Levothyroxine for a high-normal TSH in unexplained infertility.

OBJECTIVE: Unexplained infertility affects nearly one-third of infertile couples. Women with unexplained infertility are more likely to have a high-normal thyroid-stimulating hormone level (TSH: 2.5-5 mIU/L) compared to women with severe male factor infertility. Practice guidelines vary on whether treatment should be initiated for TSH levels >2.5 mIU/L in women attempting conception because the effects of treating a high-normal TSH level with levothyroxine are not known. We evaluated conception and live birth rates in women with unexplained infertility and high-normal TSH levels. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective study including 96 women evaluated for unexplained infertility at a large academic medical centre between 1 January 2000 and 30 June 2017 with high-normal TSH (TSH: 2.5-5 mIU/L and within the normal range of the assay) who were prescribed (n = 31) or not prescribed (n = 65) levothyroxine. Conception and live birth rates were assessed. RESULTS: The conception rate in the levothyroxine group was 100% compared to 90% in the untreated group (p = .086 unadjusted; p < .05 adjusted for age; p = .370 adjusted for TSH; p = .287 adjusted for age and TSH). The live birth rate was lower in the levothyroxine group (63%) compared to the untreated group (84%) (p = .05 unadjusted; p = .094 adjusted for age; p = .035 adjusted for TSH; p = .057 adjusted for age and TSH). CONCLUSIONS: Women with unexplained infertility and high-normal TSH levels treated with levothyroxine had a higher rate of conception but lower live birth rate compared to untreated women, with the limitation of a small sample size. These findings assert the need for prospective, randomized studies to determine whether treatment with levothyroxine in women with unexplained infertility and high-normal TSH is beneficial.

Deficits in volumetric bone mineral density, bone microarchitecture, and estimated bone strength in women with atypical anorexia nervosa compared to healthy controls.

OBJECTIVE: Anorexia nervosa is associated with low bone mineral density (BMD) and deficits in bone microarchitecture and strength. Low BMD is common in atypical anorexia nervosa, in which criteria for anorexia nervosa are met except for low weight. We investigated whether women with atypical anorexia nervosa have deficits in bone microarchitecture and estimated strength at the peripheral skeleton. METHOD: Measures of BMD and microarchitecture were obtained in 28 women with atypical anorexia nervosa and 27 controls, aged 21-46 years. RESULTS: Mean tibial volumetric BMD, cortical thickness, and failure load were lower, and radial trabecular number and separation impaired, in atypical anorexia nervosa versus controls (p < .05). Adjusting for weight, deficits in tibial cortical bone variables persisted (p < .05). Women with atypical anorexia nervosa and amenorrhea had lower volumetric BMD and deficits in microarchitecture and failure load versus those with eumenorrhea and controls. Those with a history of overweight/obesity or fracture had deficits in bone microarchitecture versus controls. Tibial deficits were particularly marked. Less lean mass and longer disease duration were associated with deficits in high-resolution peripheral quantitative computed tomography (HR-pQCT) variables in atypical anorexia nervosa. DISCUSSION: Women with atypical anorexia nervosa have lower volumetric BMD and deficits in bone microarchitecture and strength at the peripheral skeleton versus controls, independent of weight, and particularly at the tibia. Women with atypical anorexia nervosa and amenorrhea, less lean mass, longer disease duration, history of overweight/obesity, or fracture history may be at higher risk. This is salient as deficits in HR-pQCT variables are associated with increased fracture risk. PUBLIC SIGNIFICANCE: Atypical anorexia nervosa is a psychiatric disorder in which psychological criteria for anorexia nervosa are met despite weight being in the normal range. We demonstrate that despite weight in the normal range, women with atypical anorexia nervosa have impaired bone density, structure, and strength compared to healthy controls. Whether this translates to an increased risk of incident fracture in this population requires further investigation.

Incidence of postoperative hyponatremia after endoscopic endonasal pituitary transposition for skull base pathologies.

