bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose‐dependent suppression of serum prolactin by cabergoline in hyperprolactinaemia: a placebo controlled, double blind, multicentre study
Authors: Webster J. , Piscitelli G. , Polli A. , D'Alberton A. , Falsetti L. , Ferrari C. , Fioretti P. , Giordano G. , L'Hermite M. , Ciccarelli E. , Crosignani P. G. , DeCecco L. , Fadini R. , Faglia G. , Flamigni F. , Tamburrano G. , Scanlon M. F. ,   (European multicentre cabergoline dose‐finding study group)
Published: March 2008

OBJECTIVE Dopamine agonists have a well established place in the treatment of hyperprolactinaemic disorders but their use is associated with a high incidence of adverse effects. We have investigated the biochemical efficacy and side‐effect profile of a range of doses of the novel, long‐acting dopamine agonist, cabergoline, in suppressing prolactin (PRL) in hyperprolactinaemic women.

DESIGN Multicentre, prospective, randomized, placebo controlled and double blind.

PATIENTS One hundred and eighty‐eight women with hyperprolactinaemia secondary to microprolactinoma (n= 113), idiopathic disease (n= 67), empty sella syndrome (n= 7) or following failed surgery for a macroprolactinoma (n= 1).

MEASUREMENTS Weekly assessment of adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function.

RESULTS Patients received either placebo (n= 20) or cabergoline 0.125 (n= 43), 0.5 (n= 42), 0 75 (n= 42) or 10 mg (n= 41) twice weekly for 4 weeks. The five treatment groups were comparable in age (mean 31.8, range 16– 46 years), diagnosis, previous therapy, and pretreatment serum PRL. PRL was suppressed to below half the pretreatment level in 5,60,90,95 and 98% and normalized in 0, 30, 74, 74 and 95% of patients taking placebo or cabergoline 0.125, 0.5, 0.75 or 1.0 mg twice weekly respectively (Armitage's test, χ2= 39.3, P < 0.01). Cabergoline therapy (all doses) restored menses in 82% of the amenorrhoeic women not previously treated with dopamine agonists. Adverse events were recorded in 45% of patients in the placebo group and in 44, 50, 50 and 58% of those taking 0.125, 0.5, 0.75 and 1.0 mg cabergoline twice weekly (Armitage's test, P < 0.05). Over 95% of reported symptoms were relatively trivial, most frequently transient nausea, headache, dizziness, fatigue and constipation. More severe adverse events, interfering significantly with the patients’ lifestyle, occurred in 13 (7.7%) patients taking cabergoline; treatment withdrawal was necessary in only one case. No adverse effects were detected on blood pressure or haematological or biochemical parameters.

CONCLUSIONS We have shown a linear dose‐response relationship for cabergoline in the treatment of hyperprolactinaemia in the range 0.125– 1.0 mg twice weekly, with normalization of PRL in up to 95% of cases and acceptable tolerability throughout the dose range.
Immunoreactive inhibin levels during ovarian stimulation may predict granulosa cell maturity
Authors: Buckler H. M. , Robertson W. R. , Sun J. G. , Morris I. D.
Published: March 2008

OBJECTIVE The aim of the study was to assess whether the immunoreactive inhibin response to ovarian stimulation in polycystic ovarian syndrome was of predictive value for the outcome of ovulation induction.

DESIGN Daily injections of purified FSH (Metrodin, Serono Laboratories, UK) were administered for the purpose of inducing development and ovulation of a single follicle.

PATIENTS All patients had anovulatory infertility secondary to polycystic ovarian syndrome and were resistant to clomiphene citrate.

MEASUREMENTS Alternate day serum samples were obtained for measurement of gonadotropins, sex steroids and inhibin by radioimmunoassay. Alternate day ovarian ultrasound scans were carried out to monitor follicular development.

RESULTS There was a high incidence of multiple follicular development (MFD) (10.2 ± 7.1 (standard deviation) follicles). There was a close relationship between the number of follicles on the day of the ovulatory trigger and serum oestradiol (E2) levels (R= 0– 97, P < 0.001). This relationship was not seen with serum immunoreactive inhibin levels (R= 0.31). The cycles were divided into two groups depending whether there was or was not MFD (more than five follicles < 7 mm in diameter on day of hCG administration). The MFD group had 15.6 ± 8.5 follicles and the non‐MFD group 3.2 ± 1.6 follicles. There was no difference in the circulating E2 concentration (pmol/l) per follicle between the two groups (non‐MFD cycles, n= 6,345 ± 28.9; MFD cycles, n= 8, 308 ± 40.29). However, the immunoreactive inhibin concentration (U/ml) per follicle was lower, P < 0.001, in the MFD group (4.3 ± 1 6 vs 6.9 ± 0.5).

The maximum and mean follicle diameter were lower, P < 0.01, in the MFD group (maximum follicle size 16.5 ± 3.9 vs 21.2 ± 1.5 mm, mean follicle size 11.5 ± 2 vs 14.9 ± 2.3). When individual cycles were examined E2 and immunoreactive inhibin secretion rose in parallel in cycles with less than five follicles with a rapid rise occurring when the follicles reached about 12 mm in diameter. In cycles where there was MFD there was a disparity between E2 and immunoreactive inhibin secretion with E2 levels rising 4.3 ± 1.4 days before immunoreactive inhibin levels.

CONCLUSION These data suggest that in cycles where there are multiple small follicles, E2 secretion is maintained whereas immunoreactive inhibin secretion is substantially lower. Thus, in view of the disparity between E2 and immunoreactive inhibin secretion evident in the MFD group, measurement of immunoreactive serum inhibin concentration may be a better indicator of granulosa cell maturity. Immunoreactive inhibin secretion may occur only from healthy mature follicles.
Abnormalities of the hypothalamo‐pituitary‐gonadal axis after head injury
Authors: Clark John D. A. , Raggatt Peter R. , Edwards Owen M.
Published: March 2008

OBJECTIVE We aimed to investigate the mechanisms of hypogonadism which develops after head Injury.

