Gender-affirming hormone therapy effect on cortisol levels in trans males and trans females.

PURPOSE: Previous studies have shown differences in baseline and stimulated cortisol levels between men and women. Whether this difference is secondary to sex hormones or to other factors, such as genetic or epigenetic changes, is unknown. We investigated the effect of gender-affirming hormone treatment (GAHT) on the hypothalamo-pituitary-adrenal axis of transgender subjects in an effort to throw light on this question. METHODS: Ten transgender males (TM) and eight transgender females (TF) underwent a low-dose (1 µg) adrenocorticotropic hormone (ACTH) stimulation test before and 6 months after GAHT initiation. Serum total, free and salivary cortisol (SC) levels were measured at baseline and at 20, 30 and 40 min. RESULTS: For the TM, all three levels were significantly lower at several time points after ACTH injection compared to pretreatment levels following 6 months of treatment (p < .05). Likewise, the overall SC response as calculated by the area under the curve was significantly lower (p = .0053). For the TF, the basal total cortisol (TC) level increased after 6 months of treatment (p < .01) while ACTH-stimulated SC levels decreased significantly. The basal ACTH levels were significantly lower following hormonal therapy (p < .001). CONCLUSION: Stimulated salivary cortisol levels decreased significantly after 6 months of GAHT in both male and female transgender subjects, possibly reflecting a decreased state of anxiety associated with treatment initiation. Additionally, basal and stimulated serum TC levels increased after hormonal treatment in the TF, probably secondary to the effect of oestrogen on cortisol-binding globulin.

Lower incidence of hip fractures among elderly Ethiopian immigrants to Israel: first assessment from the Israel National Trauma Registry (INTR) 2011-2020.

The incidence hip fractures (HF) among Ethiopian immigrants is unknown. In Israel, the incidence of HF among Ethiopian immigrants aged ≥ 50 years between 2011 and 2020 was lower than in the general Israeli population, but possibly on the rise. These data should be confirmed in other countries where the Ethiopian diaspora has settled. PURPOSE: The incidence of osteoporotic fractures in the aging Ethiopian population that immigrated to Western countries has not been reported. This study sought to provide a first assessment of the incidence of hip fractures in Ethiopian immigrants in Israel, as a proxy for osteoporosis in this population. METHODS: This is an epidemiologic study of the incidence of hip fractures (HF) in people aged ≥ 50 years in Israel, between 2011 and 2020. Data were extracted from the Israel National Trauma Registry (INTR). Annual age-adjusted HF incidence rates (IR), and standardized incidence ratios (SIR) among Ethiopian-born (EB) relative to non-EB subjects (others) were computed. RESULTS: During the study period, among subjects age ≥ 50 in the INTR, only 20.1% of the EB suffered a HF, in contrast to 32.3% of subjects from other origins (P < 0.0001). Although EB subjects were generally younger than their non-EB counterparts, the age at which they sustained a HF was similar: 80.45 ± 11.7 years for EB vs. 79.44 ± 10.32 years, P = 0.19. EB men were more likely to sustain a HF, as they represented 41.8% of all HF in their respective group, in comparison with 33.6% for others (P = 0.02). Annual IR of HF were lower for EB subjects throughout the study. Despite an initial rise in the SIR, these were also lower for most of the period. CONCLUSIONS: In Israel, EB subjects ≥ 50 years still enjoy protection from HF. Our data require confirmation from other Western countries where the Ethiopian diaspora is aging. If a secular upward trend is observed, contributing risk factors should be identified to enable preventative measures.

Endocrinology specialty service for inpatients: an unmet growing need.