PURPOSE: Pituitary transposition is a novel surgical approach to access the retroinfundibular space and interpeduncular cistern. Few studies have evaluated post-surgical outcomes, including incidence of hyponatremia, following pituitary transposition. METHODS: This is a retrospective study including 72 patients who underwent endoscopic endonasal surgery involving pituitary transposition for non-pituitary derived tumors over a decade at the University of Pittsburgh Medical Center. Anterior pituitary deficiencies and replacement therapy, tumor pathology and pre-operative serum sodium (Na) were recorded. Na was assessed at postoperative day 1, 3, 5, 7, and 10. Anatomical/surgical parameters included sellar height, sellar access angle to approach the tumor, and cranial extension of the tumor above the sellar floor (B) compared to the height of the gland (A) (B/A). T-test (normally distributed variables) and Wilcoxon rank-sum test (not-normally distributed) were applied for mean comparison. Logistic regression analyzed correlations between anatomical/surgical parameters and postoperative hyponatremia. RESULTS: 55.6% of patients developed post-operative transient hyponatremia. Two patients (5%) developed severe hyponatremia (sodium level < 120 mmol/L). Eleven (15.3%) patients required desmopressin replacement immediately post-operatively, and 2 other patients needed desmopressin after discharge and after sodium nadir developed. Hyponatremia was inversely associated with sellar access angle (p = 0.02) and the tumor cranial extension above the sellar floor showing a trend towards significance (p = 0.09). CONCLUSION: More than half of patients who had pituitary transposition developed transient hyponatremia. Hyponatremia was more common in those with narrower sellar access angle and smaller cranial extension of the tumor above the sellar floor. Anatomical/surgical parameters may allow risk-stratification for post-operative hyponatremia following pituitary transposition.

Changes in serum cortisol levels after 10 days of overfeeding and fasting.

Chronic caloric deprivation and obesity are complicated by hypercortisolemia. The effects of acute overfeeding and fasting on circulating free cortisol levels and conversion of cortisone to free cortisol are unknown. We hypothesized that serum-free cortisol and free cortisol-to-cortisone ratio would increase after both overfeeding and fasting. This is a prospective study of 22 healthy volunteers who completed a 10-day high-calorie protocol followed by a 10-day fast, separated by a 2-wk washout. Morning free and total cortisol and free cortisone levels (LC/MS) were measured at baseline and after 10 days of each intervention. Both high-calorie feeding and fasting increased total and free cortisol and the free cortisol-to-free cortisone ratio (P = 0.001 to P = 0.046). There were sex interactions, with significant effects in men (P < 0.001), but not in women (P = 0.898 and 1.000, respectively) in subset analyses examining the effects of fasting on free cortisol and the free-to-total cortisol ratio. Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. Further study is warranted to determine whether elevated cortisol levels contribute to complications of starvation and obesity, such as bone fragility.NEW & NOTEWORTHY Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. The effect of fasting on free cortisol levels is modified by sex. Further study is needed to determine the mechanisms driving the increases in cortisol.

Polycystic ovary syndrome preceding the diagnosis of acromegaly: a retrospective study in 97 reproductive-aged women.

BACKGROUND: Acromegaly is a disease of growth hormone excess that results in enlargement of extremities, abnormal glucose and lipid metabolism, and gonadal disruption. Manifestations of the disease are insidious and typically lead to a diagnostic delay of 7-10 years. Classically the polycystic ovary syndrome (PCOS) phenotype is described in women with irregular menses, clinical or biochemical evidence of androgen excess, and/or multiple ovarian follicles on pelvic ultrasonography. Women with acromegaly may present with some or all of these symptoms. Our objective was to evaluate the prevalence of PCOS in patients with acromegaly and to determine if diagnosis of PCOS results in a delay in diagnosing acromegaly. METHODS: Using patient databases at two academic health centers, we identified 97 premenopausal women aged 18-49 years old presenting with acromegaly. Data were collected regarding pelvic sonography and reproductive history, including the diagnosis of PCOS. Patients carrying the diagnosis of PCOS before their diagnosis of acromegaly were identified and the remaining patients were screened using the Rotterdam criteria to identify additional patients meeting the criteria for PCOS prior to their diagnosis of acromegaly. RESULTS: Mean age of the population (n = 97) at the time of diagnosis of acromegaly was 33.4 ± 7.5 years (SD). Thirty-three percent of patients (n = 32) either carried a diagnosis of PCOS or met diagnostic criteria for PCOS before their diagnosis of acromegaly. In the subset of patients in whom data on symptom onset were available, those who met criteria for PCOS were diagnosed with acromegaly a median of 5 years [4, 9] after the onset of symptoms compared to 2 years [0.92, 3] (p = 0.006) in the patients who did not meet criteria for PCOS. CONCLUSIONS: Our data demonstrate a high prevalence of signs and symptoms of PCOS in reproductive-aged women with acromegaly and a longer time to diagnosis in women who meet the clinical criteria for PCOS. As screening for acromegaly is relatively simple and done with measurement of a random, non-fasting IGF-1 level that can be drawn at any time during the menstrual cycle, screening patients with PCOS for acromegaly may lessen the delay in diagnosis for reproductive-aged women with this disease.

