Long-term vitamin D treatment decreases human uterine leiomyoma size in a xenograft animal model

Abstract

Objective: To study the effects of short- and long-term vitamin D treatment on uterine leiomyomas in vivo through cell proliferation, extracellular matrix (ECM) degradation, and apoptosis.

Design: Preclinical study of human leiomyoma treatment with vitamin D in an nonhuman animal model.

Setting: Hospital and university laboratories.

Patient(s)/animal(s): Human leiomyomas were collected from patients and implanted in ovariectomized NOD-SCID mice.

Intervention(s): Mice were treated with vitamin D (0.5 μg/kg/d or 1 μg/kg/d) or vehicle for 21 or 60 days.

Main outcome measure(s): Vitamin D effect in xenograft tissue was assessed by monitoring tumor size (¹⁸F-FDG positron-emission tomography/computerized tomography and macroscopic examination), cell proliferation (immunohistochemistry and quantitative real-time polymerase chain reaction [qRT-PCR]), ECM (Western blot), transforming growth factor (TGF) β3 (qRT-PCR), and apoptosis (Westrn blot and TUNEL).

Result(s): Short-term treatment with vitamin D did not appear to alter leiomyoma size, based on in vivo monitoring and macroscopic examination. However, long-term high-dose treatment induced a significant reduction in leiomyoma size. Cell proliferation was not decreased in the short term, whereas 1 μg/kg/d vitamin D in the long term significantly reduced proliferation compared with control. Although collagen-I and plasminogen activator inhibitor 1 were not modified by short-term treatment, they were both significantly reduced by long-term high-dose vitamin D. Similarly, long-term high-dose vitamin D significantly reduced TGF-β3 expression. Finally, apoptosis significantly increased with both short- and long-term high-dose vitamin D treatment.

Conclusion(s): Long-term vitamin D acts as an antiproliferative, antifibrotic, and proapoptotic therapy that provides a safe, nonsurgical therapeutic option for reducing uterine leiomyoma size without side-effects.

Keywords: apoptosis; cell proliferation; extracellular matrix; uterine leiomyoma; vitamin D.