bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenal insufficiency as the first clinical manifestation of the primary antiphospholipid antibody syndrome
Authors: Satta  , Corsello  , Della Casa  , Rota  , Pirozzi  , Colasanti  , Cina  , Grossman  , Barbarino
Published: March 2003

We describe a 60‐year‐old man who developed clinical symptoms and signs of Addison's disease, which was subsequently confirmed biochemically; no cause was apparent. Several months later the patient represented with a fit, followed by a large and extensive venous thrombosis in the right iliac vein and in the veins of the right leg. He had strongly positive antibodies to cardiolipin, strongly suggesting a diagnosis of primary antiphospholipid syndrome. While Addison's disease is a well‐recognized, albeit rare, manifestation of the antiphospholipid syndrome, the Addison's disease preceded other clinical evidence of the syndrome by several months, in our patient, at variance with previous cases described in the literature. The antiphospholipid syndrome should be considered as a possible pathogenetic process in patients presenting with Addison's disease where the aetiology is not obvious.
Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1,25‐dihydroxyvitamin D3
Authors: Colin Edgar M. , Weel Angelique E. A. M. , Uitterlinden André G. , Buurman Cok J. , Birkenhäger Jan C. , Pols Huibert A. P. , Van Leeuwen Johannes P. T. M.
Published: March 2003

OBJECTIVE

In the vitamin D receptor (VDR) gene a BsmI restriction fragment length polymorphism (RFLP) in intron 8 and a translational start‐site polymorphism, identified as a FokI RFLP, have been described. Crucial for a proper interpretation of these polymorphisms in association studies is the knowledge whether they have direct consequences for 1,25‐(OH)2D3 action at cellular level. The present study was designed to assess functional significance of the FokI and BsmI VDR gene polymorphisms in peripheral blood mononuclear cells (PBMC) with a natural occurring VDR genotype for cell growth inhibition by 1,25‐(OH)2D3.

DESIGN

PBMC of women were isolated, VDR genotyped and in vitro inhibition by 1,25‐(OH)2D3 of Phytohemagglutinin (PHA)‐stimulated growth of PBMC was examined in relation to VDR genotype.

RESULTS

PHA‐stimulated growth and maximal growth inhibition were independent of VDR genotype. However, the FF genotype had a significant lower ED50 than the Ff genotype corresponding to an allele dose effect of 0.32 nm per f allele copy (P = 0.0036). For BsmI genotypes no differences in ED50 were observed.

CONCLUSION

The present study demonstrates for the first time in cells with a natural VDR genotype a direct functional consequence of the VDR gene translational start‐site polymorphism for the action of 1,25‐(OH)2D3. Especially under conditions of vitamin D insufficiency these findings might have clinical implications.
Circulating IGF‐I and its protective role in the pathogenesis of diabetic angiopathy
Authors: Janssen  , Lamberts
Published: March 2003

Poor glycaemic control in type 1 diabetes is associated with elevated serum IGFBP‐1 levels and reduced rather than elevated serum IGF‐I levels. Increasing age is accompanied by a further decrease in serum IGF‐I levels as well as an increase in IGFBP‐l levels in adult diabetic type 1 and type 2 subjects. This is especially observed in diabetic type 1 subjects with manifest microvascular complications. IGFBP‐I has been proposed as one of the IGF‐I inhibitors in the serum of diabetics. Lowered IGF‐I and increased IGFBP‐1 levels in the blood may thus result in decreased IGF‐I bioavailability at the tissue level.

We hypothesize that the premature and progressive decline in serum IGF‐I bioactivity during ageing in diabetics ultimately results in insufficient protective effects by IGF‐I in the kidneys, eyes and neurones, and thus the progression of diabetic microvascular complications. If this hypothesis is proven to be right, treatment of diabetic patients with IGF‐I (eventually complexed to IGFBPs) as an adjunct to insulin might prevent and not worsen the development of diabetic microvascular complications.
The development of a sialic acid specific lectin‐immunoassay for the measurement of human chorionic gonadotrophin glycoforms in serum and its application in normal and Down's syndrome pregnancies
Authors: Abushoufa Ramadan A. , Talbot James A. , Brownbill Kathryn , Rafferty Brian , Kane John W. , Robertson William R.
Published: March 2003

OBJECTIVE We have developed and validated a lectin‐immunoassay for the recognition of sialic acid residues on hCG glycoforms in serum. DESIGN This assay employs a hCG specific capture antibody and a sialic acid specific lectin (Wheat Germ Agglutinin) labelled with horse radish peroxidase. RESULTS The standard curve covered hCG concentrations of 0‐4000lU/I (3rd IS for hCG, 7W537) with an analytical sensitivity of 1.0 IUA. The within and between batch coefficient of variation was<7% for all doses. Cross‐reactivity of <1% with TSH, LH, FSH, hCGa, hCGβ and desialylated hCG confirmed assay specificity. Dilutions of serum of <10% final concentration were parallel to the standard curve (within and between batch CV,<6%). The assay working range was 100 – >500000 IUh and the recovery of hCG from serum was in the range of 94.5% to 115.4%, with a mean value of 102.1%. The assay detected a time dependent change in hCG sialylation during normal pregnancy with the relative abundance of sialylated hCG declining after week 9 and increasing after week 15 of gestation. In addition preliminary studies showed that maternal serum hCG concentrations measured with the lectln‐immunoassay were elevated in high risk Down's pregnancies (as defined by conventional screening tests between weeks 16‐18 gestatlon, medlan multiple of median, 3.14; range 1‐81–19.12, P< 001) and low risk (1.57, 0.49–6.14, P=0.034) compared to normal (1.00,0–32‐3.20) pregnancies. Furthermore, the lectin immunoas‐say had greater discriminatory power compared to conventional immunoassay of hCG and hCGB between normal and both low and high risk Down's pregnancies.

