide therapy under named‐patient compassionate arrangements.

RESULTS Normal prolactin in 4/5 with BCR (3/6 with side‐effects, none of them quinagolide intolerant), and normal prolactin in 2/6 with BCI (4/6 with side‐effects, two of them quinagolide intolerant).

CONCLUSIONS Results in our 12 patients are broadly in line with those in 51 patients with bromocriptine resistance and 39 with bromocriptine intolerance extracted from various published reports, which together suggest that prolactin can be normalized in 16% of patients with bromocriptine resistance by quinagolide in doses of 225 μg or less, and in a further 20% by higher doses up to 600 μg. in bromocriptine intolerance, prolactin was normalized by quinagolide in doses of 225 μg or less In 58% of published cases and in 3 more patients by higher doses up to 1050 μg. About half the patients with bromocriptine resistance or bromocriptine intolerance who are treated with quinagolide experience side‐effects, and around 7% are quinagolide Intolerant. Doses need not exceed 225 μg, until failure to respond at this dose level is demonstrated.
Adrenocorticotrophin‐independent unilateral macronodular adrenal hyperplasia occurring with myelolipoma: an unusual cause of Cushing's syndrome
Authors: Jenkins P. J. , Chew S. L. , Lowe D. G. , Reznek R. H. , Wass J. A. H.
Published: March 2008

We report a case of Cushing's syndrome due to ACTH‐independent unilateral macronodular adrenal hyperplasia that occurred with a myelolipoma and propose that these two entitles may be linked to the production of an adrenal growth factor.
Primary hyperparathyroidism masked by antituberculous therapy‐induced vitamin D deficiency
Authors: Kovacs Christopher S. , Jones Gienviiie , Yendt Edmund R.
Published: March 2008

Antituberculous chemotherapy agents, particularly rif‐ampicin and isoniazid, affect vitamin D metabolism and can create biochemical evidence of vitamin D deficiency. Vitamin D deficiency induces a state of resistance to parathyroid‐ hormone. This study sought to explain the temporary resolution of hypercalcaemia and hyper‐calciuria, during antituberculous chemotherapy with rifampicin and isonizid, in a subject with a surgically proven parathyroid adenoma and coincidental spinal tuberculosis. Serum ionized calcium, 25‐hydroxyvitamin D and 1,25‐dihydroxyvitamin D, plasma Parathyroid hormone, and 24‐hour urine excretions of calcium, inorganic phosphorus and hydroxyproline were sequentially measured over a 3‐year interval that included 18 months of antituberculous chemotherapy. Initial serum Ionized calcium was 152mmol/l (normal 1·20‐1·35 mmol/l), 24‐hour urine calcium excretion was 9·40 mmol/day (normal 1·25 to 7·50 mmol/day) and plasma intact PTH was 9·2pmol/l (normal 0·0–4·5 pmol/l). During antitubercuious chemotherapy the serum ionized calcium and 24 hour urine calcium excretion were normal but the plasma PTH rose to higher levels. Following completion of the chemotherapy, hypercalcaemia and hypercalciuria returned with levels similar to those observed pretreatment. Serum 25‐hydroxyvltamin D was low at 8·25 nmol/l (normal 20 to 90 nmol/l) during antituberculous chemotherapy, but was normal before and after. Serum 1,25‐dihydroxyvltamin D was normal throughout the 3‐year Interval. We conclude that the antituberculous chemotherapy induced relative vitamin D deficiency and resistance to parathyroid hormone action, thereby masking the hyperparathyroidism and hypercalcaemia until the chemotherapy was completed.
The effect of pharmacological dosages of glucocorticoids on free living total energy expenditure in man
Authors: Chong P. K. K. , Jung R. T. , Scrimgeour C. M. , Rennie M. J.
Published: March 2008

OBJECTIVES Weight gain had previously been thought to be due to increased calorie intake alone though no information on its effect on total energy expenditure is available in humans. We therefore assessed whether weight gain associated with glucocorticoids is due to a reduction in energy expenditure.

DESIGN We performed an open study with 1 mg of betamethasone given orally twice a day for 21 days.

SUBJECTS Seven healthy female volunteers, age range 26–55 years, body mass index 19 to 40, mean 27 kg/m2.

