bluuebunny/crossref_metadata_2025 huggingface dataset:
The significance of a single serum LH measurement in women with cycle disturbances: discrepancies between immunoreactive and bioactive hormone estimates*
Authors: Fauser Bart C. J. M. , Pache Thierry D. , Hop Wim C. J. , de Jong Frank H. , Dahl Kristine D.
Published: March 2008

OBJECTIVE We evaluated the significance of single serum LH estimates (as assessed by radiometric assay (IRMA) and Leydig cell in‐vitro bioassay (BIO)) for the diagnosis of polycystic ovary syndrome (PCOS) in women with infertility and cycle abnormalities.

DESIGN Hormonal and clinical comparisons between subgroups were made based on classification according to (a) rigid clinical and endocrine (excluding LH) characteristics of PCOS, (b) elevated IRMA‐LH concentrations, (c) BIO‐LH levels. In addition, androgen modulation of LH biopotency was studied in these patients.

PATIENTS Ninety‐nine women presenting at our infertility Unit with oligo/amenorrhoea.

MEASUREMENTS AND RESULTS Of the total study group, 35 women were diagnosed positive as PCOS and 42 showed elevated IRMA‐LH levels. Only 51% (n= 18) of PCOS patients showed elevated IRMA‐LH levels, and in PCOS significantly higher levels of BIO‐LH, androstenedione, oestrone, and BIO/IRMA‐LH ratios were found as compared to non‐PCOS patients. In the group with elevated IRMA‐LH only 43% (n= 18) of subjects were diagnosed as PCOS, and no difference in BIO/IRMA‐LH ratios was found. With increasing BIO‐LH levels the probability of PCOS rises sharply (P < 0.001), whereas this probability is of only marginal significance (P <0.06) for IRMA‐LH. In the total study group a correlation is observed between serum testosterone (T) levels and IRMA‐LH (r= 0.47), and BIO‐LH (r= 0.51) concentrations. This correlation is absent comparing serum T and BIO/IRMA‐LH ratios (r= 0.15).

CONCLUSIONS Results presented in this study indicate that (1) women with infertility and oligo/amenorrhoea classified based on signs of PCOS or IRMA‐LH levels, exhibit different clinical and endocrine characteristics, (2) only 51% of PCOS women exhibit elevated IRMA‐LH concentrations, and only 43% of women with elevated IRMA‐LH were diagnosed as PCOS, (3) IRMA‐LH levels are a poor predictor of PCOS, whereas the predictive value of BIO‐LH is better, (4) elevated BIO/IRMA‐LH ratios in PCOS are dependent on alterations in BIO‐LH, rather than IRMA‐LH concentrations, and (5) no correlation was observed between serum T levels and BIO/IRMA‐LH ratios.
Comparison of measures of body composition in a trial of low dose growth hormone replacement therapy
Authors: Orme S. M. , Sebastian J. P. , Oldroyd B. , Stewart S. P. , Grant P. J. , Stickland M. H. , Smith M. A. , Belchetz P. E.
Published: March 2008

OBJECTIVE We assessed the effects of the administration of low dose growth hormone in growth hormone deficient adults on body composition and physical performance. We compared the validity of different measures of body composition in GH treated adults.

DESIGN An uncontrolled longitudinal study of eight patients with GH deficiency who were treated with 4 units of biosynthetic growth hormone (Norditropin), three times a week. Subjects were studied for 8 weeks.

PATIENTS Eight patients with acquired growth hormone deficiency as defined by <5mU/1 GH following standard provocative investigations in whom other hormone replacement was optimized.

MEASUREMENTS IGF‐I was measured on day 1 and after 4 and 8 weeks of treatment with recombinant human growth hormone. Body composition was estimated by dual energy X‐ray absorptiometry, bioelectrical impedance, skinfold anthropometry, total body potassium measurement and by computerized tomography of a representative cross‐sectional area of thigh on day 1 and following 8 weeks of treatment. Exercise capacity was measured on an electromechanical bicycle and palmar grip strength was measured using a Jamar dynamometer on day 1 and after 8 weeks.

RESULTS IGF‐I increased significantly. Exercise capacity and maximum heart rate achieved on the electromechanical bicycle increased significantly. Grip strength did not change. There was a significant increase in fat‐free mass and a decline in fat mass as shown by dual energy X‐ray absorptiometry and bioelectrical impedance. However, this was not confirmed by other methods. No side‐effects were noted.

CONCLUSIONS This study shows that a low dose of biosynthetic growth hormone can elevate IGF‐I levels and have a pronounced physical impact in the growth hormone deficient adult without the side‐effects seen at higher dosage schedules. Over a 2 month period the increase in fat‐free mass may be due to an increase in total body water; however, the decline in fat mass is a genuine effect.
Painful thyroid gland: an atypical presentation of Graves' disease
Authors: Stanley Julia M. , Najjar Samir S.
Published: March 2008

An adolescent with Graves' disease presented with acute painful swelling of the thyroid gland and overlying erythema simulating acute suppurative or subacute thyroiditis. She had an elevated radioactive iodine uptake, thyroid stimulating antibodies, thyrotrophin binding inhibiting immunoglobulins, and a normal sedimentation rate and leucocyte count. The course of the thyrotoxicosis and painful thyroid was protracted, and the pain and tenderness of the thyroid recurred on two subsequent relapses.
Suppressive therapy with levothyroxinefor solitary thyroid nodules
Authors: Reverter J. L. , Lucas A. , Salinas I. , Audi L. , Foz M. , Sanmarti A.
Published: March 2008

objective To evaluate the effect of treatment with TSH suppressive dose of levothyroxine In patients with benig nthyroid nodules.

