[Endocrinology: what's new in 2023]. / Endocrinologie: ce qui a changé en 2023.

This overview provides a selection of studies published in 2023 with an impact on clinical practice. In reproductive endocrinology, important studies have addressed fertility preservation in men with Klinefelter's syndrome, the cardiovascular safety of testosterone replacement therapy, and a novel therapy, fezolinetant, for vasomotor symptoms of menopause. The updated European recommendations concerning adrenal incidentalomas will considerably modify current clinical practice. Based on a solid epidemiological work, the prevalence of pituitary adenomas has been confirmed to affect about 1 per 1000 individuals. Finally, a large British study allows to refine the benefit-risk profile of the three options available for the treatment of hyperthyroidism.

Cet aperçu présente une sélection d'études publiées en 2023 ayant un impact sur la pratique clinique. En endocrinologie de reproduction, des études importantes ont abordé la préservation de la fertilité chez les hommes avec un syndrome de Klinefelter, la sécurité cardiovasculaire du traitement substitutif par testostérone et une nouvelle thérapie, fezolinetant, pour les symptômes vasomoteurs de la ménopause. La mise à jour des recommandations européennes concernant les incidentalomes surrénaliens va considérablement modifier la pratique clinique. Grâce à un travail épidémiologique solide, la prévalence des adénomes hypophysaires est confirmée à environ 1 cas pour 1000 individus. Enfin, une large étude britannique permet de raffiner le profil bénéfices-risques des trois options disponibles pour le traitement de l'hyperthyroïdie.

The Enhanced Recovery After Surgery protocol for the perioperative management of pituitary neuroendocrine tumors/pituitary adenomas.

OBJECTIVE: Enhanced Recovery After Surgery (ERAS) is a multimodal perioperative care pathway that has radically modified the management of patients in multiple surgical specialties. Until now, no ERAS Society guidelines have been formulated for the management of cranial pathologies. During the process of ERAS certification for their neurosurgical department, the authors formulated an ERAS protocol for the perioperative care of patients with pituitary neuroendocrine tumors (PitNET), along with a compliance checklist to monitor the adherence to it and its feasibility. The authors describe the protocol and checklist and report the results, including a cost-minimization analysis, with the application of the ERAS philosophy. METHODS: The steps that led to the development of this ERAS protocol, including items concerning the preoperative, intraoperative, and postoperative period, are detailed. The authors report their preliminary results through the comparison of the care practice of a historical cohort with a consecutive surgical cohort of patients with PitNET who underwent operation after the implementation of this ERAS protocol. A compliance checklist with key performance indicators was useful to monitor the adherence to the protocol and the changes in the perioperative management. RESULTS: Following the introduction of this ERAS protocol, the authors significantly shortened the duration of the antibiotic therapy (p < 0.00001) and increased the use of mechanical (p < 0.00001) and pharmacological measures to prevent deep venous thrombosis (p = 0.002). The median length of hospital stay was significantly shorter for the ERAS group (p = 0.00014), and there was no increase in readmission rate or postoperative complications. The documentation and data tracking strongly improved in the ERAS cohort and the authors were more attentive in pain evaluation (p = 0.001), postoperative hormonal supplementation (p = 0.001) and early feeding and mobilization (p = 0.0008 and p < 0.00001, respectively). More patients were discharged on day 3 after surgery in the ERAS group (p < 0.00001). The compliance to the whole process increased from 64.2% to 89.5% (p = 0.016), and the compliance per patient was also found to have significantly increased (p < 0.00001). CONCLUSIONS: The introduction of a standardized ERAS protocol for the perioperative management of patients with PitNET allowed the authors to improve the multidisciplinary management of these patients. With the application of simple cost-effective interventions and with the avoidance of unnecessary measures, gains were made in terms of early mobilization and feeding, thereby resulting in a shorter in-hospital stay.

[Brittle bones]. / 5 minutes pour apprendre. Des os fragiles.

The use of corticosteroids is common in our clinical practice. Cortico-induced osteoporosis should be taken into consideration when using a dosage higher than 7.5 mg/d of prednisone or equivalent for a minimum of 3 months. We describe the case of a 69-year-old female patient who received long-term corticosteroid treatment for low back pain and developed secondary vertebral compression fractures. This case illustrates the importance of assessing fracture risk when prescribing corticosteroids, in order to offer preventive measures and introduce (in subjects with high risk) prophylactic treatments aiming to reduce the risk of irreversible consequences.

Impact of Cushing's syndrome on the gonadotrope axis and testicular functions in men.