MEASUREMENTS Total free living energy expenditure was measured by the doubly labelled water method (D218O), resting metabolic rate by ventilated hood indirect calorimetry and fat free mass from the dilution volume of oxygen‐18 labelled water. Body composition and components of energy expenditure were assessed before and during the final 14 days of betamethasone administration.

RESULTS Weight increased by a mean of 1·2 kg (P < 0·05) because of a significant rise in fat mass (1·5 kg) with no change in fat free mass. Resting metabolic rate remained unaltered on betamethasone but total energy expenditure increased in all subjects with a significant mean rise of 26% from 11·7 to 14·7 MJ/24 h (P < 0·05). The energy component of physical activity with thermogenesis increased on average 52% (from 5·8 to 8·9 MJ/24 h; P < 0·05). The rise in energy expenditure was still apparent after correction for the increase in body weight. Fasting respiratory quotient (RQ) increased from 0·81 to 0·86 with no change in fasting blood glucose. Betamethasone did not result in an energy sparing effect on the two components of energy expenditure studied.

CONCLUSIONS Body weight increased on betamethasone entirely due to an increase in fat mass. This occurred despite a rise in total energy expenditure which involved specifically that component accounted for by physical activity plus thermogenesis. The most likely explanation is that betamethasone increased dietary energy intake significantly in excess of expenditure. We estimate that an average extra energy intake of 2·8 MJ/day would have had to be consumed for this rise in fat mass to occur even before taking into account the energy intake cost of the rise in expenditure.
The overnight single‐dose metyrapone test is a simple and reliable index of the hypothalamic‐pituitary‐adrenal axis
Authors: Fiad Tarek M. , Kirby John M. , Cunningham Sean K. , McKenna T. Joseph
Published: March 2008

OBJECTIVES The ACTH stimulation test examines adrenal responsiveness but may not examine the entire hypothalamic‐pituitary‐adrenal (HPA) axis and requires parenteral administration. The cortisol response to hypoglycaemia provides an index of activity of the entire HPA axis but is demanding for patients and medical staff. The aim of the present study was to examine the performance of the overnight single‐dose metyrapone test as it provides a simple alternative test for HPA axis function.

DESIGN Audit of the overnight metyrapone test performed in one centre between 1979 and 1991.

PATIENTS Three hundred and ninety‐eight patients underwent 576 tests. Comparisons between the responses to metyrapone and the ACTH stimulation test and of the responses to metyrapone and insulin induced hypoglycaemia test were possible in 87 and 17 patients respectively.

MEASUREMENTS Following the midnight administration of metyrapone tablets, 30 mg/kg orally, blood samples were obtained between 0800 and 0930 h for radioimmunoassay of both 11‐deoxycortisol and cortisol.

RESULTS Five hundred and seventy‐six metyrapone tests were performed on 398 patients with no serious side‐effects encountered. Andrenal insufficiency was diagnosed in 105 patients. Of these, 18 had a primary adrenal disorder and 87 had a disorder of the hypothalamic‐pituitary unit. One hundred per cent concordance between the metyrapone, the ACTH and the hypoglycaemia test was seen in patients with primary adrenal insufficiency. In 19 patients with secondary adrenal insufficiency, who underwent both the metyrapone and the ACTH tests, discord between these two tests was observed in 10 patients (53%). Nine of these patients demonstrated a normal response to ACTH and a subnormal response to metyrapone. In only one patient was an abnormal cortisol response to ACTH associated with a normal response to metyrapone. In contrast, in 17 patients discord between the metyrapone and the hypoglycaemia test was seen in only 1 patient who demonstrated a normal response to the metyrapone test and a subnormal response to hypoglycaemia.

CONCLUSION Since the metyrapone test gives similar information about hypothalamic‐pituitary axis function as does the hypoglycaemia test, we recommend the use of the overnight metyrapone test as a safe, simple and reliable index of the hypothalamic‐pituitary axis integrity. The ACTH stimulation test should not be used for patients suspected of having secondary adrenal insufficiency.
Menstrual disturbances in thyrotoxicosis *
Authors: Krassas G. E. , Pontikides N. , Kaltsas Th. , Papadopoulou Ph. , Batrinos M.
Published: March 2008

OBJECTIVES In thyroid textbooks it is stated that hyperthyroidism in women may be associated in almost 50% of the cases with hypomenorrhoea, oligomenorrhoea or amenorrhoea and perhaps with reduced fertility. Our experience at a busy thyroid clinic has given a picture which differs from that described in the literature. Most of our female thyrotoxic patients had normal menstruation. This study was performed to define the menstrual abnormalities in hyperthyroidism.