CONCLUSION This assay will allow analysis of serum samples for the investigation of sialylated variants of hCG glycoforms in various pathological and physiological situations.
Vasopressin and thirst in patients with posterior pituitary ectopia and hypopituitarism
Authors: Lukezic Monica , Righini Velella , Di Natale Berardo , De Angelis Riccardo , Norbiato Guido , Bevilacqua Maurizio , Chiumello Giuseppe
Published: March 2003

OBJECTIVE

Partial diabetes insipidus has been documented in patients with congenital hypopituitarism and posterior pituitary ectopia, some cases being clinically silent except for enuresis. The objective of our study was to evaluate vasopressin (AVP) secretion and thirst appreciation in hypopituitary patients with posterior pituitary ectopia.

PATIENTS

Twelve males and three females, aged between 13 and 38 years (median 19 years). Eleven had multiple pituitary deficiencies, adequately replaced at the time of the study, and four were only growth hormone deficient. None of the patients suffered from polyuria, polydipsia or nocturnal enuresis. We tested the patients with a 5% NaCl infusion. Five patients with abnormal vasopressin production were also tested with nitroprusside, which affects baroceptor vasopressin secretion.

RESULTS

We found that only two out of 12 patients had normal AVP secretion. Thirst assessment showed severe hypodipsia in one patient, hyperdipsia in three out of 15 and more subtle abnormalities in two out of 15 patients. Concordance was found between osmotically and baroceptor‐stimulated vasopressin.

CONCLUSIONS

Patients with posterior pituitary ectopia showed a high prevalence of subclinical subnormal vasopressin response to the osmolar stimulus and moreover an impairment of thirst appreciation. Our data on nonosmotically stimulated AVP release suggest the existence of a damage in the hypothalamic vasopressin secreting centres.
Isocaloric carbohydrate deprivation induces protein catabolism despite a low T3‐syndrome in healthy men
Authors: Bisschop P. H. , Sauerwein H. P. , Endert E. , Romijn J. A.
Published: March 2003

Dietary carbohydrate content is a major factor determining endocrine and metabolic regulation. The aim of this study was to evaluate the relation between thyroid hormone levels and metabolic parameters during eucaloric carbohydrate deprivation.

We measured thyroid hormone levels, resting energy expenditure (by indirect calorimetry) and urinary nitrogen excretion in six healthy males after 11 days of three isocaloric diets containing 15% of energy equivalents as protein and 85%, 44% and 2% as carbohydrates.

In contrast to the high and intermediate carbohydrate diets, carbohydrate deprivation decreased plasma T3 values (1·78 ± 0·09 and 1·71 ± 0·07 vs. 1·33 ± 0·05 nmol/l, respectively, P < 0·01), whereas reverse T3, T3 uptake and free T4 levels increased simultaneously compared to the other two diets. TSH values were not different among the three diets. Although dietary carbohydrate content did not influence resting energy expenditure, carbohydrate deprivation increased urinary nitrogen excretion (10·91 ± 0·67 and 12·79 ± 1·14 vs. 15·89 ± 1·10 g/24 h, respectively, P = 0·03).

Eucaloric carbohydrate deprivation increases protein catabolism despite decreased plasma T3 levels. Because it has previously been shown that starvation decreases plasma T3 levels, resting energy expenditure and nitrogen excretion, these discordant endocrine and metabolic changes following carbohydrate deprivation indicate that the effects of starvation on endocrine and metabolic regulation are not merely the result of carbohydrate deprivation.
Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men
Authors: Wang Christina , Swerdloff Ronald S. , Iranmanesh Ali , Dobs Adrian , Snyder Peter J. , Cunningham Glenn , Matsumoto Alvin M. , Weber Thomas , Berman Nancy ,   the Testosterone Gel Study Group
Published: March 2003

OBJECTIVE Androgen replacement has been reported to increase bone mineral density (BMD) in hypogonadal men. We studied the effects of 6 months of treatment with a new transdermal testosterone (T) gel preparation on bone turnover markers and BMD.

DESIGN This was a prospective, randomized, multicentre, parallel clinical trial where 227 hypogonadal men, mean age 51 years (range: 19–68 years) were studied in 16 academic and research institutions in the USA. Subjects were randomized to apply 1% T gel containing 50 or 100 mg T (delivering approximately 5–10 mg T/day) or two T patches (delivering 5 mg T/day) transdermally for 90 days. At day 91, depending on the serum T concentration, the T gel dose was adjusted upward or downward to 75 mg T/day until day 180. No dose adjustment occurred in the T patch group.

MEASUREMENTS Serum T, free T and oestradiol, bone turnover markers and BMD were measured on days 0, 30, 90 and 180 before and after treatment.

RESULTS Application of T gel 100 mg/day resulted in serum T concentrations 1·4 and 1·9‐fold higher than in the T gel 50 mg/day and the T patch groups, respectively. Proportional increases occurred in serum oestradiol. Urine N‐telopeptide/creatinine ratio, a marker for bone resorption, decreased significantly (P = 0·0019) only in the T gel 100 mg/day group. Serum bone osteoblastic activity markers (osteocalcin, procollagen and skeletal alkaline phosphatase) increased significantly during the first 90 days of treatment without intergroup differences but declined to baseline thereafter. BMD increased significantly both in the hip (+1·1 ± 0·3%) and spine (+2·2 ± 0·5%) only in the T gel 100 mg/day group (P = 0·0001).