IGF-1 is positively associated with BMI in patients with acromegaly.

PURPOSE: Acromegaly is a disorder characterized by IGF-1 excess due to autonomous GH secretion. In individuals without acromegaly, IGF-1 is not only influenced by GH secretion but is also sensitive to other factors including nutritional status, as evidenced by the inverted U-shaped association between BMI and IGF-1; in low-weight individuals (BMI < 18.5 kg/m2) and those who are obese, IGF-1 levels may be frankly low. It is not known if this same relationship between BMI and IGF-1 is also observed in acromegaly. METHODS: Retrospective study including patients who underwent resection of a pituitary adenoma (n = 197) for either acromegaly (n = 32) or a nonfunctioning adenoma (NFPA, n = 165) at a large academic medical center between 1/1/2015 and 5/31/2021. RESULTS: Median BMI in acromegaly was 30.8 kg/m2 (range 20.9-42.6 kg/m2). Percent upper limit of normal (%ULN) IGF-1 was 228.2% [159.0, 271.4] in acromegaly versus 32.2% [18.5, 50] in NFPA (p < 0.0001). There was a significant positive association between BMI and %ULN IGF-1 (R = 0.35, p < 0.05) in acromegaly. In contrast, there was no association between BMI and %ULN IGF-1 in the NFPA group as a whole (p = 0.22), but a significant inverse association between BMI and %ULN IGF-1 in NFPA patients with a BMI ≥ 35 kg/m2 (rho = - 0.39, p = 0.02). CONCLUSION: In contrast to individuals without acromegaly, BMI is significantly and positively associated with IGF-1 in acromegaly across the weight spectrum. Future studies are needed to determine if obese patients with acromegaly experience more significant symptoms related to their disease, or if patients with a low BMI may require different diagnostic criteria.

The role of stereotactic radiosurgery in the multidisciplinary management of pituitary metastases.

PURPOSE: This study evaluates the role and outcomes of Gamma Knife radiosurgery (GKRS) in the management of pituitary metastases. METHODS: The records of brain metastases patients who underwent GKRS at the University of Pittsburgh Medical Center during the 10-year interval of 2010-2020 were systematically reviewed. Outcome measures included patient survival, tumor control rate, pituitary hormonal outcomes, visual outcomes, adverse radiation effects (AREs), and need for adjuvant therapy. RESULTS: Eighteen patients with pituitary metastases (eight male; median age of 65.5 years) had sufficient clinical follow-up for analysis. The most common primary cancers were non-small cell lung cancer (n = 6) and breast cancer (n = 4). Patients presented with headache (n = 9) and visual difficulties (n = 6). One patient underwent resection before GKRS. The median tumor volume was 0.78 cc (range 0.04-6.42 cc). The median overall survival after GKRS was 6.5 months (range 0.5-58 months). The overall survival after GKRS at 3-, 6-, and 12-months were 72.2%, 50.0% and 38.9%, respectively. The tumor control rate was 94.4%. One patient had further progression that required additional GKRS. None of the patients developed AREs after GKRS. CONCLUSION: GKRS is an effective treatment modality for the multidisciplinary management of patients with pituitary metastases. This minimally-invasive strategy is associated with optimal tumor control rate and low risk to adjacent optic nerves or neurovascular structures.