BACKGROUND: There is recent concern regarding the documented mismatch between demand and supply, vis-à-vis the growing need for trained endocrinologists unmet by parallel rise in the world workforce of endocrinologist. Due to the increasing complexity of disease in inpatients, in recent years we have experienced a growing demand for inpatient endocrine consults. Surprisingly, the need for the endocrinology subspecialty in the overall care of inpatients in the current setting of general hospitals has received little attention. METHODS: A retrospective analysis of endocrine consult service based on solicited consults carried out during 3 consecutive months. RESULTS: During 3 months, there were 767 consults, comprised of 156 diabetes referrals and 611 endocrine/metabolic consult requests. The 611 "non-glucocentric" consult requests were related to 295 inpatients (2.1 ± 2.7 consults/patient). Mean patient age was 58.9 ± .18 years (range 21-92), with some F/M preponderance (58/42%). Requests for endocrine consults were evenly distributed (49.8%, 50.2%) between internal medicine and surgery wards. Case distribution was as follows: thyroid 45.4%, calcium & bone 11.5%, pituitary 12%, adrenal 10% and all others 8.1-0.7%. The mean response time was 4.4 ± 2.7 h. The consults had a discernible effect on the patients' disease management in 60% of the patients. Of these, the consults modified the hospital treatment in 74%, the discharge treatment recommendations in 19% and the diagnosis in 7%. CONCLUSION: At a large medical center, endocrine consults were requested for ~ 3.3% of all admitted inpatients. The endocrine consults modified pre-consult diagnosis or treatment in ~ 60% of the cases. Contrary to its common image as an exclusively outpatient-based subspecialty, endocrinology practiced by specialists and endocrine trainees has a notable role in the daily care of inpatients admitted to a referral general hospital.

Impaired aldosterone response to ACTH without hypoaldosteronism: An unrecognized secretory pattern in search of clinical implications.

CONTEXT: Aldosterone has been recently characterized as a 'stress hormone'. Stress per se elicits a sizable rise in aldosterone secretion, which could be replicated by the administration of a low dose (0.03-1 µg, IV) of adrenocorticotropic hormone (ACTH). Whether or not the aldosterone response to ACTH could be selectively impaired, that is, in association with intact cortisol response, is presently unknown. OBJECTIVE: To determine whether or not the aldosterone response to low dose of ACTH is impaired in subjects referred to assess the hypothalamic-pituitary-adrenal axis (HPA). DESIGN: Retrospective analysis. SETTING: Outpatient referral endocrine day care centre. PATIENTS: One hundred and ninety-five consecutive subjects who underwent the low dose (1 µg) ACTH test, in whom decreased cortisol reserve was suspected due to former/present glucocorticoid excess, pituitary disease or/and unexplained weakness. MAIN OUTCOME MEASURES: The outcome was the detection of lack of aldosterone response, defined as a rise <111 pmol/l. RESULTS: In all, 46/195 subjects had subnormal aldosterone response as compared with 52/195 subjects showing diminished cortisol response. Nine subjects had combined deficient aldosterone and cortisol response. In the 37 subjects with isolated subnormal aldosterone response common associations were the use of exogenous glucocorticoids, mostly prednisone (n = 16); former Cushing disease (n = 2); nonfunctioning pituitary adenoma (n = 8); hypothyroidism (n = 11); the use of statins (n = 11), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 6), sex steroids in transgenders and orthostatic hypotension (n = 3). Twenty-seven percent (25/93) of the subjects with recent exposure to glucocorticoids had impaired aldosterone response to ACTH. CONCLUSION: Blunted aldosterone response to ACTH in the absence of hypoaldosteronism was seen in ~27% of subjects referred for HPA assessment using the low dose 1 µg ACTH test. Exposure to glucocorticoid excess was often linked to this impairment, independent of the cortisol response to ACTH.

Low-Dose Cyproterone Acetate Treatment for Transgender Women.

BACKGROUND: Transgender women with intact gonads receive lifelong hormonal treatment to suppress physiologic androgen production, the optimal efficacious and safe cyproterone acetate (CPA) dose has not been established. AIM: To assess the effectiveness and safety of low-dose (10-20 mg/day) compared with high-dose (50-100 mg/day) CPA treatment. METHODS: We conducted a historical cohort study of transgender women treated at a tertiary center for transgender health. OUTCOME MEASURES: Serum levels of testosterone, estradiol, prolactin, gonadotrophins, liver enzymes, and lipids. RESULTS: There were 38 transgender women in the low-dose group and 26 in the high-dose group. Age (median 24.9 years, interquartile range [IQR] 21-30 vs 25 years, IQR 19-35) and follow-up time (median 12 months, IQR 6-23 vs 15 months, IQR 12-36) were similar in the low- and high-dose groups, respectively. Serum gonadotropins and testosterone were suppressed to a similar level at all time points in both groups. Prolactin levels increased significantly in both groups, however, with a more substantial increase in the high- vs the low-dose group (804 ± 121 vs 398 ± 69 mIU/ml at 12 months, respectively, P = .004). Total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were not significantly affected by the dose. CLINICAL IMPLICATIONS: We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women. STRENGTHS & LIMITATIONS: This is the first demonstration that low-dose CPA treatment of transgender women is effective. Limitations include a relatively small sample and retrospective study design. CONCLUSION: Low-dose CPA treatment of transgender women is as effective as high-dose treatment and possibly safer. Zohar NE, Sofer Y, Yaish I, et al. Low-Dose Cyproterone Acetate Treatment for Transgender Women. J Sex Med 2021;18:1292-1298.

