1 The new application of mifepristone in the relief of 1 adenomyosis-caused dysmenorrhea 2 3 Xuan Che 1,2* , Jianzhang Wang 1* , Jiayi He 1 , Xinyue Guo 1 , Tiantian Li 1 , Xinmei 4 Zhang 1# 5 1. Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China, 6 310006 7 2. Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang, P.R. China, 314000 8 9 #To whom correspondence should be addressed at: Xinmei Zhang, MD, PhD, The Department of 10 Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, 11 Hangzhou, Zhejiang, P.R. China, 310006. 12 Phone: 86-571-87061501-2131 13 Fax: 86-571-87061878 14 E-mail: [email protected]15 *These authors contributed equally to this work. 16 17 18 19 20 21 22
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The new application of mifepristone in the relief of ...47 Adenomyosis is defined as invasion of endometrial glands and stroma into the myometrium 48 and the prevalence of adenomyosis
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The new application of mifepristone in the relief of 1
Twenty adenomyosis patients were included and treated with mifepristone by oral administration 332
at 5 mg per day for 3 months. The visual analog scale (VAS) score was applied for pain 333
assessment of dysmenorrhea. The VAS score was significantly decreased after mifepristone 334
treatment for the adenomyosis patients. (B) The platelet count in serum of adenomyosis patient 335
was measured before and after three-month treatment with mifepristone. Data were expressed as 336
mean ± SEM. *P<0.05, **P<0.01 and ***P<0.001. 337
338
Discussion 339
Dysmenorrhea is a common symptom in adenomyosis and is one of the main reasons that 340
women seek medical treatment. Although medical therapies such as GnRH-a, 341
medroxyprogesterone acetate (MPA) and danazol have shown certain clinical effects for relieving 342
adenomyosis-related dysmenorrhea, the potential side effects compromise those clinical 343
applications. Afferent sensory fibers and proinflammatory mediators are correlated with 344
adenomyosis pain, which can be considered an inflammatory neuropathic pain. Recent studies 345
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A B
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showed that mifepristone may play important roles in the development of neuropathic pain 346
diseases. However, the evidence for guiding clinical use of mifepristone treatment is insufficient 347
in adenomyosis for few studies in its action of mechanism and the lack of clinical trial outcomes. 348
Therefore, the present study will elucidate the feasibility of this old drug for new use in 349
adenomyosis. 350
Inflammation is a major biological determinant in the pathogenesis of adenomyosis and 351
proinflammatory/inflammatory cytokines act as chemical neurotransmitters to stimulate uterine 352
contraction and cause dysmenorrhea [31]. In the present study, we found that mifepristone reduces 353
the secretion of IL-6 and TNF-α from endometrial epithelial and stromal cells in adenomyosis. 354
Similar to MPA and danazol treatment of adenomyosis [32, 33], mifepristone treatment inhibited 355
the secretion of IL-6 in endometrial epithelial and stromal cells of adenomyosis in our experiments. 356
Jehn-Hsiahn Yang et al. reported that MPA and danazol have no effect on the suppression of 357
TNF-α by endometrial and stromal cells in adenomyosis [34] while our data showed mifepristone 358
significantly decreased the mRNA and protein expression of TNF-α in both endometrial epithelial 359
and stromal cells of adenomyosis. Recent reports pointed that selective progesterone receptor 360
modulators may be possibly more effectively than progestins in relieving adenomyosis-associated 361
pain, but the underlying mechanism was still unclear [35, 36]. Our findings showed that 362
mifepristone significantly decreased the expression of IL-6 and TNF-α in both endometrial 363
epithelial and stromal cells of adenomyosis, which may be the reason that mifepristone is more 364
effectively than progestins in the relief of adenomyosis-associated pain. 365
Increasing evidence supports that activated and degranulating mast cells play an important 366
role in the development of pain, hyperalgesia and dysmenorrhea [37, 38]. Our previous study also 367
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demonstrate that the activity and degranulation of mast cells play an important role in 368
endometriosis-related dysmenorrhea [14]. Moreover, it is reported that mast cells contribute to the 369
development of inflammation in adenomyosis [10]. Therefore, those drugs that can inhibit mast 370
cell-activation and suppress mast cell-degranulation may be used as effective therapeutic agents 371
for adenomyosis. As we expected, our study showed that the infiltration of mast cells was 372
significantly decreased in both eutopic and ectopic endometrium after mifepristone treatment. 373
Moreover, the rate of degranulation of mast cells treated with mifepristone were decreased when 374
compared to mifepristone-untreated group. Hence, we concluded that mifepristone relieved the 375
dysmenorrhea symptom of adenomyosis patients through inhibiting the infiltration and the activity 376
of degranulation of mast cells in eutopic and ectopic endometrium. 377
It is well known that pain is mediated by sensory nerves. Afferent sensory fibers and 378
proinflammatory mediators are correlated with adenomyosis pain. Our previous study found that 379
the distribution of nerve fibers in the ectopic endometrium play an important role on the pain 380
symptoms in both endometriosis and adenomyosis [16]. The present study found that mifepristone 381
decreases the density of nerve fibers in both eutopic and ectopic endometrium of adenomyosis. 382
Furthermore, Transwell assay was then performed to confirm that mifepristone decreased the 383
migration of nerve cells in a dose-dependent manner. Taken together, our data suggested that the 384
relief of adenomyosis-associated dysmenorrhea by mifepristone is related to the decrease of 385
density of nerve fibers by inhibiting the migration capacity of nerve cells in adenomyosis. 386
At last, the efficacy of mifepristone treatment in adenomyosis was further confirmed by 387
comparing the pain assessment of dysmenorrhea in the same adenomyosis patient before and after 388
mifepristone treatment. We concluded that mifepristone effectively relieved dysmenorrhea 389
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symptoms for adenomyosis patients. Furthermore, it is reported that platelets played an important 390
role in the development of adenomyosis and anti-platelet treatment could reduce uterine 391
hyperactivity and improve generalized hyperalgesia [39]. Our data showed that mifepristone 392
significantly decreased platelet count in serum of the adenomyosis patients. Therefore, the clinical 393
results further proved that mifepristone was efficient in the treatment of adenomyosis-associated 394
dysmenorrhea and the effect of treatment in adenomyosis is similar to endometriosis [40, 41]. 395
Conclusion 396
We firstly demonstrated that mifepristone reduced the secretion of IL-6 and TNF-α from 397
endometrial epithelial and stromal cells, restricted the infiltration and degranulation of mast cells 398
in eutopic and ectopic endometrium and decreased the density of nerve fibers by inhibiting the 399
migration capacity of nerve cells in adenomyosis. Meanwhile, we proved that mifepristone could 400
significantly relieve adenomyosis-associated dysmenorrhea. The findings demonstrated that 401
mifepristone could be applied in the treatment of dysmenorrhea for the adenomyosis patients. 402
Acknowledgments 403
We deeply appreciate that the study was funded by National Key R&D Program of China 404
(Grant number: 2017YFC1001202) and National Natural Science Foundation of China (Grant 405
numbers: 81671429 and 81802591). 406
Conflict of interest 407
The authors declare no potential conflicts of interest with respect to the research, authorship, 408
and/or publication of this article. 409
References 410
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