Enhancing Metformin Effects by Adding Gut Microbiota Modulators to Ameliorate the Metabolic Status of Obese, Insulin-Resistant Hosts.

Obesity is a systemic disease and represents one of the leading causes of death worldwide by constituting the main risk factor for a series of non-communicable diseases such as type 2 diabetes mellitus (T2DM), cardiovascular diseases and dyslipidemia. Lifestyle interventions have been attempting to prevent T2DM and obesity but are difficult to maintain by most patients. However, the recent focus on the intestinal microbiota and its important role in the host's metabolism provides a new key for improving metabolic health. Modulating the composition of the gut microbiota was proposed as a method to manage these metabolic diseases and most frequently this is undertaken by using probiotics, prebiotics or synbiotics. Furthermore, the action of metformin, the most commonly prescribed drug for treating T2DM, is mediated in part by the gut microbiota, although this interplay may also be responsible for the frequent gastrointestinal adverse effects of metformin. Thus, adding a gut microbiota modulator (GMM), such as probiotics or prebiotics, to metformin therapy could amplify its anti-diabetic effects, while decreasing its adverse reactions. This review summarizes the various therapies that are used to shift the composition of the microbiome and their efficacy in alleviating metabolic parameters, it assesses the interaction between metformin and the gut microbiota, and it evaluates the existing clinical and preclinical studies that analyze the potential synergy of a combined metformin-GMM therapy.

Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development.

Differences in sex development (DSD) are often correlated with a genetic etiology. This study aimed to assess the etiology of DSD patients following a protocol of genetic testing. MATERIALS AND METHODS: This study prospectively investigated a total of 267 patients with DSD who presented to Clinical Emergency Hospital for Children Cluj-Napoca between January 2012 and December 2019. Each patient was clinically, biochemically, and morphologically evaluated. As a first intervention, the genetic test included karyotype + SRY testing. A high value of 17-hydroxyprogesterone was found in 39 patients, in whom strip assay analysis of the CYP21A2 gene was subsequently performed. A total of 35 patients were evaluated by chromosomal microarray technique, and 22 patients were evaluated by the NGS of a gene panel. RESULTS: The karyotype analysis established the diagnosis in 15% of the patients, most of whom presented with sex chromosome abnormalities. Genetic testing of CYP21A2 established a confirmation of the diagnosis in 44% of patients tested. SNP array analysis was particularly useful in patients with syndromic DSD; 20% of patients tested presented with pathogenic CNVs or uniparental disomy. Gene panel sequencing established the diagnosis in 11 of the 22 tested patients (50%), and the androgen receptor gene was most often involved in these patients. The genes that presented as pathogenic or likely pathogenic variants or variants of uncertain significance were RSPO1, FGFR1, WT1, CHD7, AR, NIPBL, AMHR2, AR, EMX2, CYP17A1, NR0B1, GNRHR, GATA4, and ATM genes. CONCLUSION: An evaluation following a genetic testing protocol that included karyotype and SRY gene testing, CYP21A2 analysis, chromosomal analysis by microarray, and high-throughput sequencing were useful in establishing the diagnosis, with a spectrum of diagnostic yield depending on the technique (between 15 and 50%). Additionally, new genetic variants not previously described in DSD were observed.

The therapeutic response of somatotropinomas according to the T2-weighted signal intensity on the MRI.

Background and aim: Identifying the predictive factors of tumoral and hormonal answer of somatotropinomas to the medical treatment with somatostatin analogs represent an important element for treatment management. The aim of this study was to assess the therapeutic answer of the somatotropinomas according to the T2-weighted signal intensity on the MRI. Methods: We included 31 acromegalic patients, mean age 51.35 ± 10.37 years, who underwent surgery. The patients were divided according to the T2-weighted MRI signal intensity - hypointense, hyperintense and isointense - of the GH-secreting pituitary adenoma and were evaluated after surgery, 3, 6 and 12 months with somatostatin analogs therapy. Results: 16 (51.61%) somatropinomas were hypointense, 9 (29.03%) were hyperintense and 6 (19.35%) were isointense. The median IGF-1 and GH level decreased significantly in macroadenomas (p<0.001, p<0.001, respectively), whereas GH decreased significantly only in microadenomas (p=0.010). A significant statistical correlation was found between IGF-1 or GH levels and tumor volume before surgery (Spearman=0.38, p<0.001; Spearman=0.64, p<0.001, respectively) and after surgery (Spearman=0.61, p=0.001; Spearman=0.74, p<0.001). The percentage of optimally controlled patients increased from 12.9% after surgery, to 28.57% after 12 months with somatostatin analogs. The highest percentage of optimally controlled patients with somatostatin analogs treatment was in hypointense somatotropinomas (50%). Conclusion: The T2-weighted MRI signal intensity classifies the somatotropinomas into groups with certain evolutive and medical treatment response particularities, of which we found that the hypointense somatotropinomas have a better therapeutic response after surgery and after long-term treatment with somatostatin analogs.

