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Background and aims: Type 1 diabetes mellitus (T1DM) represents a secondary cause of osteoporosis. Our aim was to determine bone mineral density (BMD) changes in a group of young Romanian adults with T1DM and to analyze the factors related to this disease that could have had an impact on bone mass. Material and Methods: Fifty-two young patients with T1DM were compared to 37 healthy volunteers matched for body mass index (BMI). All subjects had their BMD measured at the hip and lumbar spine. Results: We found no statistically significant differences in BMD between T1DM patients and controls (p=0.618 for lumbar spine, p=0.974 for femoral neck and p=0.883 for total hip). Multiple linear regression models detected BMI (p =0.043), smoking (p=0.001) and milk intake (p=0.004 for lumbar spine) as significant BMD determinants. In contrast, no associations were found between BMD and metabolic control, daily insulin dose or presence of diabetic retinopathy and/or neuropathy. Long diabetes duration was negatively associated with BMD in femoral neck (p=0.012). Conclusions: Although we couldn’t find differences between BMD in T1DM patients and controls, the link between diabetes duration and BMD that we found suggests that even young patients with long standing T1DM should have their BMD measured

Introduction. Adiponectin, resistin and osteoprotegerin (OPG) are cytokines expressed in the adipose tissue. Pregnancy is associated with gradually increased maternal levels of these molecules, also detected in significant amounts in umbilical cord blood serum samples. Aim, patients and methods. To establish the relationships of maternal and umbilical adiponectin, resistin and OPG levels to both maternal and fetal anthropometric measurements and insulin sensitivity, 28 mother-newborn pairs were enrolled in the study. Blood samples were collected in a fasting state, after delivery, and serum insulin, C-peptide, sex hormone-binding globulin, adipocytokines, OPG and bone specific alkaline phosphatase (BAP) were measured. Results. Compared to maternal values, umbilical serum adiponectin levels were about 3-fold higher; additionally, significantly higher resistin and lower OPG levels were observed. Stratification of umbilical and maternal adiponectin levels according to tertiles of birth body weight demonstrated significantly lower maternal adiponectin levels by tertiles of neonatal body weight. No relationships were noticed between infant birth weight and maternal or umbilical serum resistin and OPG, respectively. Umbilical resistin was significantly associated to both maternal resistin and umbilical adiponectin. Multiple regression analysis showed that maternal BMI, umbilical insulin, C-peptide and resistin explained 71.83% of umbilical serum adiponectin variability. Umbilical resistin was independently predicted by umbilical adiponectin, umbilical C-peptide and maternal BMI, and the model explained 81.49% of umbilical resistin levels. Conclusions. In human, umbilical serum adiponectin and resistin levels are significantly higher compared to adults. These adipokines may mediate the effects of maternal body mass on fetal development. The biology of the OPG/RANKL cytokine system in fetuses and newborns needs further research.

ObjectiveThere is plenty of evidence that osteoprotegerin (OPG) is linked to subclinical vascular damage and predicts cardiovascular disease in high-risk populations. Our aim is to investigate the relationships of OPG/free soluble receptor activator of nuclear factor κB ligand (sRANKL) to insulin resistance, brachial artery flow-mediated vasodilation (FMD), and the carotid artery intima-media thickness (CIMT) in polycystic ovary syndrome (PCOS), a disorder characterized by hyperandrogenism, impaired glucose control, and endothelial injury.DesignA cross-sectional, observational study.MethodsHormonal and metabolic profiles, FMD, CIMT, serum OPG, and ampli-sRANKL were assessed in 64 young PCOS patients and 20 controls of similar age. Body composition was measured by dual energy X-ray absorptiometry.ResultsOPG was significantly lower in PCOS and related negatively to free testosterone and positively to estradiol (E2) levels. In multivariate analysis, OPG but not ampli-sRANKL correlated positively to fasting insulin, insulin sensitivity indices, and FMD. Neither OPG nor ampli-sRANKL was associated with CIMT. Significantly lower adjusted FMD values were demonstrated in women in the upper OPG quartile group (>2.65 pmol/l) compared with all other quartile groups together (P=0.012). In PCOS, multiple regression analysis retained E2/sex hormone-binding globulin ratio, fat mass, and homeostasis model assessment of insulin resistance as independent predictors of OPG.ConclusionsIn PCOS, circulating OPG is related to both endothelial dysfunction and insulin resistance, independent of obesity and androgen excess, suggesting OPG as a useful biomarker of these effects. Further studies are needed to evaluate OPG in relation to cardiovascular events and cardiovascular mortality in PCOS.