CONCLUSIONS Transdermal testosterone gel application for 6 months decreased bone resorption markers and increased osteoblastic activity markers for a short period, which resulted in a small but significant increase in BMD. Ongoing long‐term studies should answer whether the observed increases in BMD are sustained or continue to be dependent on the dose of testosterone administered.
Low serum concentrations of insulin‐like growth factor I are associated with femoral bone loss in a population‐based sample of postmenopausal women
Authors: Seck Thomas , Scheidt‐Nave Christa , Leidig‐Bruckner Gudrun , Ziegler Reinhard , Pfeilschifter Johannes
Published: March 2003

OBJECTIVE Cross‐sectional studies suggest that the decline in insulin‐like growth factor‐I (IGF‐1) levels with age may contribute to age‐associated bone loss. However, prospective data on the relation between circulating IGF‐I and bone loss in old age have not yet been reported.

DESIGN A longitudinal study (follow‐up time 3·3 years) of the change of bone mineral density (BMD) at the lumbar spine and femoral neck in relation to serum IGF‐I.

PATIENTS A population‐based sample of 173 elderly men and 107 postmenopausal women without medical conditions or medication known to significantly affect BMD or serum IGF‐I levels.

MEASUREMENTS BMD at the lumbar spine and femoral neck at baseline and after a mean follow‐up‐time of 3·3 years, serum‐IGF‐I, insulin‐like growth factor binding protein 3 (IGFBP‐3), sex hormone‐binding globulin (SHBG) and biologically available testosterone (BAT).

RESULTS In women, there was a graded negative relationship between quartiles of serum IGF‐I and bone loss at the proximal femur (P = 0·04), which persisted after adjustment for potential covariables of bone loss and serum IGF‐I. In subgroup analysis the association between serum IGF‐I and change in BMD was only apparent in women more than 10 years past menopause (r = + 0,38, P = 0·01). No association between serum IGF‐I levels and changes in BMD was observed in men. IGF‐I levels were not associated with changes in spinal BMD.

CONCLUSIONS Our data suggest that low circulating levels of IGF‐I in elderly women are associated with greater femoral bone loss, and support previous findings of gender differences in the relation between serum IGF‐I and BMD in older age.
Thyroid function in survivors of childhood acute lymphoblastic leukaemia: the significance of prophylactic cranial irradiation
Authors: Lando Ane , Holm Kirsten , Nysom Karsten , Rasmussen Åse Krogh , Feldt‐Rasmussen Ulla , Petersen Jørgen Holm , Müller Jørn
Published: March 2003

OBJECTIVE Focus on long‐term side‐effects after cancer therapy in childhood has become of the utmost importance. The hypothalamic‐pituitary thyroid (HPT) axis is exposed to irradiation when some children are treated for acute lymphoblastic leukaemia (ALL) with prophylactic cranial irradiation (CIR). Whether this treatment causes hypofunction of the HPT axis remains controversal.

DESIGN We measured plasma levels of total T3 (T3), total T4 (T4) and TSH before stimulation with TRH and plasma levels of TSH, 30 and 150 minutes after stimulation with TRH in 95 patients in first continuous remission of childhood ALL.

PATIENTS Patients diagnosed with ALL before the age of 15 years between 1970 and 1991 and who were in first continuous remission and off treatment for at least one year were studied. The children were aged between 0·5 and 14·8 years (median: 3·9) at diagnosis of ALL. Thyroid function was assessed between 1·2 and 18·3 years (median: 7·6) after completion of therapy.

MEASUREMENTS We measured T4 levels before, and compared TSH levels before and after, stimulation with TRH in patients who were treated with prophylactic CIR (15–24 Gy) (n = 38) (CIR group) with patients who were treated with chemotherapy only (n = 57) (non‐CIR group).

RESULTS We found that T3 and T4 levels were normal in all individuals (excluding the women who were on oral contraceptives). The median time from end of treatment to time at follow‐up was 9·1 years in the non‐CIR group vs. 4·2 years in the CIR group (P < 0·001), and the effect on follow‐up time was significant (P = 0·04). It was estimated that just after irradiation, the TSH levels before and 30 and 150 minutes after TRH stimulation was 49% lower in the CIR group; however, after 4·0 years, TSH levels were not significantly different between the two groups. Although within normal limits, the T4 levels were significantly higher in the CIR group compared to the non‐CIR group (P = 0·003). It was estimated that, just after the end of treatment, T4 was 19·9% higher in the CIR group. However, in the CIR group, the T4 level decreased significantly over time with −1·5% per year (P = 0·025), while the difference in the non‐CIR group was not significant. There was no correlation between T4 and TSH levels and sex, age at diagnosis, age at the end of treatment or age at follow‐up.

CONCLUSIONS We conclude that, in our cohort of survivors of childhood ALL, prophylactic cranial irradiation of the central nervous system did not have an adverse effect on hypothalamo‐pituitary‐thyroid function within a median follow‐up time of 8 years.
Computer assisted learning is an effective way of teaching endocrinology
Authors: Holt Richard I. G. , Miklaszewicz Pawel , Cranston Iain C. , Russell‐Jones David , John Rees P. , Sönksen Peter H.
Published: March 2003

OBJECTIVES Computers are a part of everyday life and offer an exciting way of learning. The aim of our study was to determine the effectiveness of teaching undergraduate endocrinology using a Computer Assisted Learning (CAL) programme.

DESIGN AND SUBJECTS One hundred and eighty‐five first year clinical medical students were randomly assigned either to attend a series of conventional lectures (n = 77) or to have the same material available through a CAL programme.

MEASUREMENTS A multiple choice question examination was performed before and after the course. Lecture attendance and individual usage of the computer system were recorded. Students were asked to fill in an evaluation form at the end of the study.