DESIGN Pulsatile secretion of LH was studied in subjects 6–10 days after major head Injury.

PATIENTS We studied five male subjects admitted with major head injuries and six healthy age‐matched control subjects.

MEASUREMENTS During the pulsatility study, LH was measured at 5‐minute intervals for 4 hours and 15‐minute intervals for a further 2 hours. In addition, testosterone and LH were measured on Days 1–5, 14 and after 3–6 months.

RESULTS The analysis of pulsatile secretion of LH demonstrated an LH pulse frequency similar to control subjects, but a significantly reduced LH pulse amplitude (P < 0.001, fixed threshold method; P<0.02, Detect method). Both testosterone and LH levels were reduced after injury with the nadir occurring on Day 4.

CONCLUSIONS Hypogonadism after head Injury is due to defective LH secretion, with normal pulse frequency but a reduced pulse amplitude.
Follow‐up of ovarian endocrine function in premenopausal women after hysterectomy by daily measurements of salivary progesterone
Authors: Vuorento Taru , Mäenpää Juhanl , Huhtanleml Ilpo
Published: March 2008

OBJECTIVE The effect of hysterectomy on ovarian endocrine function of premenopausal women was studied.

DESIGN The patients collected dally salivary samples during one preoperative cycle (1), the cycle of operation (2), the subsequent period of 30 days (3) and the cycle 6 months after operation (4).

PATIENTS Forty‐one premenopausal women (aged 33–48 years) undergoing hysterectomy were studied; their preoperative cycles served as controls. The patients were also compared with a reference group of 17 younger fertile women.

MEASUREMENTS Salivary progesterone levels were measured by radiolmmunoassay.

RESULTS Cycle 1 was more frequently short (P<0.01), with short luteal phase (P<0.01) and low progesterone secretion (P<0.05), than the cycles of younger women. Cycle 2 was longer than the other cycles (P<0.01), due to prolonged follicular phase (P < 0.01). Cycle 3 differed from cycle 1 by the lesser frequency of short cycles (P<0.01). Cycle 4 and its follicular phase were longer than those measured in cycle 1 (P<0.05). Of the women with normal cycle 1,39% (P<0.01) presented with luteal insufficiency (LPD, low luteal progesterone secretion) or anovulation (8%) in at least one of cycles 2 to 4. The frequency of LPD or anovulation was significantly higher in cycle 3 (P<0.05) but not in cycle 4, compared to 1.

CONCLUSIONS Acute luteal progesterone deficiency after hysterectomy in premenopausal women is common but in most cases reversible.
Primary adrenocortical failure masked by exogenous steroid administration
Authors: Marston R. A.
Published: March 2008

This report describes an asthmatic patient in whom Addison's disease was masked by exogenous steroid treatment.
Postprandial thermogenesis is reduced in polycystic ovary syndrome and is associated with increased insulin resistance
Authors: Robinson Stephen , Chan Slew‐Pheng , Spacey Slan , Anyaoku Victor , Johnston Deamond G. , Franks Stephen
Published: March 2008

OBJECTIVE In order to investigate the possible causes and effects of obesity in polycystic ovary syndrome resting energy expenditure, postprandial thermogenesis and insulin resistance were measured in 14 polycystic ovary syndrome subjects and in 14 controls.

DESIGN A cross‐sectional study of a selected group of patients was performed.

PATIENTS Seven of the PCOS subjects were obese and seven lean. Controls were individually matched for age, race, weight, body mass index (BMI) lean body mass and percentage fat. The obese, but not lean, polycystic ovary syndrome subjects had a greater walst:hip ratio than controls (median (range) obese PCOS 0.865 (0.823–0.960) vs obese control 0.804 (0.823–0.940), P <0.025).

MEASUREMENTS Metabolic rate was measured by continuous indirect calorimetry and insulin sensitivity was assessed by a short insulin tolerance test.

RESULTS The resting energy expenditure (REE) was similar in PCOS subjects and controls (median (range), 6796 (5489–7774) vs 6833 (4893–8492) kJ/day). REE correlated with LBM in the PCOS group (r= 0.83, P <0.00) and the control group (r= 0.82, P <0.001). Postprandial thermogenesis was reduced in polycystic ovary syndrome (obese: median 45.4 (range 33.6–100.0) vs 86.5 (67.2–109.2) kJ (P <0.05); lean: 79.4 (73.5–108.4) vs 89.9 (76.0–109.2) kJ (P <0.05)). Fasting insulin (9.7 . 3.6 vs 4.4 . 0.8 mU/1, P <0.05) and postprandial incremental insulin rise (163 . 31 vs 116 . 15 mU/1, P <0.025) were higher in polycystic ovary syndrome. Insulin sensitivity was reduced in polycystic ovary syndrome (obese: median 136 (range 92–169) vs 173 (109–225) μmol/1/min (P <0.05); lean: 161 (138–225) vs 194 (161–253) μmol/1/min (P <0.05)). The reduction in insulin sensitivity correlated with the reduced postprandial thermogenesis in the polycystic ovary syndrome group (r= 0.75, P <0.01).

CONCLUSION These results confirm previous reports of hyperinsulinaemia and insulin resistance in polycystic ovary syndrome. Furthermore, polycystic ovary syndrome subjects have a reduced postprandial thermogenesis which is related statistically to the reduced insulin sensitivity. The decreased postprandial thermogenesis may predispose women with polycystic ovary syndrome to weight gain.
Pulsatile growth hormone release in normal women during the menstrual cycle
Authors: Faria Amllton C. S. , Bekenstein Lori Waranch , Booth Robert A. , Vaccaro Veronica A. , Asplin Christopher M. , Veldhuls Johannes D. , Thorner Michael O. , Evans William S.
Published: March 2008

OBJECTIVE We sought to characterize pulsatile growth hormone (GH) release in normal women during the menstrual cycle and to document possible relationships between such characteristics and concentrations of 17 β‐oestradiol and progesterone.

