Current State of Molecular Cytology in Thyroid Nodules: Platforms and Their Diagnostic and Theranostic Utility.

The high prevalence of thyroid nodules and increased availability of neck ultrasound have led to an increased incidence of diagnostic thyroid fine needle aspirations, with approximately 20% yielding indeterminate results. The recent availability of molecular tests has helped guide the clinical management of these cases. This paper aims to review and compare three main commercially available molecular cytology platforms in the U.S.-Afirma GSC, Thyroseq GC, and ThyGeNEXT + ThyraMIR. Sequential improvements of the Afirma GSC and Thyroseq GC tests have increased positive and negative predictive values, sensitivity, and specificity. Comparative studies revealed similar diagnostic performance between these tests, with considerations for factors such as cost and processing time. Thyroseq GC provides detailed genomic information and specific management recommendations. ThyGeNEXT + ThyraMIR, though less studied, presents promising results, particularly in miRNA analysis for weak driver mutations. Challenges in interpreting results include variations in reporting and the evolving nature of testing platforms. Questions persist regarding cost-effectiveness and the utility of ultrasound characteristics in selecting candidates for molecular testing. While molecular testing has primarily served diagnostic purposes, advancements in understanding genetic alterations now offer therapeutic implications. FDA-approved options target specific genetic alterations, signaling a promising future for tailored treatments.

Impact of long-acting growth hormone replacement therapy in adult growth hormone deficiency: Comparison between adolescent, adult, and elderly patients.

The predominant features of the adult growth hormone deficiency (GHD) syndrome may vary between patients of different age and age of onset of GHD. Evidence from clinical trials and long-term observational studies has informed our ability to understand the unique considerations regarding risks and benefits of daily growth hormone replacement therapy (GHRT) and specific dosing and monitoring strategies for these patient subgroups. High rates of nonadherence with daily GHRT presents a challenge to achieving optimal treatment outcomes and long-acting growth hormone (LAGH) formulations have been developed with the promise of improving treatment adherence resulting in improved therapeutic outcomes. While existing data from short-term studies have demonstrated noninferiority of efficacy and safety of LAGH compared to daily GHRT, long-term studies are needed to assess the full spectrum of outcomes of interest and long-term safety considerations specific to patients in adolescence, adulthood and the elderly GHD population. Since each LAGH formulation has a unique pharmacodynamic and pharmacokinetic profile optimal dosing and monitoring strategies will need to be developed to allow for the provision of individualized patient treatment.

Molecular Profiling of 50 734 Bethesda III-VI Thyroid Nodules by ThyroSeq v3: Implications for Personalized Management.

CONTEXT: Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine needle aspiration (FNA) samples has not been reported. OBJECTIVE: To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. METHODS: This retrospective analysis of FNA samples, tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier at UPMC Molecular and Genomic Pathology laboratory, analyzed the prevalence of diagnostic, prognostic, and targetable genetic alterations in a total of 50 734 BCIII-VI nodules from 48 225 patients. RESULTS: Among 50 734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alterations. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.9% of cases. CONCLUSION: In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutations and targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.

U-shaped association between prevalence of secondary hypogonadism and body mass index: a retrospective analysis of men with testosterone deficiency.

The prevalence of both obesity and hypogonadism in the United States has increased over the past two decades. While prior studies have shown an association between obesity and secondary hypogonadism-low testosterone and luteinizing hormone-few have used a large enough sample size to determine prevalence at each body mass index class. We aimed to compare rates of secondary hypogonadism among body mass index classes by constructing a retrospective database with men who had their body mass index, morning testosterone and luteinizing hormone levels measured during a visit to a urology clinic at a tertiary academic medical center between 2011-2020. Men previously on testosterone replacement therapy, Clomiphene, or Anastrozole were excluded. Chi-squared analysis was conducted in "R". We found that among the 7211 men studied, 45.7%, 22.6%, and 4.4% were classified as having diagnosis of secondary, primary, and compensated hypogonadism, respectively. We found that obese men and underweight men had increased prevalence of secondary hypogonadism as compared to men with normal body mass index. These findings support the need for routine screening criteria and personalized advice to patients dealing with secondary hypogonadism.

Multidisciplinary Postoperative Care Pathway to Reduce Readmissions following Endoscopic Transsphenoidal Pituitary Surgery: Improving Quality of Patient Care.