DESIGN AND PATIENTS We investigated the menstrual history, starting 6 months before the discovery of the disease, the smoking habits and the body mass index (BMI), in 214 female, premenopausal thyrotoxic patients and a similar number of normal controls matched for age and weight.

MEASUREMENTS TT4 and TT3 were measured by radioimmunoassay, while BMI was calculated from the ratio of body weight in kg to height in m2.

RESULTS Of the 214 patients, 168 (78·5%) had regular menstrual cycles and 46 (21·5%) irregular cycles. No difference in BMI was found between the patients with or without menstrual abnormalities. Out of the 46 patients with irregular periods, 23 (50%) were smokers, while only 32 out of the 168 patients (19%) with normal periods were smokers (P < 0·001). TT4 levels were higher as a group in patients with menstrual disturbances (mean±SD 267·7 ± 66·9 nmol/1) than in those with normal periods (240·6 ± 47·6 nmol/1) (P < 0·05). The 23 smokers with irregular periods had higher TT4 levels (280·5 ± 51·8 nmol/1) than the remaining non‐smokers from the same group (241·9 ± 43·7 nmol/1) (P < 0·01). No such differences were found for TT3 levels. Out of 214 normal controls, matched for age and weight, 196 (91·6%) had normal menstruation and 18 (8·4%) irregular cycles. The latter group included mainly women with oligomenorrhoea. Out of 18 normal controls with irregular periods, 6 (33·3%) were smokers, while 57 (29·1%) out of 196 with normal periods were smokers.

CONCLUSIONS These data demonstrate that hyperthyroidism in women is less frequently associated with menstrual abnormalities than was previously believed. Furthermore, no patient presented with amenorrhoea. Smoking and TT4 levels are strongly associated with the occurrence of menstrual disturbances in thyrotoxicosis.
Biochemical markers of bone turnover in girls during puberty
Authors: Blumsohn A. , Hannon R. A. , Wrate R. , Barton J. , AI‐Dehaimi A. W. , Colwell A. , Eastell R.
Published: March 2008

OBJECTIVES Bone turnover and the rate of bone growth increase dramatically during puberty. A number of new assays for the estimation of bone resorption and formation rates have been developed over recent years, and puberty acts as a convenient model for evaluation of these measurements. The aim of this study was to explore the interrelationships between pubertal development, biochemical markers of bone turnover, Insulin‐like growth factor I and oestradiol in healthy pubertal girls.

SUBJECTS Ninety‐one healthy girls (ages 11·6–15·5 years) were studied. All subjects were apparently healthy, and were not taking medications known to influence calcium homeostasls. Breast examination was performed to assess pubertal stage according to Tanner. The adult reference range for biochemical markers of bone turnover was obtained from concurrent studies on 42 healthy premenopausal women ranging in age between 20 and 45 years.

DESIGN AND MEASUREMENTS Blood samples were obtained from subjects between 0800 and 1000 h. Urine samples were collected between 1330 and 1600 h. We measured total and bone specific alkaline phosphatase, osteocalcin, and type I procollagen carboxyterminal pro‐peptide as markers of bone formation. Tartrate resistant acid phosphatase, carboxyterminal pyridinoline cross‐linked telopeptide, creatinine corrected urinary deoxypyr‐Idlnoline, immunoreactive urinary pyrldinolines, and urinary galactosyl hydroxylysine were measured as markers of bone resorption.

RESULTS Bone turnover as reflected by each of the markers was maximal in mid puberty (breast Tanner stages II and III) and decreased towards adult levels in late puberty (P< 0·001). However, the magnitude of the mid‐pubertal increase differed between markers. In particular, the pubertal increase In levels of bone specific alkaline phosphatase, osteocalcin and urinary deoxypyridinoline were higher than the Increase shown by the other markers. All markers were significantly lower after the menarche. Circulating insulin‐like growth factor I and Insulin like growth factor binding protein‐3 were not important determinants of pubertal changes In bone turnover. In contrast, there was a significant negative correlation between oestradiol and all markers of bone formation and resorption during puberty.