STUDY QUESTION: Does Cushing's syndrome (CS) differently affect the gonadotrope axis and testicular functions (GA/TF) according to the hypercortisolism intensity and underlying etiology? SUMMARY ANSWER: Endogenous cortisol excess caused by CS leads to varying degrees of hypogonadotropic hypogonadism (HH) with more severe GA/TF impairment and altered spermatogenesis in men with intense hypercortisolism associated with paraneoplastic/ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS). WHAT IS KNOWN ALREADY: CS is very rarely studied in men due to its lower prevalence in men than in women. In a few old reports focusing exclusively on a limited number of men with Cushing's disease (CD), the occurrence of hypogonadism was reported. However, a detailed assessment of the impact of CS on the GA/TF in a significant series of patients has not been performed. Yet, hypogonadism could worsen CS-associated comorbidities such as osteoporosis and myopathy. To date, the full spectrum of GA/TF impairment in men with CS of different etiologies and intensity remains unknown. STUDY DESIGN, SIZE, DURATION: In this monocentric study, 89 men with CS diagnosed at a tertiary endocrine university center (Bicêtre, Paris Saclay) between January 1990 and July 2021 were evaluated and compared to 40 normal men of similar age. PARTICIPANTS/MATERIALS, SETTING, METHODS: The CS patient cohort of 89 men included 51 with CD, 29 with EAS and 9 with CS of adrenal origin i.e. (ACTH-independent CS (AI-CS)). They all had frank hypercortisolism, with increased 24 h-urinary-free cortisol (24 h-UFC) in two separate samples. A case-control study was performed focusing on pituitary gonadotrope function and testicular sex steroids and peptides. An additional set of six CS men had an evaluation including semen analysis. In a subgroup of 20 men with available data after CS remission, a longitudinal analysis was conducted to assess the reversibility of GA/TF defects. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to controls, men with CS had significantly lower total testosterone (TT), bioavailable TT, and free TT (P < 0.0001). Hypogonadism, defined as serum TT levels <3.0 ng/ml, was present in 83% of men with EAS, in 61% of men with CD, and in 33% of men with AI-CS. Low-normal LH concentrations in the included men with hypercortisolism indicated HH. Serum sex hormone-binding globulin levels were moderately decreased in men with CD (P = 0.01 vs controls). Among the CS men, those with EAS had significantly lower TT, LH, and FSH levels than those with CD or AI-CS. When compared to controls, patients with EAS were the only group exhibiting a significant decrease in both serum FSH (P = 0.002) and the testicular peptides inhibin B (P < 0.0001) and anti-Müllerian hormone (P = 0.003). Serum INSL3 levels were significantly lower in men with CD than in the controls (P = 0.03). Of note, 24 h-UFC and ACTH were inversely and significantly associated with the majority of reproductive hormones including LH, FSH, TT, and inhibin B. Following successful curative therapy, reproductive assessment at a mean of 6.0 ± 4.3 years showed a significant increase in serum TT (P < 0.0001) and plasma LH (P = 0.02) levels, indicating a reversal of HH in 75% of the affected males. Among the six patients with available semen analysis, the two EAS cases exhibited a decrease in Sertoli cell peptides associated with a severe oligozoospermia, which completely normalized following removal of the source of hypercortisolism. LIMITATIONS, REASONS FOR CAUTION: The potential bias due to the retrospective design is counteracted by the analysis of the largest male CS cohort to date as well as the use of stringent inclusion and exclusion criteria. Due to the low number of patients with semen analysis in this study, further research is needed to unravel the full spectrum of spermatogenesis defects in men with CS. WIDER IMPLICATIONS OF THE FINDINGS: This work reveals the variable spectrum of reproductive impact in men with CS. We demonstrate that GA/TF impairment depends on the intensity of hypercortisolism which in turn is related to the underlying etiology. The causal link between hypercortisolism and GA/TF impairment was attested by its reversibility in most patients after CS remission. The wider implications of our findings lie in the potential generalization to a much commoner entity, iatrogenic CS due to chronic exposure to exogenous glucocorticoids. STUDY FUNDING/COMPETING INTEREST(S): Several research grants were attributed to J.Y.: (i) a grant from Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO); (ii) a grant from the French Association of Patients with Adrenal Diseases ('Association surrénales'); and (iii) independent Investigator Research Grants from HRA Pharma, Novartis and Recordati Pharma. A SICPA Foundation grant (Lausanne, Switzerland) allowed protected research time for G.E.P. The above sponsors were not involved in any part of the study. The authors have no competing or other conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Implementation of the Enhanced Recovery After Surgery (ERAS®) program in neurosurgery.

