bluuebunny/crossref_metadata_2025 huggingface dataset:
Medroxyprogesterone acetate enhances the spinal bone mineral density response to oestrogen in late post‐menopausal women
Authors: Grey Andrew , Cundy Tim , Evans Margaret , Reid Ian
Published: November 2003

OBJECTIVES The relative contributions of administered oestrogen and progestin to protection of the post‐menopausal skeleton remain unclear. We have compared the effect on spinal bone mineral density of continuous combined oestrogen/medroxyprogesterone therapy with that of unopposed oestrogen in late post‐menopausal women.

DESIGN Observational study.

SUBJECTS Seventy‐three osteoporotic post‐menopausal women attending the Auckland Hospital Bone Clinic. Twenty‐three hysterectomized women were treated with unopposed oestrogen (0.625 mg oral conjugated oestrogens daily), and 50 non‐hysterectomized women were treated with continuous combined oestrogen/medroxyprogesterone therapy (5 mg medroxyprogesterone acetate and 0.625 mg oral conjugated oestrogens daily).

MEASUREMENTS Baseline and one‐year measurements of lumbar spine bone mineral density were performed using dual‐energy X‐ray absorptiometry.

RESULTS After one year of therapy, spinal bone mineral density increased by 6.6% (95% confidence interval 5.6–7.6, P < 0.001 vs baseline) in the combined oestrogen/medroxyprogesterone therapy group, compared to 4.0% (CI 2.4–5.7, P < 0.001 vs baseline) in the unopposed oestrogen group (difference between means 2.6% (CI 0.8–4.4, P < 0.01).

CONCLUSION In osteoporotic post‐menopausal women, one year of continuous combined oestrogen/medroxyprogesterone therapy is associated with a 65% greater increment in spinal bone mineral density than is observed in response to unopposed oestrogen. The prescription of combined oestrogen/progestin therapy should be considered in osteoporotic post‐menopausal women who have undergone hysterectomy, in order to maximize the skeletal protection provided by hormone replacement therapy.
Circulating levels of growth hormone, insulin‐like growth factor‐I and growth hormone binding protein in normal women of advanced reproductive age
Authors: Klein Nancy A. , Battaglia David E. , Miller Paul B. , Soules Michael R.
Published: November 2003

OBJECTIVE Women experience an age‐related decline in fertility despite regular ovulatory cycles and normal production of ovarian steroids. Growth hormone and IGF‐I are both reported to decline with age, and there is evidence that both hormones promote intraovarian actions of gonadotrophins. The purpose of this study was to characterize circulating levels of GH and IGF‐I in normal, older reproductive age women with ovulatory cycles.

DESIGN Prospective, controlled.

PATIENTS Twenty‐eight regularly cycling older (n = 16) and younger (n = 12) women were recruited for daily blood sampling throughout a menstrual cycle.

MEASUREMENTS Serum obtained from daily blood sampling was analysed for LH, FSH, oestradiol (E2) and progesterone (P). Serum obtained from frequent sampling during the admission was analysed for pulsatile GH secretion. IGF‐I and GH binding protein (GHBP) were also measured in subsets of the two age groups.

RESULTS All subjects exhibited normal patterns of LH, FSH, E2 and P consistent with ovulatory cycles. There were no differences between the two age groups in integrated 24‐hour GH secretion or in GH pulse amplitude or frequency. There were no differences in GH secretion between the early follicular and midluteal phases when data were combined for the two subject groups. Plasma concentrations of IGF‐I were significantly lower throughout the cycle in the older women. There were no significant differences in levels of GHBP across the cycle or between the two age groups.

CONCLUSIONS IGF‐I decreases with age in women without identifiable changes in the amount or pattern of GH secretion or in circulating GHBP concentrations. Decreased IGF‐I production may be related to decreased ovarian gonadotrophin sensitivity in older reproductive age women.
Steroid 5α‐reductase 2 deficiency: virilization in early infancy may be due to partial function of mutant enzyme
Authors: Forti G. , Falchetti A. , Santoro S. , Davis D. L. , Wilson J. D. , Russell D. W.
Published: November 2003

Male pseudohermaphroditism due to steroid 5α‐reductase deficiency is the consequence of mutations in the gene encoding the type 2 isoenzyme. Most (60%) affected subjects have homozygous mutations, and the remainder are compound heterozygotes or presumed compound heterozygotes. We report an Italian subject with phenotypic and endocrine features of 5α‐reductase 2 deficiency who is homozygous for a substitution mutation (H231R). Although close consanguinity is not present, genealogical data demonstrated that the parents are distantly related, and both parents and the maternal grandmother are heterozygous carriers of the mutation. The fact that this particular mutation results in the formation of an enzyme with considerable residual activity may explain in part the significant degree of virilization that took place in this subject in early infancy. This same mutation (H231R) is present in heterozygous form in two other families, an African‐American family and an American family of northern European descent.
Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries
Authors: Robinson S. , Henderson A. D. , Gelding S. V. , Kiddy D. , Niththyananthan R. , Bush A. , Richmond W. , Johnston D. G. , Franks S.
Published: November 2003

OBJECTIVE Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history.

DESIGN A cross‐sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls.

PATIENTS AND METHODS We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11).

RESULTS Results are expressed as mean ± SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 ± 0.7 vs LP 35.2 ± 1.2, P < 0.01; OC 34.7 ± l.8 vs OP 37.8 ± 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 ± 9 vs LP 179 ± 9, NS; OC 168 ± 12 vs OP 133 ± 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL2‐cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38–0.62), LP 0.31 (0.26–0.44), P < 0.05; OC 0.34 (0.21–0.47), OP 0.21 (0.12–0.32) mmol/l, P < 0.01). Total HDL‐cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL‐cholesterol and with HDL2‐cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL‐cholesterol in women with polycystic ovaries.

