Daily Endocrinology Research Analysis
Analyzed 89 papers and selected 3 impactful papers.
Summary
A large multicenter randomized trial found that pre-IVF vitamin D supplementation does not improve live birth in women with polycystic ovary syndrome despite raising 25-OHD levels. Single-cell and spatial transcriptomics of KCNJ5-mutant aldosterone-producing adenomas reveal adrenal cortical plasticity and an immunosuppressive macrophage subset that may drive tumor growth and aldosterone excess. A first-in-human phase 1–2 study of autologous hematopoietic stem-cell gene therapy for cystinosis shows durable biochemical correction with acceptable safety over up to 5 years.
Research Themes
- Evidence-based reproductive endocrinology (vitamin D and IVF outcomes in PCOS)
- Adrenal tumor pathophysiology via single-cell and spatial multi-omics
- Gene and cell therapy for inherited metabolic/endocrine-related diseases
Selected Articles
1. Vitamin D supplementation before in vitro fertilisation in women with polycystic ovary syndrome: multicentre, double blind, placebo controlled, randomised clinical trial.
In a multicenter, double-blind RCT of 865 women with PCOS undergoing IVF, vitamin D 4000 IU/day for up to 90 days increased serum 25-OHD at trigger but did not improve live birth after the first embryo transfer. Pregnancy, fertility, and safety outcomes—including severe ovarian hyperstimulation—showed no clinically meaningful benefit.
Impact: This high-quality randomized trial provides definitive evidence against routine high-dose vitamin D supplementation to enhance IVF success in PCOS, addressing a common practice with inconsistent prior data.
Clinical Implications: Routine pre-IVF vitamin D at 4000 IU/day should not be used to improve live birth in PCOS; vitamin D testing and repletion may still be pursued for bone and general health, but not as a fertility-enhancing strategy.
Key Findings
- Vitamin D 4000 IU/day significantly increased serum 25-OHD at trigger compared with placebo.
- No improvement in live birth after the first embryo transfer in the vitamin D group versus placebo.
- Secondary reproductive outcomes and safety (including severe OHSS) showed no clinically meaningful benefit.
Methodological Strengths
- Multicenter, double-blind, placebo-controlled randomized design with preregistration
- Large sample size with modified intention-to-treat analysis
Limitations
- Conducted in a single country; generalizability beyond PCOS and specific IVF protocols may be limited
- Intervention limited to up to 90 days pre-IVF; effects on cumulative live birth over multiple transfers were not reported
Future Directions: Investigate whether vitamin D repletion benefits subgroups with severe deficiency, alternative dosing/timing, and cumulative outcomes over multiple embryo transfers.
OBJECTIVE: To evaluate whether vitamin D supplementation improves live birth rates in women with polycystic ovary syndrome undergoing in vitro fertilisation. DESIGN: Multicentre, double blind, placebo controlled, randomised clinical trial. SETTING: 24 fertility centres in China. PARTICIPANTS: 876 participants with polycystic ovary syndrome undergoing in vitro fertilisation. INTERVENTIONS: Participants were randomised (1:1) to receive vitamin D 4000 IU/day or placebo before in vitro fertilisation for up to 90 days until the trigger day. MAIN OUTCOMES MEASURES: The primary outcome was live birth after the first embryo transfer. Secondary outcomes included serum 25-hydroxyvitamin D (25-OHD) levels on trigger day, pregnancy outcomes, fertility outcomes, and adverse events including severe ovarian hyperstimulation syndrome. RESULTS: Of 876 participants randomised, 865 were included in the modified intention-to-treat analysis, with 435 in the vitamin D group and 430 in the placebo group. Baseline mean serum 25-OHD levels were 16.5±7.2 and 16.1±6.7 ng/mL in the vitamin D and placebo groups, respectively. On the day of triggering, the serum 25-OHD level was significantly higher in the vitamin D group than in the placebo group (32.3±11.2 CONCLUSIONS: Although vitamin D supplementation (4000 IU/day) for up to 90 days increases serum 25-OHD levels, this does not translate to improved live birth rates after the first transfer for patients with polycystic ovary syndrome. TRIAL REGISTRATION: ClinicalTrials.gov NCT04082650.
2. Adrenocortical cell and macrophage heterogeneity at single-cell spatial resolution in KCNJ5-mutant aldosterone-producing adenomas.
Single-cell and spatial profiling of three paired KCNJ5-mutant APAs and distal adrenal tissues uncovered a TSPAN8+ zona glomerulosa-like population and revealed that aldosterone synthase (CYP11B2) is enriched in ZF-like tumor cells. Two functional states of CYP11B2+ cells were identified, and an immunosuppressive APA-associated macrophage subset signaling via SPP1–(ITGAV/ITGB1) likely promotes tumor proliferation.
Impact: The study reframes APA pathogenesis by mapping adrenal cortical plasticity and delineating a macrophage–tumor interaction axis, nominating tractable cellular and signaling targets for future therapies.
Clinical Implications: While not immediately practice-changing, the identification of ZF-like aldosterone-producing cells and SPP1–integrin macrophage signaling suggests avenues for targeted medical therapy and improved molecular subtyping of APAs.