Interplay between metabolic and thyroid parameters in obese pubertal children. Does visceral adipose tissue make the first move?

Objectives: The mechanisms of obesity-associated thyroid dysfunction in children are incompletely deciphered. We aimed to evaluate whether visceral adipose tissue (VAT), insulin resistance (IR), inflammation, oxidative stress (OS) are involved in thyroid morpho-functional changes in pubertal obese children. Methods: We recruited 43 obese pubertal children without history of thyroid pathology. Metabolic and thyroid parameters (visceral fat thickness [VFT], waist/hip ratio [WHR], waist/height ratio [WHtR], insulin, glucose, liver parameters, thyroid stimulation hormone [TSH], free thyroxine [FT4], free triiodothyronine [FT3], thyroid and abdominal ultrasonography) were evaluated. Serum monocyte chemoattractant protein-1 (MCP-1) and malondialdehyde (MDA) levels were quantified as markers of inflammation and OS. Results: VFT correlated positively both with WHR (p= 0.034) and the presence of thyroid nodules (p= 0.036). WHR associated with TSH (p= 0.005), FT3/FT4 (p= 0.033) and was independently associated with FT3/FT4 increase (p< 0.001). HOMA-IR increased with visceral obesity (waist circumference, p= 0.001; WHR, p= 0.018; WHtR: p< 0.001), hepatic impairment (alanine aminotransferase, p= 0.019) and hepatic steatosis (HS; p= 0.013) and correlated positively with FT3/FT4 (p= 0.036). TSH was significantly higher in subjects with HS versus those without HS (p= 0.007) and logistic regression analysis identified TSH as a risk factor for HS (p= 0.014). MDA correlated positively with MCP-1 (p= 0.021). Conclusion: VAT and IR may be responsible for changes in thyroid parameters associated with obesity: elevated TSH, FT3/FT4 levels and increased prevalence of thyroid nodules. WHR was predictive of increased FT3/FT4. In obese children, there is an interdependent relationship between HS and thyroid function.

MicroRNAs and Treatment with Somatostatin Analogs in Gastro- Entero-Pancreatic Neuroendocrine Neoplasms: Challenges in Personalized Medicine.

Molecular predictive biomarkers represent an essential tool for the future of personalized oncotherapy. Gastro- entero-pancreatic neuroendocrine neoplasms are a heterogeneous group of epithelial tumors with a steady increase in incidence and prevalence. Their effective management depends on early diagnosis, personalized risk stratification, and monitoring response to therapy. A crucial element is identifying accurate biomarkers to predict/monitor therapeutic responses, assess drug resistance, and quantify residual disease in a reproducible and less invasive way. Taking into consideration their role in cell differentiation, cell proliferation, apoptosis and tumor development, microRNAs have gained interest as potential prognostic markers and treatment response predictors in neuroendocrine neoplasms. This review is the first to summarize the available data on the possible role of microRNAs in evaluating the efficacy of somatostatin analogs treatment in gastro- entero-pancreatic neuroendocrine neoplasms. Although the literature is scarce, the let-7 family targeting phosphoinositide 3 kinase - protein kinase B 1 - mammalian target of rapamycin signaling pathway might represent a promising biomarker with potential clinical benefit, but further research is required before their eventual clinical application. Furthermore, the ambiguous molecular mechanisms of neuroendocrine proliferation and the undefined signaling pathway of somatostatin analogs should encourage future research in this field that may lead to a different clinical approach to neuroendocrine disease.

Genomic study via chromosomal microarray analysis in a group of Romanian patients with obesity and developmental disability/intellectual disability.

