The distinct and potentially conflicting effects of tDCS and tRNS on brain connectivity, cortical inhibition, and visuospatial memory.

Noninvasive brain stimulation (NIBS) techniques, including transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS), are emerging as promising tools for enhancing cognitive functions by modulating brain activity and enhancing cognitive functions. Despite their potential, the specific and combined effects of tDCS and tRNS on brain functions, especially regarding functional connectivity, cortical inhibition, and memory performance, are not well-understood. This study aims to explore the distinct and combined impacts of tDCS and tRNS on these neural and cognitive parameters. Using a within-subject design, ten participants underwent four stimulation conditions: sham, tDCS, tRNS, and combined tDCS + tRNS. We assessed the impact on resting-state functional connectivity, cortical inhibition via Cortical Silent Period (CSP), and visuospatial memory performance using the Corsi Block-tapping Test (CBT). Our results indicate that while tDCS appears to induce brain lateralization, tRNS has more generalized and dispersive effects. Interestingly, the combined application of tDCS and tRNS did not amplify these effects but rather suggested a non-synergistic interaction, possibly due to divergent mechanistic pathways, as observed across fMRI, CSP, and CBT measures. These findings illuminate the complex interplay between tDCS and tRNS, highlighting their non-additive effects when used concurrently and underscoring the necessity for further research to optimize their application for cognitive enhancement.

Genital Surgery Outcomes Using an Individualized Algorithm for Hormone Management in Transfeminine Individuals.

CONTEXT: Transgender and gender diverse (TGD) individuals have greater access to genital surgery (GS) with improved insurance coverage and access to trained surgeons and interdisciplinary gender affirming providers. OBJECTIVE: To determine perioperative medical and behavioral health outcomes in transfeminine (TF) individuals undergoing GS with use of a specific gender-affirming hormone therapy (GAHT) algorithm based on individualized risk factor assessment. DESIGN: Retrospective observational cohort study from 2017-2022. Pre- and post-operative data collected included clinical and biochemical assessment, GAHT regimens, validated behavioral health measures, and post-operative complications. SETTING: Single-center tertiary referral center. PATIENTS: 183 TF individuals, grouped into estradiol continued (Group 1) vs estradiol temporarily discontinued for 2-6 weeks preoperatively (Group 2). MAIN OUTCOME MEASURE(S): Venous thromboembolism (VTE) incidence, non-VTE postoperative complication incidence, and change in behavioral health assessments. RESULTS: The majority of individuals continued estradiol perioperatively [Group 1; 138 (75.4%)]. Individuals who temporarily held estradiol preoperatively [Group 2; 45 (24.6%)] were statistically older (p < 0.01), had higher incidence of cardiometabolic comorbidities (p < 0.01), and higher Caprini scores (p < 0.01). Group 1 was statistically more likely to use oral estradiol (p < 0.01). One episode (0.05%) of VTE occurred (Group 1). There was no significant difference in postoperative complications or behavioral health measures between groups. CONCLUSION: An individualized algorithm for preoperative hormone management for TF GS resulted in perioperative continuation of GAHT for the majority of individuals without significantly increasing the risk for post-operative surgical complications while maintaining stable behavioral health measures perioperatively.

The clinical presentation of PIT1 positive pituitary neuroendocrine tumor immunonegative for growth hormone, prolactin, and thyroid stimulating hormone with analysis of clinical and immunostaining dissociation.