Pituitary Society Delphi Survey: An international perspective on endocrine management of patients undergoing transsphenoidal surgery for pituitary adenomas.

PURPOSE: In adults and children, transsphenoidal surgery (TSS) represents the cornerstone of management for most large or functioning sellar lesions with the exception of prolactinomas. Endocrine evaluation and management are an essential part of perioperative care. However, the details of endocrine assessment and care are not universally agreed upon. METHODS: To build consensus on the endocrine evaluation and management of adults undergoing TSS, a Delphi process was used. Thirty-five statements were developed by the Pituitary Society's Education Committee. Fifty-five pituitary endocrinologists, all members of the Pituitary Society, were invited to participate in two Delphi rounds and rate their extent of agreement with statements pertaining to perioperative endocrine evaluation and management, using a Likert-type scale. Anonymized data on the proportion of panelists' agreeing with each item were summarized. A list of items that achieved consensus, based on predefined criteria, was tabulated. RESULTS: Strong consensus (≥ 80% of panelists rating their agreement as 6-7 on a scale from 1 to 7) was achieved for 68.6% (24/35) items. If less strict agreement criteria were applied (ratings 5-7 on the Likert-type scale), consensus was achieved for 88% (31/35) items. CONCLUSIONS: We achieved consensus on a large majority of items pertaining to perioperative endocrine evaluation and management using a Delphi process. This provides an international real-world clinical perspective from an expert group and facilitates a framework for future guideline development. Some of the items for which consensus was not reached, including the assessment of immediate postoperative remission in acromegaly or Cushing's disease, represent areas where further research is needed.

The role of endoscopic endonasal surgery in the management of prolactinomas based on their invasiveness into the cavernous sinus.

PURPOSE: To review our institutional experience with the surgical management of prolactinomas through the endoscopic endonasal approach with specific focus on cavernous sinus invasion. METHODS: Clinical and radiographic data were collected retrospectively from the electronic medical record of 78 consecutive patients with prolactinomas undergoing endoscopic endonasal resection from 2002 to 2019. Immediate and late post-operative remission were defined as prolactin < 20 ng/mL within 14 days and 1-year of surgery without adjuvant therapy, respectively. Cavernous sinus invasion was quantified by Knosp score. RESULTS: A total of 78 patients with prolactinoma, 59% being male, underwent surgical resection with a mean age of 37 ± 13 years. Indications for surgery were medication resistance in 38 patients (48.7%), medication intolerance in 11 (14.1%), and patient preference in 29 (37.2%). Patients with Knosp 0-2 achieved higher immediate remission rates (83.8%) compared to patients with Knosp 3 (58.8%) and Knosp 4 (41.7%) patients (p = 0.003). Long-term remission rates were 48.7% and increased to 71.8% when combined with adjuvant treatments. Knosp 4 prolactinomas had significantly higher tumor volumes, higher preoperative prolactin levels, higher recurrence rates, higher rates of adjuvant therapy utilization, and were more likely to have failed dopamine agonist therapy compared to other tumor grades (p < 0.05). We encountered 18 complications in our series, and no cerebrospinal fluid leaks. CONCLUSION: The endoscopic endonasal approach is a safe and effective modality that can be employed in properly selected patients with invasive prolactinomas. It is associated with improved control and remission rates despite cavernous sinus invasion, though at a lower rate than without invasion.

