子宮內膜異位 | Endometriosis

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子宮內膜異位

子宮內膜異位症是一種雌激素依賴性疾病，子宮內膜組織在子宮外形成病變。據估計，10%的育齡婦女受到子宮內膜異位症的影響，不孕症和/或疼痛患者的子宮內膜異位症發病率上升到30%至50%，對她們的身體、精神和社會福利產生重大影響。現時還沒有已知的治療方法，而且由於其副作用，大多數現時的醫療方法不適合長期使用。子宮內膜異位症在美國的年費用估計為188億至220億美元（2002年的數位）。雖然子宮內膜異位症是100多年前首次被描述的，但現時對其發病機制、自發演變以及與不孕症和盆腔疼痛相關的病理生理學的認識仍不清楚。在第十届子宮內膜異位症世界大會之後召開了一次協商一致的研討會，以確定子宮內膜異位症研究優先事項的建議。影響子宮內膜異位症研究能力的一個主要問題是需要多學科的專門知識。共提出了25項研究建議，分為5個小標題：（a）診斷，（b）分類和預後，（c）治療和結果，（d）流行病學和（e）病理生理學。子宮內膜異位症的研究是資金不足相對其他疾病與高醫療負擔。這可能是由於對一種只影響婦女的複雜而缺乏瞭解的疾病製定競爭性研究建議的實際困難。通過發表這一國際研究優先事項共識聲明，研討會參與者希望鼓勵研究人員製定新的跨學科研究建議，吸引更多資金支持子宮內膜異位症的研究。 (1)


褪黑素

基質金屬蛋白酶（MMPs）在子宮內膜異位症（一種女性婦科疾病）中的作用尚不清楚。研究子宮內膜異位症發病過程中MMP-3的活性及其與MMP-9的相互作用。此外，還探討了MMP-3在子宮內膜異位症凋亡途徑中的作用及褪黑素對其的影響。隨著子宮內膜異位症的嚴重程度，MMP-3活性顯著升高，小鼠也有類似的變化。在子宮內膜異位症早期，MMP-3而非MMP-9表達新增，並與轉錄因數c-Fos的表達有關。此外，尿激酶型纖溶酶原啟動劑和金屬蛋白酶組織抑制劑（TIMP）-3參與了子宮內膜異位症過程中MMP-3的調節。此外，褪黑素預處理降低了子宮內膜異位症中與c-Fos表達平行的MMP-3活性，其特徵是啟動蛋白（AP）-1dna結合活性降低。由於細胞凋亡减少是子宮內膜異位症持續存在的一個解釋，我們檢測了褪黑素在凋亡途徑中預防子宮內膜異位症的作用。與未經治療的小鼠相比，經褪黑素治療的小鼠的腺上皮顯著退化。褪黑素治療新增了子宮內膜異位區的凋亡細胞。這與Bcl-2表達减少、Bax表達新增和caspase-9活化有關。總之，MMP-3在子宮內膜異位症早期的誘導與MMP-9不同，MMP-9受c-Fos和TIMP-3的調控。褪黑素通過caspase-3介導的途徑抑制MMP-3活性和新增細胞凋亡，同時逆轉子宮內膜異位症。囙此，褪黑素可能是解决子宮內膜異位症的治療劑。(2)

褪黑素對子宮內膜異位的作用:

  • 慢性盆腔疼痛(3)
  • 減輕慢性盆腔疼痛和痛經(4)
  • 疼痛、痛經、(5)
  • 改善睡眠質量(5)
  • 提高妊娠率(6)
  • 降低卵巢過度刺激綜合征風險 (6)



Endometriosis

Endometriosis is an estrogen-dependent disorder where endometrial tissue forms lesions outside the uterus. Endometriosis affects an estimated 10% of women in the reproductive-age group, rising to 30% to 50% in patients with infertility and/or pain, with significant impact on their physical, mental, and social well-being. There is no known cure, and most current medical treatments are not suitable long term due to their side-effect profiles. Endometriosis has an estimated annual cost in the United States of $18.8 to $22 billion (2002 figures). Although endometriosis was first described more than 100 years ago, current knowledge of its pathogenesis, spontaneous evolution, and the pathophysiology of the related infertility and pelvic pain, remain unclear. A consensus workshop was convened following the 10th World Congress on Endometriosis to establish recommendations for priorities in endometriosis research. One major issue identified as impacting on the capacity to undertake endometriosis research is the need for multidisciplinary expertise. A total of 25 recommendations for research have been developed, grouped under 5 subheadings: (a) diagnosis, (b) classification and prognosis, (c) treatment and outcome, (d) epidemiology, and (e) pathophysiology. Endometriosis research is underfunded relative to other diseases with high health care burdens. This may be due to the practical difficulties of developing competitive research proposals on a complex and poorly understood disease, which affects only women. By producing this consensus international research priorities statement it is the hope of the workshop participants that researchers will be encouraged to develop new interdisciplinary research proposals that will attract increased funding support for work on endometriosis.(1)