BACKGROUND: PIT1 is a pituitary transcription factor that is associated with either growth hormone (GH), prolactin (PRL), or thyroid-stimulating hormone (TSH) production. However, PIT1-positive pituitary neuroendocrine tumors (PitNETs) are occasionally immunonegative for GH, PRL, and TSH. This paper describes the clinical presentation of PIT1 positive however immunonegative PitNETs. METHODS: We conducted a retrospective analysis, identifying 228 PIT1-positive PitNET patients between 2017 and 2022. Out of these, ten (4%) tested negative for GH, PRL, and TSH. Functioning PitNETs were defined as those causing hormonal excess symptoms or hormonal overproduction. RESULTS: As for 10 patients immunonegative for all three hormones however PIT1-positive, the mean ( ± standard deviation) age was 46 ± 13 years with 70% women. Six patients exhibited signs of excess GH or PRL, and three had visual problems. Additionally, one patient had secondary hypothyroidism and adrenal insufficiency resulting from the mass effect. All tumors were macroadenoma, with a median volume of 2.1 cm3 (range, 0.8-17.5 cm3). Gross total resection was attained in six patients by trans-sphenoidal surgery. Postoperatively, eight patients experienced clinical improvement: three in vision, two in amenorrhea, two in headache, and one in acromegaly symptoms. Biochemical improvement was observed in six patients, with all experiencing remission in hormonal excess and one showing improvement in secondary hypothyroidism. Stereotactic radiosurgery was performed in three patients. CONCLUSIONS: Patients with functioning PitNETs may exhibit PIT1 staining without GH, PRL, or TSH staining. Hormonally active tumors exist in this patient population; therefore, close endocrine follow-up is necessary despite the lack of staining for GH, PRL, and TSH.

A False Pituitary Tumor.

A false pituitary tumor describes pituitary enlargement due to intracranial hypotension. Reported previously primarily in the neurological literature, we present this case referred to endocrinology for evaluation of a pituitary mass. A 24-year-old male was referred to endocrinology for evaluation of pituitary enlargement without a hypo-enhancing lesion on magnetic resonance imaging (MRI). The main symptom reported was headache that was worse in the standing position and in the afternoon. He had no symptoms or signs of pituitary mass-effect, or hormone excess or deficiencies. Past medical history was relevant for a history of nerve schwannoma status post resection with subsequent spinal fusion. Biochemical evaluation of pituitary hormones was normal. Upon review of his pituitary MRI, other abnormalities seen were suggestive of intracranial hypotension. Based on his history and imaging findings, he was diagnosed with intracranial hypotension causing a "false pituitary tumor" rather than pituitary enlargement or abnormality. Further evaluation revealed multiple spinal leaks that were patched. His symptoms subsided within a few days of repair. Endocrinologists should be aware of the possible misdiagnosis of a pituitary mass due to intracranial hypotension.

Hyperbaric Oxygen Therapy Adjuvant Chemotherapy and Radiotherapy through Inhibiting Stemness in Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor in adults. Despite the advances in GBM treatment, outcomes remain poor, with a 2-year survival rate of less than 5%. Hyperbaric oxygen (HBO) therapy is an intermittent, high-concentration, short-term oxygen therapy used to increase cellular oxygen content. In this study, we evaluated the effects of HBO therapy, alone or combined with other treatment modalities, on GBM in vitro and in vivo. In the in vitro analysis, we used a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess the effects of HBO therapy alone, a colony formation assay to analyze the effects of HBO therapy combined with radiotherapy and with temozolomide (TMZ), and a neurosphere assay to assess GBM stemness. In the in vivo analysis, we used immunohistochemical staining and in vivo bioluminescence imaging to assess GBM stemness and the therapeutic effect of HBO therapy alone or combined with TMZ or radiotherapy, respectively. HBO therapy did not affect GBM cell viability, but it did reduce the analyzed tumors' ability to form cancer stem cells. In addition, HBO therapy increased GBM sensitivity to TMZ and radiotherapy both in vitro and in vivo. HBO therapy did not enhance tumor growth and exhibited adjuvant effects to chemotherapy and radiotherapy through inhibiting GBM stemness. In conclusion, HBO therapy shows promise as an adjuvant treatment for GBM by reducing cancer stem cell formation and enhancing sensitivity to chemotherapy and radiotherapy.

Comparison of the Subcutaneous and Intramuscular Estradiol Regimens as Part of Gender-Affirming Hormone Therapy.

