Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses

M. Mercè Fernández-Balsells, Kalpana Muthusamy, Galina Smushkin, Julianna F. Lampropulos, Mohamed B. Elamin, Nisrin O. Abu Elnour, Khalid B. Elamin, Neera Agrwal, Juan F. Gallegos-Orozco, Melanie A. Lane, Patricia J. Erwin, Victor M. Montori, M. Hassan Murad

Context: Prenatal treatment with dexamethasone to prevent virilization in pregnancies at risk for classical congenital adrenal hyperplasia (CAH) remains controversial.

Objective: To conduct a systematic review and meta-analyses of studies that evaluated the effects of dexamethasone administration during pregnancies at risk for classical CAH because of 21-hydroxylase deficiency (CYP21A2).

Data Sources: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception through August 2009. Review of reference lists and contact with CAH experts further identified candidate studies.

Study Selection: Reviewers working independently and in duplicate determined trial eligibility. Eligible studies reported the effects on either foetal or maternal outcomes of dexamethasone administered during pregnancy compared to a control group that did not receive any treatment.

Data Extraction: Reviewers working independently and in duplicate determined the methodological quality of studies and collected data on patient characteristics, interventions, and outcomes.

Data Synthesis: We identified only four eligible observational studies (325 pregnancies treated with dexamethasone). The methodological quality of the included studies was overall low. Meta-analysis demonstrates a reduction in foetus virilization measured by Prader score in female foetuses treated with dexamethasone initiated early during pregnancy (weighted mean difference, −2·33, 95% CI, −3·38, −1·27). No deleterious effects of dexamethasone on stillbirths, spontaneous abortions, foetal malformations, neuropsychological or developmental outcomes were found although these data are quite sparse. There was increased oedema and striae in the mothers treated with dexamethasone. There were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone.

Conclusions: The observational nature of the available evidence and the overall small sample size of the whole body of the literature significantly weaken inferences about the benefits and harms of dexamethasone in this setting. Dexamethasone seems to be associated with reduction in foetus virilization without significant maternal or foetal adverse effects. However, this review underscores the current uncertainty and further investigation is clearly needed. The decision about initiating treatment should be based on patients’ values and preferences and requires fully informed and consenting parents.

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Risk of early progression to prediabetes or diabetes in women with recent gestational dysglycaemia but normal glucose tolerance at 3-month postpartum

Ravi Retnakaran, Ying Qi, Philip W. Connelly, Mathew Sermer, Anthony J. Hanley, Bernard Zinman

Objective: Both gestational diabetes mellitus (GDM) and milder glucose intolerance in pregnancy identify women who are at risk of developing type 2 diabetes. While some of these women will have prediabetes or diabetes in the early postpartum, most will have normal glucose tolerance (NGT), despite their future diabetic risk. In this context, we sought to evaluate the risk of early progression to dysglycaemia in women with NGT at 3-month postpartum and identify predictors thereof.

Methods: Three hundred and twenty-five women with varying degrees of gestational dysglycaemia but NGT on oral glucose tolerance test (OGTT) at 3-month postpartum underwent repeat OGTT at 12-month postpartum.

Results: By 12-month postpartum, 10% of the study population and 17·1% of those with recent GDM had progressed to dysglycaemia (primarily impaired glucose tolerance). At 3-month postpartum, compared to nonprogressors, the progressors had (i) higher BMI (P = 0·0023), LDL (P = 0·0017), triglycerides (P = 0·0002), leptin (P = 0·0021) and C-reactive protein (P = 0·043), and (ii) lower HDL (P = 0·0026) and adiponectin (P = 0·045). Notably, although all women had NGT at the time, each of the following glucose-related parameters from the OGTT at 3-month postpartum emerged as a significant independent predictor of progression on logistic regression analyses: area-under-the-glucose-curve (OR = 1·37, 95%CI: 1·13–1·65; P = 0·0012); sum of the glucose values (OR = 1·16, 95%CI: 1·05–1·29; P = 0·0042); and having a delayed blood glucose peak (occurring >30 min postload) (OR = 2·89, 95%CI: 1·29–6·45; P = 0·0097).

Conclusions: A normal OGTT at 3-month postpartum does not necessarily provide assurance of a low risk of progression to prediabetes. Glucose-related measures during this OGTT may identify those women at highest risk for early progression.

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Blood coagulation, fibrinolysis and lipid profile in patients with prolactinoma

Cihangir Erem, Mustafa Kocak, İrfan Nuhoglu, Mustafa Yılmaz, Ozge Ucuncu

Objective: Although the strong association between hyperprolactinaemia and platelet aggregation is well recognized, there are no studies on changes in coagulation and fibrinolytic status in patients with prolactinoma. To our knowledge, tissue plasminogen activator inhibitor-1 (PAI-1), plasma tissue factor pathway inhibitor (TFPI) and thrombin-activatable fibrinolysis inhibitor (TAFI) levels in these patients have not been investigated. Therefore, the main purpose of this study was to evaluate the markers of endogenous coagulation/fibrinolysis, including TFPI and TAFI, and to investigate the relationships between prolactin (PRL) and these haemostatic parameters and serum lipid profile in patients with prolactinoma.

Research methods and procedures: Twenty-two patients with untreated, newly diagnosed prolactinoma and 20 age-matched healthy controls were included in the study. Platelet count, mean platelet volume, prothrombin time, activated partial thromboplastin time, fibrinogen, factors V, VII, VIII, IX and X activities, von Willebrand factor, antithrombin III (AT-III), protein C, protein S, tissue plasminogen activator (t-PA), PAI-1, TFPI and TAFI, as well as common lipid variables, were measured. The relationships between serum PRL and these haemostatic parameters were evaluated.