Revisiting Cushing Syndrome, Milder Forms Are Now a Common Occurrence: A Single-Center Cohort of 76 Subjects.

OBJECTIVE: Guidelines recommend initiating testing for Cushing syndrome (CS) based on strong clinical suspicion. Our recent experience suggests the absence of classical stigmata in the majority of patients with CS. We aimed to confirm this premise by revisiting the clinical features of this syndrome in a modern series of patients from a single center. METHODS: Computerized records of subjects with CS diagnosed at Tel Aviv Sourasky Medical Center between 2000 and 2018 were reviewed. A Cushing inventory score, including all clinical components of the syndrome, was computed for each subject. Data were compared between the subtypes and evaluated in light of those in the literature. RESULTS: Of the 76 subjects with CS (60 women/16 men), 49 (64.5%) had Cushing disease; 16 (21.1%), adrenal adenoma; 7 (9.2%), adrenocortical carcinoma; and 4 (5.3%), ectopic adrenocorticotropic hormone secretion. In only 15 of 74 cases (20.3%), clinical suspicion of CS led to testing. Catabolic signs of CS were present in less than 30% of cases. The most common symptom was weight gain (52/67, 77.6%), and the most common comorbidity was hypertension (47/76, 61.8%). There were no differences in the Cushing inventory score between the subtypes. Signs, symptoms, and comorbidities were all significantly less common than in the classical syndrome. CONCLUSIONS: Modern-day CS presents with subtler features than in the past. Initiating a testing cascade solely based on a strong clinical suspicion may lead to underdiagnosis of milder cases. A concerted effort to devise cost-efficient testing for CS in the current era is needed.

Arterial properties in acromegaly: relation to disease activity and associated cardiovascular risk factors.

PURPOSE: Acromegaly is associated with increased cardiovascular morbidity and mortality when inadequately treated, which may be secondary to associated comorbidities or to direct IGF-1 effects on the cardiovascular system. By using a control group carefully matched for traditional cardiovascular risk factors, we aimed to assess the direct contribution of disease activity and IGF-1 levels to arterial damage as assessed by measurements of arterial stiffness and endothelial function. METHODS: Twenty-nine subjects with acromegaly (11 males, 52 ± 14 year; 15 active acromegaly) and 24 matched controls underwent evaluation of large and small artery compliance using applanation tonometry, pulse wave velocity (PWV), augmentation index (Alx), carotid ultrasonography intima-media thickness, (IMT) and flow-mediated dilatation (FMD). RESULTS: IGF-1 expressed as times the upper limit of the normal range (x ULN) was 2.2 ± 1.1 in patients with active disease versus 0.7 ± 0.2 in patients in remission. Irrespective of disease activity, FMD was lower in patients with acromegaly than in control subjects, (3.4 ± 2.7 % in active acromegaly, 4.4 ± 3.3 % in controlled acromegaly and 7.5 ± 3.8 % in controls; p = 0.004). There were no significant differences in PWV, Alx, and IMT between groups. A positive correlation was found between IGF-1× ULN and IMT (r = 0.4; P = 0.02). Asymmetric dimethylarginine (ADMA), a novel cardiovascular risk factor, was positively correlated to arterial stiffness (r = 0.46; p = 0.017) and negatively with small vessel compliance (r = -0.44, p = 0.02). CONCLUSIONS: Patients with acromegaly have significantly impaired endothelial function as assessed by FMD, but other tested vascular parameters were similar to a control group that was adequately matched for cardiovascular risk factors.

PANCREATIC INCIDENTALOMA: DIFFERENTIATING NONFUNCTIONING PANCREATIC NEUROENDOCRINE TUMORS FROM INTRAPANCREATIC ACCESSORY SPLEEN.