OBJECTIVE: Gender-affirming hormone therapy guidelines describe the estradiol (E2) doses for intramuscular (IM), but not subcutaneous (SC), routes. The objective was to compare the SC and IM E2 doses and hormone levels in transgender and gender diverse individuals. METHODS: This is a retrospective cohort study at a single-site tertiary care referral center. Patients were transgender and gender diverse individuals who received injectable E2 with at least 2 E2 measurements. The main outcomes were the dose and serum hormone levels between the SC and IM routes. RESULTS: There were no statistically significant differences in age, body mass index, or antiandrogen use between patients on SC (n = 74) and those on IM (n = 56). The weekly doses of SC E2, 3.75 mg (IQR, 3-4 mg), were statistically significantly lower than those of IM E2, 4 mg (IQR, 3-5.15 mg) (P =.005); however, the E2 levels achieved were not significantly different (P =.69), and the testosterone levels were in the cisgender female range and not significantly different between routes (P =.92). Subgroup analysis demonstrated significantly higher doses in the IM group when the E2 and testosterone levels were >100 pg/mL and <50 ng/dL, respectively, with the presence of the gonads or use of antiandrogens. Multiple regression analysis demonstrated that the dose was significantly associated with the E2 levels after adjusting for injection route, body mass index, antiandrogen use, and gonadectomy status. CONCLUSION: Both the SC and IM E2 achieve therapeutic E2 levels without a significant difference in the dose (3.75 vs 4 mg). SC may achieve therapeutic levels at lower doses than IM .

Artificial Intelligence-Augmented Electrocardiogram in Determining Sex: Correlation with Sex Hormone Levels.

OBJECTIVE: To study the relationship between the sex probability derived from the artificial intelligence (AI)-augmented electrocardiogram (ECG) and sex hormone levels. PATIENTS AND METHODS: Adult patients with total testosterone (TT; ng/dL) or estradiol (E2; pg/mL) levels (January 1, 2000, to December 31, 2020) with ECGs obtained within 6 months of the blood sample were identified. The closest ECG to the blood test was used. The AI-ECG model output ranges from 0.0 to 1.0, with higher numbers indicating high probability of being male. Low male probability was defined as ≤0.3, intermediate as 0.31 to 0.69, and high as ≥0.7. Continuous variables are expressed as median (interquartile range). RESULTS: Paired TT-ECGs were available in 58,084 male subjects and 11,190 female subjects. Paired E2-ECGs were available in 2835 male patients and 18,228 female patients. TT levels had moderate positive correlation with AI-ECG male sex probability (r=0.46, P<.001). Male subjects with low AI-ECG male sex probability had lower TT and higher E2 levels compared with men with high probability (TT: 303 [129-474] vs 381 [264-523], P <.001; E2: 35 [21-49] vs 32 [22-38], P=.05). Female subjects with high AI-ECG male sex probability had higher TT and lower E2 levels compared with those who had low male probability (TT: ≤50 years of age: 31 [18-55] vs 26 [16-39], P<.001; >50 years of age: 27 [12-68] vs 20 [12-34], P<.001; E2: ≤50 years of age: 58 [30-124] vs 47 [25-87], P=.001; >50 years of age: 30 [10-55] vs 21 [10-41], P=.006). CONCLUSION: In this study, TT levels were lower and E2 levels higher with decreasing AI-ECG male probability in both sexes. Male and female patients with discordant AI-ECG sex probability had significantly different TT or E2 levels. This suggests that the ECG could be used as a biomarker of hormone status.

Distinctions in PCOS Induced by Letrozole Vs Dehydroepiandrosterone With High-fat Diet in Mouse Model.

Polycystic ovarian syndrome (PCOS) is a complex health condition associated with metabolic disturbances and infertility. Recent data suggest that the prevalence of PCOS is increasing among women globally, although the etiology of these trends is undefined. Consequently, preclinical models that better reflect the biology of PCOS are urgently needed to facilitate research that can lead to the discovery of prevention strategies or improved management. The existing animal models have several limitations as they do not reflect all the PCOS features metabolically and/or phenotypically. Therefore, there is no clear consensus on the use of appropriate animal model and selection of the most appropriate PCOS-inducing agent. To that end, we have established a Swiss albino mouse model of PCOS based on 3 weeks of daily treatment with letrozole (50 µg/day; intraperitoneal) and dehydroepiandrosterone (DHEA, 6 mg/100 g body weight; subcutaneous) in 5-week-old female mice fed on normal or high-fat diet (HFD). Mice were regularly assessed for body weight, blood glucose, and estrous cycle. Three weeks after drug administration, mice were sacrificed and assessed for blood-based metabolic parameters as well as ovarian function. Our results indicate that DHEA combined with HFD produces changes mimicking those of clinical PCOS, including elevated serum testosterone and luteinizing hormone, dyslipidemia, poor ovarian microenvironment, and development of multiple ovarian cysts, recapitulating cardinal features of PCOS. In comparison, normal diet and/or letrozole produced fewer features of PCOS. The data from the experimental models presented here can improve our understanding of PCOS, a growing concern in women's health.