Background Thirty-day unplanned readmission following endoscopic transsphenoidal pituitary surgery (ETPS) occurs in up to 14% of patients. Delayed hyponatremia is one of the most common causes, accounting for 30% of readmissions and often occurs within 1 week of surgery. The authors' prior retrospective review identified endocrinology follow-up as protective factor. Objectives Implementation of a multidisciplinary postoperative care (POC) pathway: (1) to reduce 30-day hospital readmissions following ETPS and (2) improve inpatient and outpatient coordination of care with endocrinologist. Methods This study is a single institution temporal cohort study of patients prior to (control cohort) and after implementation of the POC pathway (intervention cohort). The POC pathway utilized postdischarge 1 to 1.5 L/d fluid restriction, postoperative days 5 to 7 serum sodium, and endocrinology follow-up within 1 week of discharge to stratify patients into tiered hyponatremia regimens. Results A total of 542 patients were included in the study, 409 (75%) in the control cohort and 133 (25%) in the intervention cohort. All-cause readmission was significantly reduced following implementation of the POC pathway (14 vs. 6%, p = 0.015). Coordination with endocrinologist significantly increased in the inpatient (96 vs. 83%, p < 0.001) and outpatient (77 vs. 68%, p = 0.042) settings. Patients who were not in the POC pathway had the highest risk of readmission (odds ratio: 2.5; 95% confidence interval: 1.1-5.5). Conclusion A multidisciplinary POC pathway incorporating endocrinologist in conjunction with postdischarge weight-based fluid restriction and postoperative serum sodium levels can safely be used to reduce 30-day readmissions following ETPS.

Positive predictive value and trends of inferior petrosal sinus sampling (IPSS) in diagnosing cushing disease and ectopic ACTH secretion: A systematic review and meta-analysis.

BACKGROUND: Inferior petrosal sinus sampling (IPSS) offers a means of differentiating between Cushing disease and Cushing syndrome with lower false-positive and false-negative rates relative to traditional techniques. However, consolidated data on efficiency reflecting contemporary use is lacking. We present a comprehensive meta-analysis of IPSS as a means of diagnosing ACTH-cortisol axis derangements via both CRH and desmopressin-stimulated techniques. METHODS: Searches of 7 electronic databases from inception to December 2020 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. Outcomes were pooled by random-effects meta-analyses of proportions where possible. We performed a meta-analysis of sixty-eight unique publications, assessing each technique for positive predictive value (PPV), false positive rates, and overall changes in practice patterns over time. RESULTS: A total of 68 studies satisfied all criteria, with 3685 (3471, 94.2% confirmed) and 332 (285, 85.8% confirmed) patients tested for Cushing's disease and syndrome, respectively. Pooled analyses demonstrated an overall PPV of 89.3% (95%CI[83.6%, 94.0%]) in CRH stimulation diagnosis of Cushing disease. In desmopressin stimulation, our analyses demonstrated an overall PPV of 96.5% (95%CI[94.5%, 98.1%]) in diagnosis of Cushing disease. There was a significant decline in the use of CRH-stimulation IPSS in diagnosis of both Cushing disease (p = 0.0055) and Cushing syndrome (p = 0.013). Concurrently, there was a significant increase in the use of desmopressin-stimulation IPSS in diagnosis of both pathologies (p < 0.0001). CONCLUSION: Our findings demonstrate significant changes in practice patterns with respect to IPSS stimulation technique. Our pooled analyses demonstrate improved diagnostic performance in desmopressin stimulation procedures relative to CRH stimulation procedures. Further multi-institutional studies with special attention to acquiring quality data for sensitivity, specificity, and other critical analyses are necessary to truly evaluate this promising technique.

30-Day Readmissions and Coordination of Care Following Endoscopic Transsphenoidal Pituitary Surgery: Experience with 409 Patients.