RESULTS There was no significant difference in the first examination scores between the groups. Both groups improved their scores after the course. Students spent longer performing CAL than attending lectures. Those who scored lowest in the first examination spent the most time on the CAL course. Those who spent the most time on the CAL course showed the largest improvement in examination score. Thirty‐six out of the 42 students, who completed an evaluation of the CAL programme, rated it better than the standard lectures.

CONCLUSIONS Computer assisted learning is an effective way of increasing knowledge in teaching undergraduate endocrinology. The course was easy to run and was valued more highly than conventional lectures. The module is now running routinely in the year 3 clinical firms at St Thomas' and has resulted in an increase in knowledge in the end of firm assessment.
Long‐term follow‐up of contralateral lobe in patients hemithyroidectomized for solitary follicular adenoma
Authors: Niepomniszcze Hugo , Garcia Alejandro , Faure Eduardo , Castellanos Alejandro , Del Carmen Zalazar Maria , Bur Grato , Elsner Boris
Published: March 2003

OBJECTIVES Since there are no available conclusive studies on the long‐term evolution of remnant thyroid tissue after hemithyroidectomy in patients who undergo surgery for solitary follicular adenomas, we searched for such cases in our records to elucidate this issue.

DESIGN Search criteria were as follows: (i) presence of a single palpable thyroid nodule with the remainder of the gland normal on palpation; (ii) clinically euthyroid status at the time of surgery; (iii) histological diagnosis of nodule as follicular adenoma; (iv) a hemithyroidectomy operation, sparing the contralateral lobe; (v) normal macroscopic aspect of the contralateral lobe at the time of surgery; and (vi) at least 4 years of postoperative follow‐up.

PATIENTS Only 47 female cases were found to meet above criteria, with a mean age of 45·9 years (range: 23–79) at the time of surgery and a mean follow‐up of 7·2 years (range: 4–32). Besides evaluating the presence or absence of antithyroid antibodies and the extranodular histology of tissue removed during surgery, a preoperative TRH test also allowed patients to be classified into two groups: normal extranodular thyroid (NET) (n = 32) and abnormal extranodular thyroid (AET) (n = 15).

RESULTS Eleven of the 15 patients with AET had thyroid autoimmunity, with or without overt histological thyroiditis, and the remaining four had subclinical hypothyroidism with negative antithyroid antibody titres. In the entire study population, only 28 patients received treatment with L‐T4 immediately after surgery, none of whom had any alterations in the contralateral lobe. However, six of the nineteen patients not treated with T4 (31·6%) developed overt abnormalities in the contralateral lobe, including the only three with AET who had not received L‐T4 treatment. The remaining three were two patients with NET, who showed postoperative TSH hyper‐responsiveness to TRH (peak TSH > 25 mU/l), and one who developed a new follicular adenoma 32 years later. To date, none of the patients with NET, who had a normal TRH test after surgery, have developed any kind of alterations in the contralateral lobe, even those who received no L‐T4 prophylactic treatment.

CONCLUSIONS The findings of this study suggest that: (i) there is a higher risk of follicular adenomas developing in a gland affected by thyroid autoimmunity than in a previously normal gland; (ii) L‐T4 therapy may prevent the formation of new nodules or the development of goitre in the contralateral lobe; and (iii) in the absence of prophylactic treatment after surgery, the contralateral lobe of subjects with thyroid autoimmunity and/or previous subclinical hypothyroidism develops morphological abnormalities.
Clinical features in women with polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR and birth weight
Authors: Michelmore Katherine , Ong Ken , Mason Sam , Bennett Simon , Perry Leslie , Vessey Martin , Balen Adam , Dunger David
Published: March 2003

OBJECTIVE Polycystic ovaries are a common ultrasound finding, yet few of these women have many clinical features of polycystic ovary syndrome. Clinical presentation may relate to degree of insulin resistance, common polymorphism at the insulin gene VNTR, and birth weight. We therefore examined the relationship between insulin sensitivity, insulin gene VNTR genotype, birth weight and presence of polycystic ovaries/features of polycystic ovary syndrome in a normal population study.

DESIGN AND PATIENTS In 224 young women recruited as normal volunteers, ovarian morphology was determined by transabdominal ultrasound and features of polycystic ovary syndrome were identified on clinical and biochemical examination. Insulin sensitivity was estimated from fasting glucose and insulin levels using the homeostasis model. Insulin gene VNTR genotypes were determined in women and their parents.

MEASUREMENTS AND RESULTS Thirty‐three per cent (74/224) had polycystic ovaries on ultrasound. These women had higher birth weights (P = 0·004), higher insulin sensitivity (P = 0·02) and higher leptin levels for body mass index (P = 0·04) than women with normal ovaries. However among women with polycystic ovaries, increasing severity of clinical phenotype (based on number of features of: menstrual irregularity, acne, hirsuitism, serum testosterone > 3 mmol/l and LH > 10 IU/l) was associated with decreasing insulin sensitivity (P < 0·0001) and related to paternally transmitted insulin gene VNTR class III alleles (P = 0·03).

CONCLUSION Women with polycystic ovaries on ultrasound have increased insulin sensitivity and possible leptin resistance, which could predispose to future weight gain. However, in these women the appearance of clinical features of polycystic ovary syndrome is related to insulin resistance and insulin gene VNTR class III alleles.
Relationships between the TaqI polymorphism of the dopamine D2 receptor and blood pressure in hyperglycaemic and normoglycaemic Chinese subjects
Authors: Thomas G. Neil , Critchley Julian A. J. H. , Tomlinson Brian , Cockram Clive S. , Chan Juliana C. N.
Published: March 2003

BACKGROUND We have previously reported an association of the A2 allele of the dopamine D2 receptor (DRD2) TaqI polymorphism with increased blood pressure in normoglycaemic Chinese subjects, but conversely possibly with decreased indices of obesity. Hypertension is also a common feature of patients with type 2 diabetes, with up to 50% being hypertensive.

