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Il carcinoma midollare (CMT), che origina dalle cellule parafollicolari tiroidee, presenta ancora alcune sfide dal punto di vista diagnostico, sia per la sua rarita sia per la mancanza di marcatori ecografici, citologici e bioumorali con un’elevata efficacia diagnostica, fatta eccezione per la calcitonina sierica, marcatore specifico e sensibile del CMT. Il dosaggio della calcitonina su liquido di lavaggio da agoaspirato su nodulo tiroideo rappresenta una metodica diagnostica indice, altamente specifica. Tuttavia, gli studi ad oggi pubblicati sono pochi e non vi e accordo sui valori soglia da utilizzare per escludere o confermare la patologia maligna (CMT).

Il trattamento dell’ipotiroidismo si basa sulla somministrazione orale di levotiroxina. Recenti evidenze hanno documentato l’incapacita di garantire normali livelli tissutali di ormoni tiroidei. Inoltre, e emersa la parziale inadeguatezza del TSH come marcatore universale del compenso. Alcuni studi sono stati condotti con l’obiettivo di individuare marcatori tissutali piu informativi sul compenso periferico. Ad oggi, tuttavia, non sono stati identificati marcatori utili nella pratica clinica.

Context Despite the new opportunities provided by assisted reproductive technology (ART), male infertility treatment is far from being optimized. One possibility, based on pathophysiological evidence, is to stimulate spermatogenesis with gonadotropins. Evidence Acquisition We conducted a comprehensive systematic PubMed literature review, up to January 2020, of studies evaluating the genetic basis of follicle-stimulating hormone (FSH) action, the role of FSH in spermatogenesis, and the effects of its administration in male infertility. Manuscripts evaluating the role of genetic polymorphisms and FSH administration in women undergoing ART were considered whenever relevant. Evidence Synthesis FSH treatment has been successfully used in hypogonadotropic hypogonadism, but with questionable results in idiopathic male infertility. A limitation of this approach is that treatment plans for male infertility have been borrowed from hypogonadism, without daring to overstimulate, as is done in women undergoing ART. FSH effectiveness depends not only on its serum levels, but also on individual genetic variants able to determine hormonal levels, activity, and receptor response. Single-nucleotide polymorphisms in the follicle-stimulating hormone subunit beta (FSHB) and follicle-stimulating hormone receptor (FSHR) genes have been described, with some of them affecting testicular volume and sperm output. The FSHR p.N680S and the FSHB –211G>T variants could be genetic markers to predict FSH response. Conclusions FSH may be helpful to increase sperm production in infertile men, even if the evidence to recommend the use of FSH in this setting is weak. Placebo-controlled clinical trials, considering the FSHB-FSHR haplotype, are needed to define the most effective dosage, the best treatment length, and the criteria to select candidate responder patients.

Photoperiod impacts reproduction in many species of mammals. Mating occurs at specific seasons to achieve reproductive advantages, such as optimization of offspring survival. Light is the main regulator of these changes during the photoperiod. Seasonally breeding mammals detect and transduce light signals through extraocular photoreceptor, regulating downstream melatonin-dependent peripheral circadian events. In rodents, hormonal reduction and gonadal atrophy occur quickly and consensually with short-day periods. It remains unclear whether photoperiod influences human reproduction. Seasonal fluctuations of sex hormones have been described in humans, although they seem to not imply adaptative seasonal pattern in human gonads. This review discusses current knowledge about seasonal changes in the gonadal function of vertebrates, including humans. The photoperiod-dependent regulation of hypothalamic–pituitary–gonadal axis, as well as morphological and functional changes of the gonads is evaluated herein. Endocrine and morphological variations of reproductive functions, in response to photoperiod, are of interest as they may reflect the nature of past population selection for adaptative mechanisms that occurred during evolution.

