Evalation of Vitamin D and Doxercalciferol Effect on Uterine Fibroid Growth

Uterine fibroids (UF) are the most common pelvic tumor in women of reproductive age. Despite its high prevalence, there is an unmet need in the field for a non-hormonal fertility-friendly anti-fibroid treatment. Vitamin D deficiency has been linked to a higher risk of UF, and its efficiency as a treatment to reduce UF size has been demonstrated in vitro and in vivo. However, long-term vitamin d treatments could induce hypercalcemia, and vitamin D analogs have been proposed as an alternative since they show less calcemic activity. Our study aims to describe the signaling pathways and molecular mechanisms by which Vitamin D (VD3) and Doxercalciferol (a Vitamin D analog) (DCL) reduces UF size in a UF patient-derived xenograft (PDX). Overall design: MED12-mutant human uterine fibroids (UF) were collected from African American women undergoing hysterectomy or myomectomy for symptomatic UF (n=10). Female NOD-SCID mice (n=14) were used to generate the PDX mouse model. Mice were hormonally supplemented with 60-day release pellets with 17ß-estradiol (0.2 mg) and progesterone (50 mg). One week after the xenograft surgery, animals were treated for 6 weeks with the bioactive form of Vitamin D3 (VD3), 1a,25(OH)2D3 and the synthetic Vitamin D2 analog Doxercalciferol (DCL). According to the treatment two different studies were conducted: 1) VD3 0.5 µg/kg/day (n=3) and 2) DCL 0.3 µg/kg/day (n=4). Each study had her own control group, in which animals were treated with the corresponding drug vehicle. At the end of the treatment, animals were euthanized and UF xenografts were collected. Each study had her own control group, in which animals were treated with the corresponding drug vehicle.

子宫肌瘤（Uterine fibroids, UF）是育龄女性最常见的盆腔肿瘤。尽管其患病率居高不下，但该领域仍存在未被满足的临床需求：亟需开发非激素且利于生育的抗肌瘤治疗方案。已有研究表明，维生素D缺乏与子宫肌瘤发病风险升高存在关联，且其在体外与体内实验中均被证实可缩小肌瘤体积。然而，长期维生素D治疗可能引发高钙血症，因此钙调节活性更低的维生素D类似物被提出作为替代治疗选择。本研究旨在阐明维生素D3（Vitamin D3, VD3）与多索钙化醇（Doxercalciferol, DCL）缩小患者来源异种移植瘤（patient-derived xenograft, PDX）模型中子宫肌瘤体积的信号通路与分子机制。

整体实验设计：从因症状性子宫肌瘤接受子宫切除术或肌瘤剔除术的非裔美国女性体内，采集10例携带MED12突变的人子宫肌瘤组织。选用14只雌性NOD-SCID小鼠构建PDX小鼠模型。小鼠通过植入60天缓释型激素颗粒进行激素补充，颗粒中含17β-雌二醇（0.2 mg）与孕酮（50 mg）。异种移植手术一周后，分别给予小鼠活性形式维生素D3（VD3，1α,25(OH)₂D₃）与合成维生素D₂类似物多索钙化醇（DCL），持续治疗6周。本研究分为两个独立实验组：1）VD3组：0.5 μg/kg/天（n=3）；2）DCL组：0.3 μg/kg/天（n=4）。每个实验组均设有对应的溶剂对照组，即仅给予相应的药物赋形剂。实验结束后，处死小鼠并收集子宫肌瘤异种移植瘤组织。