OBJECTIVE To compare the relationship between the DRD2 TaqI polymorphism, blood pressure and obesity in Chinese patients with and without fasting hyperglycaemia.

METHOD The DRD2 TaqI polymorphism was determined by PCR‐RFLP in 519 normoglycaemic and 471 hyperglycaemic Chinese subjects, of whom 53·2 and 48·8% were hypertensive, respectively.

RESULTS In the normoglycaemic subjects there was a significant increase in mean arterial pressure (P = 0·041) with increasing proportions of the A2 allele, 95 ± 16, 96 ± 17 and 100 ± 17 mmHg for the A1A1, A1A2 and A2A2 genotypes, respectively. However, the relationship was not observed in the subjects with fasting hyperglycaemia either in the total group or in the subgroup who were not receiving blood pressure‐lowering medication (n = 383, 97 ± 15, 98 ± 14 and 97 ± 15 mmHg, respectively). When the whole group was divided into those subjects obese by either body mass index or waist‐to‐hip ratio (n = 484) and those subjects not obese by both these criteria (n = 506), the A1 allele (49·2 vs. 43·8%, P = 0·02) and A1 allele containing genotypes (P = 0·03) were more frequent in the obese subjects. Similar relationships were seen in the normoglycaemic and hyperglycaemic groups separately, although these did not reach significance.

CONCLUSIONS In the normoglycaemic subjects, the A2 allele was associated with increased blood pressure and possibly lower indices of obesity, but in the hyperglycaemic subjects only the possible association with obesity was noted.
The genetics of male undermasculinization
Authors: Ahmed S. Faisal , Hughes Ieuan A.
Published: March 2003

A review of the genetics of male undermasculinization must encompass a description of the embryology of the genital system. The dimorphism of sex development consequent upon the formation of a testis and the subsequent secretion of hormones to impose a male phenotype is highlighted. Thus, an understanding of the causes of male undermasculinization (manifest as XY sex reversal, complete and partial) includes reviewing the genetic factors which control testis determination and the production and action of testicular hormones. The study of disorders of male sex development has contributed substantially to knowledge of normal male development before birth. This knowledge has been complimented in recent years by the use of targeted murine gene disruption experiments to study the sex phenotype, although murine and human phenotypes are not always concordant. The investigation of disorders associated with male undermasculinization of prenatal onset is described briefly to complete the review.
Reduced capillary permeability and capillary density in the skin of GH‐deficient adults: improvement after 12 months GH replacement
Authors: Oomen P. H. N. , Beentjes J. A. M. , Bosma E. , Smit A. J. , Reitsma W. D. , Dullaart R. P. F.
Published: March 2003

objective Several lines of evidence suggest that the GH–IGF‐1 axis affects capillary permeability and angiogenesis. We evaluated skin capillary permeability and capillary density in GH‐deficient adults, before and after GH replacement therapy.

patients Seven normotensive, nondiabetic GH‐deficient adults (two women) were matched with 14 control subjects.

measurements Large‐window videodensitometry with sodium fluorescein was performed in all subjects. Capillary permeability was expressed as the average relative light intensity over the first 7 min after the appearance of fluorescein in the skin capillaries; Iav(7). Skin capillary density was determined by counting the visualized capillaries and was expressed as n/mm2. The GH‐deficient patients were restudied after 12 months of GH replacement therapy (2 U/day).

results Both capillary permeability and capillary density were lower in untreated GH‐deficient patients than in control subjects (median, interquartile range): Iav(7) in GH‐deficient patients 47·1 (45·1–52·2)%vs. 57·5 (50·5–64·8)% in controls, P < 0·05; capillary density in GH‐deficient patients 18 (12–24)/mm2 vs. 32 (26–36)/mm2 in controls, P < 0·05. GH treatment normalized plasma IGF‐1 from 4·3 (1·0–13·4) to 22·2 (19·8–48·2) nmol/l (P < 0·05). Furthermore, both capillary permeability [Iav(7) 53·1 (48·8–58·4)%, P < 0·05] and capillary density [26 (17–34)/mm2, P < 0·05] increased to a level that was not different from that in control subjects.

conclusions The present study demonstrates that the growth hormone deficiency syndrome is associated with microvascular alterations, which are responsive to growth hormone replacement therapy.
The effects of hormone replacement therapy on endothelial function in women with Turner’s syndrome
Authors: Chan N. Norman , Vallance Patrick , Colhoun Helen M. , MacAllister Raymond J. , Hingorani Aroon D. , Conway Gerard S.
Published: March 2003

objectives To examine the effect of hormone replacement therapy (HRT) on endothelial function of forearm resistance vessels in women with Turner’s syndrome.

design Subjects were studied on three occasions: on their usual HRT (study 1), then after 6 weeks off HRT (study 2) and finally after a further 6 weeks on HRT (study 3).

patients Seven young women with Turner’s syndrome were studied.

measurements Forearm blood flow in response to intrabrachial infusion of bradykinin, 10, 30, 100 pmol/min (endothelium‐dependent vasodilator), glyceryl trinitrate, 4, 8, 16 nmol/min (GTN; endothelium‐independent vasodilator), noradrenaline, 60, 120, 240 pmol/min (NA, α‐adrenergic receptor agonist) and NG‐monomethyl‐l‐arginine, 1, 2, 4 µmol/min (L‐NMMA; NO synthase inhibitor) was assessed by bilateral venous plethysmography.

