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@ARTICLE{Park:300165,
      author       = {S. H. Park and P.-E. Sugier and Y. Asgari and M. Karimi and
                      R. Kaaks$^*$ and R. T. Fortner$^*$ and M. Schulze and C.
                      Agnoli and F. Pasanisi and C. Sacerdote and M.
                      Rodriguez-Barranco and A. Aizpurua and N. Cabrera Castro and
                      M. Guevara and S. Tin Tin and E. Weiderpass and F. de
                      Vathaire and F. Lesueur and P. Guénel and C. Mulot and P.
                      Laurent-Puig and E. Ostroumova and A. Boland-Auge and J.-F.
                      Deleuze and H. Thomsen and A. Försti$^*$ and R. Elisei and
                      F. Gemignani and S. Landi and S. Rinaldi and A. Elbaz and C.
                      Domenighetti and T. Truong},
      title        = {{R}eproductive {F}actors, {S}ex {H}ormone {L}evels, and
                      {D}ifferentiated {T}hyroid {C}ancer {R}isk: {A} {M}endelian
                      {R}andomization {S}tudy.},
      journal      = {Thyroid},
      volume       = {35},
      number       = {4},
      issn         = {1050-7256},
      address      = {Larchmont, NY},
      publisher    = {Liebert},
      reportid     = {DKFZ-2025-00651},
      pages        = {433-443},
      year         = {2025},
      note         = {2025 Apr;35(4):433-443},
      abstract     = {Background: Differentiated thyroid carcinoma (DTC) is
                      occurring three times more frequently in females than in
                      males. However, the underlying biological mechanisms driving
                      this discrepancy remain poorly understood. To investigate
                      the causal role of sex hormones and reproductive factors in
                      the risk of DTC, we implemented a two-sample Mendelian
                      randomization (MR) analysis. Methods: We utilized
                      genome-wide association studies (GWAS) summary statistics to
                      explore these associations. GWAS data on DTC were derived
                      from a meta-analysis of six studies including 7705 cases and
                      963,612 controls of European ancestry. GWAS summary
                      statistics on sex hormones, reproductive factors, and
                      gynecological conditions were retrieved from publicly
                      available sources. We used the inverse-variance weighted
                      (IVW) method to estimate odds ratio (OR), with additional
                      sensitivity analyses and conducted multivariable MR (MVMR)
                      to account for potential confounding by body mass index
                      (BMI) and thyrotropin (TSH). Results: We identified a
                      positive association between sex hormone binding globulin
                      (SHBG) and DTC (ORivw = 1.13, p = 0.046). After controlling
                      for TSH and BMI in a MVMR analysis, the strength of this
                      association remained similar but lost statistical
                      significance. Bioavailable testosterone also showed a
                      positive but marginally significant association with DTC
                      after adjustment for BMI in the MVMR (ORivw = 1.13, p =
                      0.07). Putative causal association was observed with uterine
                      fibroids in females under 50 years old (ORivw = 1.52, p =
                      0.017). Endometrial cancer was associated with DTC (ORivw =
                      1.15, p = 9.0 × 10-3); however, a genetic correlation of r2
                      = $13\%$ suggested potential pleiotropy. No significant
                      associations were observed for other investigated factors.
                      Conclusions: Our study does not provide strong evidence for
                      a causal role of reproductive and hormonal factors in DTC
                      risk, despite the observed sex disparity in incidence rates.
                      The associations observed with SHBG, bioavailable
                      testosterone, uterine fibroids, and endometrial cancer
                      indicate potential risk factors, but further investigation
                      is required.},
      keywords     = {Mendelian randomization (Other) / differentiated thyroid
                      cancer (Other) / genetics epidemiology (Other) / hormones
                      (Other) / reproductive factors (Other)},
      cin          = {C020 / B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)C020-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40137860},
      doi          = {10.1089/thy.2024.0548},
      url          = {https://inrepo02.dkfz.de/record/300165},
}