bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a novel mutation in the gene encoding the β‐triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone
Authors: Mixson A. J. , Renault J. C. , Ransom S. , Bodenner D. L. , Weintraub B. D.
Published: March 2008

OBJECTIVE We investigated whether the first patient (L‐F3) reported as having selective pituitary resistance had a mutation in the hTRβ gene. We compared the clinical parameters of this case with those of patients with generalized resistance to thyroid hormone.

DESIGN The patient, L‐F3, was part of a study at the NIH to identify mutations by sequencing the hTRβ gene in kindreds with thyroid hormone resistance. The clinical data of L‐F3 as well as patients with generalized resistance to thyroid hormone were compared and analysed retrospectively.

MEASUREMENT We amplified by the polymerase chain reaction and then sequenced exons 5 to 10 of the hTRβ gene in L‐F3 and a normal control. Upon finding the mutation in L‐F3, we measured the affinity constant of this mutated hTRβ receptor. Criteria developed previously were used to assess tissue responsiveness to thyroid hormone of L‐F3.

RESULTS We identified a C to T transition at base 1297 in codon 333 of the hTRβ gene in the first patient (L‐F3) reported as having apparent selective pituitary resistance. This base substitution resulted in more than a fourfold decrease in T3‐binding affinity for the hTRβ 1 receptor. The mutation of L‐F3 occurred in the dimerization domain of exon 9, a region where the majority of mutations of kindreds with generalized thyroid hormone resistance have been found. Furthermore, the nucleotide substitution at base 1297 found in the apparent selective pituitary resistant case, L‐F3, was the same as in an unrelated patient (K‐T3) with generalized resistance to thyroid hormone. As a result, we compared the clinical parameters of both patients and found that they had similar patterns of resistance in several tissues. Besides the bone resistance present in both kindreds, the apparent selective pituitary resistance case also had liver and neuromuscular resistance.

CONCLUSIONS These findings suggest that apparent selective pituitary resistance and generalized resistance to thyroid hormone are not qualitatively different syndromes. Nevertheless, identification of selective pituitary resistance is a useful clinical distinction since such patients with clinical and biochemical features of hyperthyroidism appear to benefit from reduction in serum thyroid hormone concentrations. In contrast, patients with more conventional forms of thyroid hormone resistance require no treatment or may benefit from increased concentrations of thyroid hormone.
Blood pressure and the renin‐angiotensin‐aldosterone system in children receiving recombinant human growth hormone
Authors: Barton J. S. , Hindmarsh P. C. , Preece M. A. , Brook C. G. D.
Published: March 2008

OBJECTIVE We investigated the effect of growth hormone (GH) treatment on salt and water metabolism and the renin‐angiotensin‐aldosterone system in children with short stature.

DESIGN Randomized, controlled study.

PATIENTS Twenty‐nine short, pre‐pubertal children referred to two specialist growth clinics for further assessment.

MEASUREMENTS Serial measurements of blood pressure, body weight, plasma renin activity (PRA), aldosterone, electrolytes, insulin and insulin‐like growth factor I (IGF‐I) have been made following the initiation of GH treatment.

RESULTS A small and transient increase in systolic blood pressure was observed during the first week of GH treatment. The increase in blood pressure over baseline was −1.1 mmHg in controls compared to +11.5 and +3.0 mmHg in children receiving standard (20 units/m2/week) and high dose (40 units/m2/week) GH respectively (P= 0.004). Over the same time interval body weight also tended to increase with GH compared with controls. These changes were greater in those children receiving the lower dose of GH and were not significantly related to age or prior GH status.

PRA did not change with GH treatment. Although plasma aldosterone concentration tended to increase with GH, maximal values did not differ from controls and all remained within our normal range. Plasma IgF‐I levels were increased by a similar amount in both treatment groups (1.5 and 1.12 U/ml compared to 0 44 U/ml in controls at 4 months). No difference in plasma insulin concentration was noted after 7 days of GH.

CONCLUSIONS In contrast to adult subjects, treatment with high dose GH in childhood is not associated with activation of the renin‐angiotensin‐aldosterone system. Clinical signs consistent with transient salt and water retention are observed with GH therapy, however, suggesting either a direct effect of GH or of IGF‐I on renal tubular function. Blood pressure, plasma renin activity and plasma aldosterone levels were not increased after more prolonged GH therapy. These data suggest that high dose GH therapy in childhood is unlikely to be associated with the increased risk of hypertension seen in adults with GH hypersecretion.
A role for life events in the pathogenesis of Cushing's disease
Authors: Sonino Nicoletta , Fava Giovanni A. , Boscaro Marco
Published: March 2008

OBJECTIVE We have previously reported on 30 patients with Cushing's syndrome suggesting an aetiological role for stressful life events. The investigation about life events in the year before the first signs of disease onset was extended to a larger population of patients with Cushing's syndrome, allowing us to differentiate patients with pituitary‐dependent and pituitary‐independent forms. DESIGN Case‐control study.

PATIENTS Sixty‐six consecutive patients with Cushing's syndrome of various aetiologies (46 with pituitary‐dependent forms and 20 with primary adrenal hyperfunction or ectopic ACTH production) and a control group of 66 healthy subjects, matched for sociodemographic variables, were studied.

MEASUREMENTS Paykel's Interview for Recent Life Events (a semistructured research interview covering 64 life events) was administered after the acute phase of illness while in remission.