Background Obesity with developmental disability/intellectual disability (DD/ID) is the most common association in syndromic obesity. Genomic analysis studies have allowed the decipherment of disease aetiology, both in cases of syndromic obesity as well as in cases of isolated or syndromic DD/ID. However, more data are needed to further elucidate the link between the two. The aim of this pangenomic study was to use single nucleotide polymorphism (SNP) array technology to determine the copy number variant (CNV) type and frequency associated with both obesity and DD/ID. Methods Thirty-six patients were recruited from the Clinical Emergency Hospital for Children, in Cluj-Napoca, Romania during the period 2015-2017. The main inclusion criterion was a diagnosis that included both obesity and DD/ID. Genomic analysis via SNP array technology was performed. Results Out of the 36 patients, 12 (33%) presented CNVs with a higher degree of pathogenicity (A group) and 24 (66%) presented benign CNVs (B group). The SNP array results for the A group were as follows: pathogenic CNVs in 8/12 patients (67%); variants of unknown significance (VOUS) in 2/12 patients (16%); and uniparental disomy (UPD) in 2/12 patients (16%). Conclusions Some of these CNVs have already been observed in patients with both obesity and DD/ID, but the others were noticed only in DD/ID patients and have not been described until now in association with obesity.

Vitamin D deficiency, insulin resistance and thyroid dysfunction in obese patients: is inflammation the common link?

The aim of this article is to study the possible relation of serum vitamin D concentrations to body mass index (BMI), visceral fat thickness (VFT), insulin resistance (IR), inflammation (serum monocyte chemoattractant protein-1 - MCP-1) and thyroid parameters in obese patients. A total of 158 non-diabetic, obese patients aged 19-68 without a history of thyroid pathology were recruited. Biochemical markers, insulin, 25-OH vitamin D, thyroid parameters (TSH, FT3, FT4, TPO antibodies, TG antibodies) and VFT were measured. Serum MCP-1 evaluated the inflammation. A HOMA-IR cut-off value of 2.5 defined IR. Most patients had severe (70.3%) or moderate (25.3%) vitamin D deficiency. Vitamin D level was negatively associated with BMI (p = .043) and during the cold season with VFT (p = .009). Vitamin D deficiency correlated with Hashimoto's thyroiditis prevalence during the warm season (p = .047) and was a risk factor for its occurrence (p = .021). At 15 ng/mL cut-off value, vitamin D was negatively correlated with MCP-1 (p = .0006). Also, MCP-1 was positive correlated with HOMA- IR (p = .042), TPO-Ab levels (p = .011) and with Hashimoto's thyroiditis (p = .027). MCP-1 was a risk factor for vitamin D deficiency (p < .0001). Our study supports a bidirectional interaction between vitamin D and systemic inflammation in obese patients. Moreover, systemic inflammation is related to the severity and frequency of Hashimoto's thyroiditis. Vitamin D deficiency is the single independent factor associated with Hashimoto's thyroiditis in obese patients.

The effect of Metformin treatment in obese insulin-resistant patients with euthyroid goiter.

Objective The study's objective was to evaluate the thyroid parameters in obese insulin-resistant patients with euthyroid diffuse or nodular goiter, following Metformin treatment. Patients and methods The study was experimental, open, and prospective. Fifty-three patients aged 18-68 were enrolled for two years. Obese insulin-resistant patients (cut-off Homeostasis-Model-Assessment of Insulin Resistance-HOMA-IR ≥ 2.5) with euthyroid nodular/diffuse goiter were included. Subjects with diabetes, hypo-/hyper-thyroidism, autoimmune thyroiditis, psychiatric disorders, liver or heart failure were excluded. Patients were randomly assigned to one of the following treatment: Metformin 1000 mg/day + Levothyroxine 25 µg/day (M + LT4 group) and only Levothyroxine 25 µg/day (LT4 group). Thyroid and metabolic parameters' evolution was investigated over six months. Results The two groups were comparable at baseline (p ≥ 0.10). TSH, waist/hip ratio (WHR), visceral fat thickness (VFT), insulin, and HOMA-IR decreased significantly more in M + LT4 group compared to LT4 group. TSH decrease correlated with WHR reduction (p = 0.002) only in M + LT4 group. Moreover, the multivariate regression analysis revealed that insulin's and HOMA-IR levels' decrease was an independent factor associated with FT4's increase (p = 0.031, p = 0.033) just in M + LT4 group. No other independent association between the evolution (Δ) of TSH, thyroid volume (TTV), thyroid nodules-maximum diameter (TN-MD), and metabolic parameters was found. In addition, no significant threshold between groups was reached when ΔFT4, ΔTTV, ΔTN-MD were compared (p > 0.07), although their significant improvement was recorded between the baseline and the follow-up moment in each group (p < 0.003). Conclusion Metformin added to obese insulin-resistant patients treated with Levothyroxine for diffuse/nodular goiter determined a significant decrease in TSH and metabolic parameters, compared to those treated with Levothyroxine alone, but no significant difference regarding thyroid morphology after 6 months.

