Department of Obstetrics and Gynaecology, Inselspital, Berne University Hospital, Effingerstrasse 102, Berne CH-3010, Switzerland Department of Clinical Research, University of Berne, Murtenstrasse 35, Berne CH-3010, Switzerland
Department of Obstetrics and Gynaecology, Inselspital, Berne University Hospital, Effingerstrasse 102, Berne CH-3010, Switzerland Department of Clinical Research, University of Berne, Murtenstrasse 35, Berne CH-3010, Switzerland.
Hum Reprod Update. 2016 Apr;22(3):382-403. doi: 10.1093/humupd/dmv060. Epub 2016 Jan 5.
Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment.
To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry.
The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects.
Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.
子宫内膜异位症是指子宫内膜组织在子宫腔以外的部位生长，常伴有慢性盆腔疼痛、不孕和卵巢癌风险增加。目前的治疗方法包括手术切除病变或诱导雌激素缺乏状态。然而，手术后病变的再次出现较为常见，且对于育龄妇女而言，雌激素缺乏状态并非最佳选择。需要采取其他方法。子宫内膜异位症病变存在于一种独特的微环境中，其特征是激素、炎症、氧化应激和铁的浓度增加。这种环境通过膜受体结合和随后细胞内激酶的级联激活影响细胞存活，从而刺激细胞反应。这些激酶信号通路中的许多在子宫内膜异位症中被持续激活。这些通路正在作为其他疾病的治疗靶点进行研究，因此也可能成为子宫内膜异位症治疗的靶点。
为了确定截至 2015 年与子宫内膜异位症中激酶信号通路相关的英文研究，我们使用以下搜索词在 Pubmed 数据库中进行了搜索，并以各种组合方式进行了搜索；“子宫内膜异位症”、“炎症”、“氧化应激”、“铁”、“激酶”、“NFκB”、“mTOR”、“MAPK”、“p38”、“JNK”、“ERK”、“雌激素”和“孕激素”。使用 Scopus 数据库进一步识别引用参考文献，最后在 clinicaltrials.gov 临床试验注册处搜索当前临床试验。
目前关于受子宫内膜异位症环境激活的细胞内激酶的文献可以总结为三个可能的治疗靶点：经典的 IKKβ/NFκB 通路、MAPK 通路（ERK1/2、p38 和 JNK）和 PI3K/AKT/mTOR 通路。许多针对这些通路的药物化合物已在子宫内膜异位症的体外和动物模型中成功进行了试验，尽管它们尚未进入临床试验。目前这一代激酶抑制剂可能会产生不良反应。
激酶信号通路是子宫内膜异位症治疗的可行靶点。然而，在这些化合物可用于长期子宫内膜异位症治疗之前，还需要进一步提高临床疗效和不良反应特征。更好地了解这些激酶的分子活性，包括导致子宫内膜异位症细胞中特定激活的特定细胞外化合物，将有助于改善这些激酶，并可能为子宫内膜异位症带来新的非激素治疗方法。