Oral short-chain fatty acids administration regulates innate anxiety in adult microbiome-depleted mice.

Anxiety is characterized by feelings of tension and worry even in the absence of threatening stimulus. Pathological condition of anxiety elicits defensive behavior and aversive reaction ultimately impacting individuals and society. The gut microbiota has been shown to contribute to the modulation of anxiety-like behavior in rodents through the gut-brain axis. Several studies observed that germ-free (GF) and the broad spectrum of antibiotic cocktail (ABX)-treated rodents display lowered anxiety-like behavior. We speculate that gut microbial short-chain fatty acids (SCFA) modulate the innate anxiety response. Herein, we administered SCFA in the drinking water in adult mice treated with ABX to deplete the microbiota and tested their anxiety-like behavior. To further augment the innate fear response, we enhanced the aversive stimulus of the anxiety-like behavior tests. Strikingly, we found that the anxiety-like behavior in ABX mice was not altered when enhanced aversive stimulus, while control and ABX mice supplemented with SCFA displayed increased anxiety-like behavior. Vagus nerve serves as a promising signaling pathway in the gut-brain axis. We determined the role of vagus nerve by subdiaphragmatic vagotomy (SDV) in ABX mice supplemented with SCFA. We found that the restored anxiety-like behavior in ABX mice by SCFA was unaffected by SDV. These findings suggest that gut microbiota can regulate anxiety-like behavior through their fermentation products SCFA.

Association between the Serum Coenzyme Q10 Level and Seizure Control in Patients with Drug-Resistant Epilepsy.

Drug-resistant epilepsy (DRE) is a chronic neurological disorder with somatic impacts and increased risk of metabolic comorbidities. Oxidative stress might play an important role in metabolic effects and as a regulator of seizure control, while coenzyme Q10 (CoQ10) could improve insulin sensitivity through antioxidant effects. We aimed to investigate the association between CoQ10 level and clinical outcome, represented by the seizure frequency and quality of life, in DRE patients. DRE patients (N = 33) had significantly higher serum insulin levels and lower scores on the physical domain of the World Health Organization Quality of Life questionnaire (WHOQoL) than gender-age matched controls. The serum CoQ10 level (2910.4 ± 1163.7 ng/mL) was much higher in DRE patients than the normal range. Moreover, the serum CoQ10 level was significantly correlated with the seizure frequency (r = -0.412, p = 0.037) and insulin level (r = 0.409, p = 0.038). Based on stratification by insulin resistance (HOMA-IR > 2.4), the subgroup analysis showed that patients with a greater HOMA-IR had higher CoQ10 levels and lower seizure frequency, and had a significantly worse quality of life. In summary, CoQ10 could be a mediator involved in the mechanism of epilepsy and serve as a biomarker of the clinical outcome in DER patients.

Association between Blood Pressure, Blood Pressure Variability, and Post-Stroke Cognitive Impairment.

After stroke, dynamic changes take place from necrotic-apoptotic continuum, inflammatory response to poststroke neurogenesis, and remodeling of the network. These changes and baseline brain pathology such as small vessel disease (SVD) and amyloid burden may be associated with the occurrence of early or late poststroke cognitive impairment (PSCI) or dementia (PSD), which affect not only stroke victims but also their families and even society. We reviewed the current concepts and understanding of the pathophysiology for PSCI/PSD and identified useful tools for the diagnosis and the prediction of PSCI in serological, CSF, and image characteristics. Then, we untangled their relationships with blood pressure (BP) and blood pressure variability (BPV), important but often overlooked risk factors for PSCI/PSD. Finally, we provided evidence for the modifying effects of BP and BPV on PSCI as well as pharmacological and non-pharmacological interventions and life style modification for PSCI/PSD prevention and treatment.