The study investigated the presence of early vascular damage and chronic inflammation, and their relationships with hormonal and metabolic parameters in 45 young women with PCOS in comparison with thirty-two healthy age-matched controls. Hormonal and metabolic profiles, high sensitivity C-reactive protein (hsCRP), tumoral necrosis factor-alpha (TNF-α), endothelin-1 (ET-1), brachial flow-mediated vasodilation (FMD) and carotid intima-media thickness (CIMT) were determined in both groups. Compared with the controls, women with PCOS had significantly lower FMD and respectively higher ET-1 levels (p=0.001). No differences were observed between the groups in terms of CIMT or inflammatory markers. In the PCOS group, ET-1 levels were significantly correlated with only testosterone concentrations (r = 0.31, p = 0.037), whereas the hsCRP levels were independently predicted only by body mass index (BMI). Within the total group, the PCOS status was the sole significant predictor of ET-1 levels and the only independent predictor of FMD. In conclusion, there is evidence of endothelial dysfunction associated with increased levels of androgen hormones in young women with PCOS. The combination of endothelial dysfunction and coexistent obesity promoting inflammation contributes to the progression of atherogenesis in PCOS. The PCOS status should be regarded as a predictor marker of cardiovascular risk, along with well-known cardiovascular risk factors.

Hemorrhagic or ischemic pituitary apoplexy is a rare neuro-endocrine emergency, potentially leading to coma. Neuro-ophthalmic symptoms or complications are amongst the most prevalent clinical features at onset, especially in previously asymptomatic patients. Usually, permanent pituitary insufficiency of various degrees follows, implying long-term hormone substitutive therapy. Rarely, the association of pituitary apoplexy with diabetes insipidus has been noticed. We report the case of a young, apparently healthy 32-yearold man presenting with thunderclap headache, fever, optic chiasm compression, central diabetes insipidus and central thyro-gonadic insufficiency. Magnetic resonance imaging and neurosurgery revealed a clinically non-functioning macro-adenoma developing pituitary hemorrhage. One year after the apoplectic episode, complete recovery of diabetes insipidus and pituitary function was confirmed.

We report a case of euthyroid Graves ophthalmopathy associated with isolated ocular myasthenia gravis appearing in a patient with longstanding vitiligo, compatible with an autoimmune polyglandular syndrome-3C phenotype. The coexistence of these two entities, in the absence of either overt thyroid dysfunction or generalized features of myasthenia gravis may cause diagnostic confusion.

Primary pituitary abscess is a rare pituitary pathology, particularly at a young age and is characterized by atypical clinical features making the diagnosis difficult. Correct diagnosis and therapy are mandatory due to the potentially lethal outcome of pituitary infection. We report the case of an adolescent girl presenting with headache, diabetes insipidus and central thyro-gonadic insufficiency with no history of infection, in whom the intra-operative diagnosis of primary pituitary abscess was made. Bacterial cultures indicated infection with Streptococcus spp. One year after neurosurgery and antibiotic therapy, recovery of diabetes insipidus and pituitary insufficiency was documented except for persistence of subnormal growth hormone secretion. Post-surgery, pituitary magnetic resonance imaging revealed an empty sella syndrome.