Results: Compared with the control subjects, total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, platelet count, fibrinogen, AT-III, PAI-1 and PAI-1/t-PA ratio were significantly increased in patients with prolactinoma (P < 0·0001, P < 0·001, P < 0·05, P < 0·05, P < 0·0001, P < 0·05, P < 0·0001 and P < 0·0001, respectively), whereas TFPI levels were significantly decreased (P < 0·01). Plasma TAFI Ag levels were not significantly different in patients with prolactinoma compared with the controls. In patients with prolactinoma, serum PRL was positively correlated with plasma FVII levels and apo B (r: 0·679, P < 0·05; r: 0·548, P < 0·05, respectively).

Conclusions: We found some important differences in the haemostatic parameters between the patients with prolactinoma and healthy controls. Increased platelet count, fibrinogen, PAI-1 and decreased TFPI in patients with prolactinoma may represent a potential hypercoagulable and hypofibrinolytic state, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the haemostatic system and dyslipidaemia may lead to the excess mortality in patients with prolactinoma.

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What is the best approach to an apparently nonmetastatic adrenocortical carcinoma?

Martin Fassnacht, Bruno Allolio

Summary: In suspected nonmetastatic adrenocortical carcinoma (ACC) a careful preoperative diagnostic work up is needed including comprehensive endocrine analysis as recommended by the European Network for the Study of Adrenal Tumors (http://www.ENSAT.org/ACC.htm). Staging prior surgery, in particular chest CT, is indispensable to exclude distant metastases. Open surgery is still the recommended approach in ACC. However, in localized non-invasive ACC with a diameter <10 cm laparoscopic adrenalectomy by an expert surgeon is probably similarly effective and safe. As many patients will suffer from tumor recurrence after seemingly complete removal of ACC, adjuvant treatment based on the individual risk status is recommended. Key factors for risk assessment are tumor stage, resection status and the proliferation marker Ki67. All patients considered at high risk for recurrence should receive adjuvant mitotane for a minimum of 2 years aiming at a drug level of 14–20 mg/l. In selected patients (e.g. R1 resection) we recommend additional radiotherapy of the tumor bed. Patients with a low/intermediate risk for recurrence should be included in the Adiuvo trial comparing adjuvant mitotane with observation only (http://www.adiuvo-trial.org). In low/intermediate risk patients who cannot be included in this trial observation only can be justified in cases with a tumor diameter of <8 cm and no microscopic evidence for invasion of blood vessels or tumor capsule. In all patients a structured follow-up for 10 years is strongly recommended.

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Does calcium supplementation increase cardiovascular risk?

Ian R Reid, Mark J. Bolland, Andrew Grey

Summary: Calcium supplementation is widely used for the prevention of osteoporosis in postmenopausal women and in men. While there has been ongoing debate regarding its effectiveness in fracture prevention, the underlying assumption has been that, even if it was not particularly effective, at least it was safe. The recent finding of the Auckland Calcium Study that myocardial infarctions were more common in women randomised to calcium calls this assumption into question, and consideration of vascular event data from other calcium trials does not refute the Auckland findings. Meta-analyses of these data will be necessary to settle this matter. It is already accepted that calcium supplements increase vascular risk in patients with renal compromise, even in those not yet requiring dialysis. Also, there is substantial epidemiological evidence that serum calcium levels in the upper part of the normal range are a risk factor for vascular disease, and that calcium supplements acutely elevate serum calcium – a combination of findings that lends plausibility to supplementation increasing vascular risk. As there are reasonable grounds for doubting the safety of calcium supplements, and as the evidence for their efficacy in fracture prevention remains marginal, we suggest that there should be a reappraisal of their role in the management of osteoporosis, with a greater emphasis on agents known to prevent fractures.

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Superior discriminating value of ACTH-stimulated serum 21-deoxycortisol in identifying heterozygote carriers for 21-hydroxylase deficiency?

Flávia A. Costa-Barbosa, Vânia F. Tonetto-Fernandes, Valdemir M. Carvalho, Odete H. Nakamura, Vivian Moura, Tânia A. S. S. Bachega, José G. H. Vieira, Claudio E. Kater

Background: Congenital adrenal hyperplasia caused by classic 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder with a high prevalence of asymptomatic heterozygote carriers (HTZ) in the general population, making case detection desirable by routine methodology. HTZ for classic and nonclassic (NC) forms have basal and ACTH-stimulated values of 17-hydroxyprogesterone (17OHP) that fail to discriminate them from the general population. 21-Deoxycortisol (21DF), an 11-hydroxylated derivative of 17OHP, is an alternative approach to identify 21OHD HTZ.

Objective: To determine the discriminating value of basal and ACTH-stimulated serum levels of 21DF in comparison with 17OHP in a population of HTZ for 21OHD (n = 60), as well as in NC patients (n = 16) and in genotypically normal control subjects (CS, n = 30), using fourth generation tandem mass spectrometry after HPLC separation (LC-MS/MS).

Results: Basal 21DF levels were not different between HTZ and CS, but stimulated values were increased in the former and virtually nonresponsive in CS. Only 17•7% of the ACTH-stimulated 21DF levels overlapped with CS, when compared to 46•8% for 17OHP. For 100% specificity, the sensitivities achieved for ACTH-stimulated 21DF, 17OHP and the quotient [(21DF + 17OHP)/F] were 82•3%, 53•2% and 87%, using cut-offs of 40, 300 ng/dl and 46 (unitless), respectively. Similar to 17OHP, ACTH-stimulated 21DF levels did not overlap between HTZ and NC patients. A positive and highly significant correlation (r = 0•846; P < 0•001) was observed between 21DF and 17OHP pairs of values from NC and HTZ.