Pituitary society guidance: pituitary disease management and patient care recommendations during the COVID-19 pandemic-an international perspective.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain that has caused the coronavirus disease 2019 (COVID-19) pandemic, has presented healthcare systems around the world with an unprecedented challenge. In locations with significant rates of viral transmission, social distancing measures and enforced 'lockdowns' are the new 'norm' as governments try to prevent healthcare services from being overwhelmed. However, with these measures have come important challenges for the delivery of existing services for other diseases and conditions. The clinical care of patients with pituitary disorders typically involves a multidisciplinary team, working in concert to deliver timely, often complex, disease investigation and management, including pituitary surgery. COVID-19 has brought about major disruption to such services, limiting access to care and opportunities for testing (both laboratory and radiological), and dramatically reducing the ability to safely undertake transsphenoidal surgery. In the absence of clinical trials to guide management of patients with pituitary disease during the COVID-19 pandemic, herein the Professional Education Committee of the Pituitary Society proposes guidance for continued safe management and care of this population.

Low bone mineral density in anorexia nervosa: Treatments and challenges.

Anorexia nervosa, a psychiatric disease predominantly affecting women, is characterized by self- induced starvation and a resultant low-weight state. During starvation, a number of hormonal adaptations - including hypothalamic amenorrhea and growth hormone resistance - allow for decreased energy expenditure during periods of decreased nutrient intake, but these very same adaptations also contribute to the medical complications associated with chronic starvation, including low bone mass. Almost 90% of women with anorexia nervosa have bone mineral density (BMD) values more than one-standard deviation below the mean of healthy women at peak bone mineral density and this disease is associated with a significantly increased risk of fracture. Although multiple therapies have been studied for the treatment of low bone mass in anorexia nervosa, there are currently no approved therapies and few promising long-term therapeutic options. This review will outline the mediators of low bone mass in anorexia nervosa, discuss therapies that have been studied for the treatment of low BMD in this disorder, and highlight the important challenges that remain, including the differences in bone modeling in adolescents with anorexia nervosa as compared to adults, necessitating that potential therapies be tested in these two populations separately, and the paucity of long-term therapeutic strategies for treating bone loss in this disorder.

Bone density, body composition, and psychopathology of anorexia nervosa spectrum disorders in DSM-IV vs DSM-5.

OBJECTIVE: DSM-5 revised the diagnostic criteria for anorexia nervosa (AN) by eliminating the amenorrhea requirement, liberalizing weight and psychological criteria, and adding the formal diagnosis of "atypical AN" for individuals with AN psychological symptoms without low weight. We sought to determine whether bone density (BMD) is impaired in women diagnosed with AN using the new, more liberal, DSM-5 criteria. METHOD: Cross-sectional study of 168 women, 18 - 45y: (1) AN by DSM-IV (DSM-IV AN) (n = 37), (2) AN by DSM-5 but not DSM-IV criteria (DSM-5 AN) (n = 33), (3) atypical AN (ATYPICAL AN) (n = 77), (4) healthy comparison group (HC) (n = 21). Measurements included dual energy X-ray absorptiometry, Eating Disorder Examination-Questionnaire, Eating Disorder Inventory-2, Hamilton Depression and Anxiety Rating Scales. RESULTS: BMD Z-score <-1.0 was present in 78% of DSM-IV, 82% of DSM-5, and 69% of ATYPICAL. Mean Z-scores were comparably low in DSM-IV and DSM-5, intermediate in ATYPICAL, and highest in HC. Lack of prior low weight or amenorrhea was, but history of overweight/obesity was not, protective against bone loss. Mean lean mass and percent fat mass were significantly lower in all AN groups than HC. DSM-IV, DSM-5, and ATYPICAL had comparable psychopathology. DISCUSSION: Despite liberalizing diagnostic criteria, many women diagnosed with AN and atypical AN using DSM-5 criteria have low BMD. Presence or history of low weight and/or amenorrhea remain important indications for DXA. Loss of lean mass, in addition to fat mass, is present in all AN groups, and may contribute to low BMD. The deleterious effect of eating disorders on BMD extends beyond those with current low weight and amenorrhea. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:343-351).

Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa.