Polycystic ovary syndrome (PCOS) is possibly the most common endocrinopathy of reproductive age, characterized by hyperandrogenism and oligomenorrhea. Additionally, approximately one-third to one-half of all women and adolescent girls with PCOS tend to fulfill many of the metabolic syndrome criteria, and many view PCOS as a premetabolic syndrome condition, predisposing to a high risk for cardiovascular disease. Endothelial dysfunction, impaired arterial structure, or proinflammatory markers are early features of atherosclerosis, and can be used as surrogate indicators of future coronary artery disease in women with PCOS. However, as the latest studies show, these symptoms are the result of deleterious effects that cardiovascular risk factors, in particular insulin resistance and obesity, produce on the vascular wall, rather than to the presence of PCOS per se. The relationship between hyperandrogenemia and the risk of cardiovascular disease is controversial and needs to be clarified. Further research is warranted to understand the pathogenesis of cardiovascular disease in PCOS, and to identify subtypes of PCOS in which the presence of cardiovascular risk factors may result in increased cardiovascular events, leading to high morbidity or mortality rates caused by cardiovascular disease.

Epicardial white adipose tissue (eWAT) is in close contact with coronary vessels and therefore could alter coronary homeostasis. Adrenomedullin (AM) is a potent vasodilatator and antioxidative peptide which has been shown to play a cytoprotective role in experimental models of acute myocardial infarction. We studied, using immunohistochemistry and qRT-PCR, the expression of AM and its receptors calcitonin receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP)2 and -3 in paired biopsies of subcutaneous WAT (sWAT) and eWAT obtained from patients with coronary artery disease (CAD) or without CAD (NCAD). In eWAT obtained from NCAD or CAD patients, immunoreactivity for AM, CRLR, and RAMP2 and -3 was detected in blood vessel walls and isolated stromal cells close to adipocytes. Some of the AM positive stromal cells colocalized CD68 immunoreactivity. eWAT from CAD patients showed increased AM immunoreactivity and AM gene expression. CRLR mRNA levels were comparable in sWAT of both groups and decreased by 40–50% in eWAT, irrespectively of the coronary status. RAMP2 mRNA concentrations did not change while RAMP3 mRNA levels increased in sWAT from CAD patients. There was a positive linear relationship between eWAT 11β-hydroxysteroid dehydrogenase type 1 mRNA (11β-HSD-1, the enzyme that converts inactive to active glucocorticoids) and AM mRNA. In conclusion, we demonstrate that AM and its receptors are expressed in eWAT. Our data suggest that eWAT AM, which could originate from macrophages, is related to 11β-HSD-1 expression. AM synthesis, which is increased in eWAT during chronic CAD in humans, can play a cardioprotective role.

Introduction. Vitamin D deficiency has been proven to have a deleterious effect on bone remodeling and bone mineral density, by inducing secondary hyperparathyroidism. The lack of a present consensus on optimal serum 25(OH)D levels required for the preservation of physiologic bone metabolism renders its follow-up difficult. Materials and Methods. The cross-sectional study was performed on a sample of 69 healthy men aged 50-70. Serum 25(OH)D, total testosterone, sex hormone binding globulin, s-CTX (Crosslaps), and osteocalcin were assessed. BMD was measured by DXA at lumbar spine and hip levels. Statistical relationships between these parameters were calculated. Results. We found a significantly negative correlation between 25(OH)D and s-CTX (r = -0.30. p

Thyroid hormones are involved in the regulation of basal metabolic state and in oxidative metabolism [1]. They can cause many changes in the number and activity of mitochondrial respiratory chain components. This may result in the increased generation of reactive oxygen species (ROS) [2,3]. Oxidative stress is a general term used to describe a state of damage caused by ROS [4]. ROS have a high reactivity potential, therefore they are toxic and can lead to oxidative damage in cellular macromolecules such as proteins, lipids and DNA [5].