Conclusions: This study confirms the superiority of ACTH-stimulated 21DF, when compared to 17OHP, both measured by LC-MS/MS, in identifying carriers for 21OHD. Serum 21DF is a useful tool in genetic counselling to screen carriers among relatives in families with affected subjects, giving support to molecular results.

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Targeted biological therapies for Graves’ disease and thyroid-associated ophthalmopathy. Focus on B-cell depletion with Rituximab

Laszlo Hegedüs, Terry J. Smith, Raymond S. Douglas, Claus H. Nielsen

Based on experience from the treatment of other autoimmune diseases and because of the limitations imposed by existing therapeutic options for Graves’ disease (GD) and thyroid-associated ophthalmopathy (TAO), rituximab (RTX) was recently proposed as a novel therapy option. Here, we summarize the rationale for using RTX; give an overview of the possible mechanisms of action; and give an account of its effects and side-effects when used in GD and TAO. Scant evidence, originating from only a few methodologically inhomogeneous studies, suggests that RTX may prolong remission for hyperthyroidism over that seen with antithyroid drugs, at least in mild GD. Furthermore, in patients with TAO, who are unresponsive to conventional immunosuppressive therapy, RTX seems efficacious. As we wait for larger-scale randomized studies, RTX, should be considered experimental and reserved for patients who do not respond favourably to conventional therapy. It is the first in what is likely to be a series of new and emerging treatments specifically targeting relevant components of the immune system. Further studies will hopefully lead to improved and better tailored, individualized therapy for GD and especially TAO.

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Polycystic ovarian syndrome and subclinical atherosclerosis among women of reproductive age in the Dallas heart study

Alice Y. Chang, Colby Ayers, Abu Minhajuddin, Tulika Jain, Pamela Nurenberg, James A. de Lemos, Robert A. Wild, Richard J. Auchus

Objective: Polycystic ovarian syndrome (PCOS), the most common endocrinopathy of young women, is characterized by androgen excess and is frequently associated with cardiovascular risk factors. However, it is unclear whether PCOS is a risk factor for atherosclerosis. We sought to determine in a multiethnic population-based sample whether women with PCOS have greater measures of subclinical atherosclerosis than women without PCOS.

Design: Cross-sectional study of a nested cohort from the Dallas Heart Study (2000–2002).

Participants: Women between the ages of 35 and 49 (n = 827). PCOS was defined by Rotterdam criteria. The normal control group had regular menses, total testosterone <2·78 nmol/l, no signs of hirsutism and no polycystic ovarian morphology by magnetic resonance imaging (MRI).

Measurements: Subclinical atherosclerosis defined as coronary artery calcium (CAC) by computed tomography and abdominal aortic plaque by MRI.

Results: The prevalence of PCOS in Dallas County was 19·6% (n = 144), and 8·0% (n = 56) had both oligomenorrhea and hyperandrogenism. Women with PCOS had higher body mass index, blood pressure, insulin and leptin than regularly cycling controls. Despite a greater prevalence of cardiovascular risk factors, women with PCOS did not have a greater prevalence of CAC > 10 Agatston units (PCOS 5%, controls 6·3%, P = 0·74) or abdominal aortic plaque (PCOS 25·8%, controls 34·4%, P = 0·13) than controls.

Conclusions: In a large, multiethnic, population-based sample of premenopausal women, PCOS, defined by Rotterdam criteria, was not associated with a higher prevalence of coronary artery calcium or abdominal aortic plaque.

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The value of detectable thyroglobulin in patients with differentiated thyroid cancer after initial therapy

D. van Dijk, J. T. M. Plukker, A. N. A. van der Horst-Schrivers, L. Jansen, A. H. Brouwers, A. Muller-Kobold, W. J. Sluiter, T. P. Links

Objective: To assess the prognostic value of detectable thyroglobulin (Tg) after initial surgery and radioactive iodine (131I) therapy by comparing patients with a negative post-therapeutic whole body scan (WBS) with either detectable or undetectable Tg.

Background: Differentiated thyroid cancer has a good prognosis. However, recurrences can occur up to 30 years after initial treatment. Because life-long follow-up is necessary, it is important to explore possible risk factors associated with recurrence and mortality.

Design, patients and measurements: We studied 539 patients who were treated between 1980 and 2007. After the last therapeutic dosage of 5550 MBq 131I, 72 patients had negative post-therapeutic WBS and positive Tg levels (Tg+ group) and 399 patients had negative post-therapeutic WBS and negative Tg (Tg- group). The 68 remaining patients had proven residual macroscopic disease. We investigated recurrences and overall mortality in the Tg+ and Tg- group compared with the Dutch population.

Results: In the Tg+ group, detectable recurrences occurred significantly earlier and more frequently than in the Tg- group (19%vs 13%, P = 0·024). Survival between these groups was comparable, but shorter than the general Dutch population [Standardised Mortality Rate (SMR) 1·38 (95% CI 1·12;1·63) (P = 0·003)]. Disease-free survival in the Tg groups was comparable and not significantly different from the Dutch population [SMR = 1·09 (95% CI 0·81;1·34) (P = 0·569)].

Conclusion: Patients with detectable Tg during the last 131I treatment and a negative post-therapeutic WBS have significant earlier and more recurrences than patients without detectable Tg. Survival in both groups is comparable. After initial therapy, the combination of a negative high dose post-therapeutic WBS with detectable Tg is a valuable predictor for earlier and more recurrences, but is not associated with survival.

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Does an undetectable rhTSH-stimulated Tg level 12 months after initial treatment of thyroid cancer indicate remission?

