Flores Valerie A, Sahin Cagdas, Taylor Hugh S
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
F S Sci. 2025 Feb;6(1):65-72. doi: 10.1016/j.xfss.2024.10.004. Epub 2024 Oct 10.
To use murine avatars for studying human endometriotic lesion response to 2 different hormonal regimens to determine whether progesterone receptor (PR) can prospectively predict response to progestin-based therapy. Endometriosis is a chronic gynecologic disease afflicting 1-in-10 reproductive-age women; however response to medical therapy is highly variable because endometriotic lesions do not consistently respond to first-line progestin-based therapy. We have previously demonstrated in a retrospective study that PR status in lesions is correlated with response to progestins. Here, we hypothesize that a prospective approach using PR status to predict response to medical will allow clinicians to individualize effective, timely treatment for this debilitating disease.
Patient-derived xenograft murine model.
Eight-week old NOD/SCID mice undergoing transplantation of endometrioma lesions collected from women undergoing surgery for endometriosis.
Daily subcutaneous injections with vehicle (dimethyl sulfoxide), medroxyprogesterone acetate (MPA), or gonadotropin-releasing hormone (GnRH) antagonist, cetrorelix, for 1 month.
Lesion size 1 month after treatment.
Lesions with high PR demonstrated a robust response to MPA compared with lesions with low PR. The mean post-MPA treatment size in high-PR lesions was sixfold smaller than that in low-PR lesions. Low-PR lesions respond far more completely to GnRH antagonist than to MPA. Surprisingly, there were differences in response to GnRH antagonist between low- and high-PR lesions. High-PR lesions responded almost completely to GnRH antagonist with a 21-fold smaller posttreatment size on average than low-PR lesions.
The use of murine avatars to test clinical response is a novel approach in endometriosis. Hormonal suppression of disease is a cornerstone of therapy; however, response is not fully predictable. We have previously shown that women with low-PR lesions respond poorly to progestin-based therapy. Here, we prospectively validate our previous work using a mouse xenograft model, demonstrating that lesions with low-PR expression do not respond to progestin-based therapy; PR status predicted response to progestin-based therapy. Moreover, PR status identifies a more aggressive form of endometriosis that is not only progesterone resistant but is also less dependent on estradiol for growth. Our findings highlight the need to develop novel nonhormonal therapies aimed at targeting the more aggressive forms of endometriosis that do not rely on the usual hormonal signals.
利用小鼠模型研究人类子宫内膜异位症病变对两种不同激素治疗方案的反应，以确定孕激素受体（PR）是否可前瞻性预测基于孕激素的治疗反应。子宫内膜异位症是一种困扰十分之一育龄女性的慢性妇科疾病；然而，由于子宫内膜异位症病变对一线基于孕激素的治疗并非始终有反应，其对药物治疗的反应差异很大。我们先前在一项回顾性研究中表明，病变中的PR状态与对孕激素的反应相关。在此，我们假设采用PR状态来预测药物反应的前瞻性方法将使临床医生能够为这种使人衰弱的疾病制定有效、及时的个体化治疗方案。
患者来源的异种移植小鼠模型。
8周龄的NOD/SCID小鼠，接受从因子宫内膜异位症接受手术的女性身上采集的子宫内膜瘤病变移植。
每日皮下注射溶媒（二甲基亚砜）、醋酸甲羟孕酮（MPA）或促性腺激素释放激素（GnRH）拮抗剂西曲瑞克，持续1个月。
治疗1个月后的病变大小。
与低PR病变相比，高PR病变对MPA表现出强烈反应。高PR病变在MPA治疗后的平均大小比低PR病变小6倍。低PR病变对GnRH拮抗剂的反应比对MPA的反应更完全。令人惊讶的是，低PR和高PR病变对GnRH拮抗剂的反应存在差异。高PR病变对GnRH拮抗剂几乎完全有反应，治疗后的平均大小比低PR病变小21倍。
利用小鼠模型测试临床反应是子宫内膜异位症研究中的一种新方法。激素抑制疾病是治疗的基石；然而，反应并非完全可预测。我们先前表明，PR水平低的女性对基于孕激素的治疗反应不佳。在此，我们使用小鼠异种移植模型前瞻性地验证了我们先前的研究结果，表明PR低表达病变对基于孕激素的治疗无反应；PR状态可预测基于孕激素的治疗反应。此外，PR状态可识别出一种更具侵袭性的子宫内膜异位症形式，这种形式不仅对孕激素耐药，而且生长对雌二醇的依赖性也较低。我们的研究结果凸显了开发新型非激素疗法的必要性，这些疗法旨在针对不依赖于常见激素信号的更具侵袭性的子宫内膜异位症形式。