Key Findings
- Discovery of a TSPAN8-positive zona glomerulosa-like population in distal adrenal tissue representing an intermediate ZG–ZF state.
- CYP11B2 expression predominantly in ZF-like tumor cells within KCNJ5-mutant APAs.
- Two functional CYP11B2+ cell states (steroidogenic vs. growth-promoting) and an immunosuppressive APA-associated macrophage subset signaling via SPP1–(ITGAV/ITGB1).
Methodological Strengths
- Integration of single-cell RNA-seq with spatial transcriptomics in paired tumor–normal samples
- Orthogonal validation with immunohistochemistry and immunofluorescence
Limitations
- Small sample size (three paired cases) limits generalizability
- Cross-sectional tissue analysis without functional intervention in vivo
Future Directions: Validate findings in larger multicenter cohorts, functionally target SPP1–integrin signaling and ZF-like steroidogenic cells in preclinical models, and integrate molecular states with clinical phenotypes and outcomes.
KCNJ5-mutant aldosterone-producing adenomas (APAs) represent a primary cause of primary aldosteronism, leading to severe secondary hypertension. However, the adrenal cellular heterogeneity and microenvironmental landscape of KCNJ5-mutant APAs remain to be characterized. Using single-cell RNA sequencing and spatial transcriptomics, we analyzed three paired KCNJ5-mutant APAs and distal adrenal tissues (DATs), with experimental validation by immunohistochemistry and immunofluorescence. In DATs, we identified a previously unrecognized TSPAN8-positive zona glomerulosa (ZG) cell population. Pseudotime and functional enrichment analyses indicate that these cells represent an intermediate state between ZG and zona fasciculata (ZF). Within APAs, adrenocortical cells exhibited remarkable heterogeneity. The key enzyme mediating aldosterone synthesis, CYP11B2, was predominantly expressed in ZF-like cells, suggesting that targeting ZF-like cells may be critical for controlling aldosterone overproduction in APAs. Furthermore, CYP11B2-positive cells displayed two distinct functional states: Fate 1 (aldosterone-producing cells) specialized in mitochondrial metabolism and steroid hormone synthesis, while Fate 2 (tumor growth-promoting cells) participated in anti-apoptotic pathways that may drive APA cell accumulation. In contrast, CYP11B2-negative tumor cells demonstrated enhanced proliferative and differentiation potential, potentially playing a more active role in APA tumorigenesis. Notably, we discovered a unique subset of APA-associated macrophages (AAMs) within the tumor microenvironment. These AAMs were immunosuppressive and communicated with APA cells via the SPP1-(ITGAV/ITGB1) axis, likely promoting tumor proliferation. These findings provide novel insights into the cellular complexity of KCNJ5-mutant APAs, highlighting adrenal cortical cell plasticity and tumor-associated macrophages as critical determinants of APA pathogenesis.
3. Hematopoietic Stem-Cell Gene Therapy for Cystinosis.
In an ongoing phase 1–2, open-label study, six adults with cystinosis received autologous CD34+ hematopoietic stem cells transduced with a lentiviral CTNS vector and were followed for 29–63 months. Adverse events aligned with myeloablative conditioning and disease background, and white-cell cystine levels decreased post-therapy, indicating durable biochemical correction.
Impact: This first-in-human hematopoietic stem-cell gene therapy for cystinosis demonstrates long-term biochemical efficacy, marking a pivotal step toward disease-modifying treatment for a multisystemic lysosomal disorder.
Clinical Implications: If efficacy and safety are confirmed in larger controlled studies, autologous HSC gene therapy could become an alternative or complement to cysteamine, potentially reducing cystine burden and long-term complications.
Key Findings
- Six participants received CTNS-RD-04 and were followed for 29–63 months.
- Adverse events were largely consistent with myeloablative conditioning and underlying disease profile.
- White-cell cystine levels decreased after therapy, indicating biochemical correction.
Methodological Strengths
- Prospective phase 1–2 clinical study with long-term follow-up (up to ~5 years)
- Use of standardized biochemical endpoints (white-cell cystine) and a defined autologous lentiviral product
Limitations
- Small, open-label, single-arm design without a comparator group
- Primary outcomes are biochemical; long-term clinical benefits remain to be established
Future Directions: Proceed to larger controlled or randomized studies to assess clinical outcomes, durability, integration sites, and long-term safety including oncogenic risk.
BACKGROUND: Cystinosis is a multisystemic lysosomal storage disorder caused by pathogenic variants in METHODS: In this phase 1-2, open-label, ongoing clinical study, we performed a preliminary assessment of CTNS-RD-04, which consists of autologous CD34+ cells transduced with lentiviral vectors carrying RESULTS: Six participants (20 to 46 years of age) received CTNS-RD-04 and were followed for 29 to 63 months. CTNS-RD-04 doses ranged from 3.63×10 CONCLUSIONS: In this small study, CTNS-RD-04, an ex vivo gene therapy for cystinosis, had adverse effects that were largely consistent with the myeloablative regimen and underlying disease profile. White-cell cystine levels decreased after therapy. (Funded by the California Institute for Regenerative Medicine and others; ClinicalTrials.gov number, NCT03897361.).