design Prospective randomized study. Group A (n= 20) patients received levothyroxine and group B (n= 20) patients did not. The dose of levothyroxine was adjusted to obtain an effective suppression of TSH. A clinical, analytical and morphological (with ultrasound) review was performed every 3 months. The mean ± SD follow‐upperiod was 6·10±2·2 months.

patients Forty euthyrold women with solitary thyroid nodule on palpation, cold on sclntlgraphy and cytologically benign without contraindication participated.

measurements At entry: biochemical and hormonal parameters, thyroid sclntigraphy and thyroid ultrasonography. Every 3 months additional determinations of thyroid hormones and TSH levels were carried out, if necessary, to verify effective TSH suppression. Every 6 months thyroid ultrasound imaging was performed.

results Patients were euthyroid at entry into the study. The mean dose of levothyroxine necessary to obtain TSH suppression was 2·82±0·6 μg/kg/day. No significant modification in the thyroid nodule diameter (mean ± SD 2·6±1·2 vs 2·5±1·2 cm) or in the thyroid nodule volume(10·3±11·9 vs 10·1±12·2 ml) were observed in group A. In group B the results were similar (2·8±0·9 vs 2·7±1·8 cm and 9·2±6·4 vs 9·2±9·5 ml, respectively). No differences were found in either group in the number of nodules that reduced significantly their volume (four and three, respectively).

conclusions The suppressive therapy with levothyroxine was not effective In reducing nodule sizes in patients withsolitary benign thyroid nodules.
Circadian rhythm of plasma testosterone in men with idiopathic hypogonadotrophic hypogonadism before and during pulsatile administration of gonadotrophin‐releasing hormone
Authors: Simonl Manuela , Montaninl Vanna , Fustini Marco Faustini , Rio Graziano Del , Cionl Katia , Marrama Paolo
Published: March 2008

objective The aim was to investigate whether a pulsatile discharge of LH from the pituitary Is necessary to achieve the circadian secretion of testosterone.

design The daily rhythm of the androgen has been studied in patients with idiopathic hypogonadotrophic hypogonadism (IHH) both in the absence of therapy and during pulsatile administration of gonadotrophln releasing hormone (GnRH).

patients Six patients with IHH and ten normal subjects were analysed. Blood sampling was performed at 2‐hourly intervals, for 24 hours. The IHH patients then received synthetic GnRH i.v. at the rate of one pulse every 2 hours (10 μg/pulse). On day 11 of treatment, blood samples were taken for the rhythm analysis every 2 hours, for 24 hours.

measurements Plasma testosterone and LH were measured in the individual samples by radioimmunoassay. Evaluation of the rhythm was performed by cosinoranalysis.

results A significant circadian rhythm of plasma testosterone was statistically validated In the normal subjects, whereas no rhythm was detected in the IHH patientsin the absence of therapy. On day 11 of GnRH pulsatile administration the IHH patients showed normal testosterone levels and a statistically indistinguishable from the corresponding values in the normal subjects. Plasma LH did not show statistically significant circadian variations, either In the control group or in the IHH patients before or during therapy.

conclusions We conclude that a physiological circadian rhythm of plasma testosterone can be obtained, In IHH men, by treatment with GnRH. Since the pulsatile administration of exogenous GnRH at constant dosesinduced a circadian rhythm in testosterone and no dally variations in LH were evident, we suggest that, although a pulsatile secretion of LH is probably necessary for the synchronization of the circadian rhythm with acrophase inthe morning, the testosterone variations might be theresults of a local testicular modulation of LH action.
A novel variant of growth hormone (GH) insufficiencyfollowing low dose cranial irradiation
Authors: Crowne E. C. , Moore C. , Wallace W. H. B. , Ogllvy‐Stuart A. L. , Addison G. M. , Morris‐Jones P. H. , Shalet S. M.
Published: March 2008

objective We aimed to Investigate the effect of low dose (1800 cGy) prophylactic cranial Irradiation on physiological growth hormone secretion.

design We performed an analysis of 24‐hour serum GH profiles using 20‐mlnute sampling.

patients Forty‐four children were studied, of whom 21 were long‐term survivors of acute lymphoblastlc leukaemia and 23 were normal children. They were further subdivided into prepubertal, pubertal and post‐pubertal groups.

measurements GH profiles were analysed by autocorrelation, Fourier transformation and spectral analysis of stationarlzed data, and peak detection using the Pulsar peak detection program.

results In the normal children, there was a significant increase in the median (range) area under the curve (AUC) of the GH profile between the prepubertal and pubertal groups (62 (11–124) and 137 (142–158) IU/l/h respectively, (P < 0·01)). There was also a change In the spectral analysis through puberty. The dominant frequencies were spread widely in the prepubertal and post‐pubertal groups but sharply focused in the pubertal group. In the cranlally irradiated children there was no significant increase in AUC between the prepubertal (62(13–110) IU/l/h) and pubertal groups (92 (14–163) IU/l/h). The wide range of dominant frequencies persisted in the pubertal cranially irradiated group due to the presence of additional high frequency pulses. The impression of a disturbance of the periodicity of GH secretion in the cranlally irradiated pubertal group was further supported by the finding that the autocorrelation function in this group alone was not significantly different from that which would arise from random data.

conclusions A novel form of GH Insufficiency has been observed after low dose Irradiation In childhood in which an abnormality of periodicity and a quantitative reduction In GH secretion appears restricted to puberty.
Correlation of HLA types and clinical findings in Japanese patients with hyperthyroid Graves' disease: evidence indicating the existence of four subpopulations
Authors: Inoue Daisuke , Sato Kaoru , Enomolo Tetsuya , Sugawa Hideo , Maeda Masahiro , Inoko Hidetoshi , Tsuji Kimiyoshi , Mori Toru , Imura Hlroo
Published: March 2008

objectives To re‐evaluate the associations of HLA types with Japanese patients having hyperthyroid Graves' disease, HLA types and clinical findings were correlated.

