bluuebunny/crossref_metadata_2025 huggingface dataset:
The International Standard for Thyroxine Binding Globulin
Authors: Bristow A. F. , Gaines‐Das R. E. , Buttress N. , Gallimore J. R. , Tennent G. A. , Pepys M. B.
Published: March 2008

OBJECTIVE Thyroxine binding globulin is the major thyroid hormone binding and transport protein of the plasma, and its quantitative estimation is therefore of clinical importance. The objectives of the present study were to prepare and ampoule a preparation of thyroxine binding globulin suitable to serve as an international standard, to confirm the suitability of the preparation in a multi‐centre collaborative study, and to assign an ampoule content. DESIGN The collaborative study was designed with the following aims: (1) to compare the candidate preparation with local standards; (2) to calibrate the preparation with local standards and to confirm the assigned ampoule content; (3) to assess the stability of the ampouled preparation.

MEASUREMENTS AND RESULTS Thyroxine binding globulin was purified by a combination of affinity and conventional chromatography. Analysis by gel electrophoresis, N‐terminal sequencing and electrospray mass spectroscopy showed the preparation to be ± 99% pure and to have a structure consistent with the known structure of thyroxine binding globulin. Thyroxine binding globulin assays performed in the multicentre collaborative study indicated that the preparation behaved as thyroxine binding globulin when compared to local standards and that the ampoule content was consistent with that assigned on the basis of physicochemical measurements of protein concentration.

CONCLUSIONS The thyroxine binding globulin preparation coded 88/638 was established by the Expert Committee on Biological Standardization of the World Health Organization as the International Standard for Thyroxine Binding Globulin, 30.0 International Units per ampoule, with the additional information that for the preparation in 88/638, 1 IU is equivalent to 1 μg. The preparation is available from the National Institute for Biological Standards and Control.
The relationship between endogenous testosterone and gonadotrophin secretion
Authors: Bridges N. A. , Hindmarsh P. C. , Pringle P. J. , Matthews D. R. , Brook C. G. D.
Published: March 2008

OBJECTIVE The secretion of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone in the adult male was studied by means of 48‐hour profiles. The aim of the study was to examine the effects of the endogenous circadian variation in serum testosterone concentration on LH pulsatility, and to determine the temporal relationships between FSH and LH, and between LH and testosterone by cross‐correlation, and the pulse frequency of these hormones by spectral analysis, as revealed by extended sampling periods.

DESIGN Hormone profiles were obtained by 20‐minute sampling over 48 hours.

SUBJECTS Six healthy adult males, aged between 21 and 23 years.

MEASUREMENTS LH and FSH were measured using an immunoradiometric assay and testosterone with a solid‐phase radioimmunoassay.

RESULTS The profiles showed pulsatile secretion of all three hormones, and a circadian rhythm with levels highest between 0200 and 0600 h.

Cross‐correlation analysis

There was a significant relationship between LH and FSH (r= 0.5; P=0.001) at 0 minutes (i.e. no time lag). A pulse of testosterone followed on average 60 minutes after a pulse of LH (r= 0.28; P= 0.001).

Fourier transformation

Spectral analysis showed the dominant period for LH and FSH pulsatility to be 200 minutes. The dominant period for testosterone pulsatility was 400 minutes.

The effect of endogenous variations in serum testosterone concentrations

The LH profiles were divided into periods when the serum testosterone concentration was high or low, and Fourier transformation carried out on these shorter periods. These transforms showed that the dominant period during high serum testosterone concentration was 180 minutes, and during low serum testosterone was 120 minutes (P ± 0.025).

CONCLUSIONS FSH and LH are co‐secreted, and a pulse of testosterone follows a pulse of LH by 60 minutes. The physiological changes in serum testosterone concentration that occur during the day result in changes in the pulse frequency of LH. Testosterone concentrations thus have rapidly acting feedback activity at hypothalamic level.
The relationship between hCG and relaxin secretion in normal pregnancies vs peri‐implantation spontaneous abortions1
Authors: Stewart Dennis R. , Overstreet James W. , Celniker Abbie C. , Hess David L. , Cragun Jeffry R. , Boyers Stephen P. , Lasley Bill L.
Published: March 2008

OBJECTIVE We determined the ovarian response to human chorionic gonadotrophin (hCG) in terms of relaxin and progesterone secretion during the peri‐implantation period of normal and failing pregnancies. We wished to test the hypotheses that relaxin production in failing pregnancies is different from that in normal pregnancies, that relaxin is a reliable, quantitative indicator of the biological activity of endogenous hCG, and that relaxin is a useful predictor of peri‐implantation spontaneous abortions.

DESIGN Daily blood samples were collected in a prospective longitudinal study from insemination patients.

PATIENTS Women undergoing artificial insemination in natural cycles with non‐frozen donor semen at a University clinic.

MEASUREMENTS Serum LH, hCG, relaxin and progesterone were measured and the relationship between hCG and the ovarian hormones was evaluated in the peri‐implantation period of normal pregnancies and spontaneous abortions.

RESULTS Nine of 23 conceptive cycles resulted in a spontaneous abortion between 16 and 70 days after the LH peak. In all normal and failing pregnancies there was a close qualitative relationship between hCG secretion and relaxin production. Six of nine failing pregnancies were associated with abnormally low hCG secretion. Six of the spontaneous abortions were associated with rates of relaxin secretion which were higher than the mean of 14 normal pregnancies. No such alterations in progesterone concentrations were observed. In cases where hCG was extremely low, the quantitative relationship between hCG and relaxin was different from that in cases of normal hCG concentrations.