CONCLUSION Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.
Growth hormone secretion in normal prepubertal children: importance of relations between endogenous secretion, pulsatility and body mass
Authors: Martín‐Hernández T. , Gálvez M. Díaz , Cuadro A. Torres , Herrera‐Justiniano E.
Published: November 2003

OBJECTIVE Although a negative relation between GH secretion and body mass has been described, few studies have been carried out in prepubertal subjects of normal weight and height. The aim of the present study was to examine the relations between GH secretion, pulsatility and body mass throughout the wide range of weights in normal prepubertal children.

METHODS We determined integrated GH concentrations during the day (IC‐GHD), night (IC‐GHN), and 24 hours (IC‐GH24) in 46 prepubertal children (26 males, 20 females) of normal height and growth velocity and with a Z‐score (BMI‐SD) between +2 and −2 SD. In addition, in 28 of these patients randomized by their BMI‐SD, the secretory profile was studied by the Pulsar program: area under curve (AUC), peak number (NP), high spontaneous peak of secretory profile (HSP), and area of pulses (AP) which were considered large (L) or small (S) if their amplitude was greater or less than 4 μg/l (8 mU/l).

RESULTS BMI‐SD correlated negatively with IC‐GH (IC‐GHD, r = −0.48, P < 0.01; IC‐GHN, r = −0.45, P < 0.001; IC‐GH24, r = −0.58, P < 0.001) and with Pulsar parameters (AUC‐24, r = −0.73, P < 0.0001; HSP, r = −0.65, P < 0.0001). The NP correlated negatively with BMI‐SD (r = −0.51, P < 0.005) at the expense of NLP (r = −0.54, P < 0.003) without being significantly correlated with NSP. This inverse correlation between BMI‐SD and NLP was greater during daytime (NLDP, r = −0.60, P < 0.001) and was not significant at night. NSP did not correlate with BMI‐SD. A similar relation was observed with respect to pulse area (ALP, r = −0.38, P < 0.05; ALDP, r = −0.46, P < 0.02;) and was not significant for ALP during the night or for ASP in any period.

CONCLUSIONS We suggest that it should be necessary to relate GH secretion to body mass in prepubertal children before defining their secretion as normal or pathological.
Polycystic ovaries in pre and post‐menopausal women
Authors: Birdsall Mary Ann , Farquhar Cynthia Margaret
Published: November 2003

OBJECTIVE Polycystic ovaries have been diagnosed in more than 20% of premenopausal women using ultrasound. The aim of this study was to determine whether polycystic ovaries exist in post‐menopausal women.

DESIGN Two groups of women were studied; group 1 consisted of 18 post‐menopausal volunteers and group 2 comprised 142 women, 94 of whom were post‐menopausal who had recently undergone coronary angiography.

MEASUREMENTS Transabdominal and transvaginal ultrasound scans were performed and measurements made of uterine area, endometrial thickness and ovarian volume. The morphological appearance of the ovaries was also noted. Fasting blood samples were taken. Medical and menstrual questionnaires were completed.

RESULTS Polycystic ovaries were found in 8/18 (44%) of group 1 and 60/142 (42%) in group 2. Polycystic ovaries were detected in 35/94 (37%) of the post‐menopausal women in group 2. Post‐menopausal women with polycystic ovaries had larger ovaries containing more follicles compared with post‐menopausal women with normal ovaries. Post‐menopausal women with polycystic ovaries had higher serum concentrations of testosterone and triglycerides than had post‐menopausal women with normal ovaries.

CONCLUSIONS Polycystic ovaries can be detected in post‐menopausal women and have some of the same endocrine abnormalities which are evident in premenopausal women with polycystic ovaries, that is, raised serum concentrations of testosterone and triglycerides.
Hypergastrinaemia in Cushing’s syndrome: pituitary origin or glucocorticoid‐induced?
Authors: López‐Guzmán A. , Salvador J. , Frutos R. , Díez J. J. , Iglesias P. , Sastre J. , Gómez‐Pan A.
Published: November 2003

OBJECTIVES Several reports have shown an increase in serum gastrin levels in patients with Cushing’s syndrome (CS). However, the actual origin of this hypergastrinaemia is not known. Two hypotheses have been proposed: concomitant ACTH and gastrin secretion by corticotrophic pituitary adenomas or hypergastrinaemia induced by hypercortisolism.

DESIGN AND PATIENTS We performed simultaneous, bilateral inferior petrosal sinus (IPS) sampling in nine patients with Cushing’s disease (CD), proven by histological studies. In all of them, blood samples were taken from both IPS and a peripheral vein to measure plasma ACTH and serum gastrin. In addition, we measured peripheral serum gastrin levels after an overnight fast in 10 patients with CS (seven with pituitary tumours and three with adrenal tumours) before and after surgical treatment.

RESULTS Petrosal‐peripheral and interpetrosal gradients of ACTH were higher than 2.0 and 1.4, respectively, confirming the pituitary origin of ACTH. Mean serum gastrin levels were 149.1 ± 53.6 ng/l in peripheral vein, 183.4 ± 71.7 ng/l in dominant IPS and 181.4 ± 68.9 ng/l in non‐dominant IPS. No significant differences in gastrin concentrations in these locations were found. Mean preoperative gastrin level in patients with CD was 194.6 ± 47.9 ng/l, whereas in patients with adrenal tumours it was 247.3 ± 125.9 ng/l. After surgical treatment, the gastrin levels decreased to 62.1 ± 13.2 ng/l (P  < 0.05) and 90.3 ± 50.3 ng/l (NS), respectively.