RESULTS Patients with Cushing's syndrome reported significantly more stressful life events (P < 0.001), both events that had an objective negative impact (P < 0.001) and independent events (P < 0.001), than controls, confirming previous findings. Patients with pituitary‐dependent Cushing's disease were compared with their matched controls and reported significantly more total events, events with an objective negative impact and independent events (all at P < 0.001). There were no significant differences between patients with pituitary‐independent forms and their matched controls.

CONCLUSIONS These findings indicate a causal role for stressful life events exclusively in pituitary‐dependent Cushing's disease, and suggest a limbic‐hypothalamic involvement in the pathogenesis of this condition. The results are similar to those obtained in major depression, and add to other analogies between the two disorders.
Elevated plasma 19‐hydroxyandrostenedione levels in Cushing's disease: stimulation with ACTH and inhibition with metyrapone
Authors: Mune T. , Morita H. , Yasuda K. , Murayama M. , Yamakitat N. , Miura K.
Published: March 2008

OBJECTIVE The regulation of 19‐hydroxyandrostenedione secretion has been suggested to be under the control of both the ACTH‐adrenal axis and renin‐angiotensin system. We undertook the present study to evaluate the effect of the chronic excess of ACTH, or the short‐term excess of ACTH due to metyrapone, on 19‐hydroxyandrostenedione secretion in patients with Cushing's disease

DESIGN AND PATIENTS We measured plasma 19‐hydroxyandrostenedione levels simultaneously with plasma Δ4‐androstenedione, corticosterone, 11‐deoxycorticosterone, aldosterone and Cortisol levels after HPLC separation in 13 patients with Cushing's disease under basal conditions and during a dexamethasone suppression test or metyrapone test. Seven patients with Cushing's syndrome due to adrenal adenoma were used for comparison.

RESULTS The basal levels of 19‐hydroxyandrostenedione in Cushing's disease were elevated (mean ± SD; 323 ± 193 pmol/l, n= 13), while those in Cushing's syndrome due to adrenal adenoma were low (92 ± 24 pmol/l, n= 7), compared to those in normal subjects (117 ± 33 pmol/l, n= 54). The basal levels of Δ4‐androstenedione were mildly elevated In Cushing's disease (9.0 ± 6.5 vs 3.6 ± 2.6 nmol/l of normal subjects) but not in Cushing's syndrome due to adrenal adenoma (3.1 ± 3.0 nmol/l). In the overnight 8 mg dexamethasone suppression test in Cushing's disease (n= 12), plasma levels of 19‐hydroxyandrostenedione and Δ4‐androstenedlone decreased from 277 ± 172 to 156 ± 99 pmol/l and from 9.2 ± 6.8 to 4.7 ± 3.4 nmol/l, respectively, whereas the overnight 1 mg dexamethasone suppression test did not induce significant changes. Metyrapone administration in Cushing's disease (n= 9) increased plasma Δ4‐androstenedione level from 9.5 ± 6.7 to 47.2 ± 28.1 nmol/l, but decreased plasma 19‐hydroxyandrostenedione level from 301 ± 196 to 196 ± 105 pmol/l.

CONCLUSIONS These data indicate that plasma levels of 19‐hydroxyandrostenedione in patients with Cushing's disease are elevated due to chronic ACTH excess, and that metyrapone can inhibit 19‐hydroxylation in humans.
Bone mineral density in patients with hyperthyroidism measured by dual energy X‐ray absorptiometry
Authors: Wakasugi Masakiyo , Wakao Rie , Tawata Masato , Gan Naoya , Koizumi Kiyoshi , Onaya Toshimasa
Published: March 2008

OBJECTIVE We assessed the changes of bone mass in patients with hyperthyroidism by measuring bone mineral density using a new method, dual energy X‐ray absorptiometry.

DESIGN The values of bone mineral density in patients with hyperthyroidism were compared with data obtained from the controls, and we assessed the correlation analysis between bone mineral density and several metabolic parameters.

PATIENTS We studied 52 Japanese patients with hyperthyroidism (20 males, 32 females). Healthy normal subjects served to establish the mean bone mineral density In the healthy Japanese population (Shiraki et al. 1991).

MEASUREMENT Bone mineral density was assessed by the measurement of lumbar vertebrae and femur by dual energy X‐ray absorptiometry. The bone mineral density of vertebrae for each patient was calculated as the percentage of the mean value (% bone mineral density) obtained from an age and sex‐matched control group. Blood was drawn to measure the levels of serum calcium, phosphorus, creatinine, alkaline phosphatase, free T3, free T4, TSH, TSH receptor antibody, parathyroid hormone, and serum osteocalcin.

RESULTS The percentage bone mineral density of vertebrae in patients was 92.6 as compared with that of normal controls, and was inversely correlated with serum TSH receptor antibody, osteocalcin, and alkaline phosphatase.

CONCLUSIONS These findings suggest that bone mineral density is decreased in patients with hyperthyroidism and that TSH receptor antibody, osteocalcin, and alkaline phosphatase are sensitive markers of bone metabolism alterations in hyperthyroidism.
Polycystic ovaries are a common finding in untreated female to male transsexuals
Authors: Balen Adam H. , Schachter Morey E. , Montgomery Don , Reid Russell W. , Jacobs Howard S.
Published: March 2008

OBJECTIVE We studied the pretreatment hormone profile and ovarian ultrasound appearance of female‐to‐male transsexuals.

DESIGN Female‐to‐male transsexuals who were seen in the local Gender Identity Clinic were examined after psychiatric assessment.

RESULTS Sixteen patients were assessed. Approximately 50% had symptoms and signs of the polycystic ovary syndrome (PCOS) and 15 had a pelvic ultrasound diagnosis of polycystic ovaries. The endocrine profiles of the patients were not markedly abnormal and were compatible with the diagnosis of PCOS.