CONCLUSIONS There is a close temporal relationship between the secretion of trophoblastic hCG and ovarian secretion of relaxin in the peri‐implantation period of normal and failing pregnancies. In failing pregnancies there is substantial variability in the quantitative relationship between relaxin and hCG, indicating that relaxin is not a reliable quantitative indicator of hCG bioactivity. Contrary to previous reports, relaxin concentrations in failing pregnancies tended to be higher than or equal to concentrations in normal pregnancies until the loss was imminent. Because of this relaxin is not a useful predictor of peri‐implantation spontaneous abortions.
The hypothalamo‐pituitary‐adrenal axis across the normal menstrual cycle and in polycystic ovary syndrome
Authors: Stewart P. M. , Perm R. , Holder R. , Parton A. , Ratcliffe J. G. , London D. R.
Published: March 2008

OBJECTIVE We explored the hypothesis that activation of the hypothalamo‐pituitary‐adrenal axis is involved in the pathogenesis of hyperandrogenism in the polycystic ovary syndrome.

PATIENTS Seven women with polycystic ovary syndrome (mean age 27.6 ± 1.6 (SEM) years) (hirsutism, oligo/ amenorrhoea and elevated serum testosterone and dehydroepiandrosterone sulphate) and nine normal female controls (mean age 24.6 ± 15 years) were studied. To exclude anovulation as a confounding factor, four of these normal women were studied in both the follicular and luteal phase of the menstrual cycle.

DESIGN AND MEASUREMENTS Plasma ACTH and Cortisol levels were measured at 15‐minute intervals between 0600 h and 1800 h. ACTH and Cortisol mean levels, pulse number and amplitude were calculated using established computer software, programmed to identify ACTH and Cortisol peaks.

RESULTS With the exception of mean plasma levels of ACTH over the 12‐hour period, which were reduced in the luteal phase of the menstrual cycle (1.8 ± 0.3 pmol/l) compared to the follicular phase (2.3 ± 0.2 pmol/l, P < 005), there were no differences in the pattern of ACTH or Cortisol secretion across the normal cycle. In polycystic ovary syndrome, 12‐hour ACTH pulse frequency was reduced (3.6 ± 0 7) compared with controls (5.9 ± 0.6, P<0.05), but Cortisol pulsatility and ACTH and Cortisol mean levels were similar in both groups.

CONCLUSION The hyperandrogenism of polycystic ovary syndrome cannot be explained by enhanced ACTH secretion. Normal circulating Cortisol levels, yet elevated dehydroepiandrosterone sulphate levels, suggests that polycystic ovary syndrome is yet another example of discrepant adrenal glucocorticoid and androgen secretion, and provides further evidence for a putative adrenal androgen stimulating factor.
The effects of oxandrolone on the growth hormone and gonadal axes in boys with constitutional delay of growth and puberty
Authors: Malhotra A. , Poon E. , Tse W.‐Y. , Pringle P. J. , Hindmarsh P. C. , Brook C. G. D.
Published: March 2008

OBJECTIVE We studied the effects of oxandrolone on serum concentrations of LH, FSH, testosterone, GH, SHBG, DHEAS, IGF‐I and insulin in boys with constitutional delay of growth and puberty.

DESIGN Ten boys with constitutional delay of growth and puberty, mean age 138 years (range 12 4‐15‐5) were studied. Twenty‐four‐hour serum concentration profiles of GH, LH and FSH were constructed by drawing blood samples at 20‐minute intervals. Three study occasions over a period of 6 months were chosen to assess hormone concentrations before, during and 6 weeks after a 3‐month course of oxandrolone (2–5 mg once daily) therapy.

RESULTS Growth velocity increased during oxandrolone treatment and stayed higher after therapy (pre 3.9 ± 0.5; on 6.3 ± 0.8; post 6.4 ± 0.9 cm/year (mean±SEM) two way ANOVA, F=5.3, P= 0.02). Oxandrolone had androgenic effects, suppressing mean serum LH concentrations from 1.7 ± 0.3 to 1.1 ± 0.2 U/I and serum testosterone concentrations from 1.9 ± 0.6 to 0.8 ± 0.1 nmol/l. SHBG concentrations were also reduced from 130.9 ± 14.6 to 307±73 nmol/l. Serum GH concentration fell slightly from 5.9 ± 0.6 to 4.8 ± 0.5 mU/l. After cessation of treatment, there was a significant‘rebound’in mean 24‐hour serum LH (2.6 U/l ± 0.4) and testosterone concentrations (3.2 ± 0.9 nmol/ l) but no change in serum GH concentrations. SHBG values also rose but not to the same extent as those observed before therapy (82.0 ± 84 nmol/l). There were no statistically significant differences in serum concentrations of FSH, DHEAS, IGF‐I and insulin over the study period.

In a stepwise multiple regression analysis of factors that might influence the growth rate observed, the 24‐hour mean serum testosterone concentration and the treatment (on or off) with oxandrolone were the main influences. The relationship was described by the equation Height velocity = 0.69 (24‐hour mean serum testosterone concentration) +1 70 (treatment regimen) + 3.37 (adjusted R2= 0.35, F= 8.39, P= 0.001).

CONCLUSIONS Oxandrolone has an androgenic action as shown by changes in serum LH, testosterone and SHBG concentrations and by the lack of effect on FSH. No effect of oxandrolone on the GH axis was documented. We suggest that the growth promoting effects of oxandrolone are related in part to the mild androgenic effects of the steroid and the growth acceleration following oxandrolone withdrawal may reflect increasing total serum testosterone concentrations and decreasing levels of SHBG and progress in puberty.
Effect of 131 I treatment on the calcitonin response to calcium infusion in hyperthyroid patients
Authors: Tzanela M. , Thalassinos N. C. , Nikou A. , Georgiadis G. , Philokiprou D.
Published: March 2008

OBJECTIVE The objective was to evaluate the effect of 131I treatment for hyperthyroidism on calcitonin secretion by thyroid C‐cells.