CONCLUSIONS These results suggest that hypergastrinaemia is a common finding in patients with Cushing’s syndrome. The lack of significant petrosal‐peripheral gradient in individuals with Cushing’s disease and the reduction in gastrin level following adrenal tumour resection argues against the hypothesis of a predominantly pituitary source of gastrin, suggesting a glucocorticoid related mechanism as an explanation for the hypergastrinaemia.
The maternal hypothalamic–pituitary–adrenal axis in the third trimester of human pregnancy
Authors: Magiakou Maria‐Alexandra , Mastorakos George , Rabin Douglas , Margioris Andrew N. , Dubbert Bellinda , Calogero Aldo E. , Tsigos Constantine , Munson Peter J. , Chrousos George P.
Published: November 2003

OBJECTIVE The third trimester of pregnancy is characterized by a mildly hyperactive hypothalamic–pituitary–adrenal (HPA) axis, possibly driven by elevated circulating levels of corticotrophin releasing hormone (CRH) of placental origin. In‐vitro studies have demonstrated that glucocorticoids and oestrogen stimulate while progesterone inhibits the expression of CRH mRNA and/or protein, suggesting that several potential interactions between the placenta and the HPA axis may exist.

DESIGN AND PATIENTS To investigate the detailed pattern of circulating immunoreactive (ir) CRH, ACTH, cortisol, oestradiol and progesterone during the third trimester of pregnancy, plasma samples were drawn serially every 30 minutes from 22 healthy pregnant women (age 32.0 ± 1.1 years, mean ± SE) between the 34th and 36th week of gestation. Ten women had plasma samples drawn between 0800 h and 2000 h (daytime group), and 12 between 2000 h and 0800 h (night‐time group). The hormone concentrations obtained were analysed for pulsatility by the Detect program, for detection of circadian rhythmicity by comparison between the first and second 6‐hour periods within each group by Student's t‐test, and for time‐dependent correlations by cross‐correlation analysis.

RESULTS All five hormones were secreted in a pulsatile fashion. There was no apparent circadian rhythm of CRH or oes tradiol secretion, whereas there was a clear circadian rhythm in plasma ACTH, cortisol and progesterone secretion, with the latter in reverse phase (P<0.05). No significant correlations were observed between CRH and ACTH, whereas, as expected, ACTH and cortisol concentrations were strongly correlated with each other over time (r=0.32 and 0.70 at lag time 30 minutes for the daytime and night‐time groups, respectively), with ACTH leading cortisol. A weak positive correlation was observed between CRH and cortisol concentrations for the night‐time group at lag time 0 minute, suggesting that the latter may have a positive effect on the former in vivo

CONCLUSIONS These data suggest that placental CRH, although pulsatile, drives quantitatively the maternal HPA axis in the third trimester of pregnancy in a non‐circadian, non‐pulsatile fashion. The maternal HPA axis is probably driven in a circadian and pulsatile fashion by another major ACTH secretagogue, most likely AVP of parvocellular paraventricular nucleus origin.
Comparison of methods to estimate body fat in growth hormone deficient adults
Authors: Bosaeus Ingvar , Johannsson Gudmundur , Rosén Thord , Hallgren Per , Tölli Jukka , Sjöström Lars , Bengtsson Bengt‐Åke
Published: November 2003

OBJECTIVE All of the presently used methods for in‐vivo determination of body composition have inherent methodological errors and depend on various assumptions. We have therefore compared several different methods used to measure body fat in adult GH deficiency during GH treatment.

DESIGN Comparison of body composition data from a two‐phase trial with an initial placebo‐controlled, double‐blind 6‐month period, followed by open treatment with GH until all patients had received GH for 12 months.

PATIENTS Twenty‐five patients with known GH deficiency entered the study. Baseline examinations were complete in 23 patients, and 22 patients (16 males, 6 females) completed all examinations after treatment.

MEASUREMENTS Body fat calculated from total body potassium (TBK) by whole‐body 40K counting, total body water (TBW) by tritium dilution, total body nitrogen (TBN) by neutron activation, and bioelectric impedance (BIA) measurements were compared to body fat determinations by dual‐energy X‐ray absorptiometry (DEXA) in two‐compartment and multicompartment body composition models.

RESULTS At baseline, DEXA fat mass agreed well at group level with measurements based on TBW or TBK alone, in a four‐compartment model based on TBK and TBW, and a multicompartment model based on bone mineral (by DEXA), TBN and TBW. Body fat by BIA agreed less well. After 12 months of GH treatment, body fat decreased by all methods used. This decrease was smaller by DEXA than by the other methods. The four‐compartment model based on TBK and TBW, and TBW alone, showed the best agreement with changes in DEXA fat.

CONCLUSION All methods showed a decrease of body fat with GH treatment, but variation between methods was considerable.
Urinary excretion of pyridinoline and deoxypyridinoline measured by immunoassay in hypothyroidism
Authors: Nakamura Hirotoshi , Mori Tomoko , Genma Rieko , Suzuki Yoshikazu , Natsume Hiroko , Andoh Shinichiro , Kitahara Ryo , Nagasawa Shinsuke , Nishiyama Kozo , Yoshimi Teruya
Published: November 2003

OBJECTIVE We measured pyridinium cross‐links, markers of bone resorption, by an enzyme‐linked immunosorbent assay (ELISA) in hypothyroid patients to see whether bone resorption was reduced in hypothyroidism and whether it increased with T4 treatment.

DESIGN AND PATIENTS Eight hypothyroid patients, whose initial TSH levels were 268.1 ± 87.7 mU/l (mean ± SE), were treated with T4 (100μg/day). Urinary excretion of pyridinium cross‐links was assayed before and after T4 treatment.