design Four independent clinical findings (ophthalmopathy, family history, age at onset and size of goitre) and two autoantibody titres, thyrotrophin binding inhibitor immunoglobulin (TBII) and anti‐thyroid microsmall antibody (anti‐M), were analysed.

patients Eighty‐eight Japanese patients with hyperthyroid Graves' disease and 186 control subjects were assessed.

measurement Serological HLA typing was performed on 73 antigens In HLA‐A, ‐B, ‐C, ‐DR and ‐DQ loci. HLA‐D and ‐DP (29 antigens) were determined by the restricted fragment length polymorphism (RFLP) methods. TBII and anti‐M were measured by commercially available kits.

results Patients with potent antibody tltres had HLA antigens commonly seen among all the patients with Graves' disease. Interestingly, however, HLA‐B35 and ‐Cw11 were found to relate with negative and/or weak TBII, and HLA‐B7 and absence of HLA‐Aw19 with negative antl‐M. Significant associations were observed between HLA‐DRw8 and large goitre and absence of ophthalmopathy, and between HLA‐DQw4 and a negative family history of diffuse goitre (corrected P < 0·05). Several other antigens were also found to be significant. Among these antigens, four pairs of MHC classes I and II were found to relate to the clinical findings independently. HLA‐DQw4 and negative ‐A31 pair was closely related to ophthalmopathy, negative family history and late onset of disease. The HLA‐B5 and ‐Dw12 pair was associated with ophthalmopathy, positive family history and early onset of disease. The HLA‐A11 and negative ‐DPw2 pair was associated with ophthalmopathy, negative family history and early onset of disease. The HLA‐Bw46 and ‐DRw8 pair did not increase in frequency above that seen with HLA‐DRw8 alone. These four antigen groups (HLA‐DRw8, HLA‐DQw4 and negative‐A31, HLA‐B5 and ‐Dw12, and HLA‐A11 and negative ‐DPw2) were observed in the majority (68%) of patients with Graves' disease and at a significantly higher incidence than in the control group (P < 0·05).

conclusion There are four subpopulations of Japanese patients with hyperthyroid Graves' disease. This is one of the reasons why the association of HLA types in Japanese patients is rather weak when they are studied as one group.
Thyrotoxicosis and hyperemesis gravidarum associated with a serum activity which stimulates human thyroid cells in vitro
Authors: Kennedy R. L. , Darne J. , Davies R. , Price A.
Published: March 2008

objective To investigate in‐vitro thyroid stimulatory activity In the serum of patients with hyperemesis gravidarum and thyrotoxicosis.

design Serum from hyperthyroid patients was incubated with cultures of human thyroid cells. Attempts were made to neutralize stimulatory activity with antisera to hCG.

patients Five patients presenting In early pregnancy with hyperemesis and thyrotoxicosis.

measurements Serum concentrations of thyroid hormones (total and free), TSH and hCG. Accumulation of extracellular cAMP in response to serum.

results All five patients had biochemical hyperthyroidism with no evidence of an underlying autoimmune disease. The mean cAMP accumulation over 4 hours with sera from 12 non‐pregnant controls was 130·6 (121·1–142·8), from 12 pregnant controls 132·4 (118·1–143·8), compared with values of 144·7, 159·1, 166·2, 178·9 and 320·5 for the thyrotoxic patients. The stimulatory activity could not be neutralized by addition of anti‐hCG or by depleting the sera of hCG.

conclusions Thyrotoxicosis may present with hyperemesis in early pregnancy. Clinical and biochemical features may be masked by the pregnancy or by the intercurrent illness. The hypothesis that hCG is a thyroid stimulator in patients with hyperemesis gravidarum is not supported by the immuno‐neutrallzation data in this study.
Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome
Authors: Kiddy Deborah S. , Hamilton‐Fairley Diana , Bush Anne , Short Frances , Anyaoku Vtctor , Reed Michael J. , Franks Stephen
Published: March 2008

objective Obese women with poiycystic ovary syndrome have a greater frequency of menstrual disturbance and of hirsutism than lean women with the syndrome. initial studies have demonstrated a marked improvement in endocrine function following a short‐term, very low calorie diet. The purpose of this study was to examine the effect of long‐term calorie restriction on clinical as well as biochemical abnormalities in obese women with polycystic ovary syndrome.

design We performed a wlthin‐groupcomparison of ciinical and biochemical indices before and during dietary treatment.

patients Twenty‐four obese women with polycystic ovary syndrome (mean weight 91·5 (SD 14·7) kg) were scheduled for treatment for 6–7 months with a 1000 kcal, low fat diet. Nineteen of the 24 had menstrual disturbances, 12 had infertility and 19 were hirsute.

measurements and results Thirteen subjects lost more than 5% of their starting weight (range 5·9–22%). in this group there was no significant change in gonadotrophin or total serum testosterone levels but there was a marked increase in concentrations of sex hormonebinding globulin (pretreatment: 23·6 (9·5); post‐treatment 36·3 (11·8) nmol/l, P= 0·002) and a reciprocal change in free testosterone levels (77 (26) vs 53 (21) pmol/l, P= 0·009). These changes were accompanied by a reduction in fasting serum insulin levels (median (range) 11·2 (5·2–32) vs 2·3 (0·1–13·8) mU/l, P= 0·018) and the insulin response to 75 g oral glucose. There were no significant changes in these indices in the group who lost < 5% of their inltiai body weight.

