THE INVOLVEMENT OF VDR PROMOTER METHYLATION, CDX-2 VDR POLYMORPHISM AND VITAMIN D LEVELS IN MALE INFERTILITY.

INTRODUCTION: Vitamin D (VD) levels were correlated with different health conditions, including reproductive disorders in males. Vitamin D action is mediated through vitamin D receptor (VDR), which acts as a transcription factor. VDR gene promoter is embedded in a GC-rich island. The VDR gene has been shown to have several polymorphisms that affect the receptor function. AIM: To examine the relationship between Cdx-2 polymorphism (rs17883968), the methylation status of VDR's promoter and serum levels of 25-hydroxyvitamin D in male infertility. PATIENTS AND METHODS: A total of 69 infertile men and 37 age-matched controls were enrolled in this study. Vitamin D level assessments were detected using the electrochemiluminescent method. Cdx-2 VDR polymorphism identification was performed by PCR on DNA samples from blood, followed by restriction. Methylation of VDR gene promoter was assessed by qMS-PCR using bisulfite-treated DNA from fresh sperm. RESULTS: Vitamin D levels was found to be significantly decreased in infertile groups compared the controls (p=0.0279). The GG genotype was found in a higher percentage in controls and the AA genotype was higher in infertile group (p=0.0056). Infertile homozygote (GG) and heterozygote (GA) individuals had significantly higher vitamin D levels than AA homozygote. Methylation is higher in individuals with lower vitamin D levels and AA genotype is characterized by higher methylation values. CONCLUSION: The results provide new insights of Cdx-2 polymorphism is involved in vitamin D deficiency, highlighting the important role of epigenetic modification of vitamin D receptor and male infertility along with the genetic context.

Cushing's disease: a multidisciplinary overview of the clinical features, diagnosis, and treatment.

Cushing's disease is considered a rare condition characterized by the hypersecretion of the adrenocorticotropic hormone (ACTH) due to a pituitary adenoma that ultimately causes endogenous hypercortisolism by stimulating the adrenal glands. The clinical signs suggesting Cushing's disease, such as obesity, moon face, hirsutism, and facial plethora are already present on presentation. Endogenous hypercortisolism is associated with an increased risk of cardiovascular and metabolic manifestations, as well as respiratory disorders, psychiatric complications, osteoporosis and infections, leading to high rates of morbidity and mortality. It is vital to diagnose Cushing's disease as early as possible and to implement a treatment plan to lead to a successful prognosis and a low number of complications. The goal of this article was to review the clinical, diagnostic and treatment aspects of Cushing's disease using the most recent available guidelines.

A rare case of metastasized non-functional pancreatic neuroendocrine tumor with a good long-term survival.

Background: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are a varied group of extremely rare malignancies. The majority of patients already have liver metastases at the diagnosis moment, thus, treatment options are restricted, and the survival rate is reserved. Case report: We presented the case of 59-year-old patient, diagnosed with non-functional well-differentiated pancreatic neuroendocrine tumor grade II (NET G2) with the presence of chromogranin A, synaptophysin and somatostatin receptor 2, together with liver and bone metastases. Patient underwent a surgical excision of the pancreatic tumor, started long-acting somatostatin analogues (octreotide), interferon therapy for liver metastases and local radiotherapy for bone metastases. After one year, the patient developed diabetes, needing insulin therapy. At approximately three years after the diagnosis, the patient was still living, had a good quality of life, and was free of local recurrence of the tumor or other metastases. Conclusion: Our case report presented a rare case of metastatic non-functional well-differentiated pancreatic neuroendocrine tumor, involving a multidisciplinary therapeutic approach in order to obtain a good long-term survival.

CORRELATIONS BETWEEN POLYMORPHISMS OF ESTROGEN 1, VITAMIN D RECEPTORS AND HORMONAL PROFILE IN INFERTILE MEN.

OBJECTIVE: Estrogen receptor alpha (ESR1) polymorphisms (XbaI and PvuII) and vitamin D receptor (VDR) polymorphisms (FokI, BsmI, ApaI and TaqI) are the most frequently studied regarding the correlations with the infertility in males, but the results are controversial.The purpose of this study is to evaluate possible correlations between hormonal markers, VDR and ESR1 genotypes and semen analysis, in order to bring new data for a better understanding of male infertility. SUBJECTS AND METHODS: 42 infertile men and 28 controls were enrolled. The polymorphisms of VDR gene (ApaI, TaqI, BsmI and FokI) and ESR1 (XbaI and PvuII) were performed by PCR-RFLP, along with hormonal markers. RESULTS: An important correlation between PvuII polymorphism and infertility status was revealed. A significant difference between control and infertility group regarding the presence of BsmI (A>G) and ApaI (G>T) polymorphisms was observed in infertile group, prolactin and DHEA were found to correlate significantly statistic with BsmI GG genotype, whereas ApaI AA genotype correlates with prolactin and SHBG levels. CONCLUSIONS: By a multivariate analysis, we demonstrated a cumulative effect of some genetic variants in the hormonal status of infertile patients. Therefore, we show that specific genetic variants of ESR1 and VDR genes may jointly influence human spermatogenesis.