Objective The study aimed to (1) quantify readmission rates and common causes of readmission following endoscopic transsphenoidal pituitary surgery (ETPS); (2) identify risk factors that may predict readmission within 30 days; (3) assess postoperative care coordination with endocrinology follow-up; and (4) identify patients for whom targeted interventions may reduce 30-day readmissions. Methods Retrospective quality improvement review of patients with pituitary adenoma who underwent ETPS from December 2010 to 2018 at a single tertiary care center. Results A total of 409 patients were included in the study, of which 57 (13.9%) were readmitted within 30 days. Hyponatremia was the most common cause of readmission (4.2%) followed by pain/headache (3.9%), cerebrospinal fluid leak (3.4%), epistaxis (2.7%), hypernatremia (1.2%), and adrenal insufficiency (1.2%). Patients with hyponatremia were readmitted significantly earlier than other causes (4.3 ± 2.2 vs. 10.6 ± 10.9 days from discharge, p = 0.032). Readmitted patients had significantly less frequent outpatient follow-up with an endocrinologist than the nonreadmitted cohort (56.1 vs. 70.5%, p = 0.031). Patients who had outpatient follow-up with an endocrinologist were at lower risk of readmission compared with those without (odds ratio: 0.46; 95% confidence interval: 0.24-0.88). Conclusion Delayed hyponatremia is one of the most common causes of 30-day readmission following ETPS. Postoperative follow-up with an endocrinologist may reduce risk of 30-day readmission following ETPS. Implications for Clinical Practice A multidisciplinary team incorporating otolaryngologist, neurosurgeons, and endocrinologist may identify patients at risk of 30-day readmissions. Protocols checking serum sodium within 1 week of surgery in conjunction with endocrinologist to tailor fluid restriction may reduce readmissions from delayed hyponatremia.

Corrigendum: Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

[This corrects the article DOI: 10.3389/fendo.2021.662865.].

Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

Introduction/Purpose: Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). Materials and Methods: A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%). Results: 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred. Conclusions: The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

Decline in Serum Testosterone Levels Among Adolescent and Young Adult Men in the USA.

Testosterone deficiency has a prevalence of 20% among adolescent and young adult (AYA) males. Although previous studies have shown that total testosterone (TT) levels are declining in the population compared to prior decades, no study has identified TT level trends for AYA males specifically. Using data from the National Health and Nutrition Examination Surveys, we investigated TT levels for 4045 men from 1999 to 2016. After controlling for confounders, we found that mean TT levels declined over time: TT levels were lower in the later (2011-2016) than in the earlier (1999-2000) cycles (all p < 0.001). Elevated body mass index (BMI) was associated with lower TT, but the trend remained significant even among men with normal BMI. Limitations include the influence of confounding variables such as environmental factors and the use of differing assays for TT measurement. Further studies using other data streams are needed to validate these findings. PATIENT SUMMARY: In this report we looked at data for adolescent and young adult men in a US national database on total testosterone (TT) levels. There has been a decline in mean TT levels over the past two decades and TT is lower with progressively higher body mass index. We conclude that TT levels have been declining in young adult men in recent decades.

Association of Leptin with Total and Free Testosterone: Results from the National Health and Nutrition Examination Surveys.

INTRODUCTION: Obese men can have testosterone deficiency (TD) but the etiology is uncertain. Leptin is a 16-kDa protein produced primarily by adipose tissue and, therefore, is positively associated with the amount of body fat and can affect testosterone (T) production. We hypothesized that increased leptin can be independently associated with low T. MATERIALS AND METHODS: We performed a cross-sectional analysis of men from National Health and Nutrition Examination III database to evaluate the association of leptin with serum T and calculated free testosterone (cFT). Linear regression was performed with leptin, age, waist circumference, hypertension, and diabetes as independent variables predicting cFT/T. Multiple linear regression was used to determine predictors for cFT and T using variables previously significant in the univariate analysis. RESULTS: A total of 1193 men were analyzed. As expected, older and obese men were associated with having lower T. Interestingly, increasing leptin levels were an independent predictor of decreasing T and cFT on multivariable analysis. Increasing 1ng/mL in leptin resulted in a decrease of 5.13 and 0.11 ng/dL of T and cFT, respectively (p < 0.05). Also, every additional year of life led to a T and cFT reduction of 2.87 and 0.13 ng/dL, respectively, and increasing 1 cm in waist circumference corresponded to decrease of 4ng/dL in T (p < 0.05). CONCLUSIONS: We concluded that increasing leptin, age, and waist circumference were associated with decreasing of T and cFT. Elevated leptin levels could be one of the potential etiologies of TD.