CONCLUSIONS Polycystic ovaries and the polycystic ovary syndrome are a common finding in female‐to‐male transsexuals who have had no previous exposure to exogenous androgen therapy.
Peptide α‐amidation activity in human plasma: relationship to gastrin processing
Authors: Kapuscinski Mirek , Green Michelle , Sinha Sankar N. , Shepherd Joseph J. , Shulkes Arthur
Published: March 2008

OBJECTIVE AND DESIGN C‐terminal amidation is an essential processing step towards bioactivation of many peptides including gastrin. This reaction is catalysed by peptidylglycine α‐amidating mono‐oxygenase (PAM, EC 1.14.17.3) which converts the glycine extended precursors on their carboxyl termini to the des‐glycine amidated peptide products. In the case of gastrin, most of the amidation is thought to occur in the antrum. However substantial quantities of glycine extended gastrin and PAM are present in plasma. It is unclear whether circulating PAM reflects the secretory activity of the gastrin secreting cell or whether PAM is involved in the post‐secretory processing of gastrin. The aim of the present study was to relate the circulating amidation activity to the plasma concentrations of glycine extended and amidated gastrins.

PATIENTS AND MEASUREMENTS Plasma PAM, gastrin‐amide and gastrin‐gly were measured in subjects with different gastrin secretory status: healthy subjects basally and following a meal, members of families with multiple endocrine neoplasia type 1 (MEN‐1) with normal and high plasma gastrin, and patients with hypergastrinaemic atrophic gastritis.

RESULTS Patients with MEN‐1 and hypergastrinaemia tended to have a higher plasma PAM activity than MEN‐1 subjects with normal circulating G‐NH2 indicating a co‐secretion of hormone and PAM. However in contradistinction to patients with medullary thyroid carcinoma, PAM activity does not appear to be a useful tumour marker of gastrinoma. Hypergastrinaemia from a non‐tumour source (hypergastrinaemic non‐atrophic gastritis) was associated with a lower plasma PAM activity than in normal subjects and may reflect the secretion of a greater proportion of already amidated gastrin. In general, there was no relationship between plasma PAM activity and the ratio of amidated to non‐amldated gastrin suggesting that circulating PAM was not involved in the amidation of gastrin. Feeding increased circulating gastrin but had no effect on plasma PAM activity.

CONCLUSION The results support the view that gastrin is amidated at the site of its synthesis and that hypergastrinaemia is associated with elevated plasma amidating enzyme activity only when the gastrin originates from tumour sources.
Longitudinal evaluation of adrenocorticotrophin and β‐lipotrophin plasma levels following bilateral adrenalectomy in patients with Cushing's disease
Authors: Moreira Ayrton C. , Castro Margaret , Machado Helio R.
Published: March 2008

OBJECTIVES Bilateral adrenalectomy may be indicated in patients with Cushing's disease in whom hypercortlsolism is not resolved after pituitary microsurgery. However, Nelson's syndrome is a major long‐term complication of such therapy. We have carried out a longitudinal study on patients with Cushing's disease who underwent bilateral adrenalectomy comparing plasma /Mipotrophin (β‐LPH) with ACTH levels.

PATIENTS AND METHODS Seven patients unsuccessfully treated by pituitary surgery for Cushing's disease underwent bilateral adrenalectomy. Blood samples were collected on days 8 and 15 and at 1, 2, 3, 6, 9,12,18 and 24 months after adrenalectomy in all patients. Five patients were followed up for the longer periods of 30,33,39,72 and 84 months respectively. Plasma ACTH and β‐LPH were determined by RIA after extraction. Pituitary CT scan was done at 6‐8‐month intervals.

RESULTS A pituitary tumour was detected in three patients at 14, 24 and 26 months after adrenalectomy respectively. The basal ACTH (range 8‐21 pmol/l) began to rise between 15 and 30 days and exhibited a sharp increase with a range of 36‐114 pmol/l at 3 months and a range of 53‐187 pmol/l at 6‐9 months after adrenalectomy. The ACTH levels in the three patients who later presented with a pituitary tumour were indistinguishable from those observed in the other patients up to 12 months after adrenalectomy. Only at 12 months or thereafter were their ACTH levels higher than in the other patients (958 ± 252 vs 205 ± 22 pmol/l). β‐LPH concentrations changed in parallel with ACTH levels. The ACTH levels correlated positively with β‐LPH levels (r= 0 76).

CONCLUSIONS In patients with Cushing's disease undergoing bilateral adrenalectomy, plasma ACTH and β‐LPH concentrations cannot predict the development of pituitary tumours until 12 months after surgery.
The impact of a pure anti‐androgen (flutamide) on LH, FSH, androgens and clinical status in idiopathic hirsutism
Authors: Couzinet Beatrice , Pholsena Maryse , Young Jacques , Schaison Gilbert
Published: March 2008

OBJECTIVES We assessed in women the effects of androgen suppression on gonadotrophin secretion and the therapeutic efficacy of the pure anti‐androgen flutamide (2‐methyl‐N‐[4‐nitro‐3‐(trifluoromethyl)phenyl]‐propanamide).