Melatonin

The role of matrix metalloproteinases (MMPs) in endometriosis, a gynecological disease of women, is unclear. The study investigated the activity of MMP-3 and its interplay with MMP-9 during the onset of endometriosis. Additionally, the importance of MMP-3 on the apoptotic pathway in endometriosis and effect of melatonin thereon were investigated. A Significant increase in the activity of MMP-3 with the severity of endometriosis in human was observed which was found similar in mice also. During the early phase of endometriosis, MMP-3 but not MMP-9 was increased and associated with the expression of transcription factor, c-Fos. Moreover, urokinase plasminogen activator and tissue inhibitor of metalloproteinase (TIMP)-3 were involved in MMP-3 regulation during endometriosis. Furthermore, MMP-3 activity that was parallel to c-Fos expression in endometriosis was reduced by melatonin pretreatment as characterized by diminished activator protein (AP)-1 DNA-binding activity. Because decreased apoptosis is an explanation for the perpetuation of endometriosis, we tested the role of melatonin on apoptotic pathway in preventing endometriosis. Significant regression of glandular epithelium was observed in melatonin-treated when compared to untreated mice. Melatonin treatment increased apoptotic cells in endometriotic zones. This was related to reduced Bcl-2 expression along with increased Bax expression and caspase-9 activation. In summary, early induction of MMP-3 was distinct from MMP-9 during endometriosis, which was regulated by c-Fos and TIMP-3. Melatonin suppressed MMP-3 activity and amplified apoptosis while regressing endometriosis through a caspase-3 mediated pathway. Thus, melatonin may be a therapeutic agent for resolving endometriosis.(2)

Effects of melatonin on endometriosis:

  • Chronic pelvic pain (3)
  • Relieving chronic pelvic pain and dysmenorrhea (4)
  • Pain, dysmenorrhea, (5)
  • Improving sleep quality (5)
  • Increasing pregnancy rate (6)
  • Reducing the risk of ovarian hyperstimulation syndrome (6)

Refs:

  1. Peter A. W. Rogers, BSc, PhD, Thomas M. D’Hooghe, MD, PhD, Asgerally Fazleabas, PhD, Caroline E. Gargett, PhD, Linda C. Giudice, MD, PhD, MSc, Grant W. Montgomery, PhD, Luk Rombauts, MD, PhD, Lois A. Salamonsen, PhD, and Krina T. Zondervan, DPhil. Priorities for Endometriosis Research. Reprod Sci. 2009 Apr; 16(4): 335–346. doi: 10.1177/1933719108330568
    PMCID: PMC3682634. PMID: 19196878
  2. Sumit Paul 1 , Partha Bhattacharya, Pramathes Das Mahapatra, Snehasikta Swarnakar. Melatonin protects against endometriosis via regulation of matrix metalloproteinase-3 and an apoptotic pathway. J Pineal Res. 2010 Sep;49(2):156-68. PMID: 20609072. doi: 10.1111/j.1600-079X.2010.00780.x. Epub 2010 Jul 1.
  3. André Schwertner, Claudia C Conceição Dos Santos, Gislene Dalferth Costa, Alicia Deitos. Efficacy of melatonin in the treatment of endometriosis: A phase II, randomized, double-blind, placebo-controlled trial. March 2013Pain 154(6). DOI: 10.1016/j.pain.2013.02.025. PMID: 23602498
  4. Haniyeh Hoseinalizadeh1, Shahla Cahichian 2. Evaluation of melatonin effect on pelvic pain in women with endometriosis referred to affiliated hospitals to Tehran Medical Sciences of Islamic Azad University. Volume 28, Issue 4 (winter 2018). MEDICAL SCIENCES 2018, 28(4): 277-282
  5. André Schwertner 1 , Claudia C Conceição Dos Santos, Gislene Dalferth Costa, Alícia Deitos, Andressa de Souza, Izabel Cristina Custodio de Souza, Iraci L S Torres, João Sabino L da Cunha Filho, Wolnei Caumo
    . Efficacy of melatonin in the treatment of endometriosis: a phase II,randomized, double-blind, placebo-controlled trial. Clinical Trial
    Pain. 2013 Jun;154(6):874-81.doi: 10.1016/j.pain.2013.02.025. Epub 2013 Mar 5. PMID: 23602498
  6. Nicolas Mendozaa,b, Maria Paz Diaz-Roperoc, Miguel Aragond, Vicente Maldonadoe, Placido Llanezaf,Juan Lorenteg, Raquel Mendoza-Tesarikb, Jose Maldonado-Lobonc, Monica Olivarescand Juristo Fonollac. Comparison of the effect of two combinations of myo-inositol andD-chiro-inositolin women with polycystic ovary syndrome undergoing ICSI: a randomizedcontrolled trial. GYNECOLOGICAL ENDOCRINOLOGY2019, VOL. 35, NO. 8, 695–700https://doi.org/10.1080/09513590.2019.1576620.

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