Secondary Adrenal Insufficiency and Growth Hormone Deficiency in Patients with Fibromyalgia.

PURPOSE: Patients with fibromyalgia (FM) may demonstrate low cortisol concentrations during diagnostic evaluation. However, it remains unclear whether low cortisol reflects underlying pituitary dysfunction. We aimed to determine if a subset of patients with FM have concomitant secondary adrenal insufficiency (SAI) and growth hormone deficiency (GH). PATIENTS AND METHODS: This is a retrospective study of all patients with FM diagnosed with SAI based on abnormal insulin tolerance test (ITT) between June 2002 and August 2019. Patients were excluded if they had other reasons for SAI. Measurements include cortisol and GH during ITT in all patients, and peak cortisol during cosyntropin stimulation test in a subset of patients. RESULTS: We identified 22 patients (median age of 38 years (range 19-65), 18 (82%) women) diagnosed with secondary AI based on abnormal ITT (peak median cortisol level of 11 mcg/dL (range 5.4-17)). Concomitant GH deficiency was diagnosed in 19 (86%) patients. Cosyntropin stimulation test was performed in 14 (64%) patients and was normal in 11 (79%) (peak cortisol ≥18 mcg/dL). MRI pituitary imaging was performed in 20 patients and showed no significant pituitary pathology. All patients were started on physiologic glucocorticoid replacement, and 5 patients were started on GH replacement. Of the 13 patients with follow-up, 8 (62%) reported symptom improvement after starting treatment. CONCLUSION: Patients with FM can have concurrent SAI and GH deficiency. Cosyntropin stimulation test should not be used to exclude SAI in patients with FM. Appropriate glucocorticoid and/or GH replacement may improve symptoms in some patients.

Mifepristone as Bridge or Adjunct Therapy in the Management of Challenging Cushing Disease Cases.

Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical heterogeneity, initiating effective treatment to control the effects of hypercortisolism, and managing recurrence are challenging disease aspects to address. Mifepristone is a competitive glucocorticoid receptor antagonist that is approved in the US by the Food and Drug Administration to control hyperglycemia secondary to endogenous hypercortisolism (Cushing syndrome) in patients who have glucose intolerance or type 2 diabetes mellitus and have failed surgery or are not candidates for surgery. Herein, we describe 6 patients with CD who received mifepristone as adjunct/bridge therapy in the following clinical settings: to assess clinical benefits of treatment for suspected recurrent disease, to control hypercortisolism preoperatively for severe disease, to control hypercortisolism during the COVID-19 pandemic, and to provide adjunctive treatment to radiation therapy. The patients were treated at multiple medical practice settings. Mifepristone treatment in each of the described cases was associated with clinical improvements, including improvements in overall glycemia, hypertension, and weight loss. In addition, in one case where biochemical and radiological evidence of disease recurrence was uncertain, clinical improvement with mifepristone pointed toward likely disease recurrence. Adverse events associated with mifepristone reported in the 6 cases were consistent with those previously reported in the pivotal trial and included cortisol withdrawal symptoms, antiprogesterone effects (vaginal bleeding), hypothyroidism (treated with levothyroxine), and hypokalemia (treated with spironolactone). These cases show how mifepristone can potentially be utilized as a therapeutic trial in equivocal cases of CD recurrence; as a presurgical treatment strategy, particularly during the COVID-19 pandemic; and as bridge therapy, while awaiting the effects of radiation.

A community-based study of demographics, medical and psychiatric conditions, and gender dysphoria/incongruence treatment in transgender/gender diverse individuals.