results The vasodilator response to bradykinin, expressed as the within‐subject mean difference in area under the dose–response curve between study 2 and study 1, was significantly diminished (−744·2 ± 287·2, P = 0·04) but improved 6 weeks after HRT recommencement. However, there was no significant change in response to GTN (between study 2 and study 1, 189·5 ± 247·8, P = 0·47). The vasoconstrictor response to L‐NMMA was also diminished in study 2 when compared to study 1 (−100·4 ± 35·4, P = 0·039) and was restored after HRT was recommenced (between study 3 and study 2, 117·5 ± 69·3, P = 0·17) whereas there was no significant difference in response to NA between study 2 and study 1 (76·7 ± 50·6, P = 0·18) or study 3 and study 2 (−70·8 ± 71·1, P = 0·38).

conclusions HRT improves endothelial function in women with Turner’s syndrome.
Screening for macroprolactinaemia and pituitary imaging studies
Authors: Hauache Omar M. , Rocha Antonio J. , Maia Antonio C. M. , Maciel Rui M. B. , Vieira José Gilberto H.
Published: March 2003

objective Hyperprolactinaemia is caused by high levels of monomeric, dimeric or macro forms of prolactin in circulation, the monomeric form being predominant in patients with prolactinomas. Macroprolactinaemia, however, is common and is associated with asymptomatic cases. In this study, we reviewed our records regarding clinical and imaging investigations in patients who were found to have hyperprolactinaemia predominantly due to the presence of macroprolactin and compared them with the findings observed in patients whose prolactin molecular size consisted predominantly of the monomeric form.

patients and methods We conducted a retrospective study of 113 consecutive patients (nine men and 104 women, aged 19–67 years, median age 39 years) with hyperprolactinaemia who were screened for the presence of macroprolactin by polyethylene glycol precipitation and/or chromatography and submitted to pituitary magnetic resonance imaging (MRI) and/or computerized tomography (CT).

results Fifty‐two of 113 patients (46%) had hyperprolactinaemia due to macroprolactin, whereas the remaining 61 patients (54%) had their hyperprolactinaemia confirmed by the predominance of the monomeric form. Both groups shared similar mean prolactin levels (79·9 ± 63·6 µg/l, median of 62·0 µg/l, and 97·9 ± 155·4 µg/l, median of 61·0 µg/l, respectively). Of the patients with macroprolactinaemia, 46% had no symptoms of hyperprolactinaemia, whereas only 10% of the patients who screened negative for macroprolactin were asymptomatic. There was an association between macroprolactinaemia and negative pituitary imaging findings: normal pituitary images were found in 78·9% of patients who had macroprolactinaemia and in 25% of patients with monomeric hyperprolactinaemia. In addition, none of the patients with macroprolactinoma (seven cases) had macroprolactinaemia.

conclusions The presence of macroprolactinaemia does not exclude the possibility of a pituitary adenoma and consequently may not prevent pituitary imaging studies. However, our data demonstrate that all asymptomatic patients who screened positive for macroprolactin had normal pituitary imaging studies. Patient samples showing hyperprolactinaemia should be first tested for macroprolactin, before the patient is submitted to imaging studies. We suggest that imaging studies should be ordered in patients with macroprolactinaemia when indicated by clinically relevant features. As a result, unnecessary anxiety and costly medical procedures may be prevented.
The metabolic effects of short‐term administration of physiological versus high doses of GH therapy in GH deficient adults
Authors: Yuen K. , Cook D. , Ong K. , Chatelain P. , Fryklund L. , Gluckman P. , Ranke M. B. , Rosenfeld R. , Dunger D.
Published: March 2003

objective GH treatment has demonstrated favourable effects on most features of GH deficiency in hypopituitary adults. However, most studies employed supraphysiological GH doses, resulting in deterioration in insulin sensitivity (SI). The short‐term metabolic effects of physiological doses of GH therapy in GH deficient (GHD) adults are largely unknown. We therefore compared the effects of short‐term administration of two ‘physiological’ (‘lowest’ dose: 0·0017 mg/kg/day; ‘low’ dose: 0·0033 mg/kg/day) with two ‘supraphy‐siological’ (‘high’ dose: 0·010 mg/kg/day; ‘highest’ dose: 0·025 mg/kg/day) GH doses on SI, β‐cell function, IGF‐1 and IGFBPs −1 and −3 in a group of GHD adults.

patients and methods Thirteen GHD adults were recruited (seven men, aged 23–63 years). For each of the four doses, six patients (three men) were allocated randomly to undergo a 7‐day treatment phase. Fasting blood samples were collected daily (days 1–8), and SI and β‐cell function were calculated using the homeostasis model assessment (HOMA).

results All four GH doses increased IGF‐1, IGFBP‐3 and IGF‐1/IGFBP‐3 ratio, and decreased IGFBP‐1 from day 3 onwards (P < 0·05). The highest dose increased fasting glucose (P < 0·001), insulin (P < 0·001) and β‐cell function (P < 0·001), but decreased SI (P < 0·001). The high and low doses did not modify fasting glucose and insulin, SI or β‐cell function, whereas the lowest dose enhanced β‐cell function (P < 0·05). The overall increase in the GH dose increased IGF‐1, IGFBP‐3, fasting glucose and insulin (P < 0·001), demonstrated a positive correlation with the final change in fasting glucose (r = 0·5, P < 0·05) and insulin (r = 0·8, P < 0·001) and a negative correlation with final SI (r = −0·5, P < 0·05).