OBJECTIVE: To improve the preoperative assessment of pancreatic incidentalomas (PIs) by analysis of 1 index case and characterization of the published features of intrapancreatic accessory spleen (IPAS) compared to pancreatic neuroendocrine tumor (PNET). METHODS: A search of the literature using the online database MEDLINE. RESULTS: In all, 46 cases of IPAS have been described to date: 17 were "presumed" as IPAS based on technetium-99m (Tc-99m) scanning, fine-needle aspiration (FNA) stain for CD8, or contrast-enhanced sonography; 29 were misdiagnosed as PNET and underwent surgery. The pancreatic lesions were 1) mostly solitary; 2) solid on imaging; 3) well defined; 4) located predominantly at the pancreatic tail; 5) not exceeding 3 cm in the largest diameter; 5) all detected in adults (22-81 years); 6) not related to sex. In subjects referred for surgery, standard imaging studies/imaging protocols did not differentiate between IPAS and PNET. FNA was performed in 5/46 cases, all of which were false-positive for PNET. Immunohistochemical staining for T-cells on FNA material and specific imaging features (characteristic arciform splenic enhancement pattern on dynamic computed tomography [CT]; nuclear scintigraphies with radioisotope specifically trapped by splenic tissue [Tc-99m]) or contrast-enhanced sonography offered valuable clues. Still, distal pancreatectomy and splenectomy was carried out in 72%, and the rest had distal pancreatectomies. CONCLUSION: IPAS should be considered before surgery in patients with PIs. A new practical algorithm is presented for better preoperative evaluation of such lesions; it combines the recognition of early indicators and sequential consideration of cytologic and imaging features to decrease the hazards of unnecessary major surgery. ABBREVIATIONS: CT = computed tomography EUS = endoscopic ultrasound FNA = fine-needle aspiration HDRBC = heat-damaged red blood cells IPAS = intrapancreatic accessory spleen MRI = magnetic resonance tomography NF-PNET = nonfunctioning pancreatic neuroendocrine tumor PET = positron emission tomography PNET = pancreatic neuroendocrine tumor PI = pancreatic incidentalomas SPIO = superparamagnetic iron oxide Tc-99m = technetium-99m.

GENDER DETERMINES SERUM FREE CORTISOL: HIGHER LEVELS IN MEN.

OBJECTIVE: Because only the free fraction of serum cortisol can readily access glucocorticoid receptors, we investigated whether or not a gender-related difference in serum free cortisol (FC) exists in the basal and adrenocorticotropic hormone (ACTH)-stimulated state. METHODS: Serum total cortisol (TC) and FC were measured in 323 subjects (175 men; 148 women). Additionally, the low-dose 1-µg ACTH test was performed in 56 subjects (30 women, 26 men). Subjects were healthy volunteers, recruited in a preventive medicine screening program and an outpatient clinic. RESULTS: Overall, basal serum TC and FC level were ~18 and ~33%, respectively, higher in men than in women (TC, 14.5 ± 0.33 µg/dL vs. 12.3 ± 0.33 µg/dL; P<.0001; FC, 0.68 ± 0.02 µg/dL vs. 0.51 ± 0.02 µg/dL; P<.0001). The higher FC in men relative to women was apparent across a wide age range (17 to 86 years) and persisted after adjustment for age and body mass index. The FC fraction (%FC, out of TC) was concordantly higher in men (5.4 ± 0.09% vs. 4.8 ± 0.3%; P = .046). FC was not related to the estimated menopausal status (women age below and above 47, 50, or 53 years). ACTH-stimulated FC levels were significantly higher in men compared to women, as reflected by the area under the response curve (49.4 ± 3.4 µg × min vs. 39.6 ± 2.2 µg × min; P = .0014). CONCLUSION: Gender is an unrecognized determinant of serum FC in humans. The possibility of lifelong exposure to the higher bioactive fraction of cortisol under basal conditions or daily stress involving ACTH stimulation should be further investigated in the context of gender-related phenotypic features such as "android" (visceral) fat deposition and longevity. ABBREVIATIONS: ACTH = adrenocorticotropic hormone BMI = body mass index CBG = cortisol-binding globulin FC = free cortisol HPA = hypothalamic-pituitary-adrenal TC = total cortisol.