Background We are hereby investigating for the first time the effect of the association ethinylestradiol30μg-drospirenone 3mg (DRP/EE30μg) plus metformin and weight loss on endothelial status and C-reactive protein (hsCRP) levels in polycystic ovary syndrome (PCOS). Methods 25 young women with PCOS (mean age 22.76 ± 0.83 years, body mass index (BMI): 28.44 ± 6.23) who completed the study were prospectively evaluated. The oral contraceptive- DRP/EE30μg (21 days/month) and metformin (1700 mg daily) were administered for 6 months to the PCOS group. Additionally, the 15 overweight and obese patients (BMI > 25 kg/m2) were instructed in a diet of no more than 1500 cal daily. Primary outcome measures were surrogate markers of cardiovascular disease and included endothelial function, i.e. flow-mediated dilatation (FMD) on the brachial artery and endothelin-1 levels, as well as hsCRP concentrations, body composition (measured by whole-body dual-energy X-ray-absorptiometry) and insulin resistance. Variables were assessed at baseline, as well as after our medical intervention. Results The combination between DRP/EE30μg plus metformin combined with weight loss triggered a significant improvement in the FMD values (FMD-PCOSbasal 3.48 ± 1.00 vs FMD-PCOS6 months7.43 ± 1.04, p = 0.033), as well as body composition and insulin insensitivity (p 6months – PCOSbasal) difference. Conclusion A 6-month course of metformin- DRP/EE30μg (associated with weight loss) improves the endothelial dysfunction in PCOS and shows neutral effects on hsCRP concentrations as an inflammation marker. These data demand for reevaluation of the medical therapy in PCOS, particularly in women with additional metabolic and cardiovascular risk factors (ClinicalTrials.gov Identifier: NCT01459445).

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age with a prevalence estimated at 4–8% (Azziz et al., 2004; Moran & Teede, 2009). It is associated with a range of reproductive, obstetric, metabolic and psychological features. Reproductive and obstetric manifestations include hyperandrogenism, menstrual dysfunction, infertility and pregnancy complications, such as early pregnancy loss, gestational diabetes, pregnancy-induced hypertensive disorders and neonatal complications (Boomsma et al., 2006). Additionally, women with PCOS cluster risk factors for cardiovascular disease (CVD) and type 2 diabetes mellitus (DM) as well as the metabolic syndrome (MS). As a consequence, metabolic complications and potential major long-term sequelaes include: an elevated risk of impaired glucose tolerance (IGT), type 2 DM (Legro, 1999, as cited in Moran & Teede, 2009), as well as an increased rate of hypertension and CVD (Shaw et al., 2008). Although there are still aspects to be cleared regarding the longterm consequences of these well-known cardiovascular (CV) risk factors, the research that has been conducted so far seems to indicate that patients with PCOS are at increased risk for adverse CV morbidity and mortality. Of utmost importance is the fact that these women are likely to develop CV disease early, and that even very young and nonobese patients may be affected (Moran & Teede, 2009; Lorenz & Wild, 2007).

The link between bone mass and body composition is widely recognized, but the mechanism remains unclear. Most studies enrolled subjects irrespective of their body weight and only few works were selectively performed on healthy subjects with body mass index (BMI) within normal limits.We aimed to determine the relevance of body composition parameters to bone mass in healthy, young and non-obese Romanian volunteers (n=42) and in postmenopausal women (n=20) and to establish the effects of menopausal transition. Both bone mineral density (BMD) and body composition were assessed using whole-body dual X-ray absorptiometry (DXA).Despite normal mean BMI, large variability of the whole-body fat mass (FM) content was noted, ranging between 18.6-49.7% in women and 22-40.3% in men. Fat mass was not related to bone density; in contrast, BMD at all sites was positively associated to fat-free mass (FFM) in young non-obese women (r=0.34-0.53). In women, the trunk fat mass/leg fat mass ratio was significantly predicted by age (p=0.001), explaining about 20% of the pattern variability. Menopausal status appeared not to significantly influence whole-body fat or FM distribution. A tendency towards a higher trunk FM/legs FM ratio was observed after menopause, but lost after age-adjustment.In non-obese subjects, even of young age, the FM content and distribution is highly variable. FFM mass appears to be the main composition contributor to bone mass, at least in young, healthy, non-obese women. Menopause is not associated to major changes of whole-body fat and trunk adipose tissue, although a significant decrease in peripheral FM content and a tendency towards an age-dependent central redistribution of adiposity is noticed.