BACKGROUND: Current understanding about health care in the gender diverse population is limited by the lack of community-based, longitudinal data, especially in the USA. We sought to characterize a community-based cohort of transgender individuals including demographics, gender identities, social characteristics, psychiatric and medical conditions, and medical therapy for gender dysphoria/incongruence. PATIENTS AND METHODS: We performed a retrospective chart review of gender diverse residents of Olmsted County, Minnesota, who sought gender-specific healthcare from January 1, 1974, through December 31, 2015, using an infrastructure that links medical records of Olmsted County residents from multiple institutions. RESULTS: The number of patients seeking gender-specific healthcare increased from 1 to 2 per 5-year interval during the 1970s-1990s to 41 from 2011 to 2015 (n = 82). Forty-nine (59.8%) were assigned male sex at birth (AMAB), 31 (37.8%) were assigned female (AFAB), and 2 (2.4%) were intersex. Gender identities evolved over time in 16.3% and 16.1% of patients AMAB and AFAB, respectively, and at most recent follow-up, 8.2% and 12.9% of patients AMAB and AFAB, respectively, were non-binary. Depression affected 78%, followed by anxiety (62.2%), personality disorder (22%), and post-traumatic stress disorder (14.6%). 58.5% experienced suicidal ideation, 22% attempted suicide, and 36.6% were victims of abuse. The most prevalent medical conditions and cardiovascular (CV) risk factors included obesity (42.7%), tobacco use (40.2%), fracture [34.1% (86.2% traumatic)], hypertension (25.6%), hyperlipidemia (25.6%), and hypertriglyceridemia (15.9%). 67.3% of patients AMAB used feminizing and 48.4% of patients AFAB used masculinizing hormone therapy. When compared to US CDC National Health Statistics, there was a significantly greater prevalence of depression and anxiety but no difference in the prevalence of obesity, hypertension, hypercholesterolemia, type 2 diabetes, or stroke. CONCLUSION: Transgender and gender diverse individuals represent a population who express various gender identities and are seeking gender-specific healthcare at increasing rates. Psychiatric illness is highly prevalent compared to the US population but there is no difference in the prevalence of CV risk factors including obesity, type 2 diabetes, hypertension, and dyslipidemia.

An Open Pilot Study of the Effect and Tolerability of Add-On Multivitamin Therapy in Patients with Intractable Focal Epilepsy.

Observational studies have investigated the potential modulatory effect of neuronal excitability by vitamins in epilepsy. We aimed to investigate whether the addition of multivitamin therapy (B6/B9, D, E and Q) to regular antiepileptic drug therapy could ameliorate seizures in patients with refractory focal epilepsy. We conducted a prospective cohort open study to investigate the effect and tolerability of add-on multivitamin therapy (daily dose: B6 100 mg, B9 5 mg, D 1000 IU, E 400 IU and coenzyme Q10 100 mg) in patients with intractable focal epilepsy. All patients had effect and safety assessments at baseline and after one, three and six months of the supplementation. Thirty patients (11 men and 19 women) with a mean age of 42.37 ± 9.40 years were recruited and four patients discontinued. The seizure frequency significantly decreased after the six-month supplementation (9.04 ± 18.16/month and 2.06 ± 3.89/month, p = 0.045). At the final visit, 62.5% of the patients showed a ≥50% reduction in seizure frequency, and 12.5% were seizure-free. As to safety and tolerability, most patients did not experience significant adverse events, although three patients reported seizure worsening. In conclusion, this pilot study demonstrated the therapeutic potential and essentially good tolerability of add-on multivitamin therapy in patients with refractory focal epilepsy.

A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia.

CONTEXT: Patients with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic glucocorticoid doses to suppress adrenocorticotropic hormone (ACTH) and control androgen excess. Nevanimibe hydrochloride (ATR-101), which selectively inhibits adrenal cortex function, might reduce androgen excess independent of ACTH and thus allow for lower glucocorticoid dosing in CAH. 17-hydroxyprogesterone (17-OHP) and androstenedione are CAH biomarkers used to monitor androgen excess. OBJECTIVE: Evaluate the efficacy and safety of nevanimibe in subjects with uncontrolled classic CAH. DESIGN: This was a multicenter, single-blind, dose-titration study. CAH subjects with baseline 17-OHP ≥4× the upper limit of normal (ULN) received the lowest dose of nevanimibe for 2 weeks followed by a single-blind 2-week placebo washout. Nevanimibe was gradually titrated up if the primary outcome measure (17-OHP ≤2× ULN) was not met. A total of 5 nevanimibe dose levels were possible (125, 250, 500, 750, 1000 mg twice daily). RESULTS: The study enrolled 10 adults: 9 completed the study, and 1 discontinued early due to a related serious adverse event. At baseline, the mean age was 30.3 ±â€…13.8 years, and the maintenance glucocorticoid dose, expressed as hydrocortisone equivalents, was 24.7 ±â€…10.4 mg/day. Two subjects met the primary endpoint, and 5 others experienced 17-OHP decreases ranging from 27% to 72% during nevanimibe treatment. The most common side effects were gastrointestinal (30%). There were no dose-related trends in adverse events. CONCLUSIONS: Nevanimibe decreased 17-OHP levels within 2 weeks of treatment. Larger studies of longer duration are needed to further evaluate its efficacy as add-on therapy for CAH.