SUBJECTS Fifteen women with ostensibly normal menstrual function were studied during the early folllcular phase, 15 during the late follicular phase and 15 during the mid‐luteal phase of the menstrual cycle.

DESIGN The phase of the menstrual cycle having been documented, blood samples were obtained from each woman every 10 minutes for 24 hours.

MEASUREMENTS Serum GH was measured in each sample by immunoradiometric assay. Pulsatile GH release was appraised utilizing the objective, statistically‐based pulse detection algorithm Cluster.

RESULTS The mean (±SEM) integrated serum GH concentration (mU/l min) In late follicular phase women (5335 ± 848) was higher than that observed In early follicuolar phase women (3156 ± 322; P = 0.032). The integrated GH concentration calculated for mid‐luteal phase women (3853 ± 788) was intermediate between but not statistically different from that observed in early follicular (P= 048) and late follicular (P=0.14) phase women. No differences in GH pulse frequency (pulses/24 hours) were found among early follicular (8.27 ± 0.55), late follicular (7.93.0.91) or mid‐luteal (8.47 ± 0.66) phase women. Mean maximal GH pulse amplitude (mU/l) was higher in late follicular phase (8.93 ± 1.00) than early follicular phase (5.74 ± 067; P= 0008) and mid‐luteal phase (5.76 ± 0.74; P= 0.008) women. Similarly, Incremental GH pulse amplitude (mU/l) was higher in late follicular phase (7.33 ± 083) than early follicular phase (4.68 ± 0.58; P= 0.005) and mid‐luteal phase (4.36 ± 0.39; P= 0002) women. No differences In mean pulse widths or In the Interpeak valley mean GH concentrations were found among the groups. Multiple regression of each pulse parameter against serum concentrations of testosterone, 17β‐oestradiol and progesterone revealed a significant (P= 0.045) positive correlation between maximum GH pulse amplitude and oestradiol and a significant (P=0.04) negative correlation between maximal GH pulse amplitude and progesterone (r=0.41).

CONCLUSION These results suggest that late follicular phase concentrations of oestradiol may enhance circulating GH via an amplitude‐modulated rather than a frequency‐modulated effect on the endogenous GH pulse. Progesterone may blunt this oestrogen‐associated effect, thus resulting in the observed mid‐luteal phase concentrations of GH. Whether these gonadal hormones act primarily at the hypothalamus and/or anterior pituitary gland remains to be clarified, but the present observations indicate that pulsatile GH release throughout the normal menstrual cycle is significantly amplitude regulated.
Cardiac conduction in patients with hypercalcaemia due to primary hyperparathyroidism
Authors: Rosenqvist Mårten , Nordenström Jörgen , Andersson Mats , Edhag Olof K.
Published: March 2008

OBJECTIVE To assess whether hypercalcaemia due to primary hyperparathyroidism is associated with significant cardiac arrhythmias.

DESIGN AND PARTICIPANTS The prevalence of cardiac arrhythmias and conduction disturbances was evaluated by 12‐lead ECG and 24‐hour long‐term ECG during presurgical hypercalcaemia and after post‐surgical normalization of serum calcium values in 20 patients with primary hyperparathyroidism.

RESULTS After surgery, mean±SD calcium levels decreased from 2.85±0.1 to 2.40±0.1 mmol/l (P <0.001). There was a significant increase in QT‐intervals (0.36±0.05 vs 0.39 ± 0.05) and QTc‐intervals (0.38 ± 0.04 vs 0.42±0.03) after surgery (P <0.01). Long‐term ECG showed no change in the minimal heart rate 47 ± 8 vs 48 ± 7 beats/min or in the longest RR interval 1.6 ± 0.5 vs 1.6 ± 0.5 s (P NS). There was no difference in the prevalence of supraventricular or ventricular arrhythmias. No episode of high‐grade AV‐block was observed before surgery. Circadian heart rate rhythm did not change between investigations.

CONCLUSIONS It is concluded that moderate hypercalcaemia, in spite of causing a shortening of the repolarization phase (QT‐interval), has no clinically significant effect on cardiac conduction.
Comparison of methods for the determination of unbound triiodothyronine in pregnancy
Authors: Price A. , Griffiths H. , Kennedy L. , Darne J. , Cohn M. , Davies R.
Published: March 2008

OBJECTIVE To study the changes in unbound T3 concentration in the first trimester of pregnancy.

DESIGN We measured serum unbound T3 concentration before and after termination of pregnancy.

PATIENTS Twenty‐six clinically euthyrold women.

MEASUREMENTS We used one non‐analogue assay (Sciavo) and three analogue assays (Amersham, Becton Dickinson and Diagnostic Products Corporation).

RESULTS Regression analysis did not show any significant agreement between the analogue and non‐analogue assays. After termination of pregnancy, unbound T3 concentration as measured by Sciavo and Amersham assays did not change whereas unbound T3 concentration increased and decreased as measured by Becton Dickinson and Diagnostic Products assays respectively. Changes were not directly related to albumin or thyroid binding globulin.

CONCLUSION We believe unbound T3 concentrations as measured by the analogue assays used in this study are due to a balance of errors and cannot be used to determine true physiological changes in pregnancy.
Mediation of gonadotrophin‐stimulated growth and differentiation of human granulosa cells by adenosine‐3′,5′‐monophosphate: one molecule, two messages
Authors: Yong E. L. , Baird D. T. , Hillier S. G.
Published: March 2008

OBJECTIVE To determine how the second messenger adenosine‐3′,5′‐monophosphate (cyclic AMP) is able to mediate divergent actions of FSH and LH on granulosa cell growth and differentiation in human ovaries.