Of the 13 women who lost > 5% of their pretreatment weight, 11 had menstrual dysfunction. Amongst these women, nine of 11 showed an improvement in reproductive function, i.e. they either conceived (five) or experienced a more regular menstrual pattern. There was a reduction in hlrsutism in 40% of the women in this group. By contrast, in the group who lost less than 5% of their initial weight, only one of the eight with menstrual disturbances noted an improvement in reproductive function and none had a signtficant reduction in hirsutism.

conclusions These data indicate that moderate weight loss during long‐term calorie restriction is associated with a marked clinical improvement which reflects the reduction in insulin concentrations and reciprocal changes in SHBG. The improvement in menstrual function and fertility may therefore be consequent upon an increase in insulin sensitivity which, directly or indirectly, affects ovarian function.
The desmopressin stimulation test in the differential diagnosis of Cushing's syndrome
Authors: Malerbi Domingos A. , Mendonça Berenice B. , Liberman Bernardo , Toledo Sergio P. A. , Corradini Maria Cristina M. , Cunha‐Neto Malebranche B. , Fragoso Maria Candida B. V. , Leo Wajchenberg Bernardo
Published: March 2008

objective We assessed the ability of desmopressin to stimulate the pituitary‐adrenal axis in patients with Cushing's syndrome.

DESIGN AND SUBJECTS The Cortisol response to 5 or 10 fig of intravenous desmopressin was evaluated in 31 patients with Cushing's syndrome of several aetiologies and in 15 normal subjects.

RESULTS Cortisol responses were observed in 15 out of 16 patients with pituitary dependence and in two patients with adrenal nodular hyperplasia, the increase above baseline ranging from 61 to 379% in the responders. Eight patients with adrenal tumours and one with the ectopic ACTH syndrome did not respond to desmopressin, having shown changes In their Cortisol levels from ‐5 to 42% above baseline. Responses occurred in two out of the 15 normal Individuals, whose Cortisol increased 58 and 69% above baseline, respectively. Stimulation tests with standard agents as lysine vasopressin or ovine corticotrophin‐releasing hormone were performed in the same patients and there was a high degree of concordance. No serious adverse reactions were observed in the tests with desmopressin.

CONCLUSIONS Desmopressin was able to stimulate the pituitary‐adrenal axis in patients with Cushing's disease and, like corticotrophin releasing hormone, it may prove useful in the differential diagnosis of Cushing's syndrome.
Luteinizing hormone regulation by sex steroids in men with germinal and Leydig cell tumours
Authors: Reznlk Yves , Rleu Max , Kuhn Jean Marc , Mandard Jean Claude , Bottet Philippe , Lemonnier Didier , Bekka Said , Mahoudeau Jacques
Published: March 2008

OBJECTIVE We examined the gonadotrophin secretion in patients with increased plasma concentrations of testosterone and oestradiol due to hCG‐producing tumours.

DESIGN Comparison of plasma gonadotrophin concentrations before and after stimulation by GnRH, in eight men with hCG‐producing tumours resulting in Increased testosterone and oestradiol plasma levels, and In 29 men with Leydig cell tumours resulting in increased oestradiol and normal to low testosterone plasma levels.

PATIENTS Eight men with hCG‐producing tumours (six with testicular tumours, two with extratesticular tumours), 29 men with Leydig cell tumours and 15 normal men. The six men with germinal cell tumours of the testis were studied before and after unilateral orchidectomy.

MEASUREMENTS Plasma concentrations of hCG, testosterone and oestradiol were measured before and after intramuscular injection of hCG. LH and FSH were measured before and after intravenous Injection of 100 μg GnRH.

RESULTS Plasma LH and FSH concentrations were low In patients with germ cell tumours, who exhibited increased plasma testosterone and oestradiol concentrations, and were normal in patients with Leydig cell tumours, in whom oestradiol only was increased. Plasma LH and FSH were normalized in the five patients with successful (e.g. normal hCG, testosterone and oestradiol) unilateral orchldectomy. Basal plasma testosterone concentrations correlated positively (P <001) with plasma oestradiol concentrations in patients with germ cell tumours and negatively (P <0 01) in patients with Leydig cell tumours.

CONCLUSIONS In patients with hCG‐secreting germ cell tumours complete suppression of plasma LH and FSH with increased plasma concentrations of both testosterone and oestradiol are often discovered. No such gonadotrophin suppression is found In patients with Leydig cell tumours, but the negative correlation observed between plasma testosterone and oestradiol in these patients suggests a weak negative feedback effect of oestradiol on LH secretion, which cannot be demonstrated by basal LH measurements in plasma.
Localization of neuroendocrine tumours and insulinomas using radiolabeled somatostatin analogues, 123 I‐Try3‐octreotide and 111in‐pentatreitide
Authors: Ur E. , Bomanji J. , Mather S. J. , Britton K. E. , Wass J. A. H. , Grossman A. B. , Besser G. M.
Published: March 2008

OBJECTIVE A number of neoplasms are known to express somatostatin receptors; the use of somatostatin receptor imaging in their localization has recently been described, but the resolution and discrimination of the isotopes used remains sub‐optimal. We have looked at the use of a new” In‐labelled analogue of somatostatin, pentatreotide, in the visualization and functional characterization of a number of neoplastic conditions.

PATIENTS Thirteen patients with proven neoplasms were scanned using this agent. Planar and single‐photon‐emission computerized tomographic (SPECT) images of the relevant part of the body were obtained using a gamma‐camera at 10 minutes and 4 and 21 hours after injection of the radiopharmaceutical. In six patients (three carcinoid, three insulinomas) scanning was also performed using 123l‐Tyr‐3‐octreotide.