Loss-of-function mutations of CYP24A1, the vitamin D 24-hydroxylase gene, cause long-standing hypercalciuric nephrolithiasis and nephrocalcinosis.

PURPOSE: Hypercalciuria is the most common cause of kidney stone disease and genetic factors have an important role in nearly half of these cases. Recently loss-of-function mutations of CYP24A1, the gene encoding vitamin D 24-hydroxylase, were identified in idiopathic infantile hypercalcemia. We describe the clinical and molecular basis of severe long-standing kidney stone disease in adults caused by CYP24A1 mutations. MATERIALS AND METHODS: Three subjects from 2 Israeli families with nephrolithiasis and nephrocalcinosis were clinically characterized. Genomic DNA was isolated from peripheral blood and sequencing of CYP24A1 was performed. RESULTS: All subjects presented with severe kidney stone disease, the cause of which was not discovered for decades despite extensive evaluation. They all had hypercalciuria, nephrocalcinosis and intermittent hypercalcemia, and chronic kidney insufficiency developed in the oldest subject. All patients had a typical pattern of test results, including normal-high serum calcium, low parathyroid hormone levels, high vitamin D 25-(OH)D3 and 1,25-(OH)2D3, and low 24,25-(OH)2D3. Overall 3 CYP24A1 loss-of-function mutations were identified, including a homozygous deletion (delE143) in consanguinous family 1, and compound heterozygous mutations L409S and the novel W268-stop in family 2. CONCLUSIONS: Loss-of-function mutations of CYP24A1 gene, encoding for 1,25-dihydroxyvitamin D3 24-hydroxylase, cause severe hypercalciuric nephrolithiasis and nephrocalcinosis. The mutations may present in adults and may lead to chronic renal insufficiency. Our results support a recessive mode of inheritance. CYP24A1 mutations should be considered in the differential diagnosis of hypercalciuric nephrolithiasis, especially as many adults are now prescribed supplemental oral vitamin D.

Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study.

Purpose: Chronic gender-affirming hormone therapy (GAHT) with sublingual estradiol (SLE) has not been studied. We aimed to compare GAHT with SLE only, to combined oral (CO) estradiol and cyproterone acetate, in treatment-naive trans women. Methods: Twenty-two trans women enrolled into either the CO arm or the SLE-only arm (0.5 mg four times daily) in this 6-month prospective study. Anthropometric and laboratory variables were collected at baseline and 3 and 6 months. At the study beginning and end, body composition was measured by dual-energy X-ray absorptiometry and bioelectrical impedance, and gender dysphoria, sexual desire, and function were assessed by validated questionnaires. Results: Subjects in the SLE were older, 26.3±5.8 years versus 20.1±2.3 years, p=0.006. All anthropometric, body composition, and laboratory variables were identical at baseline. Although dysphoria appeared greater, and sexual function lower at baseline in the CO group, this canceled out after age adjustment. Both treatments induced similar biochemical and hormonal changes. Creatinine, hemoglobin and cholesterol decreased significantly, while testosterone was suppressed to the same level in both groups: 3.22 [1.47-5.0] nmol/L in the SLE group and 2.41 [0.55-8.5] nmol/L in the CO, p=0.65. Significant changes in body composition toward a more feminine body were noted in both groups. Dysphoria did not significantly improve in either group, while sexual desire and function decreased at six months in both, p<0.001. Conclusions: Both treatments achieved similar clinical changes. At this stage, SLE, which repeatedly induces alarming excursions of serum estradiol throughout the day, appears to offer no advantage over the CO approach.

Dysglycemia in non-functioning pancreatic neuroendocrine tumors (NF-PNET): Further insights into an under recognized entity.