Joanna Klubo-Gwiezdzinska, Kenneth D. Burman, Douglas Van Nostrand, Leonard Wartofsky

Objectives: Routine monitoring after the initial treatment of differentiated thyroid cancer (DTC) includes periodic cervical ultrasonography (US) and measurement of serum thyroglobulin (Tg) during thyrotrophin (TSH) suppression and after recombinant human TSH (rhTSH) stimulation. The aim of our study was to evaluate the utility of repeated rhTSH-stimulated Tg measurements in patients with DTC who have had no evidence of disease at their initial rhTSH stimulation test performed 1 year after the treatment.

Material and methods: A retrospective chart review of 278 patients with DTC who had repeated rhTSH stimulation testing after an initial undetectable rhTSH-stimulated serum Tg level.

Results: The number of rhTSH stimulation tests performed on individual patients during the follow-up period (3–12 years, mean 6·3) varied from two to seven. Biochemical and/or cytological evidence of potential persistent/recurrent disease based on detectable second or third rhTSH-stimulated Tg values and US findings was observed in 11 (4%) patients. Subsequent follow-up data revealed that in five cases, the results of the second stimulation were false positive, in one case – false negative. Combined with the negative neck US, the negative predictive value for disease-free survival was 98% after the first undetectable rhTSH-stimulated Tg and 100% after the second one.

Conclusions: In patients with DTC, the intensity of follow-up should be adjusted to new risk estimates evolving with time. The first rhTSH-stimulated Tg is an excellent predictor for remission, independent of clinical stage at presentation. Second negative rhTSH-Tg stimulation is additionally reassuring and can guide less aggressive follow-up by the measurement of nonstimulated Tg and neck US every few years.

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Plasma chromogranin A levels are increased in a small portion of patients with hereditary head and neck paragangliomas

Nicolette van Duinen, Ido P. Kema, Johannes A. Romijn1, Eleonora P.M. Corssmit

Context: The majority of patients with head and neck paragangliomas (HNPGL) have biochemically silent tumours. Chromogranin A (CgA) is a tumour marker for neuroendocrine tumours.

Objective: To assess the role of CgA as a tumour marker in patients with hereditary HNPGL.

Patients and Methods: We included 95 consecutive patients with hereditary HNPGL for screening of plasma CgA levels and catecholamine excess by measurement of 24-h urinary excretion of (nor)metanephrine, (nor)adrenaline, VMA, dopamine and 3-methoxytyramine. In all patients with catecholamine excess, abdominal/intrathoracic paragangliomas were excluded by 123I-MIBG scintigraphy, MRI and/or CT.

Results: Plasma CgA levels were increased in only 15 of 95 patients (16%). Thirty-three of the 95 patients (35%) had increased urinary excretion rates of catecholamines. Six of these 33 patients (18%) had increased plasma CgA levels. Nine of the 62 patients (15%) with a biochemically silent tumour, i.e. no increased urinary excretion of catecholamines or their metabolites, had increased CgA levels. Increased plasma CgA levels were positively correlated with urinary excretion rates of noradrenaline (r = 0·68, P = 0·005) and normetanephrine (r = 0·68, P = 0·005). There was a positive correlation between maximal HNPGL diameter and plasma CgA levels in the 57 patients with a single HNPGL (r = 0·57, P = 0·001).

Conclusions: Plasma CgA levels are increased in only a small portion of patients with hereditary HNPGL and have limited additional value to the combination of radiological and routine biochemical assessment of patients with HNPGL. Increased plasma CgA levels are associated with increased noradrenergic activity and tumour size in patients with a single HNPGL.

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Quality of life is less impaired in adults with congenital adrenal hyperplasia because of 21-hydroxylase deficiency than in patients with primary adrenal insufficiency

Nicole Reisch, Stefanie Hahner, Benjamin Bleicken, Linda Flade, Francesco Pedrosa Gil, Melanie Loeffler, Manfred Ventz, Andreas Hinz, Felix Beuschlein, Bruno Allolio, Martin Reincke, Marcus Quinkler

Objective: Current replacement regimens fail to restore well-being in patients with primary adrenal insufficiency (PAI). Data on health-related quality of life (HRQoL) in patients with congenital adrenal hyperplasia (CAH) are scarce, inconsistent and largely restricted to women. The objective of the study therefore was to study HRQoL in CAH because of 21-hydroxylase deficiency in comparison with PAI and healthy controls.

Design/patients: In a cross-sectional study, 81 German CAH patients from two tertiary care centres (45 women, 36 men; 71 classical, 10 nonclassical, age 18–65 years) completed three validated self-assessment questionnaires [Short Form-36 (SF-36), Giessen Subjective Complaints List (GBB-24), Hospital Anxiety and Depression Scale (HADS)]. Results were compared to sex- and age-matched controls from questionnaire-specific German reference cohorts and German PAI patients.

Results: Congenital adrenal hyperplasia patients had impaired HRQoL in three of five GBB-24 scores whereas SF-36 and HADS scores did not differ from controls. PAI patients showed impairment in more dimensions of the applied tests and, in women, significantly worse scores in several dimensions compared to CAH patients (physical functioning, vitality, social functioning, mental health dimensions of the SF-36, P < 0·05 and HADS anxiety score, P < 0·05).

Conclusions: HRQoL in CAH is only mildly impaired and significantly less than in PAI patients. Differences between PAI and CAH in HRQoL suggest relevant modulating factors of HRQoL other than hormone replacement therapy itself.