Elevated Body Mass Index Is Associated with Secondary Hypogonadism Among Men Presenting to a Tertiary Academic Medical Center.

PURPOSE: To characterize the population of hypogonadal men who presented to a tertiary academic urology clinic and evaluate risk factors for primary vs. secondary hypogonadism. MATERIALS AND METHODS: We evaluated all men with International Classification of Diseases-9 diagnosis codes R68.82 and 799.81 for low libido, 257.2 for testicular hypofunction, and E29.1 for other testicular hypofunction at a tertiary academic medical center from 2013 to 2017. We included men who had testosterone (T) and luteinizing hormone (LH) drawn on the same day. We classified men based on T and LH levels into eugonadal, primary, secondary, and compensated hypogonadism. Risk factors including age, body mass index (BMI) over 30 kg/m², current smoking status, alcohol use greater than 5 days per week, and Charlson comorbidity index greater than or equal to 1 were investigated and measured in each group using the eugonadal group for reference. RESULTS: Among the 231 men who had both T and LH levels, 7.4%, 42.4%, and 7.4% were classified as primary, secondary, and compensated hypogonadism, respectively. Only elevated BMI was associated with secondary hypogonadism compared to eugonadal men (median BMI, 30.93 kg/m² vs. 27.69 kg/m², p=0.003). BMI, age, comorbidities, smoking, or alcohol use did not appear to predict diagnosis of secondary hypogonadism. CONCLUSIONS: Secondary hypogonadism appears to be the most common cause of hypogonadism among men complaining of low T and decreased libido at a tertiary academic medical center. Secondary hypogonadism is associated with elevated BMI and therefore obesity should be used as a marker to evaluate men for both T and LH levels.

Successful Treatment of Acromegaly and Associated Hypogonadism with First-Line Clomiphene Therapy.

Clomiphene citrate (CC) has been reported as an effective add-on therapy to somatostatin analogs and dopamine agonists in patients with acromegaly accompanied by hypogonadism; its use as a single agent to treat acromegaly and associated hypogonadism following incomplete surgery has not been previously reported. We report the first case in which clomiphene was utilized as a single agent for the dual management of acromegaly and hypogonadism, not controlled by pituitary surgery alone. The treatment was well tolerated and proved to be effective after a process of treatment withdrawal and reintroduction. We propose that clomiphene may be considered as a cost-effective oral treatment option in select cases of hypogonadal acromegaly.

Thyroid Storm Triggered by Strangulation in a Patient with Undiagnosed Graves' Disease.

Thyroid storm is the life-threatening end-organ manifestation of severe thyrotoxicosis. If left untreated, thyroid storm may cause acute heart failure, multiorgan dysfunction, and death. A high degree of suspicion is necessary to make the diagnosis and start antithyroid medications to decrease mortality. Thyroid storm is generally seen in patients with Graves' disease but should also be suspected in patients with fever, tachycardia, altered mental status, and risk factors including local trauma to the neck, such as strangulation. Based on our review, we report the first case of thyroid storm after strangulation as the presentation of previously undiagnosed Graves' disease.

Genomic Profiling of Thyroid Nodules: Current Role for ThyroSeq Next-Generation Sequencing on Clinical Decision-Making.

In recent years there has been an increased awareness of the genetic alterations underlying both benign and malignant neoplasms of the thyroid. Next-generation sequencing (NGS) is an emerging technology that allows for rapid detection of a large number of genetic mutations in thyroid fine-needle aspiration (FNA) specimens. NGS for targeted mutational analysis in thyroid tumors has been proposed as a tool to assist in the diagnosis of thyroid nodules with indeterminate FNA cytology. Results of genomic testing of thyroid nodules and thyroid cancers could also have prognostic implications and play a role in determining optimal treatment strategies including targeted therapies. We provide a critical review of existing studies assessing the performance of the ThyroSeq NGS test for the diagnosis and management of patients with thyroid nodules with indeterminate cytopathology and discuss the applicability of findings from these studies to clinical practice. While there are early indications to suggest a possible utility of data obtained from NGS to aid in prognostication and therapeutic decision-making in thyroid cancer, we recommend judicious use and cautious interpretation of such molecular testing until results of ongoing clinical trials become available. Lastly, we discuss recommendations provided from clinical practice guidelines regarding the use of mutation detection via NGS in the diagnostic evaluation of thyroid nodules.