Background: In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in diabetes remain debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist on measures of ANS function in diabetes.Methods: According to the Cochrane Collaboration and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we conducted a meta-analysis considering clinical trials in which the autonomic function was evaluated in diabetic subjects chronically treated with GLP-1R agonists. The outcomes were the change of ANS function measured by heart rate variability (HRV) and cardiac autonomic reflex tests (CARTs).Results: In the studies enrolled, HR significantly increased after treatment (PP=0.410); no changes in other measures of HRV were detected. Considering CARTs, only the 30:15 value derived from lying-to-standing test was significantly lower after treatment (P=0.002), but only two studies reported this measurement. No differences in other CARTs outcome were observed.Conclusion: The meta-analysis confirms the HR increase but seems to exclude an alteration of the sympatho-vagal balance due to chronic treatment with GLP-1R agonists in diabetes, considering the available measures of ANS function.

Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and represents the first step in the pathogenesis of cardiovascular diseases. The evaluation of endothelial health is fundamental in clinical practice and several direct and indirect markers have been suggested so far to identify any alterations in endothelial homeostasis. Alongside the known endothelial role on vascular health, several pieces of evidence have demonstrated that proper endothelial functioning plays a key role in human fertility and reproduction. Therefore, this state-of-the-art review updates the endothelial health markers discriminating between those available for clinical practice or for research purposes and their application in human fertility. Moreover, new molecules potentially helpful to clarify the link between endothelial and reproductive health are evaluated herein.

Background. In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in people with diabetes remain still debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist chronic treatment on measures of ANS function in people with diabetes. Methods. According to the Cochrane Collaboration and PRISMA statement, we conducted a meta-analysis considering clinical trials in which the autonomic function was evaluated in people with diabetes chronically treated with GLP-1R agonists. The outcomes were the change of ANS function measured by heart rate variability (HRV) and cardiac autonomic reflex tests (CARTs). Results. In the studies enrolled, HR significantly increased after treatment (pConclusion. The present meta-analysis confirms the HR increase but seems to exclude an alteration of the sympatho-vagal balance due to chronic treatment with GLP-1R agonists in diabetes, considering the available measures of ANS function.

Gonadotropins are glycoprotein hormones that regulate development and reproduction. They are a family of structurally similar hormones likely evolved from a common ancestral encoding gene and achieved relatively high complexity in humans. Two of these molecules are the luteinizing hormone (LH) and the choriogonadotropin (hCG). They are encoded by a common gene cluster and act on the same receptor (LHCGR), however, are produced in primates and specialized for regulating unique physiological functions, such as LH for gametogenesis and hCG for pregnancy. The action of the two hormones is differentiated by LHCGR, which mediates ligand-specific intracellular signals optimized for supporting LH and hCG physiological functions. Since the two hormones are used as drugs for the treatment of infertility, the knowledge of their mode of action should be helpful for interpreting gonadotropin-related pathological conditions and optimizing their clinical treatment.

Summary We present the case of a 45-year-old Caucasian woman who attended the Endocrinology Unit for a left cervical mass discovered during follow-up for autoimmune chronic thyroiditis. The ultrasound-guided fine-needle aspiration biopsy of the lesion was consistent with a metastasis of follicular thyroid carcinoma. The sonographic neck evaluation revealed no thyroid nodules but three markedly hypoechoic and highly vascularized areas, with irregular margins and hyperechoic spots. In the clinical suspicion of primary thyroid neoplasm, ultrasound-guided fine-needle aspiration biopsy of two of the three areas was performed, but both cytological reports were non-diagnostic, revealing only colloid and blood. Subsequently, the patient underwent surgical removal of the cervical mass, with the intra-operatory consultation with frozen section examination suggesting follicular-like neoplasia. For this reason, thyroidectomy with both central and lateral neck dissection was performed. Surprisingly, the final histologic examination revealed chronic thyroiditis in the thyroid specimen and no evidence of metastasis in the left neck mass. Consequently, the pathological revision of the frozen section assessment led to the final diagnosis of chronic thyroiditis on the lateral ectopic thyroid. This case represents an uncommon example of lateral ectopic thyroid tissue with coexisting normally located thyroid tissue both affected by chronic thyroiditis. Learning points Ectopic thyroid must be considered in the diagnostic work-up of lateral neck mass. Even if rare, ectopic thyroid tissue can be found lateral to the carotid sheath and with coexisting normally located thyroid tissue. As the orthotopic tissue, lateral ectopic thyroid tissue can be affected by chronic thyroiditis, which may complicate the diagnosis both on ultrasound and cytology.