DESIGN AND SUBJECTS Ten women, aged 28‐35 years, using an intrauterine device for contraception, were selected for this study. All women had idiopathic hirsutism with or without acne and seborrhoea. Flutamide was administered orally in a dose of 250 mg twice daily for 1 year. Basal body temperature was recorded and pelvic ultrasonography performed before and every 3 months during treatment. LH pulse frequency and amplitude (Cluster analysis) and basal and GnRH‐stimulated plasma LH and FSH levels were determined on day 5 of the cycle prior to flutamide treatment, and after 6 and 12 months of therapy. Plasma total testosterone (T), non‐SHBG bound T, androstenedione (A), dehydroepiandrosterone sulphate (DHEAS), androstanediol glucuronide (3α‐diol G) and sex hormone binding globulin (SHBG) levels were measured before and every 3 months during therapy, on day 5 of the cycle. Plasma oestradiol and progesterone levels were determined on day 22 of the studied cycles.

RESULTS Disappearance of acne and seborrhoea occurred after 2 months with a marked improvement of hirsutism at 6 months. At 12 months, hirsutism had disappeared with a Ferriman and Galiwey score < 7. No adverse side‐effects, apart from transient diarrhoea in two patients, were reported with this flutamide dose. None of the patients had any disturbance of menstrual cycles which remained ovulatory. The pure anti‐androgen flutamide induced no significant change in LH pulsatile profile, nor in LH and FSH responsiveness to GnRH. Plasma concentrations of steroids were not altered. Plasma SHBG and 3al‐diol G levels did not change during flutamide treatment.

CONCLUSION Flutamide, which interacts only with the androgen receptor, is effective for hirsutism, acne and seborrhoea, and does not disturb menstrual cyclicity or ovulation. It may represent a treatment of choice for essential hirsutism in women using safe contraceptive methods.
Deficient inactivation of cortisol by 11β‐hydroxysteroid dehydrogenase in essential hypertension
Authors: Walker Brian R. , Stewart Paul M. , Shackleton Cedric H. L. , Padfield Paul L. , Edwards Christopher R. W.
Published: March 2008

OBJECTIVE 11β‐Hydroxysteroid dehydrogenase protects renal mineralocorticoid receptors from Cortisol by converting Cortisol to inactive cortisone. 11β‐Dehydrogenase deficiency, either congenital or after inhibition by liquorice and carbenoxolone, results in cortisol‐dependent mineralocorticoid excess and hypertension. We tested the hypothesis that the same mechanism occurs in some patients with essential hypertension.

DESIGN/PATIENTS Twenty patients with essential hypertension were compared with 19 matched healthy controls.

MEASUREMENTS 11β‐Hydroxysteroid dehydrogenase activity was assessed by the half‐life of 11α‐3H‐cortisol, and by the ratios of Cortisol to cortisone in plasma and of their metabolites in urine. Renal mineralocorticoid receptor activation was assessed by plasma potassium, renin activity and aldosterone.

RESULTS Half‐lives of 11α‐3H‐cortisol were prolonged in a subgroup of hypertensives (mean ± SE 53.2 ± 3.6 min in hypertensivesvs42.3 ± 2.3 in controls,P<0.05; seven of the 20 hypertensives had half‐lives exceeding 2 SD of controls). Ratios of Cortisol to cortisone in plasma and of their metabolites in urine were not different. 11α‐3H‐Cortisol half‐lives correlated with blood pressure but not with indices of renal mineralocorticoid receptor activation.

CONCLUSIONS 11β‐Dehydrogenase is defective in a proportion of patients with essential hypertension. The normal ratios of Cortisol to cortisone in plasma and of their metabolites in urine, also seen after carbenoxolone administration, suggest that 11β‐reductase conversion of cortisone to Cortisol is also defective. Unlike other syndromes of 11β‐dehydrogenase deficiency, the defect was not associated with mineralocorticoid excess. We suggest that it may cause hypertension by increasing exposure of vascular steroid receptors to Cortisol.
The combined use of intravenous and oral calcium for the treatment of vitamin D dependent rickets type II (VDDRII)
Authors: Al‐Aqeel Aida , Ozand Pinar , Sobki Samia , Sewairi Wafa , Marx Stephen
Published: March 2008

OBJECTIVE Some patients with rickets are resistant to vitamin D and its analogues; we therefore assessed whether or not normal mineralization could be achieved in the absence of an intact 1,25(OH)2D3 receptor‐effector system, by the use of intravenous high dose calcium infusion, followed by high dose oral calcium.

DESIGN We studied two patients with vitamin D dependent rickets type II and with absent responses to either high dose calcitriol or to oral calcium alone. Daily infusions equivalent to up to 14 g elemental calcium supplemented with oral phosphate were given for a period of 3 5 months for the elder sister and 2 months in the younger brother. Both patients were then treated by weekly calcium infusions for 5 months, followed by maintenance on oral calcium equivalent to up to 6 g elemental calcium per day.

PATIENTS Two siblings of consanguineous parents, a girl aged 28 months and a boy aged 10 months with vitamin D dependent rickets type II.

MEASUREMENTS Measurements of serum and urine calcium, phosphate and serum alkaline phosphatase were obtained before, during and after the calcium infusions.

Twenty‐four‐hour urinary minerals, electrolytes, creatinine clearance, serum PTH and vitamin D metabolites were measured prior to calcium infusion, then repeated at 2‐monthly intervals. Glomerular filtration rate, kidney ultrasound and CT scan were done at 6‐monthly intervals. A scalp biopsy was done at the end of i.v. calcium treatment.

RESULTS The daily infusions of calcium supplemented with oral phosphate resulted in biochemical responses with normalization of calcium and phosphate in 3‐5 days, and of alkaline phosphatase and PTH in 15‐2 months. Radiological evidence of healing was seen in 42 days. A total of 3 5 months of daily calcium infusion in the elder sister and 2 months in the younger brother resulted in complete healing biochemically and radiologically, with improvement in height. The patients are under current follow‐up, with no evidence of nephrocalcinosis or deterioration of glomerular filtration rate.