Autoimmune lymphocytic hypophysitis in association with autoimmune eye disease and sequential treatment with infliximab and rituximab.

INTRODUCTION: Autoimmune lymphocytic hypophysitis associates predominantly with other autoimmune endocrinopathies and is most commonly treated with glucocorticoids and/or decompressive pituitary surgery. Here we report a new association and treatment modality for lymphocytic hypophysitis. METHODS: A 52-year-old woman presented with scleritis, uveitis, facial palsy, and central diabetes insipidus, accompanied by thickened pituitary stalk and enlarged pituitary on cranial MRI. Neurosarcoidosis was suspected and treatment with glucocorticoids and methotrexate initiated. Since symptoms persisted, infliximab (a monoclonal antibody that antagonizes tumor necrosis factor alpha) was added to her regimen. The patient initially improved but after 6 months developed recurrent pituitary enlargement, bilateral optic neuritis, and panhypopituitarism. To ascertain the nature of the pituitary lesion, she underwent transsphenoidal biopsy, which revealed lymphocytic hypophysitis with numerous CD20 positive B lymphocytes. The pathological finding suggested to us that administration of rituximab (a monoclonal antibody that lyzes B cells expressing CD20) could be useful. Following two courses of rituximab, the pituitary mass resolved and the corticotroph axis partially recovered. The patient has remained in remission during 3 years of follow up. CONCLUSION: This is the first report of hypophysitis occurring with the triad of scleritis, uveitis, and optic neuritis, as well as the first immunotherapy based on the sequential use of infliximab and rituximab.

Adipose tissue and adrenal glands: novel pathophysiological mechanisms and clinical applications.

Hormones produced by the adrenal glands and adipose tissues have important roles in normal physiology and are altered in many disease states. Obesity is associated with changes in adrenal function, including increase in adrenal medullary catecholamine output, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, elevations in circulating aldosterone together with changes in adipose tissue glucocorticoid metabolism, and enhanced adipocyte mineralocorticoid receptor activity. It is unknown whether these changes in adrenal endocrine function are in part responsible for the pathogenesis of obesity and related comorbidities or represent an adaptive response. In turn, adipose tissue hormones or "adipokines" have direct effects on the adrenal glands and interact with adrenal hormones at several levels. Here we review the emerging evidence supporting the existence of "cross talk" between the adrenal gland and adipose tissue, focusing on the relevance and roles of their respective hormones in health and disease states including obesity, metabolic syndrome, and primary disorders of the adrenals.

Adult growth hormone deficiency - benefits, side effects, and risks of growth hormone replacement.

Deficiency of growth hormone (GH) in adults results in a syndrome characterized by decreased muscle mass and exercise capacity, increased visceral fat, impaired quality of life, unfavorable alterations in lipid profile and markers of cardiovascular risk, decrease in bone mass and integrity, and increased mortality. When dosed appropriately, GH replacement therapy (GHRT) is well tolerated, with a low incidence of side effects, and improves most of the alterations observed in GH deficiency (GHD); beneficial effects on mortality, cardiovascular events, and fracture rates, however, remain to be conclusively demonstrated. The potential of GH to act as a mitogen has resulted in concern over the possibility of increased de novo tumors or recurrence of pre-existing malignancies in individuals treated with GH. Though studies of adults who received GHRT in childhood have produced conflicting reports in this regard, long-term surveillance of adult GHRT has not demonstrated increased cancer risk or mortality.

Diagnosis and treatment of growth hormone deficiency in adults.

The availability of synthetic recombinant human growth hormone (GH) in potentially unlimited quantities since the 1980s has improved understanding of the many nonstatural effects of GH on metabolism, body composition, physical and psychological function, as well as the consequences of GH deficiency in adult life. Adult GH deficiency is now recognized as a distinct if nonspecific syndrome with considerable adverse health consequences. GH replacement therapy in lower doses than those used in children can reverse many of these abnormalities and restore functional capacities toward or even to normal; if dosed appropriately, GH therapy has few adverse effects. Although some doubts remain about possible long-term risks of childhood GH therapy, most registries of adult GH replacement therapy, albeit limited in study size and duration, have not shown an increased incidence of cancers or of cardiovascular morbidity or mortality.