MEASUREMENTS Pyrilinks and Pyrilinks‐D kits were used. The Pyrilinks assay measures free forms of pyridinoline and deoxypyridinoline together (PYD), while the Pyrilinks‐D assay measures deoxypyridinoline (DPD) alone. The Pyrilinks reference ranges for normal subjects are 8–24nmol/mmol creatinine in males and 10–28nmol/mmol creatinine in normal premenopausal females. The DPD reference ranges obtained from normal men and women aged 40–50 years were 3.20 ± 0.75 (mean ± SD) nmol/mmol creatinine and 4.55 ± 1.22 nmol/mmol creatinine, respectively.

RESULTS The sensitivity of the assay was enhanced by simply using less diluted urine samples. Concentrations of both compounds of the urinary pyridinium cross‐links were low in untreated hypothyroid patients and increased gradually as thyroid hormone status improved from hypothyroidism to euthyroidism. One month after treatment when the TSH levels in the patients were still as high as 74.4 ± 44.5 mU/l, urinary PYD excretion has increased to 2.6 times the pretreatment level. When the TSH levels of the patients decreased below 10 mU/l, both PYD and DPD increased significantly to 3.8 and 3.3 times pretreatment values, respectively.

CONCLUSIONS Although hyperthyroidism or excess treatment with thyroid hormone has been known to induce bone resorption, this is the first report that urinary excretion of pyridinium cross‐links is reduced in hypothyroidism and is normalized by physiological thyroid hormone replacement.
Glucose turnover, fuel oxidation and forearm substrate exchange in patients with thyrotoxicosis before and after medical treatment
Authors: Møller Niels , Nielsen Søren , Nyholm Birgit , Pørksen Niels , George K. , Alberti M. M. , Weeke Jørgen
Published: November 2003

OBJECTIVE Accelerated metabolism is a hallmark of thyrotoxicosis, but the underlying bioche mical mechanisms are incompletely understood and the majority of studies have investigated normal subjects rendered only modestly hyperthyroid for a brief period of time. We have therefore studied a group of thyrotoxic patients using several different techniques.

DESIGN Twelve patients with newly diagnosed diffuse (10 patients) or nodular (2 patients) toxic goitre (10 women, 2 men; age 42.8 ± 3.2 years; BMI 21.6 ±0.7 kg/m2) before (‘pretreatment’) and after (‘treated’) 11.2 ± 1.0 weeks treatment with methimazole and compared these patients to a control group (‘control’) of 11 subjects (9 women, 2 men; age 40.5 ± 3.9 years; BMI 22.5 ± 1.0 kg/m2). All were studied for 3 hours in the basal state, using indirect calorimetry, isotope dilution for the measurement of glucose turnover and the forearm technique for assessment of muscle metabolism.

RESULTS Prior to treatment patients with thyrotoxicosis were characterized by increased (P < 0.05) levels of T3 (3.75 ± 0.23 nmol/l (pretreatment), 1.89 ± 0.08 (treated) and 1.75 ± 0.11 (control)), resting energy expenditure (130.5 ± 3.5 (pretreatment), 107.7 ± 2.7 (treated) and 106.3 ± 3.1 (control), % of predicted), protein oxidation (0.67 ± 0.03 (pretreatment), 0.54 ± 0.06 (treated) and 0.46 ± 0.05 (control), mg/kg/min), lipid oxidation (1.34 ± 0.08 (pretreatment), 1.00 ± 0.06 (treated) and 1.02 ± 0.04 (control), mg/kg/min), endogenous glucose production (2.51 ± 0.13 (pretreatment), 1.86 ± 0.12 (treated) and 1.85 ± 0.12 (control), mg/kg/min), non‐oxidative glucose turnover (1.28 ± 0.16 (pretreatment), 0.75 ± 0.18 (treated) and 0.71 ± 0.11 (control), mg/kg/min) and a 50% increase in total forearm blood flow. Glucose oxidation (1.23 ± 0.09 (pretreatment), 1.13 ± 0.10 (treated) and 1.21 ± 0.11 (control) mg/kg/min), exchange of substrates in the muscles of the forearm and circulating levels of insulin, C‐peptide, growth hormone or glucagon were not influenced by hyperthyroidism. Propranolol (20 mg thrice daily) given to 7 of the patients for 2 days did not affect circulating levels of thyroid hormones, energy expenditure or glucose turnover rates.

CONCLUSIONS These results suggest that all major fuel sources contribute to the hypermetabolism of thyrotoxicosis and that augmented non‐oxidative glucose metabolism may further aggravate the condition. All abnormalities diminish with medical treatment of the disease.
Expression of the transferrin receptor in human anterior pituitary adenomas is confined to gonadotrophinomas
Authors: Atkin S. L. , Burnett H. E. , Green V. L. , White M. C. , Lombard M.
Published: November 2003

OBJECTIVE The human pituitary gland is affected selectively by conditions associated with iron deposition, but the mechanisms for this are unknown. In this study we have determined whether the transferrin receptor, which mediates iron uptake by cells, could be detected immunocytochemically in human pituitary adenomas in vitro.

PATIENTS Data were derived from 35 patients undergoing transsphenoidal surgery and included 13 with clinically non‐functioning adenomas, 15 with acromegaly, 4 prolactinomas, 2 patients with Cushing’s disease and one patient with Nelson’s syndrome.

MEASUREMENTS Transferrin receptor immunopositivity was determined for each adenoma in dispersed cell culture using a specific monoclonal antibody.

RESULTS Eight of 13 clinically functionless adenomas showed immunopositive transferrin receptor expression, whilst adenomas from 15 patients with acromegaly, 4 prolactinomas, 2 Cushing’s syndrome and one patient with Nelson’s syndrome were negative. The eight transferrin receptor positive tumours were gonadotrophinomas and accounted for eight of the nine tumours which secreted and immunostained for FSH; all eight also secreted and immunostained for LH.