CONCLUSIONS The greater pubertal increase in levels of bone specific alkaline phosphatase, osteocalcin and urinary deoxypyridinoline suggests that these markers may be relatively more sensitive as indicators of skeletal health during puberty. The differences between markers may reflect differences in the bone specificity of the analytes, or differing mechanisms of production and clearance. The negative correlation between oestradiol and markers of bone resorption and formation suggests that this hormone may be responsible for the reduction in bone turnover in late puberty.
Continuous combined oestrogen/progestin therapy is well tolerated and increases bone density at the hip and spine in post‐menopausal osteoporosis
Authors: Grey Andrew B. , Cundy Tim F. , Reid Ian R.
Published: March 2008

OBJECTIVES Although oestrogen/progestin therapy is effective prophylaxis against post‐menopausal osteoporosis, its efficacy in the treatment of established disease is uncertain. In addition, cyclical oestrogen/progestin regimens are associated with low rates of patient acceptance. The present study assesses the acceptability of, and skeletal response to, continuous combined hormone replacement therapy in osteoporotic late post‐menopausal women.

DESIGN Retrospective, controlled study.

PATIENTS One hundred and four osteoporotic late postmenopausal women treated with continuous combined hormone replacement therapy (5 mg medroxyprogester‐one acetate daily and either 0·625 mg oral conjugated oestrogens or 50 μg transdermal oestradiol daily) were followed for an average of 1 year (range 2–38 months). Control subjects were 19 healthy normal women matched for menopausal age and weight.

MEASUREMENTS Adverse effects and compliance rate were monitored. Baseline and 1‐year measurements of lumbar spine bone mineral density (BMD) were performed using dual‐energy X‐ray absorptiometry in 51 women, 22 of whom also had measurements at 2 years. Twenty‐eight women had proximal femur scans at baseline and 1 year.

RESULTS Eighty‐six per cent of women continued to take continuous combined hormone replacement therapy at the end of follow‐up. Mastalgia (44%) and vaginal bleeding (29%), the most common side‐effects, were minor and self‐limiting in virtually all women. Spinal BMD increased by 7·1 ± 0·8% (mean±SEM P < 0·001) at 1 year and by 8·9 ± 1·5% (P < 0·001) at 2 years. In the proximal femur, BMD increased by 2·9 ± 0·9% at the femoral neck (P= 0·01) and by 2·5±0·9% (P= 0·001) at the trochanter at 1 year. BMD tended to decline in the control group. Among the women taking hormone replacement therapy, the increase in spinal BMD was similar in those treated with 0·3–0·44 mg/day of conjugated equine oestrogens to those receiving 0·45–0·625 mg/day.

CONCLUSION Continuous combined hormone replacement therapy is an acceptable therapy to osteoporotic late post‐menopausal women and produces substantial increases in lumbar spine and proximal femoral bone mineral density.
Expression and processing of parathyroid hormone‐related protein in a pancreatic endocrine cell tumour associated with hypercalcaemia
Authors: Ratcliffe W. A. , Bowden S. J. , Dunnet F. P. , Hughes S. , Emly J. F. , Baker J. T. , Pye J. K. , Williams C. P.
Published: March 2008

We describe a patient with a neuroendocrine tumour of the pancreas associated with hypercalcaemia which was attributed to production of parathyroid hormone‐related protein (PTHrP) by the tumour. Plasma PTHrP 1–86 was significantly raised, and fell following surgical resection of the tumour. PTHrP mRNA and peptide were identified in tumour tissue by in‐situ hybridization and immunohisto‐chemistry respectively. PTHrP was quantitated in an extract of tumour tissue by three region‐specific immunoassays (PTHrP 1–34 45.2 pmol/g, PTHrP 37–67 81.7 pmol/g, PTHrP 1–86 27.3 pmol/g) and suggested the presence of excess of amino‐terminal and mid‐region immunoreactivity. On chromatography of the tumour extract the first peak eluted as 22 kDa and comprised approximately equimolar 1–34, 37–67 and 1–86 activities. The second and major peak of 16 kDa contained only 37–67 activity, while the third peak of 6 kDa contained only 1–34 activity. This suggested that the tumour contained a native or intact form of PTHrP together with two major subfragments containing 37–67 and 1–34 activity respectively. Thus chromatographic separation and quantitation of PTHrP by region‐specific immunoassays have provided new information on in‐vivo proteolytic processing by tumour tissue by indicating that a site of cleavage is located between residues 17 and 61. Our findings are compatible with cleavage at residue 37, a site previously indicated from in‐vitro studies.
Prediction of post‐partum Graves' thyrotoxicosis by measurement of thyroid stimulating antibody in early pregnancy
Authors: Hidaka Yoh , Tamaki Haruo , Iwatani Yoshinorl , Tada Hisato , Mitsuda Nobuaki , Amino Nobuyuki
Published: March 2008