DESIGN Determination of basal calcitonin levels and calcitonin secretory reserve before and aiter 131I administration.

PATIENTS Seventeen hyperthyroid patients (15 female, two male) were studied before, and 2 months after 131I treatment, and 12 of these patients were restudied 8 months after 131I treatment.

MEASUREMENTS Calcitonin response was assessed by measuring basal and post calcium infusion calcitonin levels. Basal TSH, T3, and T4 levels were also determined at each study.

RESULTS The rise of plasma calcium resulted in statistically significant increase of plasma calcitonin levels before 131I treatment (10.9·2.4 pmol/l), while this response was significantly diminished 2 and 8 months after treatment (2.6·0.7 and 1.6·0.3 pmol/l, respectively). No correlation was found between the calcitonin response and age or plasma TSH.

CONCLUSION Our results demonstrate that 131I treatment for hyperthyroidism may seriously damage thyroid C‐cells and cause calcitonin deficiency.
Cross‐sectional and longitudinal study of the pituitary‐thyroid axis in patients with thalassaemia major
Authors: Landau H. , Matoth I. , Landau‐Cordova Z. , Goldfarbs A. , Rachmilewitz E. A. , Glaser B.
Published: March 2008

OBJECTIVE AND DESIGN Thyroid dysfunction is known to occur frequently In thalassaemla major, but Its prevalence and severity varies in different cohorts, and the long‐term natural history is poorly described. We evaluated the pituitary/thyroid axis in thalassaemia major patients in a cross‐sectional study and correlated abnormalities with indices of iron overload. Furthermore, the course of thyroid disease in thalassaemia major patients was assessed In a 15‐year longitudinal study.

PATENTS AND MEASUREMENTS Cross‐sectional study: pituitary‐thyroid axis function was examined in 37 patients (22 F, 15 M; aged 10–39 years, mean ± SE = 21 ± 1.4) out of a total of 43 who attended the Haematology and Endocrinology Clinics of Hadassah Hospital on a regular basis. The mean pretransfusion Hb level was 85·20 g/l, and all patients except one were treated with desferrioxamine (DF, mean SE dose 20.2·2.6 mg/kg/day). Twenty‐two had hypogonadotrophic hypogonadism (HH). Longitudinal study: 21 thalassaemia major patients were evaluated with TRH tests in 1976 and again in 1985. Fourteen of these and another eight were evaluated in both 1985 and 1991. RESULTS Cross‐sectional study: no patient had any clinical signs or symptoms of hypothyroidism; however, one had abnormally low T4, borderline low FT4 and normal T3 levels associated with an exaggerated TSH response to TRH consistent with mild hypothyroidism. This patient did not have a previous TRH test, but serial basal determinations over 7 years revealed a progressive decrease in thyroid function. Thirty‐six patients had thyrold hormone levels within the normal range. Nine of these (24.3%) had only an exaggerated TSH response to TRH whereas seven others (19%) also had borderline elevated basal TSH levels. TSH response to TRH was not correlated with age, serum ferrltin or liver function tests (ALT or GGT). Longitudinal study: mean TSH response to TRH decreased (P >0.002), and mean T3 levels Increased (P >0.001) between 1975 and 1985. These findings are probably related to the initiation of DF treatment in 1981. During the last 6 years, four patients with previously normal TSH responses to TRH developed elevated peak TSH levels. Mean T3 concentrations decreased and TSH response to TRH increased significantly (P >0.001 for both).

CONCLUSIONS (1) In this patient group the thyroid pituitary axis is less sensitive than the gonadal axis to iron‐induced damage; only one out of 37 patients developed mild uncompensated hypothyroidism. (2) As opposed to the gonadal axis, the thyrold gland appears to fail before the central components of the axis. (3) Abnormal thyroid function may be reversible in the early stages. (4) Progression is variable, and it may take years to progress from normal to uncompensated hypothyroidism.
Assessment of endocrine function after transsphenoidal surgery for Cushing's disease
Authors: McCance D. R. , Gordon D. S. , Fannin T. F. , Hadden D. R. , Kennedy L. , Sheridan B. , Atkinson A. B.
Published: March 2008

OBJECTIVE We assessed the endocrine outcome after transsphenoidal surgery for Cushing's disease.

DESIGN Five‐year (mean) follow‐up (range 1 month‐12 years) of patients undergoing transsphenoidal surgery for Cushing's disease between 1977 and 1990; review of case notes, current clinical and biochemical assessment including 24‐hour urinary free cortisol.

SETTING Northern Ireland.

SUBJECTS Forty‐one patients (33F:8M); mean age at dlagnosls 39 1 years (9–72 years).

MAIN OUTCOME MEASURES Measurements of early post‐operative 0800 h serum cortisol and 24‐hour urinary free cortisol at least 24 hours after withdrawal of oral hydrocortisone therapy. This was followed by low dose dexamethasone testing. Current 24‐hour urinary free cortisol measurements. Retrospective definition of cure.

RESULTS Twenty‐seven patients were either cured or improved by surgery, 14 were considered definite failures.