Regenerative medicine can be defined as the process of restoring diseased or damaged tissue by replacing it with biological substitutes and this issue represents one of the main concerns of medicine. Stem cells are likely to be used in the future for cardiac, neurologic, hepatic, orthopaedic and other applications. The stem cell populations have proved to be highly proliferative lately as isolated from a variety of embryonic, foetal and adult tissues. Their increased capacity to self-renew and to unlimitedly differentiate into derivates of all germ layers in vitro and in vivo have rendered embryonic stem cells (ESCs) the main concern of tissue engineering research and regenerative medicine (Hyslop et al., 2005). However these cell lines originate from the inner cell mass of human blastocysts. Thus, the relation of ESCs to the human blastocyst will always stir ethical, moral and emotional debate over their use in research. Moreover, besides these ethical and political issues, another drawback concerning their clinical application is their lack of accessibility, technique difficulties in purification and manipulation as well as the risk for teratoma development (Fan et al., 2011). Consequently, though ESC therapy has just come into attention and there still are unknowns, its success might result in it being followed by alternative stem cell therapies (Rogers & Casper, 2004). Adult stem cells (ASCs) originate in a mature organism, including the brain, fat, skin, kidney, peripheral blood and bone marrow and they contribute to maintaining and repairing tissue that contain them. The adult-derived stem cells are also believed to have the ability to differentiate into tissues different from their tissue of origin (Krause et al., 2001; Jiang et al, 2002). Different from ESCs, ASCs can be easily harvested from various tissues, such as skin (Riekstina et al., 2008 as cited in Fan et al., 2011), bone marrow (BM) (Gastens et al., 2007 as cited in Fan et al., 2011) and adipose (Keiser et al., 2007 as cited in Fan et al., 2011), and might be employed in the clinical treatment of disorders of vulnerable vital organs. ASCs have the advantage that allows for small samples of tissues or even the patient’s own cells to be used for implantation, avoiding problems of tissue rejection. Moreover, adult cells do not involve the typical ethical issues of embryonic research. In spite of these advantages, they are not the first choice and this is because of several reasons such

In contrast to chronic or subacute thyroiditis, Graves' disease rarely complicates IFN-alpha therapy for chronic viral C hepatitis. We report the case of a 51-year-old man in whom IFN-alpha treatment was followed by recurrence of Graves' disease 10 years after thyroidectomy was performed and the patient was declared cured. Despite severe thyrotoxicosis, combined IFN-alpha and ribavirin therapy was continued and radioiodine treatment was considered for Graves' disease.

Previous clinical studies have suggested a positive correlation between serum insulin-like growth factor components and bone mass in both men and women with or without osteoporosis. The aim of the present study was to analyze the relationship between the skeletal levels of insulin-like growth factors and transforming growth factor-b1 and bone mineral density in a group of men and postmenopausal women in whom osteoporosis was diagnosed previously. Bone matrix extraction was achieved by passive dialysis against tetrasodium EDTA-guanidine-HCL. IGF's were quantified by radioimmunoassay. TGF-b1 was assessed by a specific enzyme-linked immunoassay. No correlation between BMD and the concentration of IGF-I, IGF-II and TGF-b1 in bone matrix was detected in either men or postmenopausal women with osteoporosis. In addition, circulating growth factors levels failed to be associated with the concentration of IGF-I, IGF-II and TGF-b1 in the skeleton. Thus, our study provides no evidence for a major role of bone matrix IGF's or TGF-b1 as determinants of bone mass in men or postmenopausal women with osteoporosis.

