Daniela Esposito

Cardiovascular abnormalities in Klinefelter Syndrome

BACKGROUND Several epidemiological studies have demonstrated an increased mortality from cardiovascular causes in patients with Klinefelter Syndrome (KS). Little information is available about the nature of the underlying cardiovascular abnormalities. Aim of the study was to investigate exercise performance, left ventricular architecture and function, vascular reactivity, and carotid intima-media thickness in a group of patients with KS. MATERIALS AND METHODS Sixty-nine patients with KS and 48 age-matched controls participated in our population-controlled study. Forty-eight Klinefelter subjects were on testosterone treatment at the time of the investigation while 21 were naive and underwent a complete Doppler echocardiographic examination, a cardiopulmonary exercise test as well as a vascular study including measures of carotid intima-media thickness and endothelial function with flow-mediated dilation of the brachial artery. Patients with KS on testosterone therapy (n=48) were also matched against a population of men with treated secondary hypogonadism (n=21). RESULTS Patients with KS exhibited a wide array of cardiovascular abnormalities including left ventricular diastolic dysfunction, reduced maximal oxygen consumption (p<0.01), increased intima-media thickness (p<0.05) (-34% and +42% vs. controls, respectively) and a high prevalence of chronotropic incompetence (55% of patients, p<0.01). No significant difference was found between treated and untreated KS in variance with men treated for secondary hypogonadism. CONCLUSION Left ventricular diastolic dysfunction, impaired cardiopulmonary performance, chronotropic incompetence, and increased intima-media thickness suggest that cardiovascular abnormalities are a common finding in KS that is not reversed by testosterone replacement therapy and may represent the pathophysiological underpinnings of the increased risk of dying from heart disease.

Laparoscopic adrenal surgery: ten-year experience in a single institution

BackgroundMinimal invasive adrenalectomy has become the procedure of choice to treat adrenal tumors with a benign appearance, ≤ 6 cm in diameter and weighing < 100 g. Authors evaluated medium- and long-term outcomes of laparoscopic adrenalectomy (LA), performed for ten years in a single endocrine surgery unit.MethodsWe retrospectively reviewed 88 consecutive patients undergone LA for lesions of adrenal glands from 2003 to 2013. The first 30 operations were considered part of the learning curve. Doxazosin was preoperatively administered in case of pheochromocytoma (PCC), while spironolactone and potassium were employed to treat Conns disease. Perioperative cardiovascular status modifications and surgical and medium- and long-term results were analyzed.ResultsForty nine (55.68%) functioning tumors, and one (1.13%) bilateral adrenal disease were identified. In 2 patients (2.27%) a supposed adrenal metastasis was postoperatively confirmed, while in no patients a diagnosis of incidental primitive malignancy was performed. There was no mortality or major post operative complication. The mean operative time was higher during the learning curve. Conversion and morbidity rates were respectively 1.13% and 5.7%. Intraoperative hypertensive crises (≥180/90 mmHg) were observed in 23.5% (4/17) of PCC patients and were treated pharmacologically with no aftermath. There was no influence of age, size and operative time on the occurrence of PCC intraoperative hypertensive episodes. Surgery determined a normalization of the endocrine profile. One single PCC persistence was observed, while in a Conns patient, just undergone right LA, a left sparing adrenalectomy was performed for a contralateral metachronous aldosteronoma.ConclusionsLA, a safe, effective and well tolerated procedure for the treatment of adrenal neoplasms ≤ 6 cm, is feasible for larger lesions, with a similar low morbidity rate. Operative time has improved along with the increase of the experience and of the technological development. Preoperative adrenergic blockade did not prevent PCC intraoperative hypertensive crises, but facilitated the control of the hemodynamic stability.

Genetics of medullary thyroid cancer: An overview

Medullary thyroid carcinoma (MTC) represents 3-5% of thyroid cancers. 75% is sporadic and 25% is the dominant component of the hereditary multiple endocrine neoplasia (MEN) type 2 syndromes. Three different subtypes of MEN2, such as MEN2A, MEN2B, and Familial MTC (FMTC) have been defined, based on presence or absence of hyperparathyroidism, pheocromocytoma and characteristic clinical features. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC, but there are many other mutational patterns involved. In MEN2A, Codon 634 in exon 11 (Cys634Arg), corresponding to a cysteine in the extracellular cysteine-rich domain, is the most commonly altered codon. Many other mutations include codons 611, 618, 620. In the genetical testing of RET mutations in MTCs, Next-Generation Sequencing (NGS) is taking an increasingly important role. One of the most important benefit is the comprehensive analysis of molecular alterations in MTC, which allows rapidly to select patients with different risk levels. There is a difference in miRNA expression pathway between sporadic and hereditary MTCs. Among sporadic cases, expression of miR-127 was significantly lower in those who harbor somatic RET mutations than those with wild-type RET. CDKN1B mutations are associated with many clinical pictures of cancers, such as MEN4. V109G polymorphism is associated with sporadic MTCs negative for RET mutations, and might influence the clinical course of the patients affected by MTC. Although surgery (i.e. total thyroidectomy with neck lymph node dissection) is the elective treatment for MTCs, about 80% of patients have distant metastases at diagnosis and in this cases surgery is not enough and an additional treatment is needed. Interesting results come from two large phase III clinical trials with two targeted tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib. CONCLUSIONS New genetical testings and therapeutical approaches open new perspectives in MTC management.