RESULTS Primary tumours or metastases were visualized in six of the seven patients with neuroendocrine tumours, and three of six patients with insulinoma. One patient with an insulinoma who had a positive scan showed absent uptake when rescanned after tumour removal. A rise In blood glucose (more than twice basal) in response to octreotide was seen only in those insulinoma patients with positive scans. In cases where both 111ln‐pentatreotide and 123l‐Tyr‐3‐octreotide scans were performed, both radiopharmaceuticals identified the same 4/ 6 tumours; however, tumour definition (reflecting high tumour to background ratio) was better with pentatreotide on the 21‐hour images with minimum biliary and gut activity, allowing better resolution of the tumour image.

CONCLUSION It appears that 111ln‐pentatreotide scintigraphy is a rapid and safe procedure for the visualization of neuroendocrine tumours possessing somatostatin binding sites. A positive scan may be predictive of neuroendocrine responsiveness to octreotide therapy. In addition, it also appears that1” In‐pentatreotide has superior kinetics compared to 123I‐Tyr‐3‐octreotide, typically achieving more satisfactory tumour to background ratios, and may thus be more useful in the localization of endocrine tumours.
A prospective randomized trial of levothyroxine suppressive therapy for solitary thyroid nodules
Authors: Papini E. , Bacci V. , Panunzi C. , Pacella C. M. , Fabbrini R. , Bizzarri G. , Petrucci L. , Giammarco V. , La Medica P. , Masala M. , Pitaro M. , Nardi F.
Published: March 2008

OBJECTIVE We examined the effects of l‐thyroxine therapy versus placebo over a 12‐month period on volume of solitary thyroid nodules.

DESIGN Prospective randomized clinical trial; placebo and control groups followed for one year in three centres.

PATIENTS One hundred and one euthyroid patients with single palpable colloid thyroid nodules.

MEASUREMENTS Serum thyroid hormones, TSH, thyroglobulin, anti‐thyroglobulin and anti‐thyroid peroxidase antibodies measured at the first visit and after 2, 6 and 12 months; nodule volume and contralateral thyroid lobe thickness measured by ultrasound in double blind fashion; nodule diameter measured by palpation every 6 months.

RESULTS In the treatment group the nodule volume measured by ultrasound decreased progressively but not significantly; in the placebo group no changes were demonstrated. The number of nodules which decreased in size was however significantly larger in the treatment group. None of the initial parameters was predictive for the response. In the treatment group the nodule size assessed by palpation showed a significant decrease after 12 months when compared to baseline.

CONCLUSIONS In non‐endemic areas TSH suppression induces nodule volume reduction measured by ultrasound which, although not significant, seems to be progressive and occurring only in a subgroup of patients. Sgnificant palpatory nodule reduction is probably related to decreased thickness of the surrounding thyroid tissue still responsive to TSH.
Growth hormone releasing hormone priming increases growth hormone secretion in patients with Cushing's syndrome
Authors: Leal‐Cerro Alfonso , Pumar Alfonso , Villamil Fernando , Astorga Ricardo , Dieguez Carlos , Casanueva Felipe F.
Published: March 2008

OBJECTIVE In patients with Cushing's syndrome, decreased growth hormone (GH) secretion is observed though the basic mechanism is unknown. In states of chronic deficiency of hypothalamic growth hormone releasing hormone (GHRH) release, a blunted GH response to exogenous GHRH has been reported; such impairment can be partially normalized by repetitive GHRH administration (priming).

In order to clarify whether a deficit in hypothalamic release of GHRH is the basis of the decreased GH secretion in patients with Cushing's syndrome, GHRH plus pyridostigmine tests were undertaken, both before and after GHRH priming.

DESIGN GHRH (200 μg/day as a single s.c. injection) was given daily over 7 days. Two pyridostigmine (120 mg p.o.) plus GHRH (100 μg i.v.) tests were performed before and after priming to assess GH response.

PATIENTS Eight patients (seven women, one man), with untreated Cushing's syndrome (six Cushing's disease, one autonomous bilateral adrenal hyperplasia, one adrenal adenoma), were studied.

MEASUREMENTS Plasma GH levels were measured by immunoradiometric assay.

RESULTS GHRH plus pyridostigmine‐induced GH release was impaired in patients with untreated Cushing's syndrome (mean peak 52 ± 14 mU/l, area under the curve (AUC) 472 ± 96). Repetitive administration of GHRH over 7 days partially restored the GH response to the second pyridostigmine‐GHRH test (mean peak 150±21 mU/l. AUC 1016±104), both P < 005.

All of the eight Cushing's syndrome patients studied presented a higher GHRH plus pyridostigmine‐induced GH secretion after priming.

CONCLUSIONS Repetitive administration of GHRH increases the pyridostigmine‐GHRH‐induced GH secretion in patients with Cushing's syndrome. This suggests that impaired hypothalamic release of GHRH is a contributing factor to the decreased GH secretion observed in chronic hypercortisolism.
Potentiation of the classic ovine corticotrophin releasing hormone stimulation test by the combined administration of small doses of lysine vasopressin
Authors: Favrod‐Coune C. , Raux‐Demay M. C. , Proeschel M. F. , Bertagna X. , Girard F. , Luton J. P.
Published: March 2008

OBJECTIVE To assess the corticotrophic response to ovine corticotrophin releasing hormone (CRH) with the lowest dose of lysine vasopressin able to induce both the greatest stimulation and the lowest degree of side‐effects.

SUBJECTS Fourteen healthy young adult males.