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Effect of surgery on cardiac structure and function in mild primary hyperparathyroidism

Anita Persson, Jens Bollerslev, Thord Rosen, Charlotte L. Mollerup, Celina Franco, Gunhild A. Isaksen, Thor Ueland, Svante Jansson, Kenneth Caidahl, on behalf of the SIPH Study Group

Context: The cardiovascular (CV) risk profile is worsened in primary hyperparathyroidism (PHPT), and CV mortality is related to serum calcium levels. It is unknown whether CV mortality is increased in the most common form of PHPT and whether the increased CV risk is reversible after surgery.

Objective: To investigate reversibility of echocardiographic variables in patients with mild PHPT who were randomized to observation without surgery or operation, and followed for 2 years.

Design/Setting/Patients: Forty-nine patients (mean age 63 ± 7 years, 8 men) who had performed the 2-year visit in a randomized study on mild PHPT (serum calcium at baseline 2·65 ± 0·09 mm) (observation) vs 2·67 ± 0·06 mm (surgery) and where echocardiography had been performed, participated in the study.

Results: Calcium and parathyroid hormone (PTH) levels were normalized following surgery and were stable in the observation group. PTH levels at baseline were highly correlated with ventricular mass. Detailed echocardiography revealed a minor and borderline significant treatment effect of surgery on left ventricular mass index (LVMI) compared to observation (P = 0·066) and a significant 11% reduction in diastolic dimension of the interventricular septum (IVSd-mean) in the surgery group (P < 0·01), with no alterations in the observation group.

Conclusions: Based on detailed echocardiographic measures over a 2-year observation period, we found only minor differences between the two groups. However, the potential treatment effect on LVMI and the within-group differences in IVSd-mean suggest that longer follow-up may yield larger and clinically important differences.

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Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum

A. P. Weetman

Anyone who has been in an endocrine clinic will appreciate that associations exist between autoimmune thyroid disease (AITD) and other autoimmune disorders. However, the full extent of these associations is still not fully appreciated, and new associations are being uncovered which may shed new light on the pathogenic basis for these connections, and the underlying reasons for them are only now becoming understood. This review is based on the British Thyroid Association Pitt-Rivers Lecture 2010. The first section provides an update on studies which have detailed the strength of various autoimmune disease associations, the second section discusses the environmental and genetic factors which underlie these associations and the final section describes some recently identified, unexpected AITD associations. Unravelling these associations further will illuminate the pathogenesis of autoimmune diseases and offers the prospect of new therapeutic approaches.

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Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy

Pauline Brummelman, Martin F. Elderson, Robin P. F. Dullaart, Alfons C. M. van den Bergh, Cees A. Timmer, Gerrit van den Berg, Janneke Koerts, Oliver Tucha, Bruce H. R. Wolffenbuttel, André P. van Beek

Context and objective: Cognitive deterioration is reported in patients with a nonfunctioning pituitary macroadenoma (NFA) and after pituitary radiotherapy. However, reported results are inconsistent and are potentially confounded by different underlying pituitary disorders. The aim of this study was to examine cognitive functions in patients previously treated for NFA with or without radiotherapy.

Design: Verbal memory was assessed with the Dutch equivalent to the Rey Auditory Verbal Learning Test (15 Words Test, 15 WT). Executive functioning was examined using the Ruff Figural Fluency Test (RFFT). We compared our patient cohort with large reference populations representative of the Dutch population.

Patients: Eighty-four patients (62 ± 10 years) who underwent transsphenoidal surgery 8.6 ± 6.3 years earlier participated. Patients who underwent radiotherapy (n = 39) were compared to those who received surgery alone (n = 45). All patients were on stable hormonal replacement therapy.

Results: The total patient group scored significantly below the reference sample on all 15 WT z-scores (95%CI): short-term memory, −0.3 (−0.5 to −0.1); total memory, −0.8 (−1.1 to −0.5); learning score, −0.3 (−0.5 to −0.1); delayed memory, −0.8 (−1.1 to −0.5), all P < 0.01. The total patient group scored significantly below the reference sample on RFFT z-scores (95%CI): unique designs, −0.7 (−0.9 to −0.5) and perseverative errors, −0.5 (−0.8 to −0.2), both P < 0.001. Patients who underwent radiotherapy showed no significant differences on cognition when compared to those who received surgery alone.

Conclusion: Patients with NFA score significantly worse on cognition compared to reference populations. Radiotherapy does not appear to have a major influence on cognition.

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Low testosterone concentrations and the symptoms of testosterone deficiency according to the Androgen Deficiency in Ageing Males (ADAM) and Ageing Males’ Symptoms rating scale (AMS) questionnaires

M. H. Emmelot-Vonk, H. J. J. Verhaar, H. R. Nakhai-Pour, D. E. Grobbee, Y. T. van der Schouw

Objective: First, to assess the association between the concentration of serum testosterone and the symptoms of testosterone deficiency according to two screening questionnaires. Second, to investigate the effects in elderly men with a low-normal testosterone concentration of testosterone supplementation over a period of 6 months on symptoms of testosterone deficiency according to the screening questionnaires.

Design, Setting and Participants: A total of 587 men between 60 and 80 years of age with an eligible serum testosterone measurement and completion of the screening questionnaires were included in the study. Of these 587 men, 237 men with testosterone levels <13·7 nmol/l were included in a double-blind, randomized, placebo-controlled trial of testosterone supplementation.

Intervention: One hundred and sixty milligrams per day of oral testosterone undecanoate or a matching placebo for 6 months.

Measurements: The Androgen Deficiency in Ageing Males (ADAM) and the Ageing Males’ Symptoms rating scale (AMS) questionnaires.

Results: There was no significant association between the total testosterone concentration and the scores on the two questionnaires. However, age was significantly associated with the scores on the ADAM (OR 1·14, 95% CI 1·05–1·23) and the AMS (OR 1·03, 95% CI 1·01–1·08) questionnaire. After supplementation with testosterone, there were no effects on the scores on the two questionnaires in the testosterone group compared with the placebo group.