conclusions Our results suggest that short‐term administration of the highest GH dose induced insulin resistance, whereas the lowest dose (0·0017 mg/kg/day) could represent the optimal starting dose in GHD adults due to its beneficial effects on β‐cell function without compromising SI. It is, however, yet to be determined whether the positive effects of the lowest GH dose on β‐cell function can be demonstrated over a longer period of time.
Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference?
Authors: Wijeyaratne Chandrika N. , Balen Adam H. , Barth Julian H. , Belchetz Paul E.
Published: March 2003

objective Polycystic ovary syndrome (PCOS) is more prevalent in South Asian women residing in the UK than in Caucasians. Insulin resistance (IR) is central to the pathogenesis of PCOS, while type 2 diabetes is commoner in South Asians. We aimed to determine a possible ethnic difference in the clinical and biochemical characteristics of South Asian vs. Caucasian women with PCOS.

patients and design A case‐control cross‐sectional observational study of consecutive women with anovular PCOS (47 South Asians, 40 Caucasians) and their age‐matched controls (11 South Asians and 22 Caucasians).

measurements Index subjects: a questionnaire‐based interview on clinical symptoms and family history; anthropometric measurements, clinical observations of the presence and degree of acne, hirsutism and acanthosis nigricans; transvaginal pelvic ultrasound; biochemical analyses of fasting blood sugar, fasting plasma insulin, fasting lipids, testosterone, and SHBG concentrations. Control group: age‐ and weight‐matched unrelated women from the same ethnic backgrounds without PCOS seeking treatment for male infertility were studied by similar methods to those used with the index subjects.

results South Asians with PCOS presented at a younger age (age 26 ± 4 vs. 30·1 ± 5 years, P = 0·005). Body mass index (BMI) and waist : hip ratios were similar in the two affected cohorts. More South Asians had oligomenorrhoea commencing at a younger age. Hirsutism (Ferriman Gallwey score 18 vs. 7·5, P = 0·0001), acne, acanthosis nigricans and secondary infertility were significantly more prevalent in South Asians.

The fasting glucose was similar (4·52 ± 0·08 vs. 4·62 ± 0·09 mmol/l, P = 0·25), the fasting insulin higher (89·4 ± 8·9 vs. 48·6 ± 4·8 pmol/l, P = 0·0001) and insulin sensitivity (IS) lower (0·335 ± 0·005 vs. 0·357 ± 0·002, P = 0·0001) among South Asians. Serum SHBG was significantly less in South Asians (35 ± 3·3 vs. 55 ± 9·4 nmol/l, P = 0·02), while serum testosterone was similar (2·69 ± 0·11 vs. 2·64 ± 0·13 nmol/l, P = 0·37).

conclusions We conclude that South Asians with anovular PCOS seek treatment at a younger age, have more severe symptoms, and have higher fasting insulin concentrations and lower insulin sensitivity than Caucasians.
Effects of oestrogen‐only and oestrogen–progestogen replacement therapy upon circulating angiotensin I‐converting enzyme activity in postmenopausal women
Authors: Proudler Anthony J. , Cooper Alison , Whitehead Malcolm , Stevenson John C.
Published: March 2003

objective Levels of angiotensin I‐converting enzyme (ACE) in blood are associated with variation in cardiovascular disease risk. Serum ACE activity in women may be reduced by combined oestrogen–progestogen hormone replacement therapy (HRT). However, the relative contribution of each hormonal component to this observation is uncertain. We investigated ACE activity in two groups of healthy postmenopausal women receiving HRT regimens.

design The first group received placebo or oestrogen‐only HRT randomly (oral conjugated equine oestrogens or transdermal 17β‐oestradiol). The second group was treated with oestrogen‐only HRT (oral 17β‐oestradiol) followed by sequential oestrogen‐progestogen HRT (17β‐oestradiol and dydrogesterone).

measurements Assay of blood for soluble ACE activity before and whilst receiving HRT.

results In the first group, oral conjugated equine oestrogens significantly reduced (P < 0·01) ACE activity by 18% on average relative to pretreatment whereas non‐significant changes of −9% and +7% were seen with transdermal 17β‐oestradiol or placebo treatment, respectively. In the second group oestrogen‐only HRT significantly reduced (P < 0·001) ACE activity by 15% on average. The reduction during both the oestrogen‐only and combined phases of sequential treatment was 12% and 19%, respectively, compared with pretreatment values (P < 0·01 and P < 0·001). ACE activity also differed significantly (P < 0·05) between the two phases of sequential treatment.

conclusions Both oestrogen‐only and oestrogen‐progestogen HRT may reduce ACE activity in blood. Oestrogen and progestogen may exhibit additive effects on blood ACE activity.
The effect of growth hormone (GH) replacement therapy in adult patients with type 1 diabetes mellitus and GH deficiency
Authors: Christ E. R. , Simpson H. L. , Breen L. , P. H. Sönksen  , Russell‐Jones D. L. , Kohner E. M.
Published: March 2003

objectives Specific problems in patients with insulin‐dependent diabetes mellitus (IDDM) and GH deficiency are hypoglycaemic attacks, increased insulin sensitivity and loss of energy. These problems may be related to GH deficiency.

patients GH replacement was initiated in five patients with type 1 diabetes mellitus and GH deficiency for 6 months [four males and one female, mean age 41·6 ± 3·8 years, mean ± standard error of the mean (SEM); body mass index (BMI) 22·3 ± 1·2 kg/m2].

methods Body composition (bioimpedance), metabolic control [haemoglobin A1C (HbA1C)], insulin requirement and frequency of hypoglycaemia were measured, and quality of life was assessed using validated questionnaires. Monthly eye photographs were taken.