Of 19 patients cured, eight had unmeasurable early postoperatlve 0800 h serum cortisol levels while of 15 tested, 13 had complete suppression with dexamethasone and two suppressed normally but to still measurable levels (39 and 60 nmol/l respectively). Seventeen patients in total have subsequently had bilateral adrenalectomy of whom two have developed Nelson's syndrome. Seven of the 41 patients were shown to have definite cyclical cortisol secretlon first diagnosed post‐operatively in three patients. Hormone deficiency included TSH (5), LH/FSH (1), cortisol (1) and ADH (temporary in 7, permanent in 1). In all, seven patients had some type of permanent hormonal deficiency post‐operatively.

CONCLUSIONS Transsphenoidal surgery offers a worthwhile cure rate without the necessity of life‐long endocrine therapy. Post‐operative endocrine assessment must be rigorous so that early further management can be planned in the significant percentage of patients in whom cure is not achieved. Early complete suppression on low dose dexamethasone testing is very suggestive of cure but repeated and long‐term monitoring of 24‐hour urinary free cortisol is advisable.
The frequency and amplitude of growth hormone secretory episodes as determined by deconvolution analysis are increased in adolescents with insulin dependent diabetes mellitus and are unaffected by short‐term euglycaemia
Authors: Pal B. R. , Matthews D. R. , Edge J. A. , Mullis P. E. , Hindmarsh P. C. , Dunger D. B.
Published: March 2008

OBJECTIVE High overnight plasma growth hormone (GH) levels in insulin‐dependent diabetes mellitus (IDDM) are reflected in both an increase in the GH pulse amplitude and elevated baseline GH concentrations. To determine whether these are a result of an increase in GH secretory episodes, we undertook deconvolution analysis of overnight GH profiles using previously determined half‐life data.

DESIGN Deconvolution of overnight GH profiles (2000–0800 h) was undertaken from normal and diabetic adolescents (either on their usual insulin regime (n= 15), during overnight euglycaemic clamp using a variable rate insulin infusion (n= 29), or during clamp plus 100 mg pirenzepine to suppress endogenous GH (n= 7)).

PATIENTS Thirty‐five normal and 29 diabetic adolescents of both sexes at all stages of puberty.

MEASUREMENTS GH secretory rates were calculated from deconvolution analysis, and Fourier transformation was used to determine dominant pulsatility.

RESULTS In diabetic subjects on their usual regime, there was increased mean overnight GH secretion when analysed by sex and by puberty stage compared to normal subjects; overnight OH secretion median (range) of diabetic group 1.48 (0.56–3.81) mU/min; control group 0.62 (0.32–1.92) mU/min (P>0 001). Fourier transform analysis of these secretory episodes showed greater pulse frequency in the diabetics with dominant pulse periodicity of 90 minutes compared with 135 minutes in normal subjects.

During overnight euglycaemia, mean ± SEM overnight GH secretory rates were comparable to subjects' usual regime night (1.82 ± 0.33 vs 1.91 ± 0.37 mU/min) and there was no change in the dominant pulse periodicity of 90 minutes. Pirenzepine administration in diabetic subjects significantly reduced overnight GH secretion from 1.57 ± 0.19 to 0.71 ± 0.80 mU/min (P> 0.001) showing a median (range) reduction of 63 (9.3–82. 8)% when compared to the subjects' clamp night. However, dominant pulse periodicity was not altered by pirenzepine administration, and remained at 90 minutes.

CONCLUSION In patients with insulin‐dependent diabetes mellitus there is an increase in both the amplltude and frequency of pulsatile GH secretion compared to normal subjects, which is not affected by maintenance of overnight normoglycaemia. The anticholinergic drug pirenzepine appears to suppress the amplitude of GH pulse secretion but has no effect on frequency.
Congenital hypothyroidism: the Riyadh Military Hospital experience
Authors: Majeed‐Saidan M. A. , Joyce Brian , Khan Masood , Hamam Hisham D.
Published: March 2008

OBJECTIVE We aimed to find out the incidence of primary congenital hypothyroidism (CH) among infants born within the Riyadh Al‐Kharj Hospital Programme in addition to early detection and treatment of these infants.

DESIGN All babies born within the Riyadh Al‐Kharj Hospital Programme were screened by cord blood TSH. Blood spot TSH were done in the majority of infants between 2 and 5 days after birth. All suspected cases were recalled for confirmatory tests. 123I thyroid scan and X‐ray of the knee and maternal blood for thyroid antibodies were done for confirmed cases.

MEASUREMENTS A cut off TSH level of 30 mlU/l for cord blood and 25 mlU/l for spot blood were used. All samples were assayed by immunoassay methods.

RESULTS 44778 (99.4% of the total births) infants were screened. Twenty‐five cases were detected, four of which were excluded. The incidence of primary congenital hypothyroidism was 1/2096. Five cases were missed on the initial screen. Eight out of 17 children who had 123I thyroid scan were found to have dyshormonogenesis. Associated malformation and diseases were diagnosed in 42.85%. Two had chromosomal anomalies; ring chromosome 9 has not been previously reported in association with congenital hypothyroidism.

CONCLUSION The incidence of congenital hypothyroidism, dyshormonogenesis and the associated malformations and diseases are higher than those reported in the literature. Cord blood as a screening method is associated with a significant number of missed cases.
PCR analysis and sequencing of the SRY sex determining gene in four patients with bilateral congenital anorchia
Authors: Lobaccaro Jean‐Marc , Medlej Rita , Berta Philippe , Belon Charles , Galifer René‐Benoit , Guthmann Jean‐Paul , Chevalier Catherine , Czernichow Paul , Dumas Robert , Sultan Charles
Published: March 2008

OBJECTIVE We explored the possibility of a genetic anomaly in the sex determining region of the Y chromosome, SRY gene, known to be equated to the testis determining region.

PATIENTS Four patients with bilateral congenital anorchia, absence of testicular tissue, elevated FSH and a lack of testosterone response to human chorionic gonadotropin stimulation tests were studied.