Testicular parenchymal abnormalities in Klinefelter syndrome: a question of cancer? Examination of 40 consecutive patients

Klinefelter syndrome (KS) is a hypergonadotropic hypogonadism characterized by a 47, XXY karyotype. The risk of testicular cancer in KS is of interest in relation to theories about testicular cancer etiology generally; nevertheless it seems to be low. We evaluated the need for imaging and serum tumor markers for testicular cancer screening in KS. Participants were 40 consecutive KS patients, enrolled from December 2009 to January 2013. Lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and beta-human chorionic gonadotrophin subunit (β-HCG) serum levels assays and testicular ultrasound (US) with color Doppler, were carried out at study entry, after 6 months and every year for 3 years. Abdominal magnetic resonance (MR) was performed in KS when testicular US showed micro-calcifications, testicular nodules and cysts. Nearly 62% of the KS had regular testicular echotexture, 37.5% showed an irregular echotexture and 17.5% had micro-calcifications and cysts. Eighty seven percent of KS had a regular vascular pattern, 12.5% varicocele, 12.5% nodules <1 cm, but none had nodules >1 cm. MR ruled out the diagnosis of cancer in all KS with testicular micro calcifications, nodules and cysts. No significant variations in LDH, AFP, and β-HCG levels and in US pattern have been detected during follow-up. We compared serum tumor markers and US pattern between KS with and without cryptorchidism and no statistical differences were found. We did not find testicular cancer in KS, and testicular US, tumor markers and MR were, in selected cases, useful tools for correctly discriminating benign from malignant lesions.

Maternal hypothyroidism and subsequent neuropsychological outcome of the progeny: a family portrait

IntroductionNormal neuropsychological development depends uponadequate function of both maternal and foetal thyroid gland[1]. Previous studies suggested that even mild hypothy-roidism can interfere with normal brain development [2, 3].Maternal hypothyroidism is not a rarely diagnosedcondition during pregnancy [4]. The diagnosis and thetreatment of such condition are not troublesome [5–7], butthe possibility to predict what will be going on in thenewborn, once maternal hypothyroidism is discovered,remains difficult. As a result it is not rare that somepregnant women with severe hypothyroidism during ges-tation could consider early termination of pregnancy fear-ing that their infant might have significant mentalretardation [8, 9].We are here reporting the early and long-term neu-ropsychological development of the progeny of a thy-roidectomized woman displaying different degrees ofhypothyroidism in three subsequent pregnancies.Even if limited to three patients, analysis of this familyis of potential clinical relevance in that the three sisters,besides the parents, shared the same social and culturalenvironment, which would prevent the confounder effectsof the environment thus, allowing a more bias-free com-parison of the effects of maternal hypothyroidism on theirneurodevelopment outcome. Furthermore, the comparisonsof the early versus long-term neuropsychological outcome,provides some clinically useful informations.Patients and methodsThe case history of three sisters (F.F., A.F. and C.F.) bornto a thyroidectomized mother under levothyroxine substi-tutive treatment are reported. Briefly, the mother had beenthyroidectomized for Graves’ disease at the age of 12 yearsand was under replacement therapy with levothyroxine(200 mcg/day). The case history of the first pregnancy waspreviously reported [10]. Throughout the three pregnanciesLT4 doses were adjusted up to 300 lg/day. The LT4 doseadjustments were performed at variable timing at eachpregnancy because the patient did not attend regular fol-low-up and displayed a poor compliance to the treatment.In particular, the patient was found to be severely hy-pothyroid at 29 weeks gestation in the first pregnancy (TSHlevel of 79 lU/ml, FT4 6.0 pg/ml). A mild hypothyroidismwas found at 24 weeks gestation in the the second preg-nancy (TSH 15 lU/ml), while euthyroidism resulted at 6weeks gestation in the third pregnancy (TSH 3.5 lU/ml).(1) F.F. The case history of the first daughter waspreviously reported [10]. Briefly, she had been foundto be growth-retarded at her 29 week of intrauterinelife, when the mother was severely hypothyroid