Thyroid disorders in obese patients. Does insulin resistance make a difference?

ABSTRACT Objective: The aim of this study was to evaluate the association between insulin resistance and thyroid pathology in obese patients, and compare the results between insulin-resistant and noninsulin-resistant patients. Subjects and methods: Obese/nondiabetic patients, aged 18-70 years, attending the outpatient endocrinology service for 2 years were consecutively included. We evaluated the patients' fasting plasma glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), thyroid-stimulating hormone (TSH), free thyroxine (FT4), antithyroperoxidase antibodies (TPO-Ab), antithyroglobulin antibodies (Tg-Ab), and thyroid ultrasound. Results: We included 82 patients with a mean age 44.21 ± 12.67 years. The thyroid disorders encountered and their prevalences were: hypothyroidism (14.6%, 95% confidence interval [CI] 8.6-23.8%), hyperthyroidism (1.2%, 95% CI 2.0-6.6%), goiter (28.0%, 95% CI 19.5-3.6%), thyroid nodules (35.4%, 95% CI 25.9-46.2%), and Hashimoto's thyroiditis (32.9%, 95% CI 23.7-43.7%). HOMA-IR correlated positively with TSH levels (r = 0.24, p = 0.028), and this correlation remained after adjustment for body mass index (BMI), waist/hip ratio (WHR), serum cortisol, subcutaneous fat thickness (SFT), visceral fat thickness (VFT), triglycerides, γ-glutamyl transpeptidase (GGT), and alanine aminotransferase (ALT) in multivariate regression analysis (b = 0.207, 95% CI, 0.09-0.385, p = 0.023). TSH levels were significantly higher in patients with HOMA-IR ≥ 2.5 than in those with HOMA-IR < 2.5 (2.03 μIU/mL, interquartile range [IQR] 1.59-2.69 μIU/mL) versus 1.59 μIU/mL, IQR 0.94-2.26 μIU/mL, p = 0.023). Conclusions: The most prevalent thyroid disorder in patients attending our endocrinology clinic for investigation of obesity was thyroid nodules. One in seven patients had hypothyroidism. Our findings suggest that TSH levels correlate with insulin resistance in obese patients.

Developing and evaluating rare disease educational materials co-created by expert clinicians and patients: the paradigm of congenital hypogonadotropic hypogonadism.

BACKGROUND: Patients with rare diseases face health disparities and are often challenged to find accurate information about their condition. We aimed to use the best available evidence and community partnerships to produce patient education materials for congenital hypogonadotropic hypogonadism (CHH) and the olfacto-genital (Kallmann) syndrome (i.e., CHH and defective sense of smell), and to evaluate end-user acceptability. Expert clinicians, researchers and patients co-created the materials in a multi-step process. Six validated algorithms were used to assess reading level of the final product. Comprehensibility and actionability were measured using the Patient Education Materials Assessment Tool via web-based data collection. Descriptive statistics were employed to summarize data and thematic analysis for analyzing open-ended responses. Subsequently, translation and cultural adaption were conducted by clinicians and patients who are native speakers. RESULTS: Co-created patient education materials reached the target 6th grade reading level according to 2/6 (33%) algorithms (range: grade 5.9-9.7). The online survey received 164 hits in 2 months and 63/159 (40%) of eligible patients completed the evaluation. Patients ranged in age from 18 to 66 years (median 36, mean 39 ± 11) and 52/63 (83%), had adequate health literacy. Patients scored understandability at 94.2% and actionability at 90.5%. The patient education materials were culturally adapted and translated into 20 languages (available in Additional file 1). CONCLUSIONS: Partnering with patients enabled us to create patient education materials that met patient- identified needs as evidenced by high end-user acceptability, understandability and actionability. The web-based evaluation was effective for reaching dispersed rare disease patients. Combining dissemination via traditional healthcare professional platforms as well as patient-centric sites can facilitate broad uptake of culturally adapted translations. This process may serve as a roadmap for creating patient education materials for other rare diseases.