MEASUREMENTS Amplification by polymerase chain reaction of the SRY gene and direct double stranded DNA sequencing were performed with the same primers.

RESULTS The expected 648 basepairs band of SRY was detected in the four DNA samples from patients with bilateral congenital anorchia. Direct sequencing did not show any difference with the previous published sequence.

CONCLUSIONS These data suggest that, in the four patients, bilateral congenital anorchia is not related to an anomaly of the opening reading frame sequence of the SRY gene.
Hyperinsulinaemia in the polycystic ovary syndrome confirmed with a specific immunoradiometric assay for insulin
Authors: Conway Gerard S. , Clark P. M. S. , Wong D.
Published: March 2008

OBJECTIVE Hyperinsulinaemia in the polycystic ovary syndrome (PCOS) has previously been defined using polyclonal radioimmunoassays (RIA) in which partially processed insulin‐like molecules cross‐react. This study aimed to reassess hyperinsulinaemia in women with PCOS using specific immunoradiometric assays (IRMA) for insulin, proinsulin and 32–33 spilt proinsulin.

DESIGN Patients attended for 75 g oral glucose tolerance tests and were divided into groups depending on their degree of obesity and fasting insulin status determined by RIA. IRMA measurements for insulin‐like molecules in plasma from patients with PCOS and controls were compared.

PATIENTS Thirty‐four patients with ultrasound diagnosed PCOS presented to a reproductive endocrinology clinic. A control group comprised women with normal ovaries on ultrasound. Four groups were constructed, two with normal fasting insulin concentrations (lean PCOS and controls) and two with hyperinsulinaemia (lean and obese PCOS).

MEASUREMENTS Plasma glucose, insulin (RIA and IRMA), proinsulin and 32–33 split proinsulin concentrations were measured at time 0, 30 and 120 minutes of an oral glucose tolerance test.

RESULTS Hyperinsulinaemia determined by RIA in lean and obese women with PCOS was confirmed using a specific IRMA assay for insulin. Plasma proinsulin and 32–33 split proinsulin concentrations were higher in hyper‐insullnaemic women with PCOS compared with women with normal insulin concentrations. The proportion of circulating insulin‐like molecules represented by proinsulin and 32–33 split proinsulin was similar in all groups studied.

CONCLUSIONS Hyperinsulinaemia in PCOS is likely to reflect insulin resistance because the raised concentrations of proinsulin and 32–33 split proinsulin were in proportion to the raised insulin concentrations. Hyperinsulinaemia in PCOS, defined by RIA, therefore differs from that in non‐Insulin dependent diabetes mellitus where it Is largely accounted for by disproportionate hyperproinsulinaemla.
Influence of spontaneous or induced puberty on the growth promoting effect of treatment with growth hormone in girls with Turner's syndrome
Authors: Massa Guy , Maes Marc , Heinrichs Claudine , Vandeweghe Mark , Craen Margarita , Vanderschueren‐Lodeweyckx Magda
Published: March 2008

OBJECTIVE The aim was to evaluate the effect of 3 years treatment with recombinant human growth hormone (rhGH) on height velocity and height in girls with Turner's syndrome (TS) and to study to influence of spontaneous or induced puberty on the growth promoting effect of rhGH.

PATIENTS AND DESIGN The investigation was performed in 36 girls with Turner's syndrome treated for 3 years with rhGH in a dose of 1 IU/kg week, administered as daily subcutaneous injections. Fifteen patients remained prepubertal throughout the observation period (Group 1). During the first 2 years of rhGH therapy, four girls developed puberty spontaneously (Group 2). During the 3rd year of rhGH treatment puberty was induced with 100 ng/kg day ethinyl oestradlol orally in 17 girls requesting pubertal development and with a bone age of at least 11‘years' (Group 3).

RESULTS During the first year of rhGH therapy height velocity increased significantly in all patients. Mean ± SD height velocity was higher in the four patients with Turner's syndrome who developed spontaneous puberty than in 17 age‐matched girls with Turner's syndrome without puberty (8.9 ± 1.2 vs 7.4 ± 12 cm/year; P < 0.05). During the second and third year of rhGH treatment height velocity decreased in all patients but remained above baseline levels. The induction of puberty with 100 ng/kg day ethinyl oestradlol in the patients of Group 3 did not lead to an acceleration of height velocity, but seemed in contrast to decelerate height velocity. After 3 years of rhGH treatment, 21 out of 36 patients have obtained a height at or above the initially calculated projected adult height and five girls are already taller than 150 cm.

CONCLUSIONS The onset of spontaneous puberty during the first years of rhGH treatment seems to have an additive effect to rhGH on height velocity. Induction of puberty with oral administration of 100 ng/kg day ethinyl oestradiol did not have any beneficial effect on height velocity and seems therefore not to be the optimal way to induce puberty with an adequate pubertal growth spurt in girls with Turner's syndrome under rhGH therapy. Different doses and routes of oestrogen administration have to be evaluated in order to mimic the growth promoting effect of spontaneous puberty as well as possible.
Endothelin‐1 receptors in the human myometrium: evidence for different binding properties in post‐menopausal as compared to premenopausal and pregnant women
Authors: Schiff Eyal , Ben‐Baruch Gilad , Galron Ronit , Mashiach Shlomo , Sokolovsky Mordechai
Published: March 2008

OBJECTIVE We investigated the binding properties of the endothelin receptors in the human myometrium in clinical situations associated with different ovarian steroid levels.

SUBJECTS AND METHODS Binding properties of the endothelin receptors were studied in myometrial membranes from post‐menopausal women (n= 12), myomatous premenopausal women (n= 14) and pregnant women (n= 14), using 125I‐labelled endothelin‐1.