OBJECTIVE Autoimmune thyroid diseases often occur after delivery. However, it has been difficult to predict who will develop Graves' thyrotoxicosis after delivery. We tried to establish a systematic method for predicting postpartum onset of Graves' thyrotoxicosis. DESIGN We followed up the pregnant women with antithyroid microsomal antibody (MCAb) from early pregnancy to the post‐partum period and analysed the relation between the activities of thyroid stimulating antibodies (TSAb) in early pregnancy and post‐partum occurrence of Graves' disease.

PATIENTS Seventy‐one women with positive MCAb in early pregnancy were studied. They were randomly selected from 262 MCAb‐positive subjects found in 3405 consecutive early pregnant women who attended our maternity clinic during the last ten years.

MEASUREMENTS MCAb was measured with a commercially available agglutination kit. For 71 MCAb‐positive subjects, TSH‐binding inhibitory immunoglobulin (TBII) and TSAb were measured in early pregnancy, and serially until 6 months after delivery for the subjects with either positive TBII or TSAb. Thyroid function and goitre size were recorded at every observation.

RESULTS Among the 71 subjects, 7 showed positive TSAb in early pregnancy without any thyroid dysfunction; all 7 developed thyroid dysfunction in the post‐partum period. Five of them (70% of TSAb‐positive subjects) developed Graves' disease, two showing persistence and three transiently. None of 64 TSAb‐negative subjects developed Graves' thyrotoxicosis, though 44 developed various types of thyroid dysfunction as a result of postpartum autoimmune thyroiditis.

CONCLUSION The Individuals at high risk of post‐partum onset of Graves' thyrotoxicosis can be found early in their pregnancy by the detection of TSAb. Overall occurrence of post‐partum Graves' disease in the general population is estimated above 0–54%, that is, one in 200 post‐partum women may develop Graves' thyrotoxicosis, although thyrotoxicosis may be transient in half of the patients.
Effect of FK‐506 on xenografted human Graves' thyroid tissue in severe combined immunodeficient mice
Authors: Yoshikawa Norio , Arreaza Guillermo , Mukuta Toshio , Resetkova Erika , Miller Naomi , Jamieson Christopher , Nishikawa Mitsushige , Lnada Mitsuo , Volpé Robert
Published: March 2008

OBJECTIVE We studied the macrolide antibiotic FK‐506, an immunosuppressive agent, in an attempt to ameliorate the lesion of autoimmune thyroid disease in human thyroid tissue xenografted into severe combined immunodeficient (SCID) mice. It was not felt appropriate to employ this agent directly in patients with autoimmune thyroid disease because adequate therapeutic modalities are available and the introduction of new, experimental agents could not be justified. Moreover, the study of the tissue before and after treatment could not have been undertaken directly in patients.

DESIGN Human thyroid xenografts from four patients with Graves' disease and two normal persons were xenografted into SCID mice. Two weeks after xenograft‐ing, human immunoglobulin G (IgG) was detectable in all SCID mice xenografted with Graves' thyroid tissue. Mice were divided into two groups with human IgG levels similar to each other. Mice in the first group were treated with FK‐506 daily for 6 weeks; mice in the second (similar) group were given phosphate‐buffered saline (PBS) only (control group).