Objective: Pancreatic neuroendocrine tumors (PNETs) are rare, but their incidence has risen significantly in recent years. Whereas diabetes mellitus (DM) is recognized in association with chronic pancreatitis and pancreatic cancer, it has not been well-characterized concerning non-functioning (NF)-PNETs.Study aim: to determine whether NF-PNETs are associated with DM/ Pre-DM and characterize the features of this putative association. Methods: Retrospective study to evaluate rate of Pre-DM /DM in subjects with NF-PNETs. Results: Study cohort of 129 patients with histologically confirmed NF-PNETs, ∼60% were men (M/F: 77/52). Abnormal glucose metabolism that preceded any treatment was seen in 70% of this cohort: overt DM in 34% and Pre-DM in 36% of the subjects. However, during follow-up, the overall prevalence rose to 80.6%, owing exclusively to newly diagnosed DM in subjects who received treatment.Patients with DM/Pre-DM were older (65 ± 11; 54 ± 14; p < 0.0001), the tumor was more commonly localized in the pancreatic body and tail (76.5% vs. 23.5% p = 0.03), while BMI (27 ± 6 vs. 28 ± 5 kg/m2), and tumor size (2.4 ± 2 vs. 2.9 ± 3.2 cm) were similar. The relative prevalence of DM in our cohort of NF-PNETs was 1.6 higher than that in the age and gender-adjusted general Israeli population (95 %CI: 1.197-2.212p = 0.03). Conclusions: We found a high rate of impaired glucose metabolism, either DM or Pre-DM, in a large cohort of NF-PNETs. The high prevalence of diabetes/pre-diabetes was unrelated to obesity or tumor size. This observation should increase awareness of the presence of DM on presentation or during treatment of "NF"-PNETs.

Blood pressure measurements in a transgenic SOD1-G93A mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons, but non-motor manifestations including autonomic dysfunction have been reported. To better understand the autonomic involvement in ALS we measured blood pressure (BP) changes. We evaluated blood pressure (BP) in a transgenic (TG) SOD1-G93A mouse model of ALS. BP was recorded in awake mice from six to 19 weeks of age by the tail-cuff method. TG mice (n =15) had significantly elevated BP compared to their wild-type (WT) siblings (n =14) even prior to the clinical appearance of motor dysfunction (at age 10-11 weeks, p =0.026). BP gradually decreased in TG mice but not in WT mice from age 10-11 weeks until the advanced stages of the disease (p for trend <0.002). The results indicate impairment of cardiovascular control in this ALS model.

Serum free cortisol as an ancillary tool in the interpretation of the low-dose 1-µg ACTH test.

OBJECTIVE: Serum free cortisol, rather than serum total cortisol (TC), determines glucocorticoid activity in vivo, but how the considerable inter-subject variation in ambient serum free cortisol affects the outcome of dynamic hypothalamic-pituitary-adrenal (HPA) assessment in noncritically ill subjects is unknown. DESIGN, PATIENTS AND MEASUREMENTS: We performed the low-dose 1-µg ACTH test in 75 subjects referred for HPA evaluation. Serum TC was determined by a chemiluminescence method, and serum free cortisol was measured by the same method following equilibrium dialysis. In a subset of these patients, salivary cortisol was also measured. RESULTS: Mean fraction of free cortisol was 5·07 ± 4·08% (±SD; range 1·77-10·1%). Although no correlation was seen between TC and the fraction (%) of free serum cortisol, a positive correlation existed between baseline total and free cortisol (R = 0·539 P = 0·01), as well as between peak ACTH-stimulated total and free cortisol (R = 0·619; P = 0·01). There was no correlation between baseline salivary cortisol and serum free cortisol and between peak ACTH-stimulated salivary and serum free cortisol. Using the lowest attained peak serum free cortisol in subjects whose TC response to ACTH was normal (≥ 500 nM), the minimal 'pass' level for normal serum free cortisol response to 1 µg ACTH was set at 25·0 nM. Five of the 19 subjects showing subnormal TC response to 1 µg ACTH had normal serum free cortisol response. CONCLUSIONS: Discrepancies between the peak free and TC were noted mostly for subjects whose ACTH-stimulated TC peaked between 440 and 580 nm. At this range, the measurement of serum free cortisol allows further refinement of the assessment of borderline responses to 1-µg ACTH.

The Effect of the PCSK9 Inhibitor Evolocumab on Aldosterone Secretion among High Cardiovascular Risk Patients: A Pilot Study.