DESIGN Human granulosa cells were cultured for 96 hours in serum‐free medium 199 containing increasing doses of either FSH, LH or dibutyryl cyclic AMP. Extra and intra‐cellular cyclic AMP levels were determined by radioimmunoassay. Tritiated thymidine uptake and cell number were measured as indices of cell growth, and spent medium was assayed for steroids (oestradiol and progesterone) to reflect differentiation.

PATIENTS ‘Mature’ granulosa cells were aspirated from preovulatory follicles in the ovaries of clomiphene‐stimulated patients undergoing laparoscoplc sterilization; ‘lutelnized’ granulosa cells were aspirated from periovulatory follicles in the ovaries of gonadotrophin‐stimulated in‐vitro fertilization patients.

RESULTS LH consistently inhibited, whereas FSH maintained or stimulated, basal granulosa cell numbers. Steroidogenesis was dose‐dependently increased by both gonadotrophins, with LH having the significantly greater effect over the entire dose‐response range (1–100 μg/1). LH also induced significantly more cyclic AMP production than FSH, both intra and extra‐cellularly, providing a basis for differential post‐receptor signalling via a common second messenger. Addition of dibutyryl cyclic AMP, at low concentrations (10–250 μmol/1) to the cultured cells in the absence of gonadotrophins mimicked FSH effects with stimulation/maintenance of cell numbers and moderate steroidogenesls. High concentrations of dibutyryl cyclic AMP (500–1000 μmol/1) caused a significant inhibition of cell numbers together with maximal steroidogenesis, simulating LH action.

CONCLUSIONS These results suggest that granulosa cell maturation in the follicular phase of the menstrual cycle (controlled by FSH) is associated with a low cyclic AMP tone that favours cell growth and expression of aromatase activity in the developing preovulatory follicle. During the early luteal phase (dominated by LH), the intracellular cycle AMP tone increases to allow maximal progesterone production and inhibition of cell growth in the corpus luteum. Thereby one second messenger can mediate divergent gonadotrophic effects on granuiosa cell growth and differentiation in the human ovary.
The effect of growth hormone administration in growth hormone deficient adults on bone, protein, carbohydrate and lipid homeostasis, as well as on body composition
Authors: Binnerts Arjen , Swart G. Roel , Wilson J. H. Paul , Hoogerbrugge Nicoline , Pois Hulbert A. P. , Birkenhager Jan C. , Lamberts Steven W. J.
Published: March 2008

OBJECTIVE The effect on bone, protein, carbohydrate and lipid homeostasis as well as body composition of the administration of growth hormone to adult patients with growth hormone deficiency was studied.

DESIGN Growth hormone was administered at a dose of 25 μg/kg/day with a maximum of 1·48 mg (4 IU) a day, for 6 months in eight adults, Studies were done before the start and at 1, 3 and 6 months during therapy, as well as 3 months after treatment had been stopped.

RESULTS Subjective well‐being as assessed by a short psychological test showed an improvement in six and no change in two patients. Body composition, as assessed by body impedance assessment and D2O dilution, both showed an increase in lean body mass of 4 kg (5% of body weight), accompanied by a decrease in mean fat mass of 3 kg. Nitrogen turnover studies showed a transient increase in fed state nitrogen balance due to an increase in the rate of protein synthesis, which exceeded a smaller increase in the protein degradation rate.

Growth hormone treatment did not affect the circulating levels of 25(OH)‐vitD or PTH 1–84, while 1,25(OH)2‐vitD had significantly increased after 6 months, as well as 3 months after treatment ended. Osteocalcin, procollagen I levels, as well as 24‐hour urinary excretion of hydroxyproline and calcium rose during growth hormone administration but subsequently decreased rapidly after administration had been stopped, while the increase in alkaline phosphatase persisted. This increase in markers of both bone resorption and bone formation indicates an activation of bone remodelling, but this was not reflected by an increase in bone density.

Glucose levels, measured before and during a normal breakfast, increased during growth hormone treatment, but serum insulin levels did not. Total cholesterol levels decreased by 0·5 mmol/l. Levels of T4 and free T4 as well as rT3 decreased, while T3 increased during growth hormone treatment.

CONCLUSION Therapy with growth hormone for 6 months in a dose varying between 6 and 25 μg/kg/day increased lean body mass and decreased fat mass. The sense of general well‐being improved in most patients. Furthermore, growth hormone treatment increased bone turnover without a measurable increase in bone density, caused some minor changes in lipid and carbohydrate metabolism, and increased the metabolism of thyroxine to T3.
How common are polycystic ovaries in normal women and what is their significance for the fertility of the population?
Authors: Clayton R. N. , Ogden V. , Hodgkinson J. , Worswick L. , Rodin D. A. , Dyer S. , Meade T. W.
Published: March 2008

OBJECTIVE We wished to determine the prevalence of polycystic ovaries (PCO) and relate morphological appearance to fertility.

DESIGN We sent postal invitations to a random sample of women born in the years 1952–1969 from a list of a single Group Practice to attend for reproductive history questionnaire, examination, ultrasound scan of the ovaries and hormone measurements within 5 days of the onset of menstruation.

SUBJECTS Of 1065 women potentially available for study, 571 (54%) replied of whom 353 (62%) agreed to participate. One hundred and ninety (18%) completed the study, 163 were deferred (57 because of current or very recent pregnancy, 106 because of inconvenience at time approached), and 18 additional women volunteered.

MEASUREMENTS Prevalence of polycystic ovaries, ovarian size and morphology, menstrual history, features of androgen excess, fertility status, serum hormone levels. RESULTS The prevalence of PCO was 22% (41/190). PCO and non‐PCO women were similar with respect to age, body mass index, oral contraceptive pill (OCP) usage, acne, and menstrual pattern but hirsutism (Ferrlman and Gallwey score > 7) was significantly (P= 0.006) more frequent among PCO women. Proven prior fertility was the same in PCO (56%) and non‐PCO (64%) women and an equal proportion in each group had not yet tested their fertility. Of those women with previously proven fertility, self‐perceived difficulty in conception occurred in similar proportions of women with and without PCO. Unresolved primary or secondary infertility (2.5–4%) was similar in both groups. Ovarian volume (each ovary separately) was larger in women with PCO irrespective of current OCP usage. Serum levels of oestradiol and FSH were similar in PCO and non‐PCO women, but LH was distributed around a higher median in PCO women. Median testosterone and androstenedione levels were the same in PCO and non‐PCO women.