CONCLUSION

 The use of intravenous high dose calcium infusions followed by high dose oral calcium is an effective method of treatment of vitamin D dependent rickets type II.

 The treatment was more effective since it was started early in the course of the disease and led to early healing and better growth with prevention of bone deformities.

 Early treatment may also lead to improvement in alopecia, the mechanism for which needs to be elucidated.
Deoxycorticosterone, 11 β‐hydroxylase and the adrenal cortex
Authors: Spoudeas Helen A. , Slater J. D. H. , Rumsby Gillian , Honour John W. , Brook Charles G. D.
Published: March 2008

We report a child in whom DOC excess secondary to congenital adrenal hyperplasia (CAH, 11β‐hydroxylase deficiency) caused malignant hypertension. Clinical and metabolic control could be achieved only by replacement of both glucocorticoid and mineralocorticoid, thus confirming in clinical practice the hypothesis that DOC is produced from both the zonae fasciculata and glomeru‐losa of the adrenal cortex under the independent control of the ACTH and renin‐angiotensin systems respectively.
Thyrotoxicosis increases right to left shunt in congenital cyanotic heart disease
Authors: Orme S. M. , Sebastian J. P. , Page M. D. , Cowan C. , Belchetz P. E.
Published: March 2008

We wish to report two cases of congenital cyanotic heart disease in whom coexisting thyrotoxicosis increased the right to left shunt. We review the literature on the cardiac and respiratory effects of thyroid hormone to try to explain this phenomenon. Two patients, one with Fallot's tetralogy (diagnosed at 68 yars of age), the other with a ventricular septal defect, developed thyrotoxicosis which resulted in a dramatic but reversible deterioration in their cardiac condition.

We conclude that thyrotoxicosis increases right to left shunt in congenital cyanotic heart disease. This effect is profound but reversible. We suggest that when an unexplained rapid deterioration occurs in patients with congenital cyanotic heart disease, thyrotoxicosis should be excluded.
The long‐term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas
Authors: Brada M. , Rajan B. , Traish D. , Ashley S. , Holmes‐Sellors P. J. , Nussey S. , Uttley D.
Published: March 2008

OBJECTIVES We assessed the long‐term efficacy and toxicity of conservative surgery and radiotherapy in the control of pituitary adenomas.

DESIGN Retrospective study of patients treated at the Royal Marsden Hospital.

PATIENTS Four hundred and eleven patients with pituitary adenomas treated with conventional external beam radiotherapy at the Royal Marsden Hospital between 1962 and 1986. Two hundred and fifty‐two patients had clinically non‐functioning pituitary adenomas, 131 had hormone secreting tumours and in 28 patients the secretory status was not known. Three hundred and thirty‐eight patients had surgical intervention of whom only 11 had complete tumour excision. All patients received conventional fractionated external beam radiotherapy to a dose of 45–50Gy in 25–30 fractions.

MEASUREMENTS Actuarial progression free survival and overall survival and assessment of toxicity, particularly in terms of vision, requirement for hormone replacement therapy and incidence of second tumours.

RESULTS The actuarial progression free survival was 94% at 10 years and 88% at 20 years for all patients and 97% at 10 years and 92% at 20 years for patients with clinically non‐functioning adenomas. Only secretory status was an independent prognostic factor for disease control. The 10 and 20‐year survivals for all patients were 77 and 58% respectively. When compared with the normal population the relative risk of death was 1 76 (P<0 001) and no prognostic factors for survival were identified. The morbidity of radiotherapy was low. Visual deterioration, assumed to be radiation induced, occurred in 1–5% of patients and the risk of second brain tumour was 1.9% at 20 years. Fifty per cent of patients received hormone replacement therapy by 19 years.

CONCLUSION Conventional external beam radiotherapy as described here combined with conservative surgery is safe and effective in the control of pitutary adenomas. These results should form a baseline for comparison with new treatment strategies.
Pituitary responsiveness after administration of a GnRH agonist depot formulation: Decapeptyl CR
Authors: Broekmans F. J. , Bernardus R. E. , Broeders A. , Berkhout G. , Schoemaker J.
Published: March 2008

OBJECTIVE This study was focused on the pattern of LH release from the pituitary during the initial response to high dose GnRH agonist administration. Secondly, the pattern of LH release and the pituitary responsiveness to physiological and pharmacological stimulation during long‐term pituitary suppression by a high dose GnRH agonist was studied. In addition, the relation between serum agonist levels and pituitary function and responsiveness was investigated.

DESIGN oTrp'GnRH in microcapsules (Decapeptyl CR) was administered i.m. to 12 women on the third day of the cycle. High‐rate blood sampling was carried out during the first 48 hours after the injection. Secondly, high‐rate blood sampling for 6 hours and a GnRH challenge were performed before and weekly after administration, from week 4 till week 9. All samples were assayed for LH and FSH. LH patterns were analysed by applying a computerized pulse detection program. In the second or third week an oestradiol benzoate test was performed. Finally, trip‐torelin levels were measured before and weekly after administration.

PATIENTS Twelve patients, suffering from tubal infertility and recruited from the waiting list for in‐vitro fertilization/ embryo transfer (IVF/ET) participated in the study.

RESULTS During the first 48‐hour period, LH and FSH levels demonstrated a rapid rise to peak values after 4 hours, subsequently declining to nearly normal levels. E2 rose to peak values at 12 hours and returned to the follicular range thereafter. LH pulse patterns showed a rapid increase in pulse intervals leading to a near absence of LH pulses at the end of the 48‐hour period.