Elevated low-density lipoprotein (LDL) cholesterol is one of the leading causes of cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce LDL cholesterol levels with subsequent reductions in cardiovascular morbidity. Elevated aldosterone levels are also associated with a greater risk of cardiovascular morbidity. There are currently no published data on the impact of PCSK9 inhibitor monotherapy on the secretion of aldosterone. The aim of this study was to examine the effect of monotherapy with the PSCK9 inhibitor evolocumab on the lipid profile and aldosterone secretion level in high-risk cardiovascular patients. Lipid profile, sodium, potassium, aldosterone, cortisol, plasma renin activity, and adrenocorticotropic hormone (ACTH) levels were analyzed at baseline and after 3 months of evolocumab therapy. Each participant underwent a 250 mcg ACTH stimulation test upon study entry. Eight women and seven men were included in the study. Their median total cholesterol, LDL cholesterol, lipoprotein (a), apolipoprotein B100, and baseline and stimulated aldosterone levels were significantly lower after 3 months of evolocumab therapy. These heretofore unreported findings indicate that reductions in unstimulated and stimulated aldosterone secretion under evolocumab therapy could be associated with reductions in cardiovascular events, a possibility that warrants further investigation.

"New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis.

De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPARalpha-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPARalpha target genes in FASKOL mice were corrected with a PPARalpha agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPARalpha agonist. These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of distinct physiological pools of PPARalpha in adult liver.

Clinical update: treatment of hyperthyroidism in Graves' ophthalmopathy.

The presence of thyroid eye disease (TED) may influence the treatment of hyperthyroidism in patients with Graves' disease. Moreover, treatment of hyperthyroidism may affect the course of Graves' ophthalmopathy (GO). We review the literature and summarise recent knowledge about the impact of treatment modality for hyperthyroidism in GO. Anti-thyroid drugs (ATDs) remain the simplest and safest way to treat hyperthyroidism in patients with GO, but they are associated with a high relapse rate of hyperthyroidism and they have no effect on the course of GO. Radioactive iodine (RAI) treatment may be associated with exacerbation of GO especially in high risk patients, when glucocorticoid prophylaxis may be indicated. Large prospective trials are still lacking to define the exact effect of RAI on the course of GO, particularly in relation to other known risk factors. Likewise, clear guidelines for prophylactic glucocorticoid therapy are needed. RAI should be cautiously used in patients with more severe ophthalmopathy and concomitant I.V glucocorticoids should be considered. Thyroid surgery, whether total or subtotal thyroidectomy, has no effect on the course of ophthalmopathy. However, total thyroid ablation that combines surgery with radioactive iodine, as a means of achieving thyroid antigen disappearance, is increasingly gaining attention for the treatment of patients with GO, especially those undergoing thyroid surgery, but also for those with severe unresponsive ophthalmopathy. Studies supporting this approach are awaited.

Scarless Neck Feminization: Transoral Transvestibular Approach Chondrolaryngoplasty.

Importance: Chondrolaryngoplasty or reduction of laryngeal prominence is a gender affirmation surgery for transgender women, or for male patients desiring an aesthetic surgery. Several variations of the procedure were suggested, yet to date, all described chondrolaryngoplasty procedures involved a visible neck scar. Objective: To describe a novel technique for scarless chondrolaryngoplasty, transoral endoscopic vestibular approach (TOEVA)-chondrolaryngoplasty, and to report the results of first ever performed cases. Design, Setting, and Participants: This was a prospective cohort at an academic referral center. Adult transgender women, interested in chondrolaryngoplasty who never had previous surgery of their neck or vocal folds, were offered both transcervical chondrolaryngoplasty and scarless TOEVA-chondrolaryngoplasty. Four patients aged 21 to 33 years, who preferred TOEVA-chondrolaryngoplasty, were consented and recruited. Interventions: The surgical technique was successfully examined on two cadavers. Subsequently, all surgical procedures were conducted according to the described study protocol and technique, between April and June 2019. Main Outcomes: Vocal assessment was recorded preoperatively and repeated 4 to 6 weeks after surgery for comparison. Surgical documentations as well as adverse surgical events and complications were recorded. To measure outcome, 1-2 months postoperatively, all patients filled an outcome instrument for aesthetic chondrolaryngoplasty (seven questions on a 5-point Likert scale) based on previously designed questionnaires for chondrolaryngoplasty and facial plastic surgery. Results: Duration of operative time ranged from 90 to 150 min. No adverse events or complications were recorded during surgery. All patients were discharged 1 day postoperatively. A single patient had a mild temporary mental hypoesthesia that resolved 2 months after surgery, no other complications were encountered. Vocal folds' function remained unchanged in all four patients. All operated patients were highly satisfied with the surgical results as measured by the outcome instrument; three out of the four patients responded with perfect scores, and the fourth patient responded with 90% of the perfect score. Conclusions: This report is the first description of scarless chondrolaryngoplasty through TOEVA. On a series of four patients, TOEVA-chondrolaryngoplasty appeared to be safe, with no adverse events or major complication, and with extremely high patient satisfaction. Further clinical evidence is required to establish a widespread use of this surgical technique.