COST ACTION BM 1105 "GNRH DEFICIENCY: ELUCIDATION OF THE NEUROENDOCRINE CONTROL OF HUMAN REPRODUCTION".

COST (European Cooperation in Science and Technology) is an intergovernmental organization established to fund research networks known as "COST Actions" across the sciences. COST enables break-through scientific developments leading to new concepts and products and thereby contributes to strengthen Europe's research and innovation capacities. The Action BM1105 investigated the neuroendocrine mechanisms that are integrated at the hypothalamic level and regulate the complex organ network controlling reproduction. Through the development of a networking platform, the Action advanced the field of neuroendocrinology via: guidelines for the best clinical care of GnRH deficient patients, translating scientific understanding into improved patient care and creating a lasting European tradition of excellence in the field of reproductive medicine.

Phenotypic spectrum and hormonal profile in hypogonadotropic hypogonadism.

BACKGROUND: Hypogonadotropic hypogonadism (HH) is characterized by inappropriately low serum concentration of LH (luteinizing hormone) and FSH (follicle-stimulated hormone) in the setting of hypogonadism. A number of pathologic processes cause Hypogonadotropic hypogonadism but it can also occur as a part of various congenital syndromes. Objectives. To characterize the morphotypes and the hormonal profile of the HH patients enrolled in the COST Action BM1105 within "C.I. Parhon" National Institute of Endocrinology from May 2012 onward. Methods. The eligible patients were selected by using a general protocol that included: a detailed familial and personal history; a clinical evaluation focusing on genital development; a hormonal evaluation that aimed to exclude the acquired causes of HH and to characterize the basal/stimulated (triptoreline) profile of gonadotropins; a DNA extraction for genetic studies. RESULTS: We examinated the medical records of patients admitted in our institute with the diagnosis of hypogonadotropic hypogonadism from May 2012 onward. There were 19 patients: 12 males and 7 females, age at diagnosis 28.03 ± 11.45 years (13.4-56 years). The phenotypic expressions were variable and the hormonal evaluation showed low values of basal and stimulated gonadotropins. CONCLUSIONS: Although hypogonadotropic hypogonadism is a rare disease, the monospeciality profile of National Institute of Endocrinology enable the enrolment of a high number of patients in order to create clinical guidelines for evaluation/diagnosis and for treating GnRH deficient patients.

Serotonin and the bone assessment.

INTRODUCTION: Lately, the in vitro and in vivo studies on serotonin metabolism have been pointing its influence in bone health. Also, there are no particular recommendations in performing the serum serotonin assessment in order to evaluate the skeletal status. AIM: We aimed to correlate the bone turnover markers and lumbar bone mineral density (BMD) with serotonin. MATERIAL AND METHODS: There is a cross-sectional study in Caucasian postmenopausal women. They were not diagnosed with carcinoid syndrome, or bone anomalies, and received no treatment (including antiresorptives). The following bone formation markers were performed: serum alkaline phosphatase (AP), serum osteocalcin (OC), and the bone resorption marker: serum CrossLaps (CL). Serum serotonin (high-pressure liquid chromatography), as well as central DXA (GE Prodigy) were assessed. RESULTS: 191 women of 57.1 years mean age were grouped according to DXA (WHO criteria). The linear regression analysis between serum serotonin and CL were not statistically significant (SS), between serotonin and OC was SS in the newly diagnosed osteoporosis group (N=40, r=0.4, p=0.03), between serotonin and AP SS was found in osteopenia group (N=88, r=0.24, p=0.03), with no changes when adjusting for age and BMI. The partial correlation between serotonin and BMD was not SS. DISCUSSION: The study raises the question of serotonin as a bone metabolism marker seeing that the results were not consistent. The main limit of our study was that we did not analyze the possible use of antidepressants to these women. Overall, this was a pilot study in clinical practice where few reports have been published, but still necessary, because the use of serum serotonin in current skeletal evaluation is still unclear.

Multiple endocrine neoplasia type 2A: case report.

Multiple endocrine neoplasia type 2A (MEN 2A) is a complex autosomal dominant inherited syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary parathyroid hyperplasia. In patients with only one or two clinical features, identification of a germline RET(REarranged in Transfection) mutation or the identification of the clinical features of MEN 2A in other first degree relatives is required to make the diagnosis. We present the case of a family with MEN 2A syndrome confirmed by genetic analysis which identified RET gene mutation in 634 codon in father - DV - aged 48 years and also in daughter DM -aged 20 years. The specific feature in this case is that the index case was the daughter (diagnosed and operated for pheochromocytoma at the age of 19 years), the father being diagnosed later with medullary thyroid carcinoma by mutational screening in all family members. This family supports the phenomenon of anticipation, in which severity increases and the age of onset decreases in successive generations, the syndrome being discovered earlier and with a worse prognostic in the daughter.

The serotonin and the bone assessment.

