Melania Pulcrano

Endothelial-mediated coronary flow reserve in patients with mild thyroid hormone deficiency

CONTEXT Although coronary flow reserve (CFR) is reduced in patients with subclinical hypothyroidism (SHypo), the endothelial response of coronary vasomotion has never been explored in this clinical setting. OBJECTIVE To investigate the endothelial response of coronary flow in young and middle-aged patients with SHypo, without associated cardiovascular risk factors compared with healthy control subjects. PATIENTS AND METHODS The study population consisted of 20 women (mean age 38.4+12.1 years) with newly diagnosed, untreated and persistent SHypo due to Hashimotos thyroiditis. A total of 15 volunteers served as controls. Age, gender, body surface area, glucose, insulin levels, heart rate, systolic, diastolic, and mean blood pressure were similar in patients and controls. Body mass index was significantly higher in SHypo patients. Total cholesterol and low-density lipoprotein cholesterol, despite not significant, tended to be higher, and high-density lipoprotein cholesterol to be lower in SHypo. Coronary blood flow velocities were recorded in patients at rest and after the cold pressor test (CPT), a stimulus that can be considered totally endothelium-dependent. CFR was calculated as the ratio of hyperemic-to-resting diastolic peak velocities. RESULTS Coronary diastolic peak velocities at rest did not differ between the two groups but were significantly lower after CPT in patients with SHypo, thereby resulting in a lower CFR. The difference remained significant after adjusting resting and CPT velocities for the respective mean blood pressures. TSH was inversely correlated with CFR in the pooled population. CONCLUSION Patients with SHypo without associated cardiovascular risk factors have a coronary endothelial dysfunction that appears in response to a physiological stimulus (the CPT).

Turner’s syndrome mosaicism 45X/47XXX: An interesting natural history

Mosaicism 45X/47XXX is a sporadic form of ovarian dysgenesis. Many of the cases previously described were characterized by a variable phenotype expression. We here report the case of a 33-yr-old woman with recent secondary amen-orrhea, weight loss and breast regression. Her menarche had occurred at the age of 11 yr and 6 months and her menstrual cycles had been regular until the age of 28; then, oligomenorrhea and hypertricosis developed. A pelvic ultrasound showed enlarged polycystic-like ovaries and normal uterus. She was treated with ethynil-estradiol and cyproterone acetate for one year. At the age of 31 yr, she underwent a pelvic ultrasound — which revealed normal volume of the ovaries — and hormonal assays including FSH (69 UI/l), LH (113 UI/l), 17β-estradiol (88 pg/ml), plasma androgens and cortisol levels within normal ranges. No organ-specific autoantibodies toward ovaries, steroid-producing cells or adrenals were found. At the age of 33 yr, there was ultrasound evidence of streak-like ovaries. The patient’s height was 145 cm and her weight 45 kg. She had normal female external genitalia, abnormal upper-to-lower body segment ratio, webbed neck, low posterior hair line, cubitusvalgus, short and asymmetrical 4th metacarpi, hallux with lateral deviation and moderate scoliosis. No increase in ovarian steroids were found after GnRH-analogue triptorelin (0,1 mg sc) administration. The karyotype analysis on peripheral blood lymphocytes showed a mosaic 45X (90% cells) and 47XXX (10% cells). Diagnostic pelviscopy confirmed streak gonads. Chronic lymphocytic thyroiditis was diagnosed but no cardiovascular or kidney abnormalities were found. A neuro-psychological evaluation revealed emotional and social immaturity, disorders in motorial coordination, visual-spatial organization, as well as reading difficulties and impaired complex phrase construction. The presence of several somatic features of Turner’s syndrome, neuro-psychological disorders and an interesting natural history probably depended on the quantitative proportion of 45X to 47XXX cell-lines in different tissues and organs. Estrogen and progestin replacement therapy led to weight gain, re-appearance of secondary sexual characteristics and a mild improvement in mental equilibrium.

Screening in von Hippel-Lindau disease: concurrent pheochromocytomas, paragangliomas and spinal hemangioblastomas revealed by helical-CT, MIBG scintigraphy and MRI in an asymptomatic patient

Abstract Early detection of visceral as well as neurological abnormalities in von Hippel-Lindau (VHL) disease is highly recommended and usually accomplished by a combination of radiological and nuclear medicine techniques. We report a case of an asymptomatic 30-year-old male with VHL disease who was found to have concurrent bilateral pheochromocytomas, a carotid body tumor, sacral para-gangliomas and spinal hemangioblastomas during a screening performed by contrast-enhanced helical computed tomography, 131I-metaiodobenzylguanidine scintigraphy and magnetic resonance imaging. Despite their common embriogenetic origin from the neural crest, the concurrence of pheochromocytomas and para-gangliomas in VHL disease is rare. Although frequently asymptomatic, the occurrence of spinal hemangioblastomas in the clinical context of the screening has not been previously reported.