Plurihormonal Pituitary Tumor of Pit-1 and SF-1 Lineages, with Synchronous Collision Corticotroph Tumor: a Possible Stem Cell Phenomenon.

Thyrotropin (TSH)-secreting pituitary tumors are the rarest functioning pituitary tumors. Nonetheless, they are not infrequently plurihormonal, as they may express/secrete hormones made by other pituitary cells derived from the Pit-1 lineage such as growth hormone (GH), prolactin (PRL), and α-subunit (αSU). However, adrenocorticotropin (ACTH) or gonadotropin secretion by such a tumor is exceptional. Although double pituitary tumors are rare, they often combine ACTH and GH secretion. A 41-year-old presented almost 2 years after delivering her 10th child; she had thyrotoxicosis (goiter and palpitations) masquerading as autoimmune postpartum thyroiditis. She was still breastfeeding and amenorrheic. She proved to have TSH, GH, PRL, and ACTH hypersecretion. Imaging revealed an invasive pituitary macrotumor. She had stigmata neither of Cushing's disease nor of acromegaly. Prior to surgery, hormonal control was achieved for close to 1 year by combined octreotide and cabergoline treatment with significant shrinking of the tumor. Following surgery, pathology revealed a collision tumor; the dominant lesion was positive for GH, ßTSH, ßFSH, and αSU and expressed both Pit-1 and SF-1.The smaller lesion was a corticotroph tumor. We report an unusual plurihormonal tumor co-expressing Pit-1 and SF-1 along with hormones made by cells of both lineages. Its simultaneous occurrence adjacent to a corticotroph tumor raises questions regarding the pathogenesis of these tumors. We propose the possibility of a stem cell tumor with multiple lineage differentiation. We hypothesize that pregnancy might have played a permissive role in tumorigenesis.

Indeterminate nodules by the Bethesda system for reporting thyroid cytopathology in Israel: Frequency, and risk of malignancy after reclassification of follicular thyroid neoplasm with papillary-like features.

OBJECTIVE: We aimed to determine the frequency and risk of malignancy (ROM) for indeterminate thyroid nodules, categories III (B3) and IV (B4) of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), at a large institution in Israel. Additionally, we investigated the impact of redefining follicular neoplasm with papillary-like nuclear features (NIFTP) as non-malignant on malignancy rates. METHODS: In this retrospective study of all thyroid fine needle aspirations (FNAs) performed at Tel Aviv-Sourasky Medical Center between January 2013 and December 2015, we assessed ROM for B3 and B4 nodules. Potential risk factors thought to affect a-priori ROM were assessed. Suspected NIFTP lesions were re-examined, and if proven, reclassified as benign. RESULTS: 3701 nodules were sampled in 2919 FNAs performed on 2674 patients. B3 reports comprised 7.7% of all nodules (n = 284); B4 represented 3.6% (n = 132). In multivariate logistic regression, male gender, being of former Soviet Union origin, and smoking increased ROM for B3 nodules by a factor of 7.97 (P = 0.002; CI: 2.2-23.4), 9.15 (P = 0.021; CI:1.4-60.0), and 11.0 (P = 0.001; CI 2.8-44.8), respectively. Reclassifying NIFTP decreased ROM from 14% to 12.5% for B3, and from 26.7% to 25% for B4 nodules. NIFTP comprised 9.5% of previously diagnosed resected malignant tumors. CONCLUSIONS: The relative frequencies of B3 and B4 nodules and their associated malignancy rates were consistent with previous series. Risk factors identified for malignancy may help characterize patients most likely to benefit from surgery. Reclassifying NIFTP had a substantial impact on the ROM in the resected tumors previously diagnosed as malignant.