INTRODUCTION: Lately, the in vitro and in vivo studies on serotonin metabolism pointed their influence in bone health. In addition, there are no particular recommendations in performing the serum serotonin assessment in order to evaluate the skeletal status. Aim. We aimed to correlate the bone turnover markers and lumbar bone mineral density (BMD) with serotonin. MATERIAL AND METHODS: There is a cross-sectional study in Caucasian postmenopausal women. They were not diagnosed with carcinoid syndrome, or bone anomalies, and received no treatment (including antiresorptives). We performed the bone formation markers: serum alkaline phosphatase (AP), serum osteocalcin (OC), and the bone resorption marker: serum CrossLaps (CL). Serum serotonin (high-pressure liquid chromatography), as well as central DXA (GE Prodigy) were assessed. RESULTS: 191 women of 57.1 years mean age were grouped according to DXA (WHO criteria). The linear regression analysis between serum serotonin and CL was not statistically significant (SS), between serotonin and OC was SS in the newly diagnosed osteoporosis group (N=40, r=0.4, p=0.03), between serotonin and AP we found SS in osteopenia group (N=88, r=0.24, p=0.03), with no changes when adjusting for age and BMI. The partial correlation between serotonin and BMD was not SS. DISCUSSION: The study raises the question of serotonin as a bone metabolism marker seeing that the results were not consistent. The main limit of our study is that we did not analyze the possible use of antidepressants by these women. Overall, this is a pilot study in clinical practice in which few reports have been published yet, but still necessary because the use of serum serotonin in current skeletal evaluation is still unclear.

Evolution features of hypertensive patients with primary aldosteronism--prospective study.

BACKGROUND: Primary aldosteronism is the leading cause of secondary hypertension, the management of this disease requiring an interdisciplinary approach. OBJECTIVES: Evaluation of evolutionary features of patients with secondary hypertension and primary aldosteronism. METHODOLOGY: We have followed 26 patients diagnosed with secondary hypertension and primary aldosteronism, who were admitted consecutively to "C. I. Parhon" Endocrinology Institute between 2004-2009. Of the 26 patients, 17 had adenoma producer of aldosterone (APA), 8 had bilateral adrenal hyperplasia idiopathic (HIA) and one patient had adrenal carcinoma (with hypersecretion of aldosterone). The mean age of the cohort was of 49.3 years (44.9 years for adenomas and 52.6 years for bilateral hyperplasia). The evaluation of the patients included clinical examination, electrocardiogram, Holter BP, echocardiography and determination of plasma aldosterone and renin. RESULTS: The evolution of the patients with primary aldosteronism was different depending on the anatomoclinic type. In patients with idiopathic bilateral hyperplasia, medical treatment has improved control of hypertension and cardiac and cerebrovascular complications rate was moderate. In patients with unilateral adenoma producing aldosterone, blood pressure had higher values and more frequent complications, but surgical cure of adenomas significantly changed the prognosis of patients. In both cases, the presence of hypokalemia was an additional element of severity. CONCLUSIONS: Regardless of the primary aldosteronism, hypertension was directly involved in cardiac and cerebrovascular complications. Individualization of treatment according to the anatomoclinic type determined a significant improvement of the patients' prognosis.

Adrenalectomy by laparoscopic anterolateral transperitoneal approach for patients with previous abdominal surgery.

Adrenal surgery has been radically changed by laparoscopic approach and we wonder whether the increase in the number of adrenalectomies is entirely justified by better understanding of the pathology and a developed diagnosis methods. The type of approach (transabdominal/retroperitoneal) remains a matter of the surgeon's experience. Method: In the past 8 years, we have performed more than 200 laparoscopic adrenalectomies by transperitoneal approach, 24 of them having previously significant abdominal surgery (cholecistectomy, gastric surgery, colectomy, bowel obstruction, exploratory laparoscopy, and adrenalectomy). The patients had a variety of adrenal pathologies such as Cushing disease, Cushing syndrome, Conn syndrome, incidentaloma, pheochromocytoma and even carcinoma. Results: 3 cases were converted to open approach, only one because of the adhesions. Reasons for conversion were also: spleen intarctisation and a difficulty in mobilizing the tumor. Operating time was not significantly prolonged because of the adhesions (40-360 min, median time 127 min). Postoperative evolution was simple with no morbidity or mortality and a fast recovery was recorded. Conclusions: Choosing the type of approach is related to surgeon experience, although 79-94% of the surgeons prefer the transabdominal lateral approach. We believe that with an experienced surgical team, there is no difficulty in performing adrenalectomy by transabdominal approach, with no significantly prolonged operating time, even though the patient has previously had abdominal surgery.

[The etiopathogenetic hypotheses in polycystic ovary]. / Ipoteze etiopatogenice în ovarul polichistic.

First described in 1935, polycystic ovary syndrome (PCOS) is a frequent endocrine disease (6% in female population). However its pathogenicity is not yet completely understood. The possible etio-pathogenic mechanisms include: neuroendocrine disorders (hypothalamic, as a result of congenital androgenism or of disorders of neurotransmitters or pituitary, with excess of LH), ovarian disorders (enhanced sensibility at LH, local growth factors, hyperactivity of Cit P450cl7 alpha enzymes), adrenal disorders, insulin resistance, genetic determinism, puberty onset. The authors discuss in detail this hypothesis and these possible importance.