L’ormone luteinizzante (LH) e la gonadotropina corionica umana (hCG) sono glicoproteine che svolgono un ruolo fondamentale per la riproduzione. L’LH modula la sintesi di androgeni e la gametogenesi in entrambi i sessi, mentre l’hCG e prodotta nella donna durante la gravidanza. Questi due ormoni hanno un’origine ancestrale comune, seppure nel corso dell’evoluzione abbiano assunto specifiche funzioni fisiologiche, supportate dall’attivazione di differenti segnali intracellulari mediati da un unico recettore (LHCGR) espresso nelle gonadi. Cio comporta che queste due gonadotropine abbiano una diversa attivita endocrina, nonostante siano state utilizzate per lungo tempo come equivalenti nella pratica clinica.

This study aimed to evaluate the real-life use of BRAF-V600E mutation analysis in washout liquid from thyroid nodule fine needle aspiration (FNA), and the consequences of genetic result on clinical decision-making. We retrospectively considered subjects tested for BRAF-V600E among those attending the Endocrinology Unit of Modena for FNA between 2014 and 2018. Washing fluid was collected together with cytological sample and stored at −20 °C. If the clinician deemed it necessary, the sample was thawed, DNA extracted, and genetic test performed by high-resolution melting technique. We collected data on cytology according to the Italian Consensus for the cytological classification of thyroid nodules, type of surgery (when performed), histology, and adverse events. Out of 7112 subjects submitted to FNA, BRAF analysis was requested for 683 (9.6%). Overall, 896 nodules were analyzed: 74% were indeterminate at cytology, mainly TIR3A (low risk). Twenty-two nodules were mutant (BRAF+). Only 2% of indeterminate, mainly TIR3B, were BRAF+. Based on final histological diagnosis, BRAF test had high specificity (100%) but poor sensitivity (21%), also in indeterminate nodules. Mutant subjects underwent more extensive surgery compared to wild type (p = 0.000), with frequent prophylactic central lymph node dissection. One third had local metastases. Higher prevalence of hypoparathyroidism was found in BRAF+ compared to wild type (p = 0.018). The analysis of BRAF-V600E outside of gene panels has low sensitivity, especially in indeterminate nodules, and a positive result could lead to more extensive surgery with greater risk of hypoparathyroidism and questionable clinical utility.