CONCLUSIONS The prevalence of polycystic ovarian morphology is high but, in this sample of women, was accompanied by minimal clinical manifestations and apparently no deleterious effects on earlier fertility. An isolated finding of polycystic ovaries may be a normal variation and should not necessarily imply altered fertility potential.
The IgG subclass distribution of TSH receptor blocking antibodies in primary hypothyroidism
Authors: Kraiem Z. , Cho B. Y. , Sadeh O. , Shong M. H. , Plckerill P. , Weetman A. P.
Published: March 2008

OBJECTIVE TSH receptor stimulating antibodies are restricted to the IgG1 subclass suggesting an ollgoclonal origin. We wished to determine whether thyroid stimulation blocking antibodies, which also bind to the TSH receptor but may cause hypothyroidism, are similarly IgG subclass restricted.

DESIGN Sera containing TSH receptor blocking antibody activity were separated into IgG subclasses by negative depletion of all other subclasses on affinity columns of subclass‐specific monoclonal antibodies or protein A as appropriate.

PATIENTS Eleven patients from two centres were studied. All had autoimmune hypothyroidism and TSH receptor blocking antibodies but no thyroid stimulating antibodies. MEASUREMENTS TSH receptor blocking antibody activity was measured by assessing inhibition of TSH‐stimulated cAMP production by human thyroid cells (five Israeli samples) or by the FRTL‐5 rat thyroid cell line (six Korean samples).

RESULTS IgG1 was the most important subclass containing TSH receptor blocking antibody activity but complete restriction to this subclass was never seen. Clearly detectable activity was found in the IgG2 subclass in eight patients, in the IgG3 subclass in three patients, and in the IgG4 subclass in six patients. The percentage recovery of activity in the sum of the separated fractions generally corresponded to the activity in whole immunoglobulin, being 117 ± 66% in the nine patients in whom this could be assessed, although in one of these, the activities in the sum of the fractions was much higher (284%).

CONCLUSIONS Unlike thyroid stimulating antibodies, thyroid stimulation blocking antibodies are not subclass restricted and are therefore likely to have a polyclonal origin. The IgG subclass distribution of these blocking antibodies resembles that of thyroglobulin and thyroid peroxidase antibodies.
HLA class II gene polymorphism contributes little to Hashimoto's thyroiditis
Authors: Jenkins David , Penny Michelle A. , Fletcher Jeremy A. , Jacobs Karen H. , Mijovic Catherine H. , Franklyn Jayne A. , Sheppard Michael C.
Published: March 2008

Previous studies of HLA and Hashimoto's thyroiditis have shown weak associations between the disease and various HLA‐DR antigens.

OBJECTIVE To define better the contribution of HLA class II alleles to susceptibility to Hashimoto's thyroiditis.

DESIGN AND MEASUREMENTS Comparison of HLA‐DRB, DQA and DQB restriction fragment length polymorphisms in patients with Hashimoto's thyroiditis and control subjects, and meta‐analysis of this and other published studies.

PATIENTS Fifty Caucasian patients with Hashimoto's thyroiditis and 93 racially‐matched control subjects.

RESULTS A 4.6 kb Taq 1 DQA restriction fragment length polymorphism occurred in 60% of patients compared with 35.5% of controls, Pc < 0.025. No other restriction fragment length polymorphism was significantly associated with the disease. Meta‐analysis of several studies demonstrated weak, positive associations between the disease and DR3 and DR4. An association with DR5 was not significant.

CONCLUSIONS DR antigens are unlikely to determine disease susceptibility directly. These findings indicate that any contribution of HLA genes to inherited susceptibility to Hashimoto's thyroiditis is small and requires confirmation in family studies.

We thank Professor R. Thompson for assaying antibody litres, and Professor P. A. Peterson for the gift of the cDNA clones. DJ was supported by Eli Lilly (UK), MAP by the Medical Research Council (UK), KHJ by the British Diabetic Association, CHM by the Wellcome Trust.
Effects of oral testosterone undecanoate on growth, body composition, strength and energy expenditure of adolescent boys
Authors: Gregory J. W. , Greene S. A. , Thompson J. , Scrlmgeour C. M. , Rennle M. J.
Published: March 2008

OBJECTIVE We determined the effect of 3 months of daily, 40 mg oral testosterone undecanoate on growth, body composition, hand grip and quadriceps muscle strength, and total free‐living daily energy expenditure in boys with constitutionally delayed puberty.

DESIGN Double blind, placebo controlled study.

PATIENTS Eighteen boys with constitutionally delayed puberty, mean (SD) age 13.2 (1.6) years.

MEASUREMENTS Body composition measurements were made by skinfold thickness, bloelectrical impedance and stable isotope dilution (H214O) methods. Energy expenditure was assessed by the doubly‐labelled water (2H213O) technique.

RESULTS Height velocity increased from 5.4 (0.8) to 8.1 (0.6) cm/year (P < 0.05) in the 3 months after active therapy. Fat‐free mass increased more with therapy (2.7 (0.3) kg) over the 6‐month study period than with placebo (1.7 (0.4) kg, P < 0.5). Height velocity increases correlated with daily increases in fat‐free mass (r= 0.68, P= 0.005) in the study group as a whole. Energy expenditure and muscle strength increased similarly in both groups. Predicted adult height decreased in the group which was treated with testosterone undecanoate.