From the fourth till the seventh week after agonist administration, LH pulse patterns showed a markedly increased pulse interval, decreased pulse amplitude, and a severely decreased mean LH level. In the same period, LH responses to GnRH were severely blunted or absent. Restoration of the pre‐injection LH pulse pattern and the LH response to GnRH was observed during the eighth and ninth week. Oestradiol benzoate challenges showed an E2 rise to preovulatory levels in response to the injections. However, no changes were observed in LH and FSH concentrations. Triptorelin levels showed a peak within 48 hours and gradual decline towards pretreatment values in week eight.

conclusions It is concluded from the study, that after administration of triptorelin depot in the early follicular phase, desensitization of the pituitary starts to develop within 24 hours. Pituitary responsiveness is completely absent in the second week and continues to exist until the eighth week after injection, when the agonist has disappeared from the circulation. These findings suggest profound alterations in GnRH receptor availability and post‐receptor pathways, that prevent the pituitary from responding to physiological stimuli.
Pathophysiology of transient cranial diabetes insipidus during pregnancy
Authors: Williams David J. , Metcalfe Karl A. , Skingle Linda , Stock Antony I. , Beedham Trevor , Monson John P.
Published: March 2008

OBJECTIVE We investigated the possible mechanisms underlying transient cranial diabetes insipidus during pregnancy.

DESIGN AND PATIENTS A woman who developed clinical diabetes insipidus during the third trimester of pregnancy was studied through a total of three pregnancies and postpartum

MEASUREMENTS Plasma AVP, urine and plasma osmolality, urine volume and specific gravity were measured during water deprivation tests and hypertonic saline infusion. Plasma and urine osmolality were measured after subcutaneous injection of AVP. The water deprivation and AVP test were repeated after proven inhibition of urinary PGE2 with aspirin. Serum vasopressinase activity was measured during one of the pregnancies affected with diabetes insipidus and compared with that obtained between 26 and 38 weeks from 13 normal pregnancies.

RESULTS The patient was found to have cranial diabetes insipidus which responded to low dose intranasal 1‐desamino‐8‐D‐arginine vasopressin. Inhibition of PGE2 with aspirin did not enhance urine concentrating ability or the response to a test dose of subcutaneous AVP. Plasma levels of vasopressinase remained within the physiological range for normal pregnancy.

CONCLUSIONS These studies indicate that subclinical cranial diabetes insipidus may be unmasked in late pregnancy. This effect is not related to AVP resistance resulting from PGE2 production or excessive vasopressinase activity, but may be due to a combination of physiological vasopressinase secretion with reduced AVP secretory capacity and reduction in the thirst threshold that accompanies normal pregnancy.

We relate these findings to a previously described group of women with transient diabetes insipidus during pregnancy who had impaired liver function
Direct inhibition of ovarian steroidogenesis by Cortisol and the modulatory role of 11β‐hydroxysteroid dehydrogenase
Authors: Michael A. E. , Pester L. A. , Curtis P. , Shaw R. W. , Edwards C. R. W. , Cooke B. A.
Published: March 2008

OBJECTIVE The association of adrenal hyperactivity with ovarian dysfunction may involve direct inhibition of ovarian steroidogenesis by glucocorticoids. Therefore, the objectives of this study were to investigate the direct effects of Cortisol on luteinizing hormone (LH) action in human granulosa‐lutein cells and the modulation of this interaction by ovarian 11β‐Miydroxysteroid dehydrogenase (11βHSD).

DESIGN AND PATIENTS Effects were investigated in cultured human granulosa‐lutein cells isolated from the follicular aspirates of 14 patients undergoing oocyte collection for in‐vitro fertilization and embryo transfer.

MEASUREMENTS Pregnenolone production and 3H‐Cortisol oxidation to 3H‐cortisone (11βHSD activity) by cultured cells were measured.

RESULTS In cells from nine (of 14) patients, Cortisol inhibited LH‐stimulated steroidogenesis in a concentration dependent manner with an ID50 of 1250 ±SEM 377 nmol/t. In these cultures, the 11/JHSD activities were high (133±SEM 23 pmol/mg protein/4h) and inhibition of the enzyme with carbenoxolone potentiated the action of Cortisol. Conversely, cells from the remaining five patients lacked detectable 11β HSD activity and exhibited an increased sensitivity to the inhibitory action of Cortisol (ID50= 158 ± SEM 41 nmol/l in the absence of carbenoxolone).

CONCLUSIONS Cortisol acts directly in human granulosalutein cells to inhibit the support of steroidogenesis by LH and this interaction is modulated by ovarian 11βHSD in the majority of patients.
Evidence for a single gene effect causing polycystic ovaries and male pattern baldness
Authors: Carey A. H. , Chan K. L. , Short F. , White D. , Williamson R. , Franks S.
Published: March 2008

OBJECTIVE Polycystic ovary syndrome is one of the most common endocrine disorders but its aetiology remains unknown. It is highly prevalent within families, suggesting a genetic basic for the syndrome, but the mode of inheritance is unclear. The purpose of this study was to determine the mode of inheritance of polycystic ovary syndrome, within the families of affected individuals, by classic segregation analysis.

DESIGN All first degree relatives of affected individuals were screened for the presence or absence of polycystic ovaries in post‐menarchal‐premenopausal women and early onset male pattern baldness (MPB) in the males. In extended pedigrees, assignment of affected status in postmenopausal women was made by consideration of the clinical history alone.