Thyroid disorders in obese patients. Does insulin resistance make a difference?

OBJECTIVE: The aim of this study was to evaluate the association between insulin resistance and thyroid pathology in obese patients, and compare the results between insulin-resistant and noninsulin-resistant patients. SUBJECTS AND METHODS: Obese/nondiabetic patients, aged 18-70 years, attending the outpatient endocrinology service for 2 years were consecutively included. We evaluated the patients' fasting plasma glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), thyroid-stimulating hormone (TSH), free thyroxine (FT4), antithyroperoxidase antibodies (TPO-Ab), antithyroglobulin antibodies (Tg-Ab), and thyroid ultrasound. RESULTS: We included 82 patients with a mean age 44.21 ± 12.67 years. The thyroid disorders encountered and their prevalences were: hypothyroidism (14.6%, 95% confidence interval [CI] 8.6-23.8%), hyperthyroidism (1.2%, 95% CI 2.0-6.6%), goiter (28.0%, 95% CI 19.5-3.6%), thyroid nodules (35.4%, 95% CI 25.9-46.2%), and Hashimoto's thyroiditis (32.9%, 95% CI 23.7-43.7%). HOMA-IR correlated positively with TSH levels (r = 0.24, p = 0.028), and this correlation remained after adjustment for body mass index (BMI), waist/hip ratio (WHR), serum cortisol, subcutaneous fat thickness (SFT), visceral fat thickness (VFT), triglycerides, γ-glutamyl transpeptidase (GGT), and alanine aminotransferase (ALT) in multivariate regression analysis (b = 0.207, 95% CI, 0.09-0.385, p = 0.023). TSH levels were significantly higher in patients with HOMA-IR ≥ 2.5 than in those with HOMA-IR < 2.5 (2.03 µIU/mL, interquartile range [IQR] 1.59-2.69 µIU/mL) versus 1.59 µIU/mL, IQR 0.94-2.26 µIU/mL, p = 0.023). CONCLUSIONS: The most prevalent thyroid disorder in patients attending our endocrinology clinic for investigation of obesity was thyroid nodules. One in seven patients had hypothyroidism. Our findings suggest that TSH levels correlate with insulin resistance in obese patients.

Effects of combination therapy: somatostatin analogues and dopamine agonists on GH and IGF1 levels in acromegaly.

BACKGROUND AND AIMS: Acromegaly is a complex endocrine disorder caused by excessive secretion of GH, secondary to a GH secreting pituitary adenoma or a mixed pituitary adenoma secreting GH and PRL. METHODS: The aim of this study was to evaluate the effects of combination therapy: dopamine agonist and somatostatin analogue on GH and IGF1 levels in a group of 30 patients with acromegaly. Cabergoline in a dose of 2 mg/week and 4 mg/week respectively was associated with Sandostatin LAR in a dose of 20 mg/month and 30 mg/months respectively. Eight patients were treated with Lanreotide 30 mg/week and Cabergoline 2 mg/week and 3 patients were treated with Bromocriptine 10 mg/day and Sandostatin LAR 30 mg/month. RESULTS: Combination therapy: Cabergoline and Sandostatin achieved normal levels of IGF1 in 32% of the patients, better results being obtained after 12 months of treatment in the group treated with 4 mg Cabergoline/week. In 37% of cases the levels of IGF1 decreased by 50% after 12 months of treatment. In the group treated with Cabergoline and Somatuline a normal level of IGF1 was achieved in 25% of patients after 12 months of treatment. The outcome for the group treated with Sandostatin and Bromocriptine was similar to that obtained under Cabergoline 2 mg/week. There was no significant correlation between the level of GH and the type or dose of dopamine agonist used. CONCLUSIONS: In conclusion, combination therapy consisting of dopamine agonist and somatostatin analogue achieves a significant reduction of IGF1 levels in patients with mixed adenomas secreting GH and PRL. A decrease in IGF1 levels is directly correlated with the dose of Cabergoline used.

[Congenital hypogonadotropic hypogonadism and Kallmann syndrome in males]. / Hypogonadismes hypogonadotrophiques congénitaux et syndrome de Kallmann chez l'homme.