CONCLUSIONS These findings may reflect a special requirement for iron by gonadotrophin secreting cells in comparison to other pituitary cell types and this could underlie the reasons why in the normal pituitary these cells are especially susceptible to malfunction in iron overload syndromes such as genetic haemochromatosis and β‐thalassaemia.
The impact of liver transplantation on endocrine status in men
Authors: Madersbacher Stephan , Ludvik Georg , Stulnig Thomas , Grünberger Thomas , Maier Ulrich
Published: November 2003

OBJECTIVE There are few longitudinal data on the endocrine changes which occur after liver transplantation. We have therefore studied the impact of orthotopic liver transplantation (oLTX) on the hypothalamic–pituitary–gonadal hormone axis and sex steroid metabolism in men.

PATIENTS AND STUDY DESIGN Ten male patients with end‐stage liver failure due to alcohol induced cirrhosis (n = 2), virus‐induced cirrhosis (n=5), primary biliary cirrhosis (n=1) and idiopathic cirrhosis (n=2) were included in a prospective study analysing the impact of oLTX on endocrine status. They were studied before and after oLTX with a mean follow‐up of 11.6 months (range 4–23) following transplantation.

MEASUREMENTS Serum levels of LH, FSH, testosterone (TE), free TE, PRL, cortisol, oestradiol (E2) and sex hormone binding globulin (SHBG) were analysed with commercially available radioimmunoassays in all individuals before and after oLTX. Gonadotrophin releasing hormone stimulation tests were done in 5 patients before and after oLTX. Additionally, a complete urological assessment with a detailed questionnaire on sexual function was obtained from all individuals.

RESULTS Prior to oLTX, endocrine status was invariably abnormal, the most prominent finding being a pathological decrease of TE in 90% and of free TE in all cases. After successful oLTX, all individuals had physiological levels of TE and of free TE which increased twofold (P<0.01) and tenfold (P<0.000 1), respectively. Additionally, serum gonadotrophin (LH/FSH) levels increased in the majority of patients, while E2 decreased following oLTX. Endocrine changes extended beyond the hypothalamic–pituitary–gonadal hormone axis, as shown by a decrease in PRL (P<0.02) and SHBG (P<0.01) after transplantation. GnRH tests revealed normal stimulation of LH and FSH before and after oLTX in all cases. Libido, potency and frequency of sexual intercourse improved significantly after oLTX in the majority of patients.

CONCLUSIONS These findings demonstrate the ability of the hypothalamic–pituitary–gonadal hormone axis and sex steroid metabolism to resume physiological function following orthotopic liver transplantation in men. Correspondingly, sexual function returns to normal in the majority of patients, despite significant alterations prior to orthotopic liver transplantation.
Risk factors for secondary hyperparathyroidism in a nursing home population
Authors: Stein Mark S. , Scherer Samuel C. , Lynette Walton S. , Gilbert Richard E. , Ebeling Peter R. , Flicker Leon , Wark John D.
Published: November 2003

OBJECTIVE Secondary hyperparathyroidism may cause bone loss and structural deterioration of bone and may thus be a cause of fracture in the elderly. Vitamin D deficiency, renal impairment and medications are potential causes of hyperparathyroidism and may also directly predispose to fracture. We present the first findings of an ongoing study of hip fracture, vitamin D deficiency and hyperparathyroidism in a large Australian nursing home.

DESIGN Descriptive prevalence study.

PATIENTS Two hundred and fifty‐one nursing home residents were eligible for inclusion. Informed consent and successful venepuncture were obtained for 99. Residents were of median age 83 years with interquartile range (IR) 77–89 years.

MEASUREMENTS 25‐Hydroxyvitamin D (25OHD), intact parathyroid hormone (PTH), creatinine and biochemistry, demographic data and current medications.

RESULTS Fifty‐two per cent of 99 subjects had 25OHD below the reference range of 28–165 nmol/l and 96.5% were below the reference range mean. Those with low 25OHD had lower plasma calcium corrected for albumin than those with normal 25OHD (medians 2.34 vs 2.41mmol/l, 95% confidence interval for the difference between medians (CI) −0.10 to −0.04 mmol/l, P=0.0001) and higher PTH (medians 5.8 vs 3.9 pmol/l, CI 0.10–2.6pmol/l, P=0.0360). Twenty‐eight per cent of 97 residents had PTH above the upper reference range limit of 6.5 pmol/l. Residents receiving frusemide had higher PTH than other residents (medians 6.95 vs 3.45 pmol/l, CI 1.9–4.2pmol/l, P<0.0001). In linear modelling, the most important predictor of the natural logarithm of PTH was daily frusemide dose, adjusted R2 (Ra2)=31.8%, F=39.3, P<0.001. Creatinine and the reciprocal of 25OHD were other significant predictors with the final Ra2=39.4%, F=17.7, P<0.001.

CONCLUSIONS Vitamin D deficiency is a common risk factor for secondary hyperparathyroidism in nursing home residents despite a climate in which vitamin D nutrition is thought to be ample. However, the daily frusemide dose is a more important predictor of PTH in this population.
Determination of renin, angiotensin converting enzyme and angiotensin II levels in human placenta, chorion and amnion from women with pregnancy induced hypertension
Authors: Kalenga M. K. , Thomas K. , De Gasparo M. , De Hertogh R.
Published: November 2003

OBJECTIVE Pregnancy induced hypertension has been shown to be associated with a normal or low activity of the maternal circulating renin–angiotensin system (RAS) but little is known of the local RAS in placenta and fetal membranes. The present study attempts to determine, at full term of human preeclamptic pregnancies, the activity of the chorioplacental renin–angiotensin system.