BACKGROUND: Over the past decade, Enhanced Recovery After Surgery (ERAS®) guidelines have been proven to simplify postoperative care and improve recovery in several surgical disciplines. The authors set out to create and launch an ERAS® program for cranial neurosurgery that meets official ERAS® Society standards. The authors summarize the successive steps taken to achieve this goal in two specific neurosurgical conditions and describe the challenges they faced. METHODS: Pituitary neuroendocrine tumors (Pit-NET) resected by a transsphenoidal approach and craniosynostosis (Cs) repair were selected as appropriate targets for the implementation of ERAS® program in the Department of Neurosurgery. A multidisciplinary team with experience in managing these pathologies was created. A specialized ERAS® nurse coordinator was hired. An ERAS® certification process was performed involving 4 seminars separated by 3 active phases under the supervision of an ERAS® coach. RESULTS: The ERAS® Pit-NET team included 8 active members. The ERAS® Cs team included 12 active members. Through the ERAS® certification process, areas for improvement were identified, local protocols were written, and the ERAS® program was implemented. Patient-centered strategies were developed to increase compliance with the ERAS® protocols. A prospective database was designed for ongoing program evaluation. Certification was achieved in 18 months. Direct costs and time requirements are reported. CONCLUSION: Successful ERAS® certification requires a committed multidisciplinary team, an ERAS® coach, and a dedicated nurse coordinator.

Defective jagged-1 signaling affects GnRH development and contributes to congenital hypogonadotropic hypogonadism.

In vertebrate species, fertility is controlled by gonadotropin-releasing hormone (GnRH) neurons. GnRH cells arise outside the central nervous system, in the developing olfactory pit, and migrate along olfactory/vomeronasal/terminal nerve axons into the forebrain during embryonic development. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome are rare genetic disorders characterized by infertility, and they are associated with defects in GnRH neuron migration and/or altered GnRH secretion and signaling. Here, we documented the expression of the jagged-1/Notch signaling pathway in GnRH neurons and along the GnRH neuron migratory route both in zebrafish embryos and in human fetuses. Genetic knockdown of the zebrafish ortholog of JAG1 (jag1b) resulted in altered GnRH migration and olfactory axonal projections to the olfactory bulbs. Next-generation sequencing was performed in 467 CHH unrelated probands, leading to the identification of heterozygous rare variants in JAG1. Functional in vitro validation of JAG1 mutants revealed that 7 out of the 9 studied variants exhibited reduced protein levels and altered subcellular localization. Together our data provide compelling evidence that Jag1/Notch signaling plays a prominent role in the development of GnRH neurons, and we propose that JAG1 insufficiency may contribute to the pathogenesis of CHH in humans.

Navigating Disrupted Puberty: Development and Evaluation of a Mobile-Health Transition Passport for Klinefelter Syndrome.

Klinefelter syndrome (KS) is the most common aneuploidy in men and has long-term sequelae on health and wellbeing. KS is a chronic, lifelong condition and adolescents/young adults (AYAs) with KS face challenges in transitioning from pediatric to adult-oriented services. Discontinuity of care contributes to poor outcomes for health and wellbeing and transition programs for KS are lacking. We aimed to develop and test a mobile health tool (KS Transition Passport) to educate patients about KS, encourage self-management and support successful transition to adult-oriented care. First, we conducted a retrospective chart review and patient survey to examine KS transition at a university hospital. Second, we conducted a systematic scoping review of the literature on AYAs with KS. Last, we developed a mobile health transition passport and evaluated it with patient support groups. Participants evaluated the tool using the System Usability Scale and Patient Education Materials Assessment Tool (PEMAT). Chart review identified 21 AYAs diagnosed between 3.9-16.8 years-old (median 10.2 years). The survey revealed only 4/10 (40%) were on testosterone therapy and fewer (3/10, 30%) had regular medical care. The scoping review identified 21 relevant articles highlighting key aspects of care for AYAs with KS. An interprofessional team developed the mobile-health KS transition passport using an iterative process. Support group members (n=35) rated passport usability as 'ok' to 'good' (70 ± 20, median 73.5/100). Of PEMAT dimensions, 5/6 were deemed 'high quality' (86-90/100) and participants knew what to do with the information (actionability = 83/100). In conclusion, many patients with KS appear to have gaps in transition to adult-oriented care. Iterative development of a KS transition passport produced a mobile health tool that was usable, understandable and had high ratings for actionability.

Compromised Volumetric Bone Density and Microarchitecture in Men With Congenital Hypogonadotropic Hypogonadism.