Radiosurgical Management of Patients With Persistent or Recurrent Cushing Disease After Prior Transsphenoidal Surgery: A Management Algorithm Based on a 25-Year Experience.

BACKGROUND: Patients with persistent or recurrent Cushing disease (CD) after prior transsphenoidal surgery require further treatment to reduce the disease's metabolic consequences. OBJECTIVE: To assess patient outcomes after stereotactic radiosurgery (SRS) for persistent or recurrent CD from adrenocorticotropin hormone (ACTH)-secreting pituitary adenomas and propose a management algorithm. METHODS: Retrospective review of 38 patients without prior radiation treatment having SRS for ACTH-secreting pituitary adenomas from 1990 to 2015. Favorable outcome was defined as biochemical remission and tumor growth control. Patients were evaluated separately if they underwent bilateral adrenalectomy (Adx). RESULTS: Twenty patients (53%) were treated with Adx and SRS (median margin dose, 25 Gy) and 18 patients (47%) received SRS alone (median margin dose, 22.5 Gy). Median follow-up after SRS was 76 mo. Of patients undergoing Adx, 18/20 (90%) had a favorable outcome. Two patients (10%) had tumor growth requiring additional treatment. A favorable outcome was achieved in 13/18 patients (72%) having SRS alone (median, 14 mo; interquartile range, 8-23). Five patients (28%) required additional treatment due to persistent hypercortisolemia (n = 4) or hypercortisolemia and tumor growth (n = 1). Favorable outcomes were more frequent in the Adx and SRS group at 1 yr (100% vs 33%; P < .001) and 3 yr (100% vs 62%; P < .01), but no different at 5 yr (88% vs 77%; P = .63). CONCLUSION: SRS was effective for patients with persistent or recurrent CD. Patients with mild to moderate CD can be safely managed with SRS alone; patients with severe CD should be considered for Adx with either concurrent SRS or SRS performed at a later date if tumor growth occurs.

Effect of Metformin on Microvascular Endothelial Function in Polycystic Ovary Syndrome.

OBJECTIVE: To investigate the factors that are associated with the effect of metformin on endothelial dysfunction in polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: From March 24, 2014, to November 18, 2016, 48 women with PCOS were randomly assigned to 1500 mg/d of metformin (N=29) or no treatment (N=13) for 3 months; 42 patients (29 in the initial treatment group and 13 in the no treatment group) completed the study. Study variables were measured at baseline and after 3 months. Participants who did not receive metformin initially were then treated with metformin for another 3 months, and study variables were measured again. Endothelial function was measured as reactive hyperemia-peripheral arterial tonometry (RH-PAT) from the index finger. RESULTS: The age and baseline endothelial function (mean ± SD) of the participants were 32.7±6.9 years and 1.8±0.5, respectively. No notable change was observed in endothelial function after 3 months with metformin compared with no treatment. However, after stratifying participants who received metformin based on baseline endothelial function, there was a significant improvement following metformin treatment in participants with abnormal baseline endothelial function (1.3±0.3 vs 1.7±0.3; P<.001) but not in those with normal baseline endothelial function (2.1±0.4 vs 2.0±0.5; P=.11). CONCLUSION: Metformin improves endothelial function in women with PCOS and endothelial dysfunction independent of changes in glucose metabolism, dyslipidemia, or presence of prediabetes. Metformin has a direct effect on endothelial function in PCOS, and measurement of endothelial function can stratify and follow response to metformin treatment in PCOS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02086526.