PATIENTS AND MEASUREMENTS We analysed the concentrations of active renin, prorenin, angiotensin converting enzyme (ACE) and angiotensin II in homogenates of human placenta and fetal membranes from preeclamptic patients at full term pregnancy. The values of renin, ACE and angiotensin II found in the patients with moderate preeclampsia (gestosis index 0–1) (n = 10) were compared with those of normal pregnant women (n = 8).

RESULTS Our experiments showed that in preeclamptic pregnancies, the chorion membrane contained the highest concentrations of active renin (2905 ± 152 pg/g, mean ± SD), prorenin (21 315 ± 2849 pg/g) and ACE (1258 ± 302 U/g) whereas the placenta had more angiotensin II than the chorion and amnion (741 ± 45 vs 456 ± 40 and 428 ± 64 pg/g, respectively). In the placenta, as in the fetal membranes, no significant difference was found in the levels of active renin, ACE or angiotensin II between hypertensive patients and normal subjects but a slightly lower level of chorionic prorenin (P < 0.05) was observed in pregnancy induced hypertension.

CONCLUSION These findings indicate that in moderate preeclampsia (gestosis index 0–1), the activity of the renin–angiotensin system in term human placenta and fetal membranes remains essentially normal.
The development, reliability and validity of a disease specific quality of life model for adults with growth hormone deficiency
Authors: Wallymahmed Maureen E. , Baker Gus A. , Humphris Gerry , Dewey Michael , MacFarlane Ian A.
Published: November 2003

OBJECTIVE Adults with GH deficiency frequently complain of lack of energy, fatigue, social isol ation and problems with sexual relationships resulting in a low perceived quality of life. Previous studies of quality of life (QOL) in GH deficient adults have involved small numbers of patients and used measures not specifically designed for this patient population. We have devised a health related QOL model specifically designed for use in adults with GH deficiency and to assess the impact of future GH replacement therapy.

DESIGN Six measurements were chosen for inclusion in the model. Two were adapted for use after clinical interviews with 12 adult GH deficient patients: the Impact and the Life Fulfilment scales. The others were the Nottingham Health Profile, the Hospital Anxiety and Depression Scale, the Self‐Esteem Scale and the Mental Fatigue Questionnaire. The reliability of the 6 measures was assessed by 2 methods: test re‐test correlation and internal consistency (Cronbach's α). The validity of the Impact and Life Fulfilment scales was assessed by correlation with the other 4 scales.

PATIENTS Questionnaires were completed by 32 adults with hypothalamic pituitary disorders and GH deficiency (11 male, mean age 35.1 years), with a stimulated maximum serum GH response less than 10 mU/l (mean 2.96).Two had previously received GH injections in childhood. The questionnaires were also completed by 32 age and sex matched control subjects.

RESULTS The 6 scales had test re‐test correlations of 0.70–0.92 indicating reliability over time. The Impact and Life Fulfilment Scales and the Mental Fatigue Questionnaire had Cronbach's α scores of greater than 0.6 indicating their potential for use in clinical trials. The Impact and Life Fulfilment scales correlated significantly with many physical and psychological domains from the other 4 scales indicating these were valid in the assessment of health related QOL in GH deficient adults. Compared to the controls the patients with GH deficiency were significantly psychosocially disadvantaged in terms of depression, self‐esteem, mental fatigue and life fulfilment.

CONCLUSION The results of the reliability and validity studies indicate that this health related quality of life model for use with adults with GH deficiency is a potentially valid and reliable tool that could be used to assess the effect of GH treatment.
Thyroid peroxidase: evidence for disease gene exclusion in Pendred's syndrome
Authors: Gausden Eleanor , Armour John A. L. , Coyle Beth , Coffey Rebecca , Hochberg Ze'ev , Pembrey Marcus , Britton Keith E. , Grossman Ashley , Reardon William , Trembath Richard
Published: November 2003

OBJECTIVE Pendred's syndrome is an association between congenital neurosensory deafness and goitre with abnormal discharge of iodide following perchlorate challenge, indicating a defect of iodide organification. Although Pendred's syndrome may cause up to 7.5% of all cases of congenital deafness, the molecular basis of the association between the hearing loss and the thyroid organification defect remains unknown. We chose to investigate the role of the thyroid peroxidase (TPO) gene as the genetic defect in Pendred's syndrome.

DESIGN A highly informative variable number tandem repeat (VNTR), located 1.5kb downstream of exon 10 of the TPO gene,was used to search for genetic linkage in multiple sibships affected by Pendred's syndrome.

PATIENTS Seven kindreds were recruited from the UK, each with at least two affected members. We have also examined a large inbred Israeli family with two affected offspring and five unaffected children.

MEASUREMENTS Individuals were assigned affected status based on the characteristic clinical features of Pendred's syndrome, namely the presence of congenital sensorineural hearing loss and the appearance in early life of a goitre. Additionally, at least one affected member from each sibship had a characteristic positive perchlorate discharge test (Morgans & Trotter, 1958). PCR amplification of genomic DNA at the TPO VNTR allowed assignment of genotypes to each individual and the calculation of a two‐point LOD score

RESULTS In six of the nine sibships analysed we found obligatory recombination between TPO and Pendred's syndrome. Non‐complementation observed in affected parents with an affected offspring excluded TPO in an affected sibship with genotype sharing and supports a hypothesis of genetic homogeneity for Pendred's syndrome. In two sibships, mutation of the TPO gene as the cause of Pendred's syndrome could not be excluded.