results IGF‐I concentrations were below the age‐adjusted range at baseline and increased significantly following GH replacement therapy [analysis of variance (anova), P < 0·05]. Diabetes control as assessed by HbA1C remained stable (8·2 ± 0·2 vs. 8·0 ± 0·4), but needed a 1·75‐fold increase in insulin dose/day. Lean body mass tended to increase (P = 0·07) and body fat mass decreased significantly (P > 0·01). Number of severe hypoglycaemic (< 3 mmol/l) attacks decreased significantly (P < 0·04) and quality of life assessed by validated questionnaires improved significantly in all patients [Psychological and General Well‐Being Schedule (PGWBS), P < 0·04; Nottingham Health Profile (NHP), P < 0·05]. Monthly eye photographs revealed no changes in the retina in any patients.

conclusion GH replacement therapy has a beneficial effect at the dose used. It restores body composition and decreases frequency and severity of hypoglycaemic episodes, thus improving quality of life. Long‐term trials are needed to determine the safety of GH replacement therapy in these patients.
Office and laboratory blood pressures as predictors of daily blood pressure level in normotensive subjects and borderline and mild hypertensive subjects
Authors: Majahalme  , Turjanmaa  , Weder  , Lu  , Tuomisto  , Uusitalo
Published: March 2003

A series of standardized laboratory tests [10 min sitting and supine, 9 min standing, dynamic; cycle ergometer (ERG) and isometric exercise; handgrip (HG)] were performed during intra‐arterial blood pressure (BP) recording in 97 healthy unmedicated men, initially classified as normotensive (NT, n = 34), borderline hypertensive (BHT, n = 29) or mildly hypertensive (HT, n = 34) by repeated office blood pressure (OBP) measurements. After testing, a 24‐h intra‐arterial ambulatory BP (IABP) recording was obtained while subjects performed their normal activities. Day and night periods were analysed as well as 24‐h averages for systolic BP (SBP) and diastolic BP (DBP) using Pearson correlations and multiple linear regressions. In normotensive subjects, the supine SBP predicted IABP measurements best (r range 0·39–0·69, P<0·05–0·001). In multiple regression, supine SBP explained 49% of 24‐h SBP variance (F = 12·4, P = 0·001). For BHT, supine SBP was also the best predictor (r range 0·09–0·64, P NS to P<0·001), and it explained 37% of 24‐h SBP variance (F = 15·6, P = 0·0005). In HT, ERG DBP correlated best with IABP (r range 0·52–0·75, P<0·01–0·001). ERG SBP explained 49% of 24‐h SBP (F = 31·0, P = 0·0000) and ERG DBP explained 56% of 24‐h DBP (F = 35·4, P = 0·0000) variance. Laboratory BP correlations were generally better with day than with night measurements. OSBP correlated moderately well with IABP in NT, and weakly in BHT and HT; ODBP instead correlated with IABP in NT and HT but not significantly in BHT. In conclusion, OBP is less closely related to IABP than laboratory BP, but even laboratory BP generally explains less than 50% of IABP variance. Stressors such as exercise are useful only in HT. For BHT, the prediction of IABP with laboratory measures was even weaker than in other groups, and thus ambulatory measurements cannot be replaced by short‐duration laboratory measurements and stress tests.
Whole‐body cooling increases plasma endothelin‐1 levels in women with primary Raynaud's phenomenon
Authors: Leppert J. , Ringqvist Å. , Karlberg B. E. , Ringqvist I.
Published: March 2003

To understand better the role of endothelin‐1 (ET‐1) in the pathogenesis of primary Raynaud's phenomenon (PRP), we investigated the basal ET‐1 plasma levels and changes after whole‐body cooling in healthy women and those with PRP. The study was performed as an open parallel‐group comparison during the month of February. The Raynaud group included 21 female patients (mean age 45·3 years, range 21–57 years) who had had disabling Raynaud's phenomenon for a mean period of 17 years (range 2–26 years). The control group consisted of 25 healthy women (mean age 43·6 years, range 27–56 years). Plasma levels of ET‐1 were measured on two separate occasions: once after 30 min of rest at room temperature and after 40 min of whole‐body cooling. There were no significant differences in baseline plasma ET‐1 levels between the two groups of women. The plasma ET‐1 levels increased significantly in the PRP group after cold exposure (mean difference 0·11 pmol l−1, 95% CI 0·005–0·214, P = 0·012). In contrast, the levels of plasma ET‐1 in the control group did not change significantly after cold provocation. In conclusion, no differences in plasma basal levels of ET‐1 were observed between the two groups. However, women suffering from Raynaud's phenomenon responded with a slight but significant elevation in plasma levels of ET‐1 after whole‐body cooling, whereas the healthy control subjects did not. The results from the present study confirm previous observations that endothelial dysfunction may be of aetiological importance in PRP.
An echocardiographic study of right ventricular adaptation to physical exercise in elite male orienteers
Authors: Henriksen  , Kangro  , Jonason  , Landelius  , Hedberg  , Ekstrand  , Ringqvist
Published: March 2003

Considerably more publications appear on left ventricular morphology than on the right ventricle. The reasons for this imbalance are related to the complex shape of the right ventricular cavity and its position beneath the sternum, making imaging, measurement and functional assessment much more complex than the left ventricular chamber. Little attention has been directed towards right ventricular changes because of training, therefore the present study was designed to assess right ventricular changes due to extensive training by comparing cavity and wall dimensions in 29 sedentary men (mean age 23 years) and 82 elite male orienteers (mean age 22 years). The elite orienteers had on average significantly larger right ventricular outflow (10%) and right ventricular inflow (12%) tract 2 and 3 dimensions. The right ventricular wall measurements were on average 13% larger in the orienteers than the sedentary men. The right ventricular enlargement in endurance athletes probably reflects the increased haemodynamic loading that is caused by prolonged and extensive physical training. The thicker right ventricular wall in endurance athletes increases the contractile reserve and decreases wall stress in the right ventricle.