DESIGN Increasing intravenous doses (either 0, 0.03, 0.1, 0.3, or 1 IU) of lysine vasopressin, infused over 20 minutes, combined with a bolus of 100 μg ovine CRH.

MEASUREMENT Radioimmunoassay of plasma ACTH, lipotrophin hormones and Cortisol levels.

RESULTS (1) Responses to stimulation tests were evaluated as the area under the curves of plasma levels versus sample times, from 0 to 120 minutes after injection or start of perfusion (six subjects). The lowest dose of lysine vasopressin that induced an additional stimulation in the CRH‐stimulated ACTH response was 0 3 IU. The combination of 1 IU lysine vasopressin with CRH doubled values of the area under the curve for the ACTH. Lysine vasopressin alone (0 3 and 1 IU) failed to stimulate ACTH responses. (2) The combined test (100 μg CRH and 1 IU lysine vasopressin) was carried out on eight additional control subjects. From a mean basal level of 23 ± 5.6 (SEM), plasma ACTH peaked to 104.5±8 ng/l (23.0 ± 1.8 pmol/l) as early as 20–30 minutes after the start of injection. When repeated after a two‐week interval, the combined test induced identical stimulation in a given subject. Results of lipotrophin hormone determinations roughly paralleled those of ACTH. However the effects on Cortisol levels were less clear. Subjects injected with CRH experienced slight facial flush. Following the 1 IU lysine vasopressin dosage, side‐effects were reduced to skin pallor. No changes in heart‐rate or blood‐pressure were observed.

CONCLUSIONS Under these conditions, the combination of 100 μg CRH with 1 lU lysine vasopressin constitutes a powerful test for direct assessment of the pituitary reserve and therefore can be employed as a routine investigational tool.
Prenatal diagnosis of congenital adrenal hyperplasia by direct detection of mutations in the steroid 21‐hydroxylase gene
Authors: Rumsby G. , Honour J. W. , Rodeck C.
Published: March 2008

OBJECTIVE Our aim was to develop a rapid and accurate method for the prenatal diagnosis of congenital adrenal hyperplasia using the polymerase chain reaction to detect mutations in the steroid 21‐hydroxylase gene. These procedures will help to minimize exposure to dexametha‐sone treatment of either affected males or unaffected females.

DESIGN AND PATIENTS Chorionic villus biopsy samples were obtained between 10 and 11 weeks gestation from three females carrying fetuses at risk of steroid 21‐hydroxylase deficiency. Blood samples were taken from parents and the index case in each family.

MEASUREMENTS Three common mutations in the 21‐hydroxylase B gene were detected following DNA amplification.

RESULTS Prenatal diagnosis of congenital adrenal hyperplasia was successful in all three cases. One affected female was treated with dexamethasone to term. In the other two cases, one affected male and one carrier also male, dexamethasone was withdrawn at an early stage.

CONCLUSIONS First trimester prenatal diagnosis of steroid 21‐hydroxylase deficiency was achieved in three pregnancies with a strategy based on direct detection of gene mutations.
The effects of growth hormone on protein metabolism in adult growth hormone deficient patients
Authors: Russell‐Jones D. L. , Weissberger A. J. , Bowes S. B. , Kelly J. M. , Thomason M. , Umpleby A. M. , Jones R. H. , Sönksen P. H.
Published: March 2008

OBJECTIVE Growth hormone treatment given to adult growth hormone deficient patients leads to an increase in lean body mass by an unknown mechanism. The aim of this study was to investigate the actions of growth hormone treatment on protein metabolism in adult growth hormone deficient patients.

DESIGN Double‐blind, placebo controlled trial of recombinant human growth hormone (0 018 U/kg/day for 1 month followed by 0.036 U/kg/day for 1 month) with isotopic whole body protein turnover studies at 0 and 2 months.

PATIENTS Eighteen adult growth hormone deficient patients (nine male, nine female of mean age 46.6 (range 30–56).

MEASUREMENTS Whole body isotopic leucine turnover using L‐1‐13C‐leucine measuring leucine R a (a measure of protein degradation), non‐oxidative leucine R d (a measure of protein synthesis) and leucine oxidation rate.

RESULTS Lean body mass (P<0.02), circulating insulinlike growth factor I (P<0 01) and insulin (P<0.02) were significantly increased at 2 months in the treatment group but there was no change in the placebo group. When expressed in relation to body weight, leucine fia and non‐oxidative leucine fid increased (P<0.01) and leucine oxidation decreased (P<0.02) after 2 months growth hormone treatment. When expressed in relation to lean body mass non‐oxidative leucine R d increased (P<0.02) and leucine oxidation decreased (P<0.02) but there was no significant change in leucine R a after 2 months growth hormone treatment. In the placebo group there were no significant changes in leucine metabolism expressed as lean body mass or body weight after 2 months. changes in leucine metabolism expressed as lean body mass or body weight after 2 months.

CONCLUSION These results indicate that the increase in lean body mass resulting from growth hormone treatment in adult growth hormone deficient patients is due to an increase in protein synthesis.
Coincidental occurrence of primary hyperparathyroidism and cancer‐associated hypercalcaemia in a middle‐aged man
Authors: Gallacher S. J. , Fraser W. D. , Farquharson M. A. , Logue F. C. , McArdle C. , Boyle I. T. , Nairn E. R. , McNicol A. M.
Published: March 2008

Primary hyperparathyroidism (PHPT) is found not uncommonly in patients with cancer. In this report, however, we describe a patient where both humoral hypercalcaemia of malignancy and PHPT were present coincidentally.