CONCLUSIONS These data suggest that defects at the thyroid peroxidase locus on chromosome 2 are not the major cause of Pendred's syndrome.
Homozygous nonsense mutation in the insulin receptor gene of a patient with severe congenital insulin resistance: leprechaunism and the role of the insulin‐like growth factor receptor
Authors: Kaplowitz Nicholas , Furlanetto Richard W.
Published: November 2003

Severe congenital insulin resistance in the syndrome of leprechaunism is caused by mutations in the insulin receptor gene. We report a patient with leprechaunism who was homozygous for a mutation resulting in the absence of cell surface insulin receptors. To determine whether the receptor for Insulin‐like growth factor‐I (IGF‐I) is involved in the phenotype of leprechaunism, we studied the effect of insulin and of IGF‐I on cells from this patient.

The patient had a homozygous C → T substitution at base pair 8212 in exon 12 of the insulin receptor gene, creating a premature stop codon. This nonsense mutation is in the extracellular portion of the receptor and truncates the insulin receptor proximal to its transmembrane anchor, resulting in the absence of cell surface insulin receptors. This finding indicates that complete absence of the insulin receptor is compatible with life. Secondly, DNA synthesis was studied in skin derived fibroblasts in response to increasing concentrations of either insulin or Insulin‐like growth factor ‐I (IGF‐I), and was assessed by 3H‐thymidine incorporation. In this patient’s cells, both of these hormones increased 3H‐thymidine incorporation, and the effect was blocked by α‐IR3, a monoclonal antibody that blocks activation of the IGF‐I receptor.

These findings confirmed the absence of the insulin receptor and indicated that insulin acts here through activation of the IGF‐I receptor. These data support the contention that the phenotypic and metabolic abnormalities of leprechaunism result from the combination of lack of insulin receptor action and over‐activation by insulin of the type 1 IGF receptor.
Vasopressin levels in Cushing's disease: inferior petrosal sinus assay, response to corticotrophin‐releasing hormone and comparison with patients without Cushing's disease
Authors: Colao Annamaria , Ferone Diego , Di Sarno Antonella , Tripodi Francesca S. , Cerbone Gaetana , Marzullo Paolo , Boudouresque Françoise , Oliver Charles , Merola Bartolomeo , Lombardi Gaetano
Published: November 2003

BACKGROUND Higher vasopressin (AVP) levels have been found in the inferior petrosal sinus ipsilateral to the ACTH‐secreting adenoma than in the contralateral one, suggesting a potential pathogenetic role of AVP in Cushing's disease.

DESIGN In order to investigate AVP release, plasma ACTH and AVP concentrations were assayed in the inferior petrosal sinuses and in the peripheral blood before and after CRH stimulation.

PATIENTS Twenty patients with Cushing's disease and 12 with other pituitary diseases were subjected to simultaneous and bilateral inferior petrosal sinus sampling for diagnostic purposes. Ten healthy sex and age‐matched subjects served as control for peripheral AVP values.

MEASUREMENTS Plasma ACTH concentrations were measured by RIA using commercial kits. Plasma AVP concentrations were assayed by RIA in acetone extracts of 1–2 ml plasma.

RESULTS Plasma AVP levels in the inferior petrosal sinuses were significantly higher in Cushing's disease than in patients with other pituitary diseases (P<0.05) and in both groups AVP levels were higher in the inferior petrosal sinuses than in the peripheral blood (P<0.01). In Cushing's disease, ACTH, but not AVP levels, were higher in the inferior petrosal sinus ipsilateral to the adenoma than in the contralateral one (P<0.01). Seven patients showed a significant ACTH and AVP increase (greater than 50% of baseline) after CRH stimulation in the inferior petrosal sinus ipsilateral to the adenoma. Conversely, no change was found in AVP levels in the remaining 13 patients. When AVP values were analysed in relation to surgical cure, higher inferior petrosal sinus levels (P<0.05) were found in 6 patients with poor outcome: 4 of these patients had significantly decreased plasma AVP concentrations (by 32–43% of baseline) after CRH bolus. Peripheral AVP levels were similar in healthy subjects and patients with Cushing's disease whereas they were significantly reduced in patients with other pituitary diseases (P<0.002).

CONCLUSIONS The results of this study show that patients with Cushing's disease and poor surgical outcome had the highest AVP levels in our series. CRH administration caused different effects on AVP levels: it increased them in 35% of patients whereas there was no response in the remaining patients. On the basis of these findings, it is hypothesized that AVP might be involved in the persistence of ACTH hypersecretion in a subset of patients poorly responsive to surgery.
Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism
Authors: Al‐Shoumer Kamal A. S. , Ali Kamsiah , Anyaoku Victor , Niththyananthan Ratnam , Johnston Desmond G.
Published: November 2003

BACKGROUND Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours.

OBJECTIVE To investigate the metabolic consequences of conventional hormone replacement in hypopituitary adults by measuring circulating levels of the major fuels, glucose, non‐esterified fatty acids (NEFA), glycerol and 3‐hydroxybutyrate (3‐OHB) over 24 hours in hypopituitary subjects and controls.

SUBJECTS Ten GH and adrenocorticotrophin deficient hypopituitary adults on conventional replacement and 13 controls matched for age, sex and body mass index were studied. The patients received replacement with hydrocortisone twice daily (at 0730 and 1730 h; mean (range) daily dose 22 (10–30) mg/24 h) but not with GH. Other hormones were replaced as clinically necessary.

MEASUREMENTS Circulating glucose, NEFA, glycerol and 3‐OHB levels were measured over 24 hours together with concentrations of cortisol (total and free), GH and insulin, and urinary free cortisol.