Adjuvant treatment with thyrotropin alpha for remnant ablation in thyroid cancer

Various studies have demonstrated the safety and efficacy of recombinant human thyroid-stimulating hormone (rhTSH) for radioiodine remnant ablation. On this basis, rhTSH was approved in Europe for the radioiodine ablation of low-risk differentiated thyroid cancer (DTC) during thyroid hormone therapy with L-thyroxine (L-T4). Moreover, in December 2007, the US Federal Drug Administration approved the use of rhTSH for adjuvant treatment with radioiodine in patients with DTC without evidence of metastatic thyroid cancer. Quality of life was found to be better with rhTSH preparation than with L-thyroxine withdrawal, thereby resulting in benefits for society as a whole. Furthermore, rhTSH for radioiodine remnant ablation results in a longer effective radioiodine half-life within remnant thyroid tissue and a lower specific absorbed dose in the blood and exposure of bone marrow to X-rays. More studies are required to establish the amount of radioiodine to be administered especially in high-risk patients.

Long-term efficacy of doxazosin plus atenolol in the management of severe and sustained arterial hypertension and reversibility of the cardiac damage induced by chronic cathecolamine excess. A case report in a young girl with recurrent, functioning paraganglioma

Herein we report on a young girl with recurrent, functioning paraganglioma of the organ of Zuckerkandl and severe and sustained arterial hypertension (systolic pressure >200, diastolic pressure >120 mmHg); with evidence of cardiac damage induced by chronic cathecolamine excess. She promptly and steadily improved after the institution of doxazosin (6 mg/day) plus atenolol (50 mg bid) treatment. This case demonstrates that a correct therapeutic strategy in the longterm management of patients with inoperable catecholamine-producing neuroendocrine tumors (pheochromocytomas and paragangliomas) can maintain arterial pressure in the normal range and reverse the cardiac damage induced by chronic cathecolamine excess.