High circulating levels of CCL2 in patients with Klinefelter's syndrome

We would like to thank Dhindsa and colleagues for their interest and comments on our recent review article published in Clinical Endocrinology entitled ‘The Role of Obesity and Type 2 Diabetes Mellitus in the development of Male Obesity-associated Secondary Hypogonadism’. We would also like to thank the Editor for the opportunity to respond. We would like to confirm that we agree with the useful comments raised and provide further comment below. In our published review, we commented that the mechanisms implicated in the pathogenesis of secondary hypogonadism in men and its association with obesity and type 2 diabetes mellitus are multiple, complex and incompletely understood. We also stated that one of the pathogenic mechanisms implicated in the development of male obesity-associated secondary hypogonadism is increased aromatase activity within adipocytes. This results in increased peripheral conversion of testosterone into oestradiol and subsequent negative feedback on secretion of luteinizing hormone secretion from the pituitary. The suppressive effect of such a mechanism on the male hypothalamo–pituitary–gonadal axis results in a reduction in plasma testosterone levels and secondary hypogonadism. Consistent with this hypothesis, it has been reported in the literature that obese men show increased levels of oestrogens and decreased levels of bioavailable androgens within the serum. It has also been noted that use of aromatase inhibitors in men with obesity-related hypogonadism may normalize serum testosterone, again consistent with an important pathogenic role for aromatization in this condition. However, we acknowledge that there is controversy in the literature regarding the role of aromatization in the pathogenesis of male obesity-associated secondary hypogonadism. There is some inconsistency in the literature regarding relationships between serum levels of testosterone and oestradiol and the severity of obesity in this condition. We acknowledge that in some studies on obese men, serum levels of free oestradiol directly correlate with free testosterone. One explanation for this direct correlation is that with increasing obesity in men, as serum levels of testosterone fall (following suppression of the male gonadal axis), serum oestradiol levels would also be expected to fall eventually due to lack of substrate (testosterone) for the aromatase enzyme. This hypothesis has been supported by the European Male Ageing Study. We feel that it is important to emphasize that there are many potential mechanisms that underlie the complex pathogenesis of male obesity-associated secondary hypogonadism other than enhanced aromatase activity, as outlined in our published review article. These include the increasingly important roles of leptin, inflammatory mediators (TNF-a, IL-1b, CRP), the role of sleep disruption and the serotoninergic system and endogenous kisspeptin. We also outline the effects of insulin resistance at various levels including lipases, suppression of hepatic SHBG synthesis and the suppression of the hypothalamo–pituitary unit as potentially important pathogenic mechanisms. There may also be other, as yet unknown mechanisms at play. Clearly, there is a need for further focused studies in this field to develop a clear understanding of pathogenesis and to inform future novel treatment strategies.

Increased platelet reactivity in Klinefelter men: something new to consider.

Patients with Klinefelter syndrome (KS) exhibit an increased cardiovascular risk, but underlying mechanisms are largely unknown. The present cross‐sectional study has been conducted to evaluate platelet reactivity and the expression of platelet activation markers (8‐iso‐prostaglandin F2α[8‐iso‐PGF2α] and 11‐dehydro‐thromboxane‐B₂[11‐dehydro‐TXB2]) in KS patients and healthy controls. Twenty‐three consecutive KS patients under testosterone replacement therapy have been included as case group and 46 age‐matched healthy males recruited among hospital staff served as controls. Light transmission aggregometry was performed in both cases and controls and maximal platelet aggregation (max‐A%) was defined as maximal light transmittance reached within 5 min after the addition of 0.2 or 0.4 mm arachidonic acid (AA). A ≥ 50% irreversible light transmittance (LT‐50%) following platelet stimulation defined an adequate platelet aggregation and AC‐50% was defined as the minimal agonist concentration needed to achieve LT‐50%. The AC‐50% was 0.26 mm AA for KS and 0.36 mm for controls (p < 0.001). Whereas AA (0.2 mm) induced LT‐50% in 69.6% of KS and in 15.2% of controls (p < 0.001), the stimulation with AA (0.4 mm) determined LT‐50% in all cases and controls. However, max‐A% was higher in KS than in controls both after AA (0.2 mm) (65.61% vs. 46.30%, p = 0.002,) and after AA (0.4 mm) (96.43% vs. 81.04%, p < 0.001). 8‐iso‐PGF2α and 11‐dehydro‐TXB2 were higher in KS than in controls (446.54 pg/mg creatinine vs. 230.00 pg/mg creatinine, p < 0.001 and 1278.36 pg/mg creatinine vs. 595.08 pg/mg creatinine, p = 0.001, respectively) and AC‐50% inversely correlated with 8‐iso‐PGF2α (ρ = −0.548, p < 0.001) and with 11‐dehydro‐TXB2 (ρ = −0.523, p < 0.001). In a linear regression model, KS independently predicted a lower AC‐50% (β = −0.597, p < 0.001) and higher levels of 8‐iso‐PGF2α (β = 0.709, p < 0.001) and 11‐dehydro‐TXB2 (β = 0.605, p < 0.001). In contrast, no correlation has been found between max‐A%, testosterone and estradiol levels in KS. We observed increased platelet reactivity in KS. This might, at least in part, explain the increased thrombotic risk associated with this disease.