OBJECTIVE: To (i) compare fracture prevalence in adolescent females with anorexia nervosa (AN) versus normal-weight controls and (ii) examine whether reductions in areal bone mineral density (aBMD) predict fracture risk in females with AN. METHOD: Four-hundred eighteen females (310 with active AN and 108 normal-weight controls) 12- to 22-years-old were studied cross-sectionally. Lifetime fracture history was recorded by a physician during participant interviews. Body composition and aBMD measurements of the whole body, whole body less head, lumbar spine, and hip were assessed by dual-energy X-ray absorptiometry, and bone mineral apparent density (BMAD) was calculated for the lumbar spine. RESULTS: Participants with AN and normal-weight controls did not differ for chronological age, sexual maturity, or height. The lifetime prevalence of prior fracture was 59.8% higher in those with AN as compared to controls (31.0% vs. 19.4%, p = 0.02), and the fracture incidence rate peaked in our cohort after the diagnosis of AN. Lower aBMD and lumbar BMAD were not associated with a higher prevalence of fracture in the AN or control group on univariate or multivariate analyses. Compared to controls, fracture prevalence was significantly higher in the subgroup of girls with AN who had normal aBMD or only modest reductions of aBMD (Z-scores > -1 or -1.5). DISCUSSION: This is the first study to show that the risk of fracture during childhood and adolescence is significantly higher in patients with AN than in normal-weight controls. Fracture prevalence is increased in this cohort of participants with AN even without significant reductions in aBMD.

Bone metabolism in anorexia nervosa.

Anorexia nervosa (AN), a psychiatric disorder predominantly affecting young women, is characterized by self-imposed, chronic nutritional deprivation and distorted body image. AN is associated with a number of medical comorbidities including low bone mass. The low bone mass in AN is due to an uncoupling of bone formation and bone resorption, which is the result of hormonal adaptations aimed at decreasing energy expenditure during periods of low energy intake. Importantly, the low bone mass in AN is associated with a significant risk of fractures and therefore treatments to prevent bone loss are critical. In this review, we discuss the hormonal determinants of low bone mass in AN and treatments that have been investigated in this population.

Methionine as a regulator of bone remodeling with fasting.

Caloric restriction improves metabolic health but is often complicated by bone loss. We studied bone parameters in humans during a 10-day fast and identified candidate metabolic regulators of bone turnover. Pro-collagen 1 intact N-terminal pro-peptide (P1NP), a bone formation marker, decreased within 3 days of fasting. Whereas dual-energy x-ray absorptiometry measures of bone mineral density were unchanged after 10 days of fasting, high-resolution peripheral quantitative CT demonstrated remodeling of bone microarchitecture. Pathway analysis of longitudinal metabolomics data identified one-carbon metabolism as fasting dependent. In cultured osteoblasts, we tested the functional significance of one-carbon metabolites modulated by fasting, finding that methionine - which surged after 3 days of fasting - affected markers of osteoblast cell state in a concentration-dependent manner, in some instances exhibiting a U-shaped response with both low and high concentrations driving putative antibone responses. Administration of methionine to mice for 5 days recapitulated some fasting effects on bone, including a reduction in serum P1NP. In conclusion, a 10-day fast in humans led to remodeling of bone microarchitecture, potentially mediated by a surge in circulating methionine. These data support an emerging model that points to a window of optimal methionine exposure for bone health.

Sinonasal Outcomes after Endoscopic Pituitary Surgery in Patients With Cushing's Disease.

PURPOSE: The endoscopic endonasal approach (EEA) has become the preferred treatment for pituitary tumors, with minimal sinonasal morbidity. However, patients with Cushing's disease (CD) may represent a subgroup with prolonged impairment of sinonasal quality of life (QOL). METHODS: We retrospectively identified patients with CD who underwent EEA at our institution. Control patients with non-functional tumors were matched by age, gender, and extent of EEA. The primary outcome was post-operative 22-item Sino-Nasal Outcome Test (SNOT-22) scores. RESULTS: Ten patients with CD met the selection criteria and 20 controls were selected for comparison. Nine of the CD patients achieved persistent endocrinologic remission post-operatively. Comparing the CD and control groups, there was no difference in post-operative SNOT-22 score at 1 or 3 months. At 6 months, SNOT-22 scores were significantly worse in the CD group (27.4 ± 21.6 vs. 2.8 ± 2.3, P = .039). SNOT-22 scores improved to normal from 1 to 6 months in the control cohort (P = .007), but not in the Cushing's group (P = .726). Morbidity was present across all SNOT-22 domains, but was highest in the sleep domain (P = .023). Only morbidity in the facial domain improved over time (P = .032). CONCLUSIONS: Patients with CD have significantly prolonged postoperative sinonasal QOL impairment following EEA compared to patients with non-functioning tumors, who normalize within 6 months. In CD patients, only morbidity in the facial domain, likely related to post-operative pain and nasal packing, improved over time, while the sleep domain was the most affected.