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are a group of rare disorders responsible for complete or partial pubertal failure due to lack or insufficient secretion of the pituitary gonadotropins LH and FSH. The underlying neuroendocrine abnormalities are classically divided into two main groups: molecular defects of the gonadotrope cascade leading to isolated normosmic CHH (nCHH), and developmental abnormalities affecting the hypothalamic location of GnRH neurons, but also olfactory bulbs and tracts morphogenesis and responsible for KS. Identification of genetic abnormalities related to CHH/KS has provided major insights into the pathways critical for the development, maturation and function of the gonadotrope axis. In patients affected by nCHH, particularly in familial cases, genetic alterations affecting GnRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GnRH sensitivity of gonadotropic cells (GNRHR) have been found. Mutations in KAL1, FGFR1/FGF8/FGF17, PROK2/PROKR2, NELF, CHD7, HS6ST1, WDR11, SEMA3A, SOX10, IL17RD2, DUSP6, SPRY4, and FLRT3 have been associated with KS but sometimes also with its milder hyposmic/normosmic CHH clinical variant. A number of observations, particularly in sporadic cases, suggest that CHH/KS is not always a monogenic mendelian disease as previously thought but rather a digenic or potentially oligogenic condition. Before the age of 18 years, the main differential diagnosis of isolated nCHH is the relatively frequent constitutional delay of growth and puberty (CDGP). However, in male patients with pubertal delay and low gonadotropin levels, the presence of micropenis and/or cryptorchidism argues strongly in favor of CHH and against CDGP. CHH/KS are not always congenital life-long disorders as initially thought, because in nearly 10 % of patients the disease seems not permanent, as evidenced by partial recovery of the pulsatile activity of the hypothalamic-pituitary-gonadal axis after discontinuation of treatment in adulthood (the so-called reversible CHH/KS). The clinical and hormonal diagnosis and the therapeutic management as well as the genetic counseling of these patients will be discussed here based on the experience acquired in our department during the past 30 years, from monitoring more than 400 patients with these rare conditions.

Parathyroid incidentaloma detected during thyroid sonography - prevalence and significance beyond images.

INTRODUCTION: Parathyroid incidentaloma (PTI) designates a nodule discovered incidentally during thyroid sonography, and whose location and aspect suggests an abnormal parathyroid. Our aim was to assess the prevalence of PTI, their functional characteristics and to identify the factors correlated with their presence. PATIENTS AND METHODS: We recorded all patients detected with PTI between January 2009 and December 2011, in our department. Serum calcium, parathyroid hormone (PTH), thyroid stimulating hormone (TSH), free thyroine (FT4) and anti thyroid peroxidase antibodies (anti-TPO Ab) were measured. RESULTS: From a total of 2662 thyroid ultrasounds, 32 patients were identified with PTI (prevalence 1.2%). The diagnosis of a functional parathyroid adenoma was confirmed in 12 patients (37.5%). There was no significant difference in size, location, echogenicity or vascular pattern between the functioning adenomas and the other PTI. The only parameter correlated with the non functioning lesion was the multinodular pattern of the thyroid (multinodular goiter or macronodular autoimmune thyroiditis). CONCLUSIONS: Although rare, the ultrasound identification of an image suggestive for a pathological parathyroid gland requires the evaluation of the functioning character of the lesion, more than one third PTI being hyperfunctional. The concomitance of a nodular goiter decreases the probability of a primary hyperparathyroidism.

Ectopic intrathyroid parathyroid adenoma: diagnostic and therapeutic challenges due to multiple osteolytic lesions. Case report.

Intrathyroid parathyroid adenoma is a rare lesion. Its location is usually achieved by cervical ultrasound and scintigraphy. We present the case of a 48-years old woman admitted for malaise, weight loss, generalized bone pain, and important limitation of hip and scapular-humeral joints mobility. Cervical ultrasound identified a 4 cm nodular mass in the right thyroid lobe. Computed tomography revealed multiple osteolytic lesions in the pelvis, femur, ribs, phalanx, and humerus. Imagery and elevated serum levels of calcium and parathormone led to primary hyperparathyroidism, right parathyroid adenoma and bone "brown tumors". Intraoperatively, the adenoma was found in intrathyroid location. Total right lobectomy was performed. Postoperatively, the patient developed "hungry bone" syndrome requiring prolonged calcium and vitamin D treatment.