Conclusion: The findings do not support the use of the ADAM or AMS questionnaire in the evaluation of late-onset hypogonadism in ageing men. Moreover, 6 months of oral testosterone supplementation had no significant effect on scores of the ADAM and AMS questionnaire in this group of elderly men with low-normal testosterone levels.

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Effects of exercise training on maternal hormonal changes in pregnancy

Sarah A. Hopkins, James C. Baldi, Wayne S. Cutfield, Lesley McCowan, Paul L. Hofman

Context & Objective: A recent paper by our group reported that regular aerobic exercise during pregnancy led to lower foetal IGF-I and IGF-II concentrations and a modest reduction in offspring birth weight when compared with the offspring of nontraining control participants. Maternal hormonal alterations in response to exercise training may be associated with the regulation of nutrient availability for foetal growth through placental regulation of maternal metabolism.

Objective: To determine whether the reduction in offspring size was associated with changes in the maternal IGF axis [including placental growth hormone (PGH)], leptin and/or free fatty acids (FFA) in response to aerobic exercise training in the second half of pregnancy.

Design and Setting: A randomized, controlled trial of exercise in pregnancy.

Patients: Eighty-four healthy nulliparous women (mean ± SD age 30 ± 4 year, BMI 25·5 ± 4 kg/m2).

Measurements: Serum samples were drawn at 19 and 35 weeks gestation to determine serum IGF-I, IGF-II, IGF-binding protein-1, IGF-binding protein-3, PGH, leptin and FFA.

Results: Exercise training in pregnancy had no impact on the pregnancy-related changes in the maternal IGF axis. Women in the exercise group experienced a 29% increase in leptin in late gestation (P = 0·026 vs control) and a trend towards lower FFA (P = 0·07 vs control). Late pregnancy changes in maternal leptin were inversely related to offspring birth weight (r = −0·24, P < 0·05) and BMI (r = −0·25, P < 0·05).

Conclusions: An increase in leptin in exercising pregnant women may reflect subtle changes within the placenta in response to regular exercise and may contribute to the reduction in offspring size previously reported in this cohort.

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Prospective echocardiographic evaluation of patients with endogenous subclinical hyperthyroidism and after restoring euthyroidism

Grzegorz Kaminski, Dariusz Michalkiewicz, Karol Makowski, Zbigniew Podgajny, Norbert Szalus, Marek Ruchala, Ewelina Szczepanek, Grzegorz Gielerak

Objectives: Clinical significance of, and the need for, treatment in subclinical hyperthyroidism (sHT) is still a matter of debate. The aim of the study was to assess the impact of sHT on echocardiographic parameters.

Design: Patients with endogenous sHT of nonautoimmune origin underwent full echocardiographic assessment at diagnosis and after restoring euthyroidism with radioiodine treatment.

Patients: Studied group consisted of 44 patients (37 women, 7 men), aged 22–65 years (mean 45·9 ± 11·0).

Measurements: Full echocardiographic assessment included estimation of cardiac chamber diameters and volume as well as cardiac contractility, according to the guidelines of the American Society of Echocardiography. Left ventricular mass was calculated according to Penn’s convention. For estimation of left ventricle diastolic function, the following echocardiographic parameters were obtained: maximal early filling wave velocity (E), maximal late filling wave velocity (A), E/A ratio, isovolumetric relaxation time and early filling wave deceleration time.

Results: In the studied group, phase of sHT was associated with increased volume of heart chambers, increased diameter of ascending aorta, increased left ventricle mass and disturbed left ventricle relaxation (P < 0·05). The systolic function of the left ventricle was unaffected; however, the ejection time was shortened. The changes were reversible with restoring biochemical euthyroidism (P < 0·05). Moreover, a significant correlation between some of the parameters and thyroid hormones concentration was demonstrated.

Conclusions: sHT was associated with significant changes in echocardiographic parameters, which may contribute to increased cardiovascular risk in these patients. The alterations were reversible with restoring biochemical euthyroidism, what supports the necessity of treatment introduction in sHT.

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Thyroid autoimmunity and miscarriage: a meta-analysis

Lili Chen, Renming Hu

Objective: To investigate whether thyroid autoimmunity (TAI) is associated with increased risk of miscarriage in euthyroid women.

Methods: An electronic search was conducted using the databases Medline, PubMed, EMBASE and the Cochrane library, from inception to October 2010. A systematic review of the studies on the association between TAI and miscarriage was performed. The odd ratios of case–control studies and relative risks of cohort studies were pooled respectively. The software Review Manager (version 4.3.1) was applied for meta-analysis.

Results: The search strategy identified 53 potentially relevant publications, 22 of which were included in the meta-analysis. A clear association between thyroid autoimmunity and miscarriage was observed with a pooled odds ratio of 2·55 (95% CI 1·42–4·57, P = 0·002) in eight case–control studies and a pooled relative risk of 2·31 (95% CI 1·90–2·82, P < 0·000 01) in 14 cohort studies. Women with TAI were found to have slightly higher age [age difference, 1·29 years] (95% CI 0·43–2·16, P = 0·003) and thyroid-stimulating hormone (TSH) levels [TSH difference, 0·61 mIU/l] (95% CI 0·51–0·71, P < 0·000 01) compared with those without TAI.

Conclusion: Based on the currently available evidence, it appears that the presence of thyroid autoimmunity is associated with an increased risk of spontaneous miscarriage in euthyroid women.