Impact of Resistance to Thyroid Hormone on the Cardiovascular System in Adults

Background: The clinical manifestations of resistance to thyroid hormone (RTH) are highly variable, and the impact of RTH on the cardiovascular system has been poorly investigated. Aim: The objective of the study was to evaluate the cardiovascular characteristics of 16 untreated and asymptomatic patients with RTH compared with 16 euthyroid healthy controls to define the cardiovascular involvement in RTH syndrome. Patients and Methods: Sixteen untreated and asymptomatic RTH patients (eight males; aged 33 12 yr, range 21–45 yr) and 16 controls (nine males; aged 33 5 yr, range 24–42 yr) were enrolled. Clinical data, thyroid status, and echocardiographic results were recorded. Results: Heart rate was comparable with that of controls, whereas arterial pressure was higher than controls. Mean interventricular septum diastolic thickness and mean left ventricular (LV) posterior wall diastolic thickness were significantly lower in RTH patients than controls with a consequent significant decrease of the mean LV mass and LV mass indexed by body surface area. Patients also had abnormalities of myocardial relaxation as indicated by a significant increase of peak A and consequent reduction of the early to late ratio. Finally, systemic vascular resistance was significantly higher in RTH patients than controls. Conclusions: Our results suggest the presence of cardiovascular alterations in asymptomatic and untreated RTH patients similar to those reported in hypothyroid patients. Our strict selection likely created a bias in the inclusion of a particular type of RTH patients, who could represent a minority of patients with RTH. However, no correlation was found between the type of mutation and cardiovascular characteristics of RTH patients. Nerve Growth Factor Induces Vascular Endothelial Growth Factor Expression in Granulosa Cells via a trkA Receptor/Mitogen-Activated Protein Kinase-Extracellularly Regulated Kinase 2-Dependent Pathway Marcela Julio-Pieper, Patricia Lozada, Veronica Tapia, Margarita Vega, Cristian Miranda, David Vantman, Sergio R. Ojeda, and Carmen Romero (J Clin Endocrinol Metab, published May 19, 2009, 10.1210/jc.2009-0542) ABSTRACT Context: Acquisition of ovulatory competence by antral follicles requires development of an adequate vascular supply. Although it iswellestablishedthatovarianangiogenesis is cyclically regulatedbyvascularendothelialgrowthfactor (VEGF), thefactorscontrolling VEGF production by ovarian follicles remain largely unknown. Nerve growth factor (NGF) may be one of these factors, because NGF promotes angiogenesis and synthesis of angiogenic factors in other tissues and is produced by human granulosa cells (hGCs). Objective: The aim of the study was to determine whether NGF influences the production of VEGF by hGCs and to identify a potential signaling pathway underlying this effect. Design: We conducted a prospective experimental study. Patients: hGCs were obtained from 41 women participating in the in vitro fertilization program of our institution. Methods: Changes in VEGF mRNA after exposure to NGF were evaluated in cultured hGCs by PCR and real-time PCR. The effect of NGF on VEGF secretion was determined by ELISA. The involvement of trkA, the high affinity NGF receptor, was examined by inhibiting the receptor’s tyrosine kinase activity with K252a. The contribution of an ERK1/ERK2-mediated signaling pathway was identified by detecting NGF-dependent phosphorylation of these proteins and by blocking their activity with the inhibitor U0126. Results: NGF promotes VEGF production in cultured hGCs. Blockade of trkA receptor tyrosine kinase activity blocks this effect. NGF induces MAPK-ERK2 phosphorylation, and blockade of this signaling pathway prevents the NGF-induced increase in VEGF production. Conclusions: NGF promotes ovarian angiogenesis by enhancing the synthesis and secretion of VEGF from hGCs via a trkAand ERK2-dependent mechanism. Endocrine Reviews, August 2009, 30(5):536–543 edrv.endojournals.org 541Context: Acquisition of ovulatory competence by antral follicles requires development of an adequate vascular supply. Although it iswellestablishedthatovarianangiogenesis is cyclically regulatedbyvascularendothelialgrowthfactor (VEGF), thefactorscontrolling VEGF production by ovarian follicles remain largely unknown. Nerve growth factor (NGF) may be one of these factors, because NGF promotes angiogenesis and synthesis of angiogenic factors in other tissues and is produced by human granulosa cells (hGCs). Objective: The aim of the study was to determine whether NGF influences the production of VEGF by hGCs and to identify a potential signaling pathway underlying this effect. Design: We conducted a prospective experimental study. Patients: hGCs were obtained from 41 women participating in the in vitro fertilization program of our institution. Methods: Changes in VEGF mRNA after exposure to NGF were evaluated in cultured hGCs by PCR and real-time PCR. The effect of NGF on VEGF secretion was determined by ELISA. The involvement of trkA, the high affinity NGF receptor, was examined by inhibiting the receptor’s tyrosine kinase activity with K252a. The contribution of an ERK1/ERK2-mediated signaling pathway was identified by detecting NGF-dependent phosphorylation of these proteins and by blocking their activity with the inhibitor U0126. Results: NGF promotes VEGF production in cultured hGCs. Blockade of trkA receptor tyrosine kinase activity blocks this effect. NGF induces MAPK-ERK2 phosphorylation, and blockade of this signaling pathway prevents the NGF-induced increase in VEGF production. Conclusions: NGF promotes ovarian angiogenesis by enhancing the synthesis and secretion of VEGF from hGCs via a trkAand ERK2-dependent mechanism. Endocrine Reviews, August 2009, 30(5):536–543 edrv.endojournals.org 541

Ipotiroidismo subclinico: indicazioni al trattamento

RiassuntoL’ipotiroidismo subclinico è una condizione caratterizzata da un incremento del TSH con ormoni tiroidei normali. Benché la secrezione di ormoni tiroidei sia apparentemente normale, i soggetti con tale pattern ormonale possono essere sintomatici e presentare alterazioni a carico dei loro organi e tessuti bersaglio, che, se non corrette, possono indurre spesso complicanze in grado di modificare la qualità e le aspettative di vita. L’ipotiroidismo subclinico è relativamente frequente nella popolazione generale e, specie negli anziani determina un elevato rischio cardiovascolare per la possibilità di alterazione di vari parametri cardiovascolari e per l’aumentato rischio di aterosclerosi. Tra i fattori di rischio per aterosclerosi un ruolo importante sembra essere svolto dall’ipertensione, dalla disfunzione endoteliale, dalla dislipidemia e dalle alterazioni dei parametri di coagulazione. La terapia con T4 riesce a prevenire o a correggere l’aumentato rischio cardiovascolare associato all’ipotiroidismo subclinico, nonché a migliorare la qualità di vita, i disturbi psichici, cognitivi e muscolari che pure possono essere presenti. Il trattamento dell’ipotiroidismo subclinico è imperativo in gravidanza per le gravi alterazioni che può indurre nel nascituro.