RESULTS Levels of glucose, NEFA and 3‐OHB were lower in patients than controls (mean ± SEM) (4.3 ± 0.1 vs 5.3 ± 0.1 mmol/l, P = 0.0001; 291 ± 46 vs 448 ± 48 μmol/l, P = 0.015; 78 ± 8 vs 136 ± 24 μmol/l, P = 0.035, respectively) before breakfast. This decrease in glucose, NEFA and 3‐OHB was observed in the patient group throughout the night, from midnight to breakfast. For NEFA, the decrease persisted throughout the 24 hours. Glycerol did not differ significantly in patients and controls. Integrated levels of total and free plasma cortisol, and 24‐hour urine cortisol excretion, were normal in patients but total and free plasma cortisol concentrations overnight were markedly decreased (overnight area under the curve (AUC) of total cortisol: 440 ± 154 vs 1593 ± 267 nmol/l h, P = 0.0024; overnight AUC of free cortisol: 24 ± 8 vs 161 ± 26 nmol/l h, P = 0.0001). GH levels were low throughout the whole 24 hours in the patient group (24‐hour AUC: 10.6 ± 5.1 vs 74.6 ± 19.6 mU/l h, P = 0.008).

CONCLUSIONS Hypopituitary adults on conventional hormone replacement regimens have low concentrations of metabolic fuels, glucose, non‐esterified fatty acids and 3‐hydroxybutyrate throughout the night, possibly related to GH deficiency or to decreased overnight circulating cortisol levels. This overnight fuel deficiency may underlie the mechanism for the non‐specific symptoms, such as fatigue and headache in the early morning, which are frequent in this group of patients.
Cytokine expression in human anterior pituitary adenomas
Authors: Green V. L. , Atkin S. L. , Speirs V. , Jeffreys R. V. , Landolt A. M. , Mathew B. , Hipkin L. , White M. C.
Published: November 2003

OBJECTIVE There is increasing evidence for the role of cytokines in pituitary differentiated function and tumorigenesis, but the spectrum of cytokines found in the pituitary is unknown. Therefore profiles of cytokine expression were determined in different human anterior pituitary adenoma sub‐types.

DESIGN The reverse transcriptase‐linked polymerase chain reaction (PCR) was used to identify the presence of cytokine mRNA within human pituitary adenomas.

PATIENTS Seventeen pituitary adenoma biopsies removed at transsphenoidal surgery were examined: 4 somatotrophinomas, 7 non‐functional adenomas, 4 prolactinomas, one case of Cushing’s disease and one case of Nelson's syndrome.

MEASUREMENTS RNA was extracted from each adenoma biopsy and reverse transcribed into cDNA. This was specifically amplified in a PCR using oligonucleotide primers complementary to each cytokine. The cytokines investigated were interleukin (IL) ‐lα, IL‐lβ, IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, tumour necrosis factor (TNF)‐α, TNF‐β and transforming growth factor (TGF)‐β1, β2 and β3. The products of each PCR were visualized using agarose gel electrophoresis.

RESULTS All 17 adenomas expressed IL‐8 transcripts, but no expression of IL‐2, IL‐5 or IL‐7 was found. IL‐6 was expressed in all 4 somatotrophinomas, 3 of 7 non‐functional tumours, 2 of 4 prolactinomas and in the single case of Nelson's syndrome. At least one of the 3 isoforms of TGF‐β was found in all but 2 tumours; one prolactinoma and one non‐functional adenoma. IL‐1α, IL‐β, IL‐4, TNF‐α and TNF‐β were expressed sporadically by individual adenomas.

CONCLUSION These data suggest that whilst IL‐8 may be important, the local expression of the cytokines IL‐2, IL‐5 and IL‐7 is not important in human anterior pituitary tumorigenesis.
Follicle stimulating hormone‐β subunit gene is expressed in parallel with a transcription factor Ad4BP/SF‐1 in human pituitary adenomas
Authors: Ikuyama Shoichiro , Ohe Kenji , Sakai Yoshiyuki , Nakagaki Hiroyuki , Fukushima Takeo , Kato Yukio , Morohashi Ken‐ichirou , Takayanagi Ryoichi , Nawata Hajime
Published: November 2003

OBJECTIVES A transcription factor Ad4BP/SF‐1 is implicated in the differentiation of gonadotrophs in the pituitary gland, but it is not known whether human pituitary cells express this factor. The present study aimed to disclose (1) whether human pituitary adenomas express Ad4BP/SF‐1, and (2) if this is the case, what kinds of adenoma express the factor.

MATERIAL Total RNA was extracted from 23 pituitary adenomas obtained by transsphenoidal surgery, and subjected to Northern blot analyses using cDNAs of bovine Ad4BP/SF‐1, porcine FSH‐β, LH‐β and glycoprotein hormone‐β (GPH‐α) subunits as radiolabelled probes. These adenomas included 13 clinically non‐functioning adenomas, 1 GH/PRL‐producing adenoma, 6 GH‐producing adenomas, 2 PRL‐producing adenomas and 1 ACTH‐producing adenoma.

RESULTS The expression of Ad4BP/SF‐1 exactly coincided with the expression of FSH‐β. Thus 5 out of 13 clinically non‐functioning adenomas expressed Ad4BP/SF‐1 and only these 5 adenomas expressed FSH‐β. Interestingly, only one of the GH‐producing adenomas also expressed Ad4BP/SF‐1 as well as FSH‐β. GPH‐α was expressed in 4 non‐functioning adenomas and 2 hormonally functioning adenomas, but did not necessarily coincide with Ad4BP/SF‐1 expression. None of the 23 adenomas we tested expressed LH‐β, probably because LH‐β‐producing adenomas are rather rare.

CONCLUSIONS The expression of FSH‐β was parallel with Ad4BP/SF‐1 expression, indicating that the expression of Ad4BP/SF‐1 is restricted to cells derived from gonadotroph lineages in human pituitary adenomas.