CONCLUSIONS Testosterone undecanoate (40 mg daily for 3 months) significantly increased height velocity and fat‐free mass velocities after 6 months but not muscle strength, endurance or total daily energy expenditure.
Long‐term in‐vitro treatment of human growth hormone (GH)‐secreting pituitary adenoma cells with octreotide causes accumulation of intracellular GH and GH mRNA levels
Authors: Hofland L. J. , Velkeniers B. , v. d. Lely A. J. , van Koetsveld P. M. , Kazemzadeh M. , Waaijers M. , Hooghe‐Peters E. L. , Lamberts S. W. J.
Published: March 2008

OBJECTIVE We studied the effects of long‐term in‐vitro exposure of human GH secreting pituitary adenoma cells to octreotide on GH release, intracellular GH concentrations and GH messengerbonuclelc acid (mRNA) levels.

DESIGN Human GH‐secreting pituitary adenoma cells were cultured for periods from 4 days up to 3 weeks without or with octreotide (10 PM) and/or bromocriptine (10 nM). The effects of these drugs were measured on GH release, intracellular GH concentrations and intracellular GH mRNA levels.

PATIENTS Thirteen patients with GH‐secreting pituitary adenomas were studied. Twelve patients were untreated, one had been pretreated with octreotide (12 weeks, 3 ± 100 μg daily).

MEASUREMENTS GH, PRL, α‐subunlt and IGF‐I concentrations in plasma, media and cell extracts were determined by Immunoradiometric or radloimmunoassays. GH mRNA levels were determined by automatic quantification of grain numbers in individual adenoma cells.

RESULTS Incubation of the adenoma cells for 4 days with 10 Nm octreotide induced a dose‐dependent inhibition of GH release and a parallel increase (increase varying between 124 and 617% of control) In the intracellular GH levels was observed in six of seven adenomas. In addition, bromocriptine, when effective in inhibiting GH release by the adenomas, also induced an increase in intracellular GH levels. Even after 3 weeks of exposure to 10 nM octreotide in vitro there was a statistically significant increase in intracellular GH levels (between 191 and 923% of control). Withdrawal of octreotide after 6 days of incubation resulted in a lowering of intracellular GH levels to control values, showing that the octreotide‐induced increase in intracellular GH is reversible. In a 96‐hour incubation with 10 nM octreotide, GH mRNA levels were increased in two, and slightly decreased in one of the three adenomas tested. This effect was time dependent in that there was no significant effect of 10 nM octreotide on GH mRNA levels in a 24‐hour incubation.

CONCLUSIONS (1) Long‐term in‐vitro exposure of GH‐adenoma cells to octreotide causes an increase in intracellular GH levels in the majority of the adenomas, probably because of an increase in GH mRNA levels in the adenoma cells; and (2) this considerable increase in intracellular GH levels may be one of the explanations for the relatively poor effect of octreotide on tumour shrinkage In patients with GH‐secreting pituitary adenomas.
Usefulness of thyroglobulin antibody detected by ultrasensitive enzyme immunoassay: a good parameter for immune surveillance in healthy subjects and for prediction of post‐partum thyroid dysfunction
Authors: Tamaki Haruo , Katsumaru Hiroyuki , Amino Nobuyuki , Nakamoto Hidetaka , Ishikawa Eiji , Mlyal Kiyoshi
Published: March 2008

OBJECTIVE Using newly developed ultrasensitive enzyme immunoassay (EIA) for thyroglobulin antibody (TgAb), we have evaluated physiological and pathological implications of the antibody in healthy subjects as well as in autoimmune thyroid diseases.

MEASUREMENTS This EIA was based on the immune complex transfer method, and was 104‐fold more sensitive compared with the conventional haemagglutination assay (HA); the detection limit was 0.1 μg lgG/l, and the specificity of the assay was confirmed from the unequivocal decrease in the fluorescence intensity by the preincubation of test serum with Tg and/or inactive β‐D‐galactosidase which blocks antibodies to the enzyme.

RESULTS TgAb was detectable in 159 (91%) of 175 healthy subjects aged 3rd to 7th decade (96 men and 79 women), and did not exhibit age or sex‐associated change. In nine healthy women, the TgAb level significantly decreased as pregnancy progressed but increased transiently after delivery. TgAb was detectable in 52 (98%) of 53 patients with Graves' disease and all (100%) of 107 patients with chronic thyroiditis. Abnormal high TgAb values (>40 μg/l), determined from the 95th percentile in healthy subjects, were shown in 40 (75%) with the former disease and 94 (88%) with the latter disease. Moreover, in 14 goltrous patients with biopsy‐proved chronic thyroiditis with negative HA results, 12 (86%) showed abnormal high TgAb levels. In 69 patients with post‐partum thyrotoxicosis in Graves' disease, 15 (79%) of 19 patients with the TgAb level of more than 2 ± 103μg/l in early pregnancy showed destructive thyrotoxicosis and 46 (92%) of 50 with less than this level showed stimulative thyrotoxicosis. This TgAb test could discriminate the two types of thyrotoxicosis more clearly than could the conventional TGHA test. In chronic thyroiditis, the mean TgAb value in early pregnancy was significantly higher in patients with postpartum hypothyroidism than in those without thyroid dysfunction. Hypothyroidism developed in 80% of the patients with a TgAb value of more than 103μg/l.

CONCLUSIONS The ultrasensitive TgAb EIA was useful for detecting the physiological changes in autoantibody formation in healthy subjects and the TgAb value was useful for predicting post‐partum thyroid dysfunction in autoimmune thyroid diseases. This EIA is useful for the evaluation of the immune surveillance in patients with autoimmune thyroid diseases as well as in healthy subjects.
Thyroid cells in Graves' disease and Hashimoto's thyroiditis stimulate allogeneic T cells when pretreated with phorbol ester
Authors: Tandon N. , Weetman A. P.
Published: March 2008

OBJECTIVE To assess the capacity of thyroid follicular cells to function as antigen presenting cells, we have examined their ability to stimulate allogeneic T cells.

DESIGN Thyroid follicular cells were pretreated with interferon‐γ or phorbol myristate acetate, washed thoroughly, and their capacity to induce allogeneic T cell proliferation was determined.