A 47‐year‐old man was found to have PHPT due to parathyroid hyperplasia. Serum parathyroid hormone (PTH) levels, which were elevated before parathyroidectomy, were undetectable post‐operatively; however, hypercalcaemia persisted. Nephrogenous cyclic adenosine monophosphate was elevated along with this undetectable PTH, indicative of the presence of a PTH‐like factor in the serum. This was confirmed by the finding of an elevated level of PTH‐related protein (PTHr P) in plasma (91 pmol/l, normal <2.6 pmoI/I). Secondary carcinoma was identified in a lesion in the region of the manubrium sternii. This stained positively for PTHr P by immunocyto‐chemistry and PTHr P messenger RNA was detected by insitu hybridization.

This case illustrates the value of sensitive PTH assays in distinguishing PHPT from other causes of hypercalcaemia and also shows the importance of considering primary hyperparathyroidism in the differential diagnosis of the patient with cancer and hypercalcaemia.
Endemic juvenile hypothyroidism in a severe endemic goitre area of Sudan
Authors: Moreno‐Reyes Rodrigo , Boelaert Marleen , El Badawi Salah , Eltom Mohamed , Vanderpas Jean B.
Published: March 2008

OBJECTIVE The aim of the study was to assess thyroid function, Iodine Intake and exposure to dietary goitrogens of children living in an area with a high prevalence of goitre, in the region of Darfur, Sudan.

DESIGN In a village where goitre affected approximately 85% of children, a cross‐sectional survey of thyroid function was performed in children 0–7 years old.

PATIENTS Twenty neonates and 190 children, aged 1 month to 7 years, were included.

measurements Thyroid hormones, urinary iodide and thiocyanate excretion were measured.

RESULTS MeanSD serum T4 was below the normal range at birth (82 ± 50 nmol/l) and in the age group less than 2 years (73·46). Children older than 2 years had even lower serum 14: 37·37 (P >0 001) at 3–4 years and 36·38 (P >0 001) at 5–7 years. Mean serum TSH was 25 8(6 2–107 7) mU/I at birth, 8.3(2. 5–27. 8) In the group less than 2 years, 15. 3(2.9–79.1) at 3–4 years and 16. 4(2.7–98.3) at 5–7 years. The overall prevalence of hypothyroidism (TSH>50 mU/I) was 24%. Mean urinary thiocyanate was high at birth(107·69 pmol/l), normal in the group less than 2 years and higher in children older than 2 years (126·69 pmol/l) (P > 0.001). All age groups had a low urinary iodide concentration.

CONCLUSION Hypothyroidism was very frequent in each age group. The higher frequency of hypothyroidism observed in weaned children (< 2 years) was attributed to the combined effects of Iodine deficiency and goitrogens (thiocyanate and glycosylflavones) derived from millet.
Adjunctive cholestyramine therapy for thyrotoxicosis*
Authors: Solomon Barbara L. , Wartofsky Leonard , Burman Kenneth D.
Published: March 2008

OBJECTIVE Initial therapy of thyrotoxicosis usually includes beta‐blockade for symptom relief and thionamides to block new thyroid hormone synthesis. In view of the increased enterohepatic circulation of thyroxine (T4) and triiodothyronine (T3) in thyrotoxicosis, we proposed that cholestyramine, an anion exchange resin which binds iodothyronines, when used adjunctively with thionamides and a beta‐blocker, would lower serum iodothyronine levels faster than would standard therapy alone.

DESIGN A double blind placebo‐controlled cross‐over design was used with patients randomly assigned to either the treatment or control groups. They received their initial treatment for two weeks (Phase 1) followed by a one‐week washout period, and then crossed to the opposite treatment for two weeks (Phase 2). Standard therapy included atenolol 50 mg daily, individualized dosages of methimazole and either 4 g of cholestyramine or 4 g of placebo powder four times per day.

PATlENTS Fifteen patients with thyrotoxicosis (14 Graves' disease, 1 toxic adenoma) participated in this study.

MEASUREMENTS Total and free thyroxine and triiodothyronine, as well as thyroid‐stimulating immunoglobulin and thyrotrophin‐binding inhibitory immunoglobulin, were measured weekly.

RESULTS Seven patients received cholestyramine and eight patients received placebo during Phase 1. A more rapid decline in all thyroid hormone levels was seen in the cholestyramine‐treated group (F= 4–7, P >0.01) than in the placebo group (F= 2–3.1, P= 0 05).

In Phase 2, the eight patients who received cholestyramine showed an additional decline in free thyroxine from weeks one to two, but the overall rate of decline in hormone levels was not different between the groups. Immunoglobulin levels remained unaffected regardless of group, treatment, or time.

CONCLUSIONS We conclude that cholestyramine is a safe and effective adjunctive agent in the treatment of thyrotoxicosis and that its greatest efficacy may be during the first few weeks of treatment.
The effects of TSH receptor antibodies on protein kinase C in the thyroid
Authors: Ginsberg Jody , Murray Patricia G.
Published: March 2008

OBJECTIVE There is increasing evidence that TSH activates a non‐cyclic‐AMP‐dependent pathway in the thyroid resulting in protein kinase C activation. We have previously demonstrated that TSH activates protein kinase C by causing translocation of protein kinase C from an inactive cytosolic site to its active membrane‐bound form in porcine thyroid cells. In addition, TSH can modify the protein kinase C translocation induced by the phorbol ester, 12‐O‐tetradecanoylphorbol‐13‐acetate. We tested six TSH receptor antibodies for their ability to activate protein kinase C in vitro.

DESIGN Porcine thyroid cells were incubated with either TSH receptor antibody or immunoglobulin from pooled normal sera. Subsequently, cytosol and membrane compartments were separated and protein kinase C assessed in each compartment.