PATIENTS Fourteen women (probands), presenting with a variety of clinical symptoms, were identified sequentially as having polycystic ovaries (PCO) by ultrasound scan. They were examined in detail to determine their family structure, clinical and endocrine status. Ten families were found to have sufficient members for further study.

MEASUREMENTS All family members had their body mass index calculated, their degree of hirsutism assessed using the Ferriman and Gallwey score and serum levels of gonadotrophins (FSH and LH), testosterone, prolactin and 17α‐hydroxyprogesterone measured by radioimmunoassay. A careful reproductive history was taken for each woman and any menstrual disturbance was noted. Obese probands had their glucose and insulin response to a standard 75‐g oral glucose tolerance test determined. Each male family member was also assessed for the degree and time of onset of balding.

RESULTS First degree female relatives of affected individuals had a 51 % chance of being affected. Early onset male pattern baldness (MPB) was found to be an accurate phenotype for obligate male carriers. Each family showed autosomal dominant inheritance for PCO with greater than 90% penetrance.

CONCLUSIONS We postulate that PCO and male pattern baldness are caused by alleles of the same gene which affect androgen production or action. The different frequencies of PCO and male pattern baldness arise from differing thresholds for phenotypic expression in females and males respectively. The modifying effects of other genes is the most likely explanation of the somewhat variable phenotype.
Prospective study of the hypothalamic‐pituitary axis in thalassaemic patients who developed secondary amenorrhoea
Authors: Chatterjee R. , Katz M. , Cox T. F. , Porter J. B.
Published: March 2008

OBJECTIVE We aimed to prospectively evaluate during 10 years the GnRH‐gonadotrophin secretory dynamics in a cohort of 15 menstruating girls with beta‐thalassaemia major to determine whether they sustained progressive damage to this axis.

DESIGN Patients were characterized by 12‐hour gonadotropin profiles (by sampling blood at 15‐minute intervals) and assessment of gonadotrophin responses to 100 μ g GnRH bolus (by sampling blood at 20‐minute intervals for 1 hour and at 2 hours) sequentially during the follicular and luteal phases of their menstrual cycles, 12–14 months and 5–6 years after the onset of secondary amenorrhoea.

SUBJECTS We studied 15 post‐menarcheal thalassaemic girls and five age‐matched control subjects who were the healthy siblings of the patients.

MEASUREMENTS FSH and LH assays were determined using commercial RIA systems and double antibody techniques. Pulse detection used the Pulsar technique of Merriam and Wachter.

RESULTS We demonstrated that during their amenorrhoeic period, all thalassaemic patients had gonadotrophin pulse abnormalities and low‐normal GnRH‐stimulated gonadotrophin levels indicating that they had GnRH‐gonadotrophin secretory insufficiency. During the subsequent 10 years there was progressive deterioration of hypothalamic‐pituitary function in all patients; 66% became apulsatile and all had marked reduction in their GnRH‐stimulated gonadotrophin levels.

CONCLUSIONS Our investigation suggests that thalassaemic patients with secondary amenorrhoea had severe and progressive damage to their hypothalamic‐pituitary axes despite intensive chelation therapy.
Adrenocorticotrophin and Cortisol secretion in children after low dose cranial irradiation
Authors: Crowne E. C. , Wallace W. H. B. , Gibson S. , Moore C. M. , White A. , Shalet S. M.
Published: March 2008

OBJECTIVE We investigated the effect of low dose cranial irradiation (18–24 Gy) on spontaneous ACTH and Cortisol secretion in children.

DESIGN We analysed 24‐hour plasma ACTH and Cortisol profiles sampled at 20‐minute intervals.

PATIENTS Twenty long‐term survivors of acute lymphoblastic leukaemia were studied and results compared with those in 14 normal children.

MEASUREMENTS ACTH and Cortisol profiles were analysed by Fourier transformation and spectral analysis of stationarized data, autocorrelation and coherency analysis.

RESULTS The normal circadian rhythms of ACTH and Cortisol were preserved in the children after cranial irradiation. The median 0900 h and midnight values were 1 50 (0 8–6 4)pmol/l and 1 0(0 6–3–7)pmol/l respectively for ACTH and 282(48–1913) nmol/l and 57 5(44–637)nmol/l respectively for Cortisol, and were not significantly different from those in the normal group. Fourier transformation revealed dominant periodicities for ACTH at 0–7–11 h, equivalent to 22–34 ACTH secretory bursts per 24 hours, and for Cortisol at 0 7–11 h and 2–4 8 h. Similar results were found in the normal group.

Coherency analysis indicated a significant shared periodicity of 0 7–1 2 h in nine children, corresponding to 20–34 related secretory bursts in 24 hours for ACTH and Cortisol. After pooling the coherency spectra in the cranially irradiated group, comparison with the pooled data from the normal group revealed no significant difference between the two groups in the relationship between the two hormones.

CONCLUSION No significant disruption of spontaneous ACTH or Cortisol secretion, either in the amount or pattern of hormones secreted, was found in children after low dose cranial irradiation (18–24 Gy).
Comparison of computerized tomography and magnetic resonance imaging for the examination of the pituitary gland in patients with Cushing's disease
Authors: Escourolle H. , Abecassis J. P. , Bertagna X. , Guilhaume B. , Pariente D. , Derome P. , Bonnin A. , Luton J. P.
Published: March 2008

OBJECTIVE The vast majority of patients with Cushing's disease have a corticotroph adenoma, the selective removal of which, through the transsphenoidal route, has the potential to offer a definitive and complete cure. This study was designed to compare the diagnostic accuracy of computerized tomography (CT) and magnetic resonance imaging (MRI) to identify the presence, evaluate the size, and assess the topographic characteristics of pituitary corticotroph adenomas.