PATIENTS Thyroid cells were prepared using thyroidectomy specimens from eight patients with Graves' disease, one with Hashimoto's thyroiditis and two with non‐toxic multinodular goitre.

MEASUREMENTS T cell 3H‐thymidine incorporation was measured after a 16‐hour incubation period with the isotope, 3 days after co‐culture of T cells and thyroid cells.

RESULTS Four of the eight thyroid cell preparations from thyroid autoimmunity patients failed to stimulate T cells, although there was a significant, weak stimulation for the whole group (P <0.05): interferon‐γ pretreatment had no effect on this. Phorbol myristate acetate pretreatment significantly increased the ability of thyroid cells (from both autoimmune and multinodular glands) to stimulate T cells (P <0.05); this was time and concentration dependent. Cell fixation after PMA treatment did not abolish this stimulatory activity, which could be transferred by supernatants from unfixed cells; exogenous interleukin‐1 did not mimic the activity.

CONCLUSIONS Thyroid cells expressing major histocompatibility complex class II molecules only weakly and inconsistently stimulate allogeneic T cells, compared to thyroid cells pretreated with phorbol myristate acetate, a difference which may be due to the expression of an unidentified co‐stimulatory signal induced by phorbol ester.
Circulating levels of midregional parathyroid hormone‐related protein in hypercalcaemia of malignancy
Authors: Blind Eberhard , Raue Friedhelm , Götzmann Joachim , Schmidt‐Gayk Helnrich , Kohl Brigitte , Ziegler Reinhard
Published: March 2008

OBJECTIVE We have developed and evaluated a sensitive radioimmunoassay directed against the midregional part of parathyroid hormone‐related protein (PTHrP), which is involved in the syndrome of humoral hypercalcaemia of malignancy.

PATIENTS Midregional PTHrP levels were studied in 41 consecutive inpatients with malignancy and hypercalcaemia, 32 normocalcaemic patients with malignancy, 21 patients with primary hyperparathyroidism, 34 patients with renal failure, and 87 normals.

MEASUREMENTS The assay used an antiserum against the midregional amino acid residues 53–84 of PTHrP and PTHrP(1–86) as label and standard. Midregional PTHrP was stable in serum and plasma and could be measured directly without sample extraction.

RESULTS Normal plasma concentrations ranged from undetectable (<5 pmol/l) to 21 pmol/l. In renal failure, PTHrP was positively correlated with serum creatinine, but PTHrP elevations of up to 30 pmol/l were found only in severe renal dysfunction with creatinine > 850 μmol/l. In hypercalcaemia caused by solid tumours, midregional PTHrP was elevated in 81% (22 of 27) of patients, ranging from undetectable to 203 pmol/l (median: 40 pmol/l). In these patients serum calcium correlated positively with PTHrP (P<0.01). Mean PTHrP levels were indistinguishable in subgroups with and without metastatic skeletal disease. The mechanism of hypercalcaemia in 14 patients with haematological malignancy was apparently different, since all but one had normal or only marginally elevated PTHrP levels. In 21 patients with primary hyperparathyroidism midregional PTHrP was normal in 20. The assay was therefore especially useful in distinguishing the latter condition from humoral hypercalcaemia of malignancy as the second major cause of hypercalcaemia. PTHrP was normal in all 32 patients with normocalcaemic malignancy.

CONCLUSION This radioimmunoassay of midregional PTHrP provides high diagnostic sensitivity in the identification of humoral hypercalcaemia of malignancy caused by solid tumours. The assay should therefore be useful in the differential diagnosis of hypercalcaemia.
Phaeochromocytomas as a cause of hypotension
Authors: Baxter M. A. , Hunter P. , Thompson G. R. , London D. R.
Published: March 2008

A patient presented with apparent septicaemic shock. Full invasive cardiovascular monitoring revealed systemic hypotension, high normal cardiac output, and a low systemic vascular resistance. Maintenance of systemic vascular resistance and blood pressure was shown to be highly dependent on noradrenaline. Subsequent investigation reveaied the presence of a phaeochromocytoma producing adrenaline. The mechanisms by which phaeochromocytomas may produce hypotension are discussed.
Subtle changes in serum thyrotrophin (TSH) and sex‐hormone‐binding globulin (SHBG) levels during long‐term follow‐up after radioactive iodine in multinodular non‐toxic goitre.
Authors: Jarlev A. E. , Faber J. , Hegedüs L. , Hansen J. Mølholm
Published: March 2008

OBJECTIVE We investigated possible changes in the pituitary‐thyroid axis after radioactive iodine (RAI) treatment of multinodular non‐toxic goitre.

DESIGN Consecutive patients with multinodular non‐toxic goitre, who remained euthyroid after radioactive iodine (RAI) treatment.

PATIENTS Twenty‐three women with multinodular nontoxic goitre were followed after treatment with RAI.

MEASUREMENTS Free T4 index (FT4I), FT3I, free T4, SHBG (Immunoradiometric assay), and a third‐generation TSH assay (chemiluminetric assay) TSH were measured. RESULTS Three weeks after RAI treatment TSH had decreased and SHBG Increased (P <0.05). Only 2/18 patients actually had suppressed TSH values, while 12/18 had values in between euthyroid and toxic levels. Trend analysis from 1.5 to 24 months after RAI treatment demonstrated a progressive increase in TSH (P <0.01) and gradual decrease in SHBG (P <0.02). No changes in FT4I, FT3I, or free T4 were found.