RESULTS The mean (SD) maximal receptor density (Bmax) was significantly higher in samples from premenopausal and pregnant women than from post‐menopausal women (983 ± 196, 1116 ± 201 and 490 ± 145 pmol/g protein, respectively). Receptor affinity (Kd) did not differ significantly between these groups. Among the pregnant women, mean Bmax and Kd values were similar in those who electively underwent Caesarean section prior to the onset of labour and those operated on during the second stage of spontaneous labour. Binding properties of myometrial membranes of either pre or post‐menopausal women were unaffected by the presence of high levels of beta‐oestradiol or progesterone in the medium. Among samples of premenopausal women, no significant difference was found in binding properties between those operated on either during mid‐follicular phase or during mid‐luteal phase.

CONCLUSIONS In clinical situations associated with relatively high levels of ovarian steroids, the density of endothelin receptors in the myometrium is higher than in situations associated with low ovarian steroid level. Ovarian steroids may exert their influence via the production of other mediators. Changes in density of the endothelin receptor, induced by change in ovarian steroids activity, might play a role in the regulation of myometrial contractility.
A case of papillary carcinoma of the thyroid with more than 30 years long‐term asymptomatic pulmonary metastases
Authors: Maruyama Masayuki , Sugenoya Akira , Kobayashi Shinya , Masuda Hiroyuki , Shimizu Tadahiro , Lida Futoshi
Published: March 2008

This is a case report of a patient with thyroid cancer with asymptomatic pulmonary metastases, and without obvious progression over 34 years.

The patient, a 47‐year‐old male, was shown to have miliary shadows on chest radiographs from the age of 13; indeed, he was temporarily treated for pulmonary tuberculosis without success. A tumour appeared in the right neck in December 1988 (at age 47). A diagnosis of lymph node metastasis of papillary carcinoma of the thyroid was made by biopsy; he then underwent total thyroidectomy with radical dissection of the neck (April 1989). However, the bilateral metastatic lymph nodes in the neck had invaded the vasculature, preventing complete dissection. Post‐operative whole body 131I scintigraphy revealed diffuse intensive uptake in the bilateral lung fields, demonstrating for the first time that the pulmonary lesions were metastases of the thyroid cancer. He remains under periodic effective treatment with 131I.
Proinsulin, proinsulin intermediate and insulin in cystic fibrosis
Authors: Hamdi I. , Green M. , Shneerson J. M. , Palmer C. R. , Hales C. N.
Published: March 2008

OBJECTIVE We determined the changes in insulin, intact proinsulin and 32‐33 split proinsulin as markers of β cell damage in assessing the state of carbohydrate intolerance in patients with cystic fibrosis.

DESIGN Measurements of insulin, proinsulin and 32‐33 proinsulin concentrations in cystic fibrosis following oral glucose tolerance test (OGTT).

SUBJECTS Sixteen cystic fibrosis patients attending the chest outpatient clinic for follow‐up, age range 14–42 years, and 14 healthy controls matched for age and body mass index.

MEASUREMENTS Insulin, intact proinsulin and 32‐33 split proinsulin were measured immunoradiometrically at 0, 30, 60, 90 and 120 minutes after an OGTT. Glucose and HbA1 were also measured.

RESULTS Cystic fibrosis patients were divided into two groups according to their OGTT results: those with diabetes mellitus or impaired glucose tolerance and those with normal glucose tolerance.

Insulin concentrations and insulin/glucose ratios at 30 minutes were lower in both cystic fibrosis groups in comparison with the control. There was also a significant increase in the time to reach peak insulin levels in both cystic fibrosis groups.

Fasting intact proinsulin concentrations and the proportion of proinsulin‐like molecules were significantly higher in cystic fibrosis with diabetes mellitus or impaired glucose tolerance than in the control group, but not in the normal glucose tolerance cystic fibrosis group. There was no significant difference in the plasma concentrations of 32‐33 split proinsulin amongst the three groups.

CONCLUSIONS Abnormal β cell function in cystic fibrosis patients was reflected initially in a diminished 30‐minute insulin response to oral glucose. A significant rise in fasting intact proinsulin and the proportion of proinsulin‐like molecules was seen only in cystic fibrosis patients who had progressed to impaired glucose tolerance or diabetes mellitus. Cystic fibrosis patients with normal glucose tolerance showed changes intermediate between the control and the other group.
Effect of varying concentrations of follicle stimulating hormone on the production of gonadotrophin surge attenuating factor (GnSAF) in women
Authors: Messinis I. E. , Lolis D. , Papadopoulos L. , Tsahallna Th. , Papanikolaou N. , Seferiadis K. , Templeton A. A.
Published: March 2008

OBJECTIVE We studied the time‐course of production of gonadotrophin surge attenuating factor (GnSAF) in relation to varying serum concentrations of FSH in women. DESIGN Normally cycling women were investigated in four cycles, i.e. a spontaneous cycle treated with placebo (cycle P) and three cycles treated with three different FSH dosages (1 ampoule, cycle 1; 3 ampoules, cycle 3 and 6 ampoules, cycle 6). Placebo or FSH were given as a single i.m. injection on cycle day 2 (0900 h). The response of LH to an i.v. injection of 10 μg GnRH (GnSAF bioactivity) was investigated 4, 8, 12 and 24 hours after the injection of placebo or FSH.

PATIENTS Six normally ovulating women with long‐standing unexplained infertility were studied. The women were used as their own controls during the cycle treated with placebo.

MEASUREMENTS Pituitary response to GnRH was calculated as the net increase in LH at 30 minutes (ΔLH) above the basal value.

