Pituitary Tumor Risk: What Metabolites Matter?

Key Findings

This Mendelian randomization (MR) study found no evidence that Acetyl-L-Carnitine (ALCAR) or other plasma/cerebrospinal fluid (CSF) metabolites causally influence pituitary tumor (PT) risk. Key results included:
- Glutamine showed a potential protective association with PTs (OR = 0.86, 95% CI: 0.75–0.98, p = 0.026).
- Phosphatidylcholine (PC aa C36:6) had a suggestive risk-increasing link (OR = 1.18, 95% CI: 1.02–1.37, p = 0.028).
- ALCAR was not analyzed as a specific metabolite in the study. No metabolites reached strict genome-wide significance (p < 0.05 after multiple-testing correction), and sensitivity analyses (MR-Egger, weighted median) showed inconsistent results, indicating potential pleiotropy.

Study Design

This was a two-sample Mendelian randomization study using genetic data to infer causal relationships. It leveraged:
- Genetic instruments: 136 plasma and 108 CSF metabolites from large metabolomics GWAS (sample sizes: plasma n = 8,330; CSF n = 679).
- Outcome data: Pituitary tumor cases (n = 1,455) vs. controls (n = 360,897) from the UK Biobank and FinnGen.
- Methodology: Inverse-variance weighted (IVW) as primary analysis, supplemented by MR-Egger, weighted median, and MR-PRESSO to assess pleiotropy. No human subjects received interventions; analyses were entirely genetic/in silico.

Dosage & Administration

Not applicable. This was an observational genetic study. No supplements were administered, and ALCAR was not investigated as a specific intervention or metabolite. Metabolite levels reflected endogenous concentrations, not exogenous dosing.

Results & Efficacy

The primary IVW analysis identified two metabolites with nominal significance (p < 0.05) for PT risk:
- Glutamine: OR = 0.86 (95% CI: 0.75–0.98, p = 0.026) – suggesting 14% lower PT risk per SD increase.
- PC aa C36:6: OR = 1.18 (95% CI: 1.02–1.37, p = 0.028) – suggesting 18% higher PT risk per SD increase.
However, neither survived multiple-testing correction (Bonferroni threshold p < 3.7 × 10⁻⁴). Sensitivity analyses showed directional heterogeneity (MR-Egger intercept p < 0.05 for some metabolites), and MR-PRESSO detected outliers, undermining causal claims. ALCAR was not among the 244 metabolites tested.

Limitations

1. Weak instrument bias: Some metabolite genetic instruments had F-statistics <10, increasing false-positive risk.
2. Pleiotropy: MR-Egger intercept tests indicated horizontal pleiotropy for multiple metabolites (p < 0.05), violating MR assumptions.
3. Limited generalizability: European-ancestry cohorts only; PT subtypes (e.g., prolactinomas) were not analyzed separately.
4. Metabolite coverage: ALCAR was not profiled in the source metabolomics datasets. Future studies need targeted ALCAR measurement and diverse populations.

Clinical Relevance

This study provides no evidence supporting ALCAR supplementation for pituitary tumor prevention or treatment. The nominal links for glutamine and phosphatidylcholine are hypothesis-generating only and require replication in prospective cohorts with direct metabolite measurements. For supplement users:
- ALCAR’s role in brain health (e.g., mitochondrial function) remains unrelated to PT risk based on this specific analysis.
- Clinicians should not alter ALCAR recommendations due to these findings. Rigorous randomized trials—not genetic associations—are needed to evaluate metabolite-based interventions for PTs.