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Aromatase inhibitors for ovulation induction and ovarian stimulation

Vivian Chi Yan Lee, William Ledger

Aromatase inhibitors (AIs) were originally developed for the treatment of advanced breast cancer in postmenopausal women. Their use in reproductive medicine has been extensively studied in the past decade. We reviewed the current strategies for ovulation induction for anovulatory women, mostly women with polycystic ovarian syndrome (PCOS), and the scientific basis for use of AIs in reproductive medicine. The AI, letrozole, is effective in ovulation induction in women with PCOS resistant to clomifene citrate and ovarian stimulation for intrauterine insemination and in vitro fertilization (IVF). Letrozole is an attractive option with its oral route of administration, cost, safety profile and effectiveness in ovulation induction and ovarian stimulation. Letrozole has the potential to be the first-line treatment option for ovulation induction in PCOS women, while its use in ovarian stimulation for IVF deserves further study.

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Cardiac valve disease and low-dose dopamine agonist therapy: an artefact of reporting bias?

Haotian Gu, Sara Luck, Paul V. Carroll, Jake Powrie, John Chambers

Introduction: Chronic low-dose cabergoline treatment for microprolactinoma may cause cardiac valve pathology, but the evidence is contradictory. We investigated whether the expectation of the echocardiographer could influence the report.

Methods: Transthoracic echocardiograms from 40 patients aged 49·3 ± 9·6 (mean ± SD) years (Men:Women 7:33) on long-term cabergoline and bromocriptine therapy (duration 9·94 ± 4·5 years) were randomly assigned to two groups of echocardiographers so that each echocardiogram was reported twice. One group was told that ‘the patients were control subjects’ (Group A) and the other that ‘the patients were on dopamine agonist therapy which is known to cause valve disease’ (Group B). An observer who was blind to the group scored the reports for regurgitation at each valve (scores 0–4; max 16 per case).

Results: Mean total regurgitation score was significantly higher in Group B (1·43 ± 1·28; P = 0·014) than in Group A (0·73 ± 1·30). The difference was mainly from reporting trivial regurgitation: (mitral 16 vs 5, P = 0·005; tricuspid 17 vs 6, P = 0·007 and pulmonary 8 vs 1, P = 0·013). Mild regurgitation was uncommon (mitral 1 vs 1 and tricuspid 3 vs 6). Moderate regurgitation occurred in only one case and was associated with restriction of the leaflets consistent with the effects of cabergoline. Valve thickening was not reported in Group A, but in 9 (23%) mitral and 4 (10%) aortic valves in Group B.

Conclusion: Long-term, low-dose dopamine agonist therapy rarely causes cardiac valve disease, but operator bias can lead to over-reporting of both valve thickening and trivial regurgitation.

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Brown fat and obesity: the next big thing?

Mark Stephens, Marian Ludgate, D. Aled Rees

Brown adipose tissue (BAT) is well recognised to have an important role in the maintenance of body temperature in animals and human neonates, its thermogenic action affected by a tissue-specific uncoupling protein; fatty acid oxidation within the numerous brown adipocyte mitochondria is rendered inefficient leading to heat, rather than adenosine triphosphate (ATP), production. BAT was believed to show rapid involution in early childhood, leaving only vestigial amounts in adults. However, recent evidence suggests that its expression in adults is far more common than previously appreciated, with a higher likelihood of detection in women and leaner individuals. It is conceivable that BAT activity might reduce the risk of developing obesity since fat stores are used for thermogenesis, and a directed enhancement of adipocyte metabolism might have value in weight reduction. However, it is as yet unclear how such manipulation of BAT might be achieved; even in animal models, the control of thermogenic activity is incompletely understood. Even so, there is still much to interest the endocrinologist in BAT, with a range of hormones affecting adipocyte activity. This may either contribute to normal physiological function, or the phenotypical presentation of states of pathological hormone excess or deficiency. Thus, the gender differences in BAT distribution may be attributable to the differential effects of male and female sex hormones, whilst BAT expansion may drive the weight loss associated with catecholamine-producing phaeochromocytomas. These observations support an important influence of the endocrine system on BAT activity and offer new potential targets in the treatment of obesity.

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What should be done when thyroid function tests do not make sense?

Mark Gurnell, David J. Halsall, V. Krishna Chatterjee1

Interpretation of thyroid function tests (TFTs) is generally straightforward. However, in a minority of contexts the results of thyroid hormone and thyrotropin measurements either conflict with the clinical picture or form an unusual pattern. In many such cases, reassessment of the clinical context provides an explanation for the discrepant TFTs; in other instances, interference in one or other laboratory assays can be shown to account for divergent results; uncommonly, genetic defects in the hypothalamic–pituitary–thyroid axis are associated with anomalous TFTs. Failure to recognize these potential ‘pitfalls’ can lead to misdiagnosis and inappropriate management. Here, focusing particularly on the combination of hyperthyroxinaemia with nonsuppressed thyrotropin, we show how a structured approach to investigation can help make sense of atypical TFTs.

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Six-month preoperative octreotide treatment in unselected, de novo patients with acromegaly: effect on biochemistry, tumour volume, and postoperative cure

Sven M. Carlsen, Johan Svartberg, Thomas Schreiner, Sylvi Aanderud, Øivind Johannesen, Svein Skeie, Morten Lund-Johansen, Stine L. Fougner, Jens Bollerslev on behalf of the POTA study group

ObjectiveTreatment with somatostatin analogues is the primary medical treatment of acromegaly. Controversies still exist whether acute octreotide effect predicts long-term biochemical effects, tumour regression or surgical cure. This prospective study investigates effect of 6-month treatment with octreotide long-acting repeatable (LAR) on insulin-like growth factor-1 (IGF-1) and growth hormone (GH) levels, pituitary function, tumour regression and postoperative cure in de novo acromegalic patients.