RESULTS Serum FSH concentrations increased after the injection of FSH in a dose dependent manner. Compared with cycle P, Δ LH was significantly attenuated in cycle 3 and cycle 6 at 8,12 and 24 hours and in cycle 1 at 12 hours after the injection of FSH. Basal concentrations of oestra‐diol (E2) and LH did not differ significantly among the four cycles at any point except in cycle 6 at 24 hours after the FSH injection when E2 values were significantly higher and LH values significantly lower than in cycle‐P.

CONCLUSIONS These results suggest that GnSAF bioactivity increases significantly as early as 8 hours from a single injection of FSH before any significant increase in serum E2 values. We conclude that in women the effect of FSH on the production of GnSAF in the early follicular phase is concentration dependent.
Calcitonin gene‐related peptide in small cell lung carcinomas
Authors: Schifter Søren , Johannsen Lis , Bunker Chris , Brickell Paul , Bork Ellen , Lindeberg Henning , Faber Jens
Published: March 2008

OBJECTIVE Calcitonin gene‐related peptide (CGRP) is a regulatory peptide encoded by the calcitonin gene. CGRP is expressed in increased amounts by the cells of medullary thyroid carcinomas and has been demonstrated by immunohistochemistry to occur in neuroendocrine cells and nerve fibres of lung tissue.

MEASUREMENTS Serum CGRP levels were measured in patients with small cell lung carcinomas before treatment (n= 74) and immediately before the second course of chemotherapy (n= 30). In‐situ hybridization and immunohistochemistry were performed on tumour tissue and CGRP was extracted from two tumours and characterized by gel chromatography and high pressure liquid chromatography.

RESULTS Serum CGRP levels were elevated in small cell lung carcinomas when compared with healthy controls of similar age and sex (median values 55.0 vs 36.6 pmol/l, P<0.001), and 27% had levels above the upper normal range. Serum CGRP levels decreased following the initial course of chemotherapy (P < 0.05) but remained elevated when compared to the controls (P < 0.001). In‐situ hybridization for CGRP mRNA was positive in three of 17 tumours and immunohistochemistry was positive in seven of 31 tumours investigated. CGRP immunoreactivity extracted from two tumours was characterized by gel chromatography and high pressure liquid chromatography. A major part of the immunoreactivity was demonstrated to represent the intact molecule.

CONCLUSIONS We found that patients with small cell lung carcinomas had elevated concentration of serum calcitonin gene‐related peptide but only 27% had values above the upper normal range. Serum CGRP is therefore of limited value as a tumour marker. Intact CGRP can be extracted from tumour tissue, but in‐situ hybridization and immunohistochemistry showed positive reactions in only a few of the tumours investigated. The elevated serum CGRP levels are therefore likely to be largely of extratumoral origin.
Relation between phenotype and intra‐cellular thyroid hormone effect in patients with altered peripheral thyroid hormone sensitivity
Authors: Kvetny J. , Bollerslev J.
Published: March 2008

OBJECTIVE We wished to ascertain whether different phenotypic appearances in patients with altered cellular sensitivity to thyroid hormones were related to the type of altered intra‐cellular thyroid hormone effect.

DESIGN Blood samples were obtained from two members of a family suffering from generalized thyroid hormone resistance (GTHR) for hormone assays and examination of the cellular thyroid hormone effect, and the results compared with results from other families with signs of altered peripheral thyroid hormone sensitivity.

PATIENTS Two members of a family with thyroid hormone resistance and nine normal persons were studied.

MEASUREMENTS Basal thyroid hormone function tests were measured. The thyroid hormone effect on mononuclear blood cells was determined by measuring the thyroid hormone stimulated oxygen consumption and glucose uptake.

RESULTS The two family members appeared phenotypically normal except for nodular goitre. Thyroid hormone stimulated glucose uptake was depressed whereas thyröid hormone stimulated oxygen consumption was normal.

CONCLUSION Comparison of the present results of the cellular examination in two patients with GTHR, with the results obtained in other families with altered peripheral thyroid hormone sensitivity, suggest that the classic GTHR (phenotype: normal or with goitre) is linked to impaired thyroid hormone stimulated glucose uptake, whereas in patients with osteopetrosis, the thyroid hormone insensi‐tivity seems located at the mitochondrial level (impaired thyroid hormone stimulated oxygen consumption).
Effects of growth hormone therapy on the developmental changes of follicle stimulating hormone and insulin‐like growth factor‐I serum concentrations in Turner's syndrome
Authors: Bourguignon Jean‐Pierre , Gérard Arlette , Deby‐Dupont Ginette , Franchlmont Paul
Published: March 2008

OBJECTIVE The aim was to investigate whether, in the absence of gonads, GH could bring forward the age of neuroendocrine activation resulting in onset of puberty. DESIGN In girls with Turner's syndrome, we evaluated the effects of GH therapy on developmental changes in FSH serum concentrations used as an indicator of neuroendocrine maturation in the absence of gonads.

PATIENTS Thirty‐nine girls with Turner's syndrome aged 4.0‐17.1 years were treated using GH (25 IU/m2 week) for 1 year.

MEASUREMENTS Serum levels of FSH and IGF‐I were measured before initiation of GH therapy and 12 months later, after interruption of GH treatment for 2 days.

RESULTS Pretreatment FSH levels were low between 6 and 10 years and increased markedly at 10‐11 years of age. This pattern was unchanged after 1 year of GH therapy. Pretreatment IGF‐I levels were positively correlated with age and they were uniformly increased after 1 year of GH therapy.