Suprarenal solitary fibrous tumor associated with a NF1 gene mutation mimicking a kidney neoplasm: implications for surgical management.

Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm, usually occurring in the pleura. Pararenal SFT, mimicking an adrenal gland or renal tumor, as here described, is extremely rare. We report a case of a right suprarenal SFT, incidentally discovered by abdominal ultrasound in a 54-year-old woman carrying a point neurofibromatosis 1 (NF1) gene mutation. Preoperative diagnostic work-up was ineffective in evaluating its origin, and an open radical right nephrectomy was therefore undertaken. Immunohistochemical assay showed a positivity for CD34, CD99 and Bcl-2, so suggesting a diagnosis of SFT. According to our knowledge, the association between this type of tumor and NF1 gene mutation has never been described. In cases of pararenal tumors, a more detailed preoperative diagnosis could be useful to better plan the extension of resection, allowing, in selected cases, nephron-sparing surgery. More studies are needed to better analyze the relationship between NF1 gene mutation and SFT.

Sexual function and sex hormones in breast cancer patients

PurposeBreast cancer patients (BCP) are at risk of female sexual dysfunction (FSD). Our aim was to clarify the effects of treatment strategies, and steroid hormones levels on FSD.MethodsWe enrolled 136 BCP (46.9 ± 0.8 years), and 122 completed questionnaires. BCP were divided into four groups: 22 women with advanced breast cancer on neoadjuvant therapy (NAT), 48 on adjuvant therapy (AT), 30 taking hormonal therapy (HT) and 22 with metastatic cancer on first line chemotherapy (FLT). Fifty-eight healthy women (43 ± 2.8 years) were enrolled as controls. FSD was evaluated by FSFI, and sexual distress was assessed with FSDS-R. We have collected demographic data, laboratory values, and LH, FSH, total testosterone (T), and estradiol (E2) levels.ResultsBCP showed a prevalence of FSD of 69%, total FSFI score was 17. FSDS-R was 8.3. FSD had a prevalence of 72 % in NAT, 65% in AT, 77% in metastatic BCP under FLT, 67% in HT, compared with a prevalence of 20% in controls. BCP showed lower E2 than normal values, as well as T. LH and FSH were significantly elevated than normal values. Total FSFI score was positively correlated with T in 122 BCP, no significant correlation was found between E2 and FSFI. Significant differences were found between NAT and HT in lubrication, pain domains and total FSDS-R score, AT and HT in pain domain, AT and NAT in lubrication domain.ConclusionsBCP are at high risk of developing FSD both for treatment choice and hormonal status, but they have not sexually related personal distress.

Insulinoma: il valore diagnostico della PET-TC 64Cu-Dotanoc

Una donna di 41 anni si presentava in Pronto Soccorso per tachicardia, astenia, tremore, sudorazione, nausea e intenso malessere generale. Gli esami ematochimici rilevavano livelli di glicemia di 26 mg/dl, mentre gli altri esami risultavano nei limiti della norma. All’esame obiettivo la paziente presentava stato confusionale, con letargia e disforia. Tale sintomatologia regrediva con la somministrazione di una soluzione glucosata al 33%. Successivamente, per inquadramento diagnostico di questo severo episodio di ipoglicemia e per sospetto di insulinoma, veniva eseguito un esame ecoendoscopico che evidenziava una piccola area di circa 6 mm lievemente ipoecogena in sede istmica pancreatica. Praticava, altresì, una TC addome con mezzo di contrasto, che confermava il reperto eco-endoscopico; in particolare, l’area nodulare, in sede istmica sopra descritta, era caratterizzata da netta iperperfusione arteriosa, orientando verso una lesione neuroendocrina. La paziente veniva inviata ad intervento chirurgico, nel corso del quale, tuttavia, non fu possibile isolare la lesione nodulare istmica descritta agli esami strumentali. Pertanto, in corso di esplorazione laparotomica, si effettuava una biopsia incisionale della regione dell’istmo pancreatico. L’esame istologico risultava negativo per neoplasia. La sintomatologia, tuttavia, persisteva, con ricorrenti episodi di ipoglicemia severa per cui la paziente veniva sottoposta ad una RM dell’addome completo con m.d.c., con riscontro di lesione pseudo-nodulare di sfumato iper-enhancement