Intermittent fasting for systemic triglyceride metabolic reprogramming (IFAST): Design and methods of a prospective, randomized, controlled trial.

BACKGROUND: Caloric restriction prolongs lifespan in model organisms and improves metrics of aging-related diseases in humans, but daily compliance is challenging. Intermittent fasting improves metrics of lipid and glucose metabolism in the setting of weight loss but whether these metrics are improved independent of weight loss is not known. METHODS: We seek to address this gap with IFAST, a single-center, three-arm, prospective, randomized, controlled clinical trial. Eligible study participants are adults with no chronic medical conditions beyond prediabetes or overweight but who are at high risk for type 2 diabetes mellitus (T2D), defined as having a history of gestational diabetes or a first-degree relative with T2D. Participants will be randomized in a 1:2:2 schema to either a control group, a fasting group, or a fasting/weight maintenance group. The fasting groups will complete a 24-h fast one day per week for 12 weeks. The key mechanistic endpoint is change in triglyceride composition (defined by carbon content and degree of saturation) as measured by longitudinal metabolomics. The key safety endpoint is percent change from baseline in bone volume fraction (BV/TV; high-resolution peripheral quantitative CT) at the radius in the fasting group. Secondary endpoints include measures of insulin sensitivity (hyperinsulinemic-euglycemic clamp), clinical lipid profiling, systemic inflammation markers, hunger assessment, bone density, and bone microarchitecture with high-resolution peripheral quantitative CT. CONCLUSION: IFAST will investigate intrinsic metabolic benefits of intermittent fasting beyond weight loss. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05722873.

Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

BACKGROUND AND OBJECTIVE: Conventional protocols for inferior petrosal sinus sampling (IPSS) during the workup of hypercortisolemia require adrenocorticotrophic hormone (ACTH) measurement at multiple time points with corticotropic-releasing hormone (CRH) used as a stimulator. Modernized evidence-based protocols must also reflect the increased utilization of desmopressin (DDAVP) for ACTH stimulation as the manufacturing shortage of traditionally used CRH continues. We model the diagnostic accuracy and potential economic savings of DDAVP utilization and reduced time point sampling. METHODS: A single-institution, retrospective review of patients undergoing IPSS between 2007 and 2021 was performed. A computational search for the minimal set of time points which preserves conventional diagnostic accuracy was performed by testing all 1 through 5-point combinations generated using a binomial expansion. Economic savings were modeled using a publicly available hospital chargemaster. RESULTS: A total of 50 patients qualified for inclusion, 47 of whom were diagnosed with Cushing disease and 3 with ectopic Cushing syndrome. Single-point diagnostic accuracy for DDAVP-stimulated tests was 71.4%-92.9%, and seven 2-point combinations (5-25 procedural minutes) were found, which preserved conventional diagnostic accuracy. Single-point accuracy for CRH-stimulated tests was 67.9%-89.3%, and two 2-point combinations ( t = -15, t = +2 and t = -15, t = +10) preserved accuracy. For every time point removed, the cost of ACTH laboratory tests was reduced by $507 from $3042 for 6-point IPSS). The shortest and most economical stimulator and time point combination that preserved conventional accuracy was DDAVP sampling at t = 0 and t = +5 or t = +2 and t = +5 minutes, which cost $2028 total compared with the most expensive 6-point IPSS option with CRH ($6392). CONCLUSION: DDAVP is a cost-efficient and effective alternative to CRH during IPSS. Our results encourage prospective evaluation of potentially fewer sampling time points in the interest of time and cost efficiency balanced with preserved accuracy.