METHODS Forty‐two patients with Cushing's disease were included in this prospective study, of whom 16 were subsequently explored transsphenoidally. Computerized tomography used a CE12000 CGR apparatus with 1 5‐mm coronal slices and a 2‐mm interslice gap. Magnetic resonance imaging used an MR Max 0 5T GE apparatus; adjacent 3‐mm slices were obtained with a T1‐weighted gradient echo before and after gadolinium injection.

RESULTS Lesions compatible with an adenoma were identified in 29 patients by MRI and in 21 patients by CT (69 vs 50%, P < 0 02). Seven macroadenomas were identified as well by the two methods. Eight of the 22 microadenomas detected by MRI were not identified by CT. Evidence for intracavernous tumour extension was found in nine patients: it was more frequently detected by MRI (8 patients) than by CT (4 patients). Fourteen patients with positive MRI had a pituitary examination: in one case the adenoma could not be reached because of purely suprasellar location; of the other 13 all were found by the surgeon and the surgical outcome was successful in 12 cases.

CONCLUSION MRI is superior to CTfor the examination of the pituitary gland in patients with Cushing's disease.
Bilateral adrenalectomy: low mortality and morbidity in Cushing's disease
Authors: McCance David R. , Russell Colin F. J. , Kennedy Terence L. , Hadden David R. , Kennedy Laurence , Atkinson A. Brew
Published: March 2008

OBJECTIVE We assessed the current role of bilateral adrenalectomy in the overall management strategy of hypercortisolism.

DESIGN Retrospective review of case notes.

PATIENTS Twenty‐six patients (20F/6M); mean age 46 years (range 15–70 years), median duration of follow‐up 5 25 years (0 6–19 1 years) who had undergone bilateral adrenalectomy at the Royal Victoria Hospital since 1972. Eighteen had had prior transsphenoidal surgery which did not control the hypercortisolism.

MEASUREMENTS Morbidity, mortality, incidence of Nelson's syndrome.

RESULTS Surgery was performed through bilateral postero‐lateral incisions (20 patients) or a long eplgastric incision (six patients). The mean combined weight of the adrenals at surgery was 11 2 g. Twenty patients received subcutaneous heparin and 18 antibiotic prophylaxis peri and post‐operatively. There was no operative mortality. Minor complications included one post‐operative wound infection and a small pneumothorax requiring drainage. Major complications occurred in two other patients, both with pre‐existing invasive pituitary tumours and considered at high risk because of age and general debility. One patient had a massive pulmonary embolus and the other a subphrenic abscess post‐operatively. This latter patient, the only mortality, died from an unrelated cause three years post‐operatively. Six patients have subsequently undergone pituitary surgery and three have received external pituitary irradiation therapy for expanding tumours.

CONCLUSIONS Bilateral adrenalectomy, in experienced hands, is a relatively safe and useful management option in patients with hypercortisolism. Growth of a pituitary adenoma post‐operatively is now the most worrying complication.
The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries
Authors: Robinson S. , Kiddy D. , Gelding S. V. , Willis D. , Niththyananthan R. , Bush A. , Johnston D. G. , Franks S.
Published: March 2008

OBJECTIVE Insulin insensitivity is a recognized feature of polycystic ovary syndrome (PCOS) but previous studies have suggested that circulating insulin concentrations are normal in hyperandrogenaemic women with regular cycles. The aim of this study was to examine the relationship between insulin sensitivity and menstrual pattern in women with PCO.

DESIGN A cross‐sectional study of insulin sensitivity in a cohort of PCO subjects with oligomenorrhoea compared to women with PCO and regular menstrual cycles and a group of normal control subjects.

SUBJECTS Seventy‐two women with polycystic ovaries on ultrasonography were studied. PCO subjects had clinical and/or biochemical evidence of hyperandrogenism; 53 had oligo/amenorrhoea (olig) and 19 had regular menses (reg). Results were compared with 31 control subjects. The groups were matched for age, weight and ethnic origin.

METHODS Glucose and insulin responses to 75 g oral glucose were measured. Insulin sensitivity was assessed by the decline in plasma glucose following intravenous insulin (0.05 U/kg).

RESULTS Glucose area (mean±SEM) after oral glucose was increased slightly in both PCO groups compared with controls (olig 37.6±1.4, reg 36.0±1.8, control 33.7±0.9 mmol/l h, both P < 0.01). Insulin area median (interquartile range) in response to glucose was significantly greater in the oligomenorrhoeic group (346 (239–734) mU/l h), compared with both PCO with regular cycles (246 (148–355), P<0.01) and controls (221 (147–277), P<001). Insulin sensitivity was reduced (P< 0.01) in the oligomenorrhoeic group (147 ±9.2 /imol/l min) compared to controls (185 ±7.4) but was normal in PCO with regular cycles (182 ±12.5). Insulin sensitivity did not correlate significantly with plasma testosterone or with SHBG levels, but plasma insulin concentrations correlated negatively with SHBG levels (fasting insulin vs SHBG, r= ‐0.47, P<0.01; insulin area vs SHBG, r= ‐0.47, P<0.01).

CONCLUSIONS Insulin insensitivity in polycystic ovary syndrome occurs when there is oligo/amenorrhoea but not when the menstrual cycle is regular. This is consistent with PCO and insulin insensitivity being separate abnormalities which when combined are associated with anovulation.