Parathyroid cyst, a rare cause of cystic cervical lesion. Case report.

Parathyroid cyst is a very rare abnormality. The diagnosis can be made based on ultrasound and the analysis of the aspirated cystic fluid for parathyroid hormone (PTH). We report the case of a nonfunctional parathyroid cyst in a 50-year-old female patient with an anterior neck mass. The patient was complaining of pain in the anterior cervical region, dysphagia, dyspnea and dysphonia started three weeks previously. Ultrasound demonstrated an anechoic and avascular lesion located in the left lobe of the thyroid. Fine needle aspiration (FNA) revealed a clear, colorless and watery cystic fluid, that showed a high concentration of parathyroid hormone (PTH) in both the native and the diluted content of the cyst, while serum PTH was normal, indicating a nonfunctional parathyroid cyst. The patient was in remission by percutaneous aspiration and there was no relapse of the parathyroid cyst after one-year follow-up.

Thyroid and parathyroid ultrasound.

Thyroid ultrasound is easy to perform due to the superficial location of the thyroid gland, but appropriate equipment is mandatory with a linear high frequency transducer (7.5 - 12) MHz. Some pathological aspects of the thyroid gland are easily diagnosed by ultrasound, like the enlargement of the thyroid volume (goiter) or the presence of nodules and cysts; while other aspects are more difficult and need more experience (diffuse changes in the structure, echogenicity and vascularization of the parenchyma, differential diagnosis of malignant nodules). Ultrasound has become the diagnostic procedure of choice in guidelines for the management of thyroid nodules; most structural abnormalities of the thyroid need evaluation and monitoring but not intervention. A good knowledge of the normal appearance of the thyroid gland is compulsory for an accurate ultrasound diagnosis.

Genetics defects in GNRH1: a paradigm of hypothalamic congenital gonadotropin deficiency.

Gonadotropin-releasing hormone (GnRH) is a crucial neurohormone regulating puberty and reproduction in non primate mammals, monkeys and humans. This neuropeptide is released in synchronized pulses from the nerve endings of several hundred GnRH neurons into the hypophyseal portal system to stimulate the biosynthesis and secretion of LH and FSH from pituitary gonadotrophs. These two dimeric glycoprotein hormones in turn travel through the circulation to the gonads, stimulating the synthesis and secretion of male and female sex steroid hormones and gametogenesis in both genders. Congenital hypogonadotropic hypogonadism (CHH) is a clinical syndrome that results from a decrease in gonadotropin secretion and is characterized by a complete or partial lack of pubertal development. CHH is caused mainly by defective GnRH production or release by the hypothalamus or by defective GnRH-receptor function in the pituitary. The syndromes of GnRH deficiency, either with anosmia or hyposmia, termed Kallmann Syndrome (KS), or with a normal sense of smell, called normosmic non syndromic CHH, (nCHH) are important disease models that have revealed respectively much about the developmental and functional abnormalities that can befall the GnRH neurons. For more than three decades, GNRH1 was an obvious candidate gene for nCHH in human beings. Indeed, in the natural hpg mouse model discovered in 1977, the hypogonadotropic hypogonadal phenotype, secondary to a hypothalamic GnRH deficiency, was caused by a homozygous deletion within the ortholog Gnrh1 gene. In 2009, homozygous inactivating mutations in the GNRH1 gene causing hypothalamic nCHH patients were at last reported in one female and two young male subjects, validating definitively the pivotal role of GnRH in human pubertal development and reproduction.

Hypogonadotropic hypogonadism and GNRH1 mutations in mice and humans.

The neuropeptide gonadotropin-releasing hormone (GnRH) plays a key regulatory role in mammalian reproduction. It is synthesized by hypothalamic neurons and released from nerve endings into the portal circulation. After binding to membrane GnRH type 1 receptors on gonadotropic cells of the anterior pituitary, it stimulates the synthesis and release of luteinizing hormone and follicle-stimulating hormone. These two peptides travel through the general circulation to the gonads, where they stimulate the synthesis and secretion of sex steroid hormones and trigger gametogenesis. The discovery in 1977 of a hypogonadal mouse lacking GnRH (hpg mice) and, in 1986, that the gnrh1 gene was deleted in this mouse, suggested that GNRH1 mutations might also cause human congenital idiopathic (or isolated) hypogonadotropic hypogonadism. This was finally demonstrated in 2009.