PATIENTS The sera utilized in this study were obtained from patients with confirmed Graves' disease as defined by clinical evidence of thyrotoxicosis, increased free thyroxine index and suppressed TSH and increased radioactive iodine uptakes.

MEASUREMENTS Protein kinase C was measured in the cytosol and membrane compartments of the porcine thyroid cells using an enzyme assay.

RESULTS Compared to immunoglobulin from pooled normal sera, none of the six TSH receptor antibodies affected either cytosolic or membrane‐bound protein kinase C in porcine thyroid cells. The tumour‐promoting phorbol ester, 12‐O‐tetradecanoylphorbol‐13‐acetate, caused protein kinase C translocation. However, the presence of TSH receptor antibody did not modify the phorbol‐induced protein kinase C transiocation.

CONCLUSION These results indicate that unlike TSH, TSH receptor antibodies neither cause translocation of protein kinase C nor modify phorbol‐mediated protein kinase C translocation In porcine thyrold cells.
Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency
Authors: Rosen Thord , Bosaeus Ingvar , TöIli Jukka , Lindstedt Göran , Bengtsson Bengt‐Åke
Published: March 2008

OBJECTIVE Growth hormone deficiency in adults with hypopituitarism has previously received little attention. Recent data, however, suggest that GH deflciency might be essential for the long‐term prognosis of these patients. Earlier studies have documented that GH regulates body composition; in this, body composition in adult patients with hypopituitarism including GH deficiency was studied. DESIGN A follow‐up study of patients with hypopituitarism on routine replacement therapy with l‐thyroxine, cortisone acetate and sex steroids.

PATIENTS One hundred and six patients (69 males, mean age 52.5 years and 37 females, mean age 53.4 years) diagnosed as having growth hormone deficiency on the basis of low IGF‐I concentration or a maximum GH‐response less than 5 mU/I after an insulin/glucagon tolerance test.

MEASUREMENTS Body composition was estimated from body weight, total body water and total body potassium and the results were compared with values predicted from height, weight, age and sex, using data from a large number of healthy subjects.

RESULTS The total body water was slgnificantly lower than that predicted from the observed body weight (P >0.001), as was the extracellular water (P >0.001) and the extracellular/intracellular water quotient (P >0.001). On average, the body cell mass was similar to the predicted value, but the observed/predicted body cell mass ratio correlated positively with age at follow‐up. The body cell mass was lower than predicted in subjects below the age of 50 years (P >0.01). The body fat was higher than predicted (P >0.001); the increase was also noted in lean subjects.

The observed body weight in male subjects was 7.5 kg higher (P >0.001) than that predicted from healthy subjects of the same body height, a difference explained by an average increase of 6 6 kg in the body fat (P >0.001) and 1.6 kg in the body cell mass, with a simultaneous reduction of 0.7 kg in the extracellular water (NS). Male patients suffering from untreated androgen deficiency had lower body cell mass than those on androgen treatment. Female subjects weighed 3.6 kg (NS) more on average than healthy women, a difference explained by an increase in the body fat of 6.0 kg (P >0.001) with a simultaneous decrease of 2.4 kg in the extracellular water (P >0.001). The body cell mass was similar to that seen in the controls. CONCLUSIONS Adult patients with growth hormone deficiency have an increased body weight compared to normals of the same age, sex and height, due to an increment of the body fat with a simultaneous reduction in the total body water.
Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successfuI treatment
Authors: Trainer P. J. , Lawrie H. S. , Verhelst J. , Howlett T. A. , Lowe D. G. , Grossman A. B. , Savage M. O. , Afshar F. , Besser G. M.
Published: March 2008

OBJECTIVE We tested the hypothesis that in Cushing's disease, ACTH secretion from the normal pituitary surrounding an ACTH‐secreting adenoma is inhibited and hence removal of the entire adenoma should result in an undetectable serum cortisol in the immediate post‐operative period.

DESIGN A retrospective study of patients undergoing transsphenoidal selective adenomectomy, hemi‐hypophysectomy or total hypophysectomy for Cushing's disease at St Bartholomew's Hospital between 1985 and 1990. PATIENTS Forty‐eight consecutive patients (33 women, mean age 43, range 7–69 years) undergoing transsphenoidal hypophysectomy for Cushing's disease. Ten patients who underwent a second operation were re‐evaluated; the patients were followed for a median time of 40 months after operation (range 15–70).

MEASUREMENTS Post‐operatively, serum cortisol was measured daily at 0900 h. Serum TSH, T4, prolactin, LH, FSH, testosterone or oestradiol plus plasma and urine osmolality were measured.

RESULTS After initial surgery, post‐operative serum cortisol was undetectable (>50 nmol/l) in 20 out of 48 patients (42%) and >300 nmol/l in 32 out of 48 patients (67%). Re‐exploration of the pituitary fossa in 10 patients found undetectable cortisol levels in 25 (52%) and levels >300 nmol/l in 39 (81%) patients. Cushing's syndrome has not recurred, clinically or biochemically, in any patient in whom the post‐operative cortisol was > 50 nmol/l.

Post‐operatively, hypothyroidism was present in 40% of patients and hypogonadism in 53% of men and 30% of premenopausal women. Diabetes insipidus, persisting for at least six months, occurred in 46% of patients.

CONCLUSIONS Cushing's disease has not recurred in any patient with an undetectable serum cortlsol (>50 nmol/l) post‐operatively. Serum cortisol should be regarded as a tumour marker in Cushing's disease and the aim of transsphenoidal hypophysectomy for Cushing's disease should be to render the immediate post‐operative serum cortisol undetectable.