MEASUREMENTS Blood samples were taken every 2 weeks from the tail veins for human IgG, thyroid stimulating antibody, thyroperoxidase antibodies, thyroglobulin antibodies, and interferon‐gamma (IFN‐7). After 8 weeks treatment, animals were sacrificed; thyroid tissue was examined histologically and for thyrocyte HLA‐DR expression. FK‐506 was also added to thyrocytes in in‐vitro tissue culture conditions. RESULTS After 4–6 weeks of FK‐506 therapy, human IgG, all thyroid antibodies and IFN‐7 were suppressed, while the levels remained elevated in the control group. Lymphocytic infiltration virtually disappeared in the human thyroid tissue of the FK‐506‐treated mice and thyrocyte HLA‐DR expression markedly declined; in the control mice, lymphocytic infiltration remained heavy and HLA‐DR expression remained high. On the other hand, FK‐506 added directly to thyrocytes in vitro (without lymphocytes) did not reduce thyrocyte HLA‐DR expression.

CONCLUSIONS FK‐506 appears to suppress the activation of intrathyroidal lymphocytes, but not thyrocytes. From these observations, it is concluded that this agent, by its action on intrathyroidal lymphocytes, is able to ameliorate the immunologically mediated histological and serological disturbance in human autoimmune thyroid disease, at least under these circumstances.
Renal leak of calcium in post‐menopausal osteoporosis
Authors: Nordin B. E. Christopher , Horowitz Michael , Need Allan , Morris Howard A.
Published: March 2008

BACKGROUND Urine calcium after an overnight fast is higher in osteoporotic than in normal post‐menopausal women. The question is whether this is the cause or effect of the bone‐losing state.

OBJECTIVE To establish whether the elevated obligatory calcium loss In osteoporotic women is due to a raised filtered load of calcium or to reduced renal tubular reabsorption of calcium.

DESIGN Covariance analysis using total plasma calcium and its fractions as the covariates.

PATIENTS Eighty‐two untreated post‐menopausal women without vertebral compression and 137 untreated postmenopausal with vertebral compression all between the ages of 61 and 75 years.

MEASUREMENTS After an overnight fast, calcium, albumin, globulins, anion gap and bicarbonate were measured in the plasma, and calcium, sodium and creatinine In the urine. The calcium fractions in plasma and the calcium/creatinine and sodium/creatinine ratios in urine were calculated. Bone density was measured in the distal forearm.

RESULTS The ultrafiltrable and Ionized calcium in the plasma and the calcium/creatinine ratio in the urine were significantly higher in the women with vertebral compression than in those without. On covariance analysis, neither total plasma calcium nor any of the plasma calcium fractions made a significant contribution to the difference in fasting urine calcium between normal and osteoporotic women, whether bone status was defined by vertebral compression or by bone density.

CONCLUSIONS The increased obligatory calcium loss in osteoporotic women is not due to an increase in the filtered load of calcium and must therefore reflect reduced renal tubular reabsorption. This implies that the calcium loss in the urine Is not the result of increased bone resorption but is more likely to be causal.
A hormonal and radiological evaluation of adrenal gland in patients with acute or chronic pulmonary tuberculosis
Authors: Keleştimur Fahrettin , Ünlü Yalçin , Özesmi Mustafa , Tolu Ismet
Published: March 2008

OBJECTIVE The adrenal glands may be involved in tuberculosis. The exact frequency and extent of adrenal involvement in tuberculosis are not well known. Although there are some studies regarding adrenal gland involvement, they are not sufficient because of inadequate endocrinological tests and radiological procedures. The aim of this study was to assess the adrenal gland in acute and chronic pulmonary tuberculosis and to compare it with the findings obtained in healthy subjects.

DESIGN AND PATIENTS We studied 20 patients with acute pulmonary tuberculosis, 41 patients with chronic pulmonary tuberculosis and 20 healthy subjects. Involvement of the adrenal gland was assessed by basal Cortisol level, Cortisol response to Synacthen and adrenal computed tomography.

MEASUREMENTS Cortisol levels were measured before, 30 and 60 minutes after Synacthen (250 μg i.v.) injection. Computerized tomography of the adrenals was carried out in 61 patients with tuberculosis and 20 healthy subjects.

RESULTS Mean basal Cortisol level and 60‐minute Cortisol response to Synacthen were significantly higher in acute pulmonary tuberculosis than in chronic pulmonary tuberculosis and healthy subjects. Two patients with Addison's disease were diagnosed among the chronic tuberculous patients. Both length and thickness of the right and left adrenal gland were greater in patients with acute tuberculosis.

CONCLUSION Adrenal enlargement demonstrated by computerized tomography is common in patients with acute pulmonary tuberculosis, but our findings show that Cortisol reserve is normal, in contrast to previous suggestions.