CONTEXT: Men with congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) have both low circulating testosterone and estradiol levels. Whether bone structure is affected remains unknown. OBJECTIVE: To characterize bone geometry, volumetric density and microarchitecture in CHH/KS. METHODS: This cross-sectional study, conducted at a single French tertiary academic medical center, included 51 genotyped CHH/KS patients and 40 healthy volunteers. Among CHH/KS men, 98% had received testosterone and/or combined gonadotropins. High-resolution peripheral quantitative computed tomography (HR-pQCT), dual-energy x-ray absorptiometry (DXA), and measurement of serum bone markers were used to determine volumetric bone mineral density (vBMD) and cortical and trabecular microarchitecture. RESULTS: CHH and controls did not differ for age, body mass index, and levels of vitamin D and PTH. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal bone mineral density (aBMD) in CHH/KS at lumbar spine, total hip, femoral neck, and distal radius. Consistent with persistently higher serum bone markers, HR-pQCT revealed lower cortical and trabecular vBMD as well as cortical thickness at the tibia and the radius. CHH/KS men had altered trabecular microarchitecture with a predominant decrease of trabecular thickness. Moreover, CHH/KS men exhibited lower cortical bone area, whereas total and trabecular areas were higher only at the tibia. Earlier treatment onset (before age 19 years) conferred a significant advantage for trabecular bone volume/tissue volume and trabecular vBMD at the tibia. CONCLUSION: Both vBMD and bone microarchitecture remain impaired in CHH/KS men despite long-term hormonal treatment. Treatment initiation during adolescence is associated with enhanced trabecular outcomes, highlighting the importance of early diagnosis.

Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing on de novo rare variants in CHH genes. METHODS: We evaluated 60 trios for de novo rare sequencing variants (RSV) in known CHH genes using exome sequencing. Potential mosaicism was suspected among RSVs with altered allelic ratios and confirmed using customized ultradeep sequencing (UDS) in multiple tissues. RESULTS: Among the 60 trios, 10 probands harbored de novo pathogenic variants in CHH genes. Custom UDS demonstrated that three of these de novo variants were in fact postzygotic mosaicism-two in FGFR1 (p.Leu630Pro and p.Gly348Arg), and one in CHD7 (p.Arg2428*). Statistically significant variation across multiple tissues (DNA from blood, buccal, hair follicle, urine) confirmed their mosaic nature. CONCLUSIONS: We identified a significant number of de novo pathogenic variants in CHH of which a notable number (3/10) exhibited mosaicism. This report of postzygotic mosaicism in CHH patients provides valuable information for accurate genetic counseling.

Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations.

STUDY QUESTION: Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility? SUMMARY ANSWER: PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility. WHAT IS KNOWN ALREADY: PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD. STUDY DESIGN, SIZE, DURATION: In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Five women aged 19-38 years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients. MAIN RESULTS AND THE ROLE OF CHANCE: All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies. LIMITATIONS, REASONS FOR CAUTION: The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD. WIDER IMPLICATIONS OF THE FINDINGS: The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used for this study. There are no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

The Metabolic Benefits of Menopausal Hormone Therapy Are Not Mediated by Improved Nutritional Habits. The OsteoLaus Cohort.

Menopause alters body composition by increasing fat mass. Menopausal hormone therapy (MHT) is associated with decreased total and visceral adiposity. It is unclear whether MHT favorably affects energy intake. We aimed to assess in the OsteoLaus cohort whether total energy intake (TEI) and/or diet quality (macro- and micronutrients, dietary patterns, dietary scores, dietary recommendations)-evaluated by a validated food frequency questionnaire-differ in 839 postmenopausal women classified as current, past or never MHT users. There was no difference between groups regarding TEI or consumption of macronutrients. After multivariable adjustment, MHT users were less likely to adhere to the unhealthy pattern 'fat and sugar: Current vs. never users [OR (95% CI): 0.48 (0.28-0.82)]; past vs. never users [OR (95% CI): 0.47 (0.27-0.78)]. Past users exhibited a better performance in the revised score for Mediterranean diet than never users (5.00 ± 0.12 vs. 4.63 ± 0.08, p < 0.04). Differences regarding compliance with dietary recommendations were no longer significant after adjustment for covariates. Overall, these results argue against a major role of TEI and diet quality as possible mediators of the MHT metabolic benefits. Future research on this relationship should focus on other potential targets of MHT, such as resting energy expenditure and physical activity.

Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.

Clinical Management of Congenital Hypogonadotropic Hypogonadism.

The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (∼10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development.

Uptake of 99mTc-MIBI by Sclerosing Pneumocytoma Raising a False Suspicion of Metastasis From Medullary Thyroid Carcinoma.