Mechanisms regulating the selection of antral ovarian follicles are poorly understood and supposed to rely on low estrogen levels, decline of follicle-stimulating hormone (FSH) levels and receptor (FSHR) expression. These concepts are challenged in vitro, where apoptosis of human granulosa cells (hGLC) and transfected cell lines is induced by high doses of FSH or FSHR overexpression, while estrogens induce anti-apoptotic signals via nuclears and a G protein-coupled estrogen receptor (GPER). Therefore, in vitro data suggest that antral follicle selection may be driven by underestimated, FSH/FSHR-dependent apoptotic signals due to transiently maximized FSHR expression and overload of cAMP signalling, prevailing on estrogen-dependent signals. Here we demonstrate how FSHR/GPER physical interaction rescue ovarian follicles from FSH-mediated death. 10 nM FSH induces high intracellular levels of cAMP, measured by bioluminescence resonance energy transfer (BRET), and apoptosis in cultured hGLC under conditions where GPER levels are depleted by siRNA. This result was confirmed in transfected HEK293 cells overexpressing FSHR. Using BRET, photo-activated localization microscopy (PALM) and bioinformatics prodiction, we also demonstrate FSHR/GPER heteromers at the cell surface. The role of FSHR/GPER heteromers may be relevant to inhibit FSH-induced death signals, since increasing GPER expression levels in HEK293 cells co-expressing FSHR results in displacement of the Gαs-protein to FSHR, blockade of FSH-induced cAMP production and inhibition of apoptosis. However, in HEK293 cells coexpressing GPER/FSHR, FSH-induced activation of the anti-apoptotic AKT-pathway via a Gβγ-dependent mechanism, as demonstrated by Western blotting in cells treated using the inhibitor gallein. Inhibition of both FSH-induced cAMP production and apoptosis was lost when FSHR is coexpressed together with a mutant GPER, unable to heteromerize with FSHR, as well as in KO HEK293 cells unable to produce a molecular complex associated with GPER inhibiting cAMP. GPER/FSHR coexpression is confirmed in secondary follicles from paraffin-embedded tissues of human ovary by immunohistochemistry, suggesting that FSHR-GPER heterodimers could be physiologically relevant in vivo for inhibiting cAMP-linked apoptosis. Most importantly, FSHR and GPER co-expression correlates in hGLC from FSH-normo-responder women undergoing assisted reproduction, while it is not in hGLC from FSH-poor-responders, where increasing FSHR mRNA levels do not correspond to increasing GPER mRNA levels. We demonstrate that death signals in atretic follicles are delivered through overexpressed FSHR and inhibited by FSHR/GPER heteromerization, activating anti-apoptotic pathways. This finding unveils a novel working model of the physiology of dominant follicle selection and the relationship between FSH and estrogens.

Classically, follicle stimulating hormone receptor (FSHR) driven cAMP-mediated signaling boosts human ovarian follicle growth and would be essential for oocyte maturation. However, contradicting in vitro suggest a different view on physiological and clinical significance of FSHR-mediated cAMP signaling. We found that the G protein coupled estrogen receptor (GPER) heteromerizes with FSHR, reprogramming cAMP/death signals into proliferative stimuli fundamental for sustaining oocyte survival. In human granulosa cells, survival signals are effectively delivered upon equal expression levels of both receptors, while they are missing at high FSHR:GPER ratio, which negatively impacts follicle maturation and strongly correlates with FSH responsiveness of patients undergoing controlled ovarian stimulation. Consistent with high FSHR expression levels during follicular selection, cell viability is dramatically reduced in FSHR overexpressing cells due to preferential coupling to the Gαs protein/cAMP pathway. In contrast, FSHR/GPER heteromer formation resulted in FSH-triggered anti-apoptotic/proliferative signaling delivered via the Gβγ dimer while heteromer impairment or GPER-associated Gαs inhibitory protein complexes resulted in cell death. GPER-depleted granulosa cells have an amplified FSH-dependent decrease in cell viability and steroidogenesis, consistent with the requirement of estrogen signaling for successful oocyte growth. Therefore, our findings indicate how oocyte maturation depends on the capability of GPER to shape FSHR selective signals, indicating hormone receptor heteromers may be a marker of cell proliferation.One Sentence SummaryFSHR/GPER heteromers block cAMP-dependent selection of ovarian follicles and target tumor growth and poor FSH-response in women.

International audience; Background: Human reproduction is regulated by the combined action of the follicle-stimulating hormone (FSH) and the luteinizing hormone (LH) on the gonads. Although FSH is largely used in female reproduction, in particular in women attending assisted reproductive techniques to stimulate multi-follicular growth, its efficacy in men with idiopathic infertility is not clearly demonstrated. Indeed, whether FSH administration improves fertility in patients with hypogonadotropic hypogonadism, the therapeutic benefit in men presenting alterations in sperm production despite normal FSH serum levels is still unclear. In the present review, we evaluate the potential pharmacological benefits of FSH administration in clinical practice. Methods: This is a narrative review, describing the FSH physiological role in spermatogenesis and its potential therapeutic action in men. Results: The FSH role on male fertility is reviewed starting from the physiological control of spermatogenesis, throughout its mechanism of action in Sertoli cells, the genetic regulation of its action on spermatogenesis, until the therapeutic options available to improve sperm production. Conclusion: FSH administration in infertile men has potential benefits, although its action should be considered by evaluating its synergic action with testosterone, and well-controlled, powerful trials are required. Prospective studies and new compounds could be developed in the near future.