CONCLUSIONS Our data suggest that GH and its effector, IGF‐I, do not influence the timing of the onset of puberty through an effect on its neuroendocrine control.
An audit of dynamic function tests: errors in the timing of blood specimens
Authors: Barth J. H. , Page M. D. , Bailey I. R.
Published: March 2008

OBJECTIVE The interpretation of dynamic endocrine investigations is dependent on the timing of blood sampled after a stimulus. We have studied the accuracy with which doctors adhered to a prescribed protocol. DESIGN A new request form for dynamic tests was designed to include both the planned and the actual time of blood sampling in order to allow assessment of the variance of sample timing.

MEASUREMENTS We followed 152 investigation procedures comprising 791 planned specimens. A total number of 627 timing intervals could be analysed of which 366 timing intervals did not differ from the planned Interval. Protocols were divided into long and short (greater or less than 6 hours) and into those governed by clock times or ‘stopwatch’, i.e. minutes elapsed, Intervals. RESULTS A total of 22% specimens were taken more than 10 minutes earlier or later than planned. Six per cent of specimens were taken more than 30 minutes earlier or later than planned.

CONCLUSIONS The data presented in this study suggest that in order to improve the interpretative accuracy of dynamic tests, it would appear prudent to pay more attention to the accuracy of sample timing. New dynamic test publications should include time tolerance for the normal response.
Severe peripheral neuropathy and elevated plantar pressures causing foot ulceration in pituitary gigantism
Authors: Jennings A. M. , Robinson A. , Kandler R. H. , Betts R. P. , Ryder R. E. J. , Cullen D. R.
Published: March 2008

We report two patients with treated pituitary gigantism and peripheral neuropathy, one of whom has chronic foot ulceration. Detailed neurophysiologfcal assessment was performed on both patients. The patient with foot ulceration had clinical and neurophysiological evidence of severe neuropathy, whereas the patient without ulceration had only neurophysiological abnormalities. The sweating response to acetylcholine was markedly impaired in the feet of both patients, suggesting pedal autonomic denervation. Neither patient had evidence of diabetes mellitus and detailed investigation failed to reveal an alternative cause of peripheral neuropathy. Optical pedobarography revealed abnormally high pressure (>10 kg/cm2) under the metatarsal heads of both patients, one such area coinciding with the area of ulceration. Thus in pituitary gigantism elevated plantar pressures may contribute to the development of foot ulceration when severe peripheral neuropathy Is present. Furthermore, as in diabetes mellitus, impaired sweating may also increase the risk of ulceration as the resultant dry skin may develop fissures.
The effect of recombinant human insulin‐like growth factor‐I treatment on growth hormone secretion in two subjects with growth hormone insensitivity (Laron syndrome)
Authors: Cotterill Andrew M. , Camacho‐Hübner Cecilia , Holly Jeffrey M. P. , Savage Martin O.
Published: March 2008

OBJECTIVE Growth hormone (GH) secretion Is increased in conditions of GH insensitivity such as Laron syndrome, with elevation of both basal and peak levels. We have studied the effect of recombinant IGF‐I therapy on the pattern of GH secretion in two subjects with GH insensitivity.

SUBJECTS Two pubertal subjects with GH insensitivity (female, 16.4 years, breast stage 3; male 13.6 years, genital stage 2) were investigated after 6 months of IGF‐I therapy (120 μg/kg twice daily s.c. at 0800 and 1900 h). GH profiles taken before the start of IGF‐I therapy, when both subjects were prepubertal (aged 14 0 and 11 5 years respectively), were used for comparison.

METHODS GH profiles were performed with blood samples taken every 20 minutes between 2000 and 0800 h from an indwelling cannula.

MEASUREMENTS Serum samples were assayed for GH by immunoradiometric assay and IGF‐I, IGFBP‐1 and insulin by radioimmunoassay.

RESULTS Before IGF‐I therapy, GH profile studies demonstrated pulsatile GH secretion. Basal GH was elevated with no value falling below the limit of detection of the assay and an increase in peak levels (maximum 203 and 206 μ/I at 0000 h and 0020 h respectively). After 6 months IGF‐I therapy, the GH profiles were significantly different. With the onset of puberty a further increase in GH secretion would have been expected; nevertheless, following administration of IGF‐I at 1900 h, GH secretion decreased with a reduction in mean overnight GH levels from 65 to 33 μ/l and 53 to 11 μ/l respectively. GH pulsatility was also suppressed in the two subjects, for the first 3.5 and 6 hours overnight respectively. Pulsatile GH secretion then returned with peak levels reaching 130 and 63 μ/l respectively.

Prior to therapy IGF‐I levels were at the lower limit of assay detection. On IGF‐I therapy serum IGF‐I levels reached a peak within 3 hours (298 and 438 μg/l) coinciding with the suppression of GH secretion. IGF‐I levels fell rapidly overnight to 92 and 101 μg/l at 0800 h prior to the next injection. The fall in serum IGF‐I coincided with the return of GH secretion.

IGFBP‐1 levels increased overnight both before and during IGF‐I therapy, rising from 24 to 83 and 22 to 110 μg/l before therapy and 13 to 60 and 13 to 71 μg/l during therapy. This rise in IGFBP‐1 appeared to be inversely related to the fall in serum insulin levels overnight and appeared not to be affected by IGF‐I therapy.

CONCLUSION GH secretion is suppressed by exogenous IGF‐I therapy in GH insensitive subjects. The failure to maintain high serum IGF‐I levels overnight, presumably due to a persisting defect in serum IGFBP‐3 levels, was associated with an early return of GH secretion. These findings may have implications for the dose and regimen of IGF‐I therapy in subjects with growth hormone insensitivity.