Background: XX males range phenotypically from completely masculinised individuals to true hermaphrodites and include a subset of SRY negative patients. The correlation between genotype (SRY+/-) and phenotype is still unclear. Aim: To report three new patients with this rare condition, one of whom was diagnosed prenatally and another was SRY negative, and to verify in our patients whether the presence of SRYresults in a more masculinised phenotype. Patients and Methods: We present two phenotypically normal XX male patients (10 and 13.5 years) and one 3.1 years old XX male with ambiguous external male genitalia Prader IV. The patients were diagnosed by clinical, hormonal, sonographic, genetic and histological criteria. Results: Basal hormonal status was normal for phenotype but an excessive response to GnRH testing was noticed in the second patient together with insufficient hCG stimulation in all three patients. Pelvic ultrasound displayed male structures without Mullerian ducts; testicular biopsy, performed only in the intersex patient, showed Sertoli and Leydig cell hypoplasia. Chromosome analysis confirmed 46,XX karyotype. FISH analysis and molecular analysis by PCR were positive for Yp fragments/SRY gene on Xp in two patients and negative in the patient with ambiguous external genitalia. Conclusions: In our observation Y chromosome-specific material containing the SRY gene translocated to the X chromosome results in a completely masculinised phenotype. In the intersex patient, incomplete masculinisation without SRY suggests a mutation of one or more downstream non-Y testis-determining genes.

Objective: To evaluate the impact of hydrocortisone dosage, age at diagnosis, compliance, genotype and phenotype on growth and height outcome in 21-hydroxylase-deficient patients. Methods: We analyzed 37 patients with 21-hydroxylase deficiency (17 had completed growth, 20 still growing). Final (FH)/predicted final height (pFH) and loss of height potential related to target height (TH) were calculated and the impact of 4 hydrocortisone (HC) dosage regimens on height outcome and growth velocities was evaluated. Mean FH SDS and pFH SDS were analyzed in accordance to age at diagnosis, compliance, genotype and phenotype. Results: Mean (FH SDS, pFH SDS) was –1.8 ± 1.06 SD, with 35.1% of all 37 patients exhibiting short stature. Doses >20 mg/m2/day during the first year and >15 mg/m2/day during age 1–5 and at puberty resulted in significantly lower FH SDS, pFH SDS and greater height losses. Age at diagnosis, compliance, genotype and phenotype played only a minor role in growth development. Conclusions: Hydrocortisone substitution in 21-hydroxylase-deficient patients should be kept at the lowest efficient level, if possible 2/day until age 5 and during puberty. Normal growth and not complete androgen suppression should be aimed for.

The regional incidence of 21-hydroxylase deficiency, its mutational spectrum and the correlation of genotype and phenotype has been studied by European, American and Latin-American groups. However, little information is known about the molecular background of the disease in patients from Central-Eastern Europe. The present study aimed to genotype a group of patients from Transylvania, the north-western part of Romania, in order to gain some insight into the molecular pattern and the genotype-phenotype correlation of congenital adrenal hyperplasia (CAH) in this region. We genotyped 17 patients with classic 21-hydroxylase deficiency and, whenever available, their parents in order to verify mutational segregation. The patients came from 13 unrelated families. DNA was prepared from peripheral blood leucocytes and four gene fragments were amplified by PCR. The 21-hydroxylase gene (CYP21B) was completely sequenced and analyzed for point mutations or deletions. Percentage distribution of mutations was as follows: 12G--34.6%, deletions and large conversions (del)--19.2%, P30L--15.4%, 1172N--15.4%, P30L+I2G+del8bp (triple mutation)--11.5%, and R356W--3.8%. Mutational percentage distribution compared to other Latin populations is higher for I2G and I172N and lower for deletions, while the P30L mutation was found at a higher rate than in any other analyzed population. Some differences may arise from the low patient number and from ethnic particularities. The incidence of compound heterozygotes in our group was 76.5%. The genotype seemed to correlate fairly well to phenotype, with a general concordance rate of 82.35%. Clear divergence was found in two patients with the simple virilizing form, exhibiting a homozygous status for I2G and del, respectively. This study offers the first information about the molecular pathology of CAH in Romania and should help to improve management and clinical outcome for patients with CAH in Transylvania. Hopefully, it might also be the first step towards exact and accurate prenatal diagnosis in our country.