Design and methods: After a baseline evaluation including fasting hormone levels, MRI scan and an acute 50 μg octreotide test, 32 patients were treated with octreotide LAR 20 mg every 28th day for 6 months before surgery. Treatment effects on IGF-1 and GH levels, serum hormone levels and tumour volume were monitored. Surgical cure was evaluated 3 months postoperatively.

Results: Mean tumour volume reduction was 35%, in one-third of the patients more than 50%, while approximately one-third achieved biochemical remission evaluated by normalized IGF-1 levels. The GH reduction following an acute octreotide test was 81 ± 19% and associated with long-term GH reduction (r = 0·78, P < 0·0005). However, neither acute (r = 0·29, P = 0·12) nor the long-term octreotide effect (r = 0·11, P = 0·58) on GH levels was associated with tumour volume reduction and did not predict subsequent surgical cure.

Conclusion: Six months of long-acting octreotide using a fixed dose, 1/3 of the patients came in biochemical remission, while 2/3 had significant tumour reduction. Moreover, an acute effect of octreotide seemed to be a prerequisite for long-term effect.

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UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development

Faisal Ahmed, John C. Achermann, Wiebke Arlt, Adam H. Balen, Gerry Conway, Zoe L. Edwards, Sue Elford, Ieuan A. Hughes, Louise Izatt, Nils Krone, Harriet L. Miles, Stuart O’Toole, Les Perry, Caroline Sanders, Margaret Simmonds, A. Michael Wallace, Andrew Watt, Debbie Willis

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional DSD team acts as the first point of contact. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents are as fully informed as possible and have access to specialist psychological support. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

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Asymptomatic primary hyperparathyroidism – we have half the answers

Peter Selby

No abstract is available for this article.

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New therapeutic options for metastatic malignant insulinomas

Wouter W. de Herder, Ellen van Schaik, Dik Kwekkeboom, Richard A. Feelders

Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver–bone) metastases have a median survival of <2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the ‘tailor-made’ approach of patients with metastatic insulinomas is further expanded.

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Who should have genetic testing for maturity-onset diabetes of the young?

Rochelle Naylor, Louis H. Philipson

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic disorders characterized by autosomal dominant inheritance of young-onset, non-insulin-dependent diabetes. The genes involved are important in beta cell development, function and regulation and lead to disorders in glucose sensing and insulin secretion. Heterozygous GCK mutations cause impaired glucokinase activity resulting in stable, mild hyperglycaemia that rarely requires treatment. HNF1A mutations cause a progressive insulin secretory defect that is sensitive to sulphonylureas, most often resulting in improved glycaemic control compared with other diabetes treatment. MODY owing to mutations in the HNF4A gene results in a similar phenotype, including sensitivity to sulphonylurea treatment. HNF1B mutations most frequently cause developmental renal disease (particularly renal cysts) but may also cause MODY in isolation or may cause the renal cysts and diabetes syndrome (RCAD syndrome). Mutations in NEUROD1, PDX1 (IPF1), CEL and INS are rare causes of MODY. MODY is often misdiagnosed as type 1 or type 2 diabetes. However, a correct genetic diagnosis impacts treatment and identifies at-risk family members. Thus, it is important to consider a diagnosis of MODY in appropriate individuals and to pursue genetic testing to establish a molecular diagnosis.

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What medical options should be considered for the treatment of primary hyperparathyroidism?

Mara J. Horwitz

Primary hyperparathyroidism (PHPT) is a common, often asymptomatic, endocrine disorder characterized by hypercalcaemia in the face of a nonsuppressed parathyroid hormone (PTH) level. For those with symptomatic disease or who meet surgical criteria, parathyroidectomy is the treatment of choice. However, those patients who do not meet surgical criteria or who cannot undergo or refuse surgery must be managed medically. Medical management of PHPT involves continual assessment to determine who will benefit from surgical intervention, replacement of vitamin D, treatment of parathyroid bone disease and management of hypercalcaemia and renal stone disease.

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Comparison of primary octreotide-lar and surgical treatment in newly diagnosed patients with acromegaly

Z. Karaca, F. Tanriverdi, G. Elbuken, I. Cakir, H. Donmez, A. Selcuklu, A. C. Durak, H. S. Dokmetas, R. Colak, K. Unluhizarci, F. Kelestimur

Objective: The primary aim of the study was to compare the efficacy of Oct-LAR and surgery in terms of controlling IGF-1 and GH levels and tumour volumes. The second aim was to compare two primary treatment modalities in terms of side effects such as pituitary insufficiency, cholelithiasis, metabolic parameters and the effect on quality of life (QoL).

Design: The study was a randomized, prospective study.

Patients: The 22 patients were consecutively randomized to Oct-LAR and surgical treatment groups.

Results: Baseline serum IGF-1 level, tumour volume and GH levels were comparable in the Oct-LAR and surgery groups. No significant differences were detected between the Oct-LAR and the surgery groups in terms of IGF-1 and GH levels at the 3rd and 6th months, but at 12th month, preglucose GH was found to be lower in the surgical treatment group. IGF-1 control and complete biochemical response rates were found to be 27% and 64%, in the Oct-LAR and surgical treatment groups, respectively. The mean percentage of tumour volume reduction was found to be 26%, 30% and 31% in the Oct-LAR group vs 64%, 74% and 79% in the surgery group at the 3rd, 6th and 12th months, respectively.

Conclusion: Primary surgical treatment seems to be slightly more effective than Oct-LAR in terms of biochemical response and IGF-1 control, besides tumour volume reduction, in patients with acromegaly with noninvasive tumours. Oct-LAR is associated with more side effects such as cholelithiasis and glucose metabolism disorders and is more expensive.

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