International audience; Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility

Several controlled ovarian stimulation (COS) protocols have been developed to increase the yield of mature oocytes retrieved in assisted reproductive techniques (ARTs). The ovarian reserve (OR) influences the COS response, and it represents the main parameter that helps clinicians in refining clinical treatments in the perspective of a "personalized" ART. This approach is even more needed in particular conditions such as poor OR or polycystic ovary syndrome. Follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin are currently used in COS at different combinations and with different efficacies, even if the best approach definition is controversial. Differences in individual-specific ovarian response to gonadotropin stimulation can be due to alterations of genes encoding for hormones or their receptors. In particular, FSHB c.-211G>T, FSHR p.Asn680Ser, and c.-29G>A SNP allelic combinations may be used as OR and COS response markers. The purpose of this review is to highlight the evidence-based relevance of mutations and polymorphisms in gonadotropins and their receptor genes as predictive markers of OR and COS response to achieve fine-tuned therapeutic regimens.

Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) originated from an ancestral gene in primates and act on the same receptor expressed in the gonads. In humans, their physiological functions are different and reflect specific molecular features. LH has a relatively short half-life, mediates androgen synthesis and gametogenesis. hCG is encoded by six genes and exists in several glycosylation isoforms produced during pregnancy to support progesterone production. These differences were revealed by several studies in the last decade, highlighting hormone-specific effects both at the intracellular level and in vivo. hCG and LH are commonly available as drugs for assisted reproduction, where they are used for supporting follicle-stimulating hormone (FSH) and inducing multifollicular development, in spite of their diversities. However, these practices should be revisited in light of LH- and hCG-specific actions.

Summary A 74-year-old man was referred to the Endocrinology Unit because of multinodular goiter. The dominant nodule (1.7 × 1.9 × 2.4 cm), at the medium-superior third of the left lobe, was inhomogeneously hypoechoic, with irregular margins, macrocalcifications and intranodular vascularization. Fine-needle aspiration biopsy (FNAB) was performed. The cytological diagnosis was TIR 2, benign, according to the 2013 Italian thyroid cytology classification system. Moderately high serum calcitonin (s-Ct) (61.5 pg/mL, n.r. 0–7.5) and normal CEA were detected. The Ct level in FNAB wash-out fluid (Ct-FNAB) was 1450 pg/mL. Based on s-Ct and Ct-FNAB levels, patient underwent total thyroidectomy. Macroscopically, a dominant circumscribed nodule of 2 ecm was described; the histological and immunohistochemical features identified medullary thyroid carcinoma (MTC) with paraganglioma (PG)-like pattern positive for Ct, CEA and chromogranin and negative for S-100 sustentacular cells (SC). Moreover, papillary carcinoma of 3 mm in the right lobe was also associated. No areas of hyperaccumulation of the tracer were documented at Ga68 PET/CT. No RET-proto-oncogene mutations were found. Post-surgery s-Ct levels were within normal range (4 pg/mL). Two years after thyroidectomy, the patient is still disease-free. We reported a case of sporadic and rare variant of MTC: this is the ninth described case of PG-like MTC. In this case, cytologically benign, the clinical suspicion arose from high Ct values at FNAB wash-out fluid. Even if clinical behavior of this variant seems indolent, additional studies are necessary to understand prognoses and predictive factors. Learning points: Several unusual histological variants of medullary thyroid carcinoma (MTC) have been described such as spindle cell, giant cell, clear cell, melanotic, squamous, angiosarcoma-like variants; even rarer is the paraganglioma (PG)-like pattern. We here describe a case of medullary PG-like thyroid carcinoma in a 74-year-old man. This is a rare histological variant of MTC hardly diagnosed by cytology, since immunohistochemical investigations are necessary. Measurement of calcitonin both in serum and in wash-out fluid from fine-needle aspiration could be an additional tool for an early and non-invasive identification of these variants.