Daily Endocrinology Research Analysis

Diminished ovarian reserve (DOR) is common in women with infertility and is associated with poorer in vitro fertilization (IVF) outcomes. Testosterone is widely used off-label in this patient group, although evidence for its efficacy and safety is limited. To address this, we conducted a triple-blind, placebo-controlled, randomized clinical trial evaluating whether transdermal testosterone gel prior to IVF improves clinical pregnancy rates in women with DOR. Females aged 18-43 with infertility and DOR according to the Bologna criteria were recruited at 10 fertility clinics in Europe between April 2015 and November 2022. Of 316 assessed for eligibility, 290 were enrolled and randomized. Two were excluded from the primary analysis as their treatment coincided with the onset of the COVID-19 pandemic, and they did not start ovarian stimulation, leaving 288 participants. Participants were randomized to 5.5 mg of transdermal testosterone or matching placebo once daily for ~9 weeks prior to ovarian stimulation. All participants received ovarian stimulation in a long GnRH-agonist cycle with 300IU/day of highly purified human menopausal gonadotropin; fresh embryo transfer was performed if an embryo was available. The primary outcome was clinical pregnancy rate following fresh embryo transfer, defined as an intrauterine gestational sac with an embryo demonstrating cardiac activity at ≥7 weeks' gestation. Of the 288 participants, 134 were randomized to testosterone and 154 to placebo. Clinical pregnancy rates did not differ significantly, occurring in 21 women (15.7%) in the testosterone group and 23 (14.9%) in the placebo group (risk ratio (RR), 1.05; 95% confidence interval (CI) 0.61 to 1.81, p = 0.86). The study was terminated for futility at the prespecified interim analysis based on a conditional power calculation once 70% of the target sample size were randomized. In this study, transdermal testosterone did not improve clinical pregnancy rates compared with placebo in patients with infertility and DOR. Trial Registration: ClinicalTrials.gov: NCT02418572, EudraCT: 2014-001835-35.

BACKGROUND: Primary aldosteronism, an overt form of renin-independent aldosterone production, leads to steeper eGFR decline compared to primary hypertension. Mounting evidence suggests that milder forms of renin-independent aldosterone production ("subclinical primary aldosteronism") are highly prevalent; however, the link between subclinical primary aldosteronism and eGFR decline remains unknown. METHODS: This prospective cohort study included 976 Canadian adults aged 40-69 years, with predominantly normal blood pressure or mild untreated hypertension, from the randomly sampled, population-based CARTaGENE cohort. Aldosterone and renin concentrations were measured at enrollment (2009-2010). Creatinine and cystatin C were measured at enrollment and 5-7 years post-enrollment. Multivariable linear mixed regression models were used to measure the associations of aldosterone, renin, and the aldosterone-to-renin ratio (ARR) with eGFR decline over time. RESULTS: The mean (SD) age of participants was 53 (7) years; 51% were female. Mean blood pressure was 121 (15)/72 (10) mmHg, and 11% had blood pressure ≥140/90 mmHg. Mean eGFRCrCysC was 109 (16) mL/min/1.73m2. At higher ARR levels, there was steeper mean eGFR decline over time [Tertile 1 (ARR ≤0.49 ng/dL per mU/L): -1.40 (1.77) mL/min/1.73m2/year, Tertile 2 (ARR 0.50-0.87 ng/dL per mU/L): -1.48 (1.75) mL/min/1.73m2/year, Tertile 3 (ARR >0.87 ng/dL per mU/L): -1.57 (1.79) mL/min/1.73m2/year; p=0.01], representing 11% steeper decline in the highest versus lowest ARR tertile. At lower renin levels, there was steeper mean eGFR decline over time [Tertile 1 (renin ≤9.2 mU/L): -1.59 (1.80) mL/min/1.73m2/year, Tertile 2 (renin 9.3-15.9 mU/L): -1.53 (1.77) mL/min/1.73m2/year, Tertile 3 (renin >15.9 mU/L): -1.33 (1.72) mL/min/1.73m2/year; p=0.04], representing 16% steeper eGFR decline in the lowest versus highest renin tertile. There was no significant association between aldosterone and eGFR change over time (p=0.50). All aforementioned associations were independent of blood pressure and were consistent among participants with normal blood pressure in isolation. CONCLUSIONS: Independent of blood pressure, elevated ARR and suppressed renin were associated with steeper eGFR decline over time.

BACKGROUND: Exploitation of the sodium iodide symporter (NIS) has potentially broad clinical application across different tumour ablative settings but often fails in aggressive cancer due to diminished transport activity. We aimed to discover whether enhancing NIS function by modulating proteostasis was targetable in vivo, as well as the clinical relevance to radioiodide (RAI) treatment of patients with cancer. METHODS: We used 3D modelling, iterative design, reformulation, RAI uptake, RNA-Seq, cell surface biotinylation assays and NanoBRET in transformed cell lines and primary thyroid cells from patients to identify new drugs targeted at enhancing NIS function and to uncover their respective mechanisms. Systemic drug responses were monitored via FINDINGS: Copper diethyldithiocarbamate (Cu(DDC) INTERPRETATION: Our findings reveal a mechanistic pathway towards enhancing radionuclide uptake in vivo, with clinical relevance for RAI therapy and identifying survival indicators of recurrent disease. FUNDING: This work was funded by the U.S. Department of Defense (BC201532P1), Medical Research Council (CiC/1001505 and MR/Z504828/1), British Thyroid Foundation (1002175). We further acknowledge support from the Wellcome Trust and EPSRC funded Centre for Medical Engineering at King's College London (203148/Z/16/Z), the Wellcome Multiuser Equipment Radioanalytical Facility (212885/Z/18/Z), and the EPSRC programme for Next Generation Molecular Imaging and Therapy with Radionuclides (EP/S019901/1).