CONCLUSION A third‐generation TSH assay gave detailed information about changes in thyroid status when TSH was below normal values. FT4I, FT3I, and free T4 seem to be less sensitive parameters than TSH and SHBG for recording subtle changes in thyroid status after RAI treatment of nodular non‐toxic goitre. We demonstrated that changes in the pituitary‐thyroid axis continue for a long time after RAI treatment of multinodular non‐toxic goitre. These patients should be followed up in order to detect possible late hypothyroidism.
Genetic linkage studies of X‐linked hypophosphataemic rickets in a Saudi Arabian family
Authors: Thakker R. V. , Farmery M. R. , Sakatl N. A. , Mllner R. D. G.
Published: March 2008

OBJECTIVE, PATIENTS AND DESIGN X‐linked hypophos‐phataemic rickets (HYP) is the most common inherited form of rickets and the gene causing this disorder has been localized to Xp22.3‐p21.3 by linkage studies of affected families of Northern European origin. In addition, the locus order Xpter‐(DXS207‐DXS43, DXS197)‐HYP‐DXS41‐Xcen has been established and the flanking markers are useful for the presymptomatic diagnosis of HYP. However, a recent study indicates locus heterogeneity and this may hinder the use of the flanking markers for presymptomatic diagnosis in additional families and in particular those from different populations. We have therefore investigated one Saudi‐Arabian family (13 affected and six unaffected members) with hypophosphataemic rickets for linkage to these and other X‐linked markers. A total of 17 cloned human X chromosome sequences identifying restriction fragment length polymorphisms were used to localize the mutant gene causing this disorder in the Saudi Arabian family.

RESULTS Nine (four from Xp and five from Xq) of the 17 X‐linked DNA probes proved informative and linkage was established between HYP and the DSX41 locus, peak LOD score = 4.22 (recombination fraction, ±= 0.00). A positive peak LOD score of 2.32 (. = 0.05) was also obtained between HYP and the DXS207 locus. Thus, the HYP gene in this Saudl Arabian family is linked to two of the four flanking markers which demonstrated linkage in families of Northern European origin.

CONCLUSION We conclude that the X‐linked hypophosphataemic rickets gene in a Saudl Arabian family is located in the Xp22.3–p21.3, a region where this gene has previously been mapped by linkage studies of families of Northern European origin. Our studies have not demonstrated locus heterogeneity, so the flanking markers for HYP previously established in the families of Northern‐European origin will be useful in the genetic counselling and presymptomatic diagnosis of this disorder in the Saudi Arabian family.
Normal pattern of parathyroid response to blood calcium lowering in primary hyperparathyroidism: a citrate clamp study
Authors: Schwarz P. , Serensen H. A. , Momsen G. , McNair P. , Transbel I.
Published: March 2008

OBJECTIVE The objective of the present study was to elucidate the parathyroid responsiveness by measurements of blood Ionized calcium and serum intact parathyrold hormone (PTH) concentrations, before and during trisodium citrate induced hypocalcaemia.

PATIENTS AND CONTROLS Sixteen patients with primary hyperparathyroidism and 32 healthy volunteers.

DESIGN Blood ionized calcium concentration was lowered by about 0.20 mmol/l and maintained at this level for 2 hours by blood ionized calcium controlled trisodium citrate infusion.

MEASUREMENTS Serum PTH(1–84) was measured by an Immunoradiometric assay.

RESULTS In patients and controls, baseline measurements of blood Ionized calcium were 1.39±0.07 vs 1.24±0.04 mmol/l (mean.SD) (P <0.001) and of serum PTH (1–84) 9.7.5.4 vs 3.2 1.1pmol/l (P<0.001). During a trisodium citrate clamp, serum PTH(1–84) rose to a maximal concentration after 5–10 minutes in both groups, the patients to 2–10 times baseline, whereas controls rose to 4–7 times baseline values. In both groups the peak of serum PTH(1–84) declined to a steady state concentration around 2–4 times baseline.

CONCLUSIONS in conclusion, adenoma cells seem to react in almost the same way as normal parathyroid cells. They respond to initiation of hypocalcaemia by the release of preformed PTH(1–84), and continue to secrete increased amounts of PTH(1–84) during the maintenance of relative hypocalcaemia. The increased baseline concentrations of blood ionized calcium and serum PTH(1–84) and the serum PTH(1–84) response during blood ionized calcium lowering all suggest a shift upwards in the calcium set point.
A randomized double blind placebo controlled trial of the effects on bone metabolism of the combination of nafarelin acetate and norethisterone
Authors: Eldred J. M. , Haynes P. J. , Thomas E. J.
Published: March 2008

OBJECTIVE We observed the effects on bone metabolism of the addition of different doses of oral norethisterone during treatment with the GnRH agonist nafarelin (Synarel, Syntex).

PATIENTS Ninety‐four women with a subjective complaint of heavy menstrual blood loss or objective evidence of endometriosis received intra‐nasal nafarelin 400 μg daily for 6 months and also received, in a randomized, double blind manner, either 0.7 mg (n= 24), 1.4 mg (n= 23) or 2.45 mg (n= 23) of oral norethisterone or placebo (n= 24) daily. Follow‐up was continued for a further 6 months after treatment.

RESULTS Thirty‐one patients (33%) left the study prematurely and three patients were non‐compliant with the study drug. By 6 months significant increases in urinary calcium/creatinine ratio were seen, compared to baseline, in the nafarelin and placebo (P=0.001, n= 14), 0.7 mg (P=0.04, n= 13) and 1.4 mg norethisterone groups (P=0.009, n= 17) but not in the nafarelin or 2.45 mg norethisterone groups (P= 0.72, n= 16). Densltometry of the spine, however, showed decreases at 6 months in all groups: 6.14% (P=0.0004, n= 11), 5.46%n= 0.0006, n= 13), 3.93% (P=0.008, n= 14) and 4.04% (P= 0.004, n= 16) for the groups receiving nafarelin and placebo, nafarelin and norethisterone 0.7, 1.4 and 2.45 mg respectively. Six months after stopping nafarelin, with or without norethisterone, bone mass was not different from baseline.

CONCLUSION The concomitant daily use of up to 2.45 mg of norethisterone does not eliminate the bone deminerallzation seen during GnRH agonist therapy with nafarelin in premenopausal women.