Technetium-99m methoxy isobutyl isonitrile (99mTc-MIBI; sestamibi) single-photon emission computed tomography (SPECT)/computed tomography (CT) performed for preoperative localization of parathyroid adenomas or for other indications can reveal incidentalomas. Interpretation of such findings can be challenging, particularly when thyroid or other endocrine tumors are also present. Preoperative staging of a 59-year-old female patient with medullary thyroid carcinoma (MTC) showing moderate hypermetabolism on 18F-fluorodeoxyglucose positron emission tomography/CT also detected a slightly hypermetabolic pulmonary nodule (standardized uptake value normalized by body weight max = 2.0 g/mL). A sestamibi SPECT/CT performed because of concomitant primary hyperparathyroidism showed increased uptake by both the MTC and the pulmonary nodule, raising suspicion of MTC metastasis. Lung wedge resection biopsy revealed a sclerosing pneumocytoma (SPC), a rare benign pulmonary tumor not previously known to retain sestamibi. In contrast to classical knowledge that sestamibi uptake by tumors is associated with its retention by mitochondria, immunohistochemical analyses showed that the mitochondrial content of the patient's SPC was low. This case illustrates the behavior of SPC in sestamibi scintigraphy and indicates that SPC is a potential cancer mimicker in this setting.

The Bethesda System for Reporting Thyroid Cytopathology Explained for Practitioners: Frequently Asked Questions.

BACKGROUND: The recent update of The Bethesda System for Reporting Thyroid Cytology (TBSRTC) is a very important development in the evaluation of thyroid nodules. Clinical experience and scientific literature both show that practitioners performing thyroid fine-needle aspiration are accustomed to basing the clinical management of patients on reports using TBSRTC. Specifically, clinicians are familiar with the percent risk of malignancy corresponding to each TBSRTC diagnostic category (DC), as well as with the respective recommendation for clinical management. However, most clinicians are much less familiar with the specific considerations that lie between a given DC, on the one end, and the respective risk of malignancy and associated management recommendation, on the other end. SUMMARY: A deeper understanding of the system can enlighten the clinician's thinking about the specific nodule under examination and can guide the decision-making process in a more meaningful way. Such an understanding can only be developed via close two-way communication between cytopathologists and clinicians. Through this type of interaction in the authors' tertiary medical center, recurring issues of particular importance for clinical practice were identified, which are reported here in the form of 16 frequently asked questions posed by the clinician to the cytopathologist. CONCLUSIONS: For each frequently asked question, an answer is provided based on the literature, the authors' experience, the new version of TBSRTC, and the new World Health Organization classification of tumors of endocrine organs.

Menopausal Hormone Therapy Is Associated With Reduced Total and Visceral Adiposity: The OsteoLaus Cohort.

Context: After menopause, fat mass (FM) and visceral adipose tissue (VAT) increase and nonbone lean body mass (LBM) decreases. Whether menopausal hormone therapy (MHT) reverses these changes remains controversial. Objective: To assess the effect of MHT on FM, VAT, and LBM before and after its withdrawal and evaluate potential confounders. Design: Cross-sectional study. Setting: General community. Patients or Other Participants: Women of the OsteoLaus cohort (50 to 80 years old) who underwent dual-energy X-ray absorptiometry (DXA) with body composition assessment. After we excluded women with estrogen-modifying medications, the 1053 participants were categorized into current users (CUs), past users (PUs), and never users (NUs) of MHT. Intervention: None. Main Outcome Measures: VAT measured by DXA was the primary outcome. We assessed subtotal and android FM, LBM, muscle strength (hand grip), and confounding factors (caloric intake, physical activity, biomarkers). Results: The groups significantly differed in age, NU < CU < PU. Age-adjusted VAT was lower in CUs than NUs (P = 0.03). CUs exhibited lower age-adjusted body mass index (BMI) (-0.9 kg/m2) and a trend for lower FM (-1.3 kg). The 10-year gain of VAT (P < 0.01) and subtotal and android FM (P < 0.05) was prevented in CUs. No difference in LBM or hand grip was detected. No residual effect was detected for PUs, including for early MHT discontinuers. The confounding factors did not significantly differ between groups except for higher caloric intake in PUs compared with NUs. Conclusions: MHT is associated with significantly decreased VAT, BMI, and android FM. No benefit is detected for LBM. The benefits are not preserved in PUs, suggesting caution when MHT is discontinued.

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.

OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. DESIGN: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. METHODS: Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). RESULTS: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10-11) or controls (18%, P = 5.5 × 10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10-7). CONCLUSIONS: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.