Endometriosis – a severely life-limiting disease affecting millions of women
190 million women worldwide live with endometriosis, a painful chronic, inflammatory, and estrogen-dependent disease caused by uterine-like tissue establishing itself outside the uterine cavity. Despite the large number of women affected by endometriosis, very little progress has been made with regard to new treatments and the medical need is high.
Endometriosis affects 10% of women of childbearing age and usually emerges during or shortly following adolescence – a formative time with a major impact on the rest of life. The disease may therefore have long-term consequences for educational achievement, career, income, family formation, and social life. The time from onset of first symptoms to diagnosis is between 4 and 11 years, but many patients remain undiagnosed.
The hallmark of endometriosis are the endometrial lesions formed mainly in the abdominal cavity and on its organs. The disease causes local inflammation and burdensome adhesions, resulting in excruciating pain which over time may develop into a chronic condition. Afflicted women describe the pain as deeply throbbing, sharp and cramping. Many patients with endometriosis also suffer from heavy menstrual bleeding, and pain during bowel movements, urination, and sexual intercourse. Endometriosis is clearly linked to reduced fertility and infertility. Furthermore, endometriosis has a significant impact on quality of life and often leads to depression and other mental health issues.
Current treatments have significant shortcomings
Standard of care for endometriosis consists mainly of pain-relieving agents and hormone-based therapies including contraceptives and other, more potent drugs.
Endometriotic lesions require estrogen to grow, leading to the use of hormone-based therapies. Drugs which suppress estrogen production to a varying degree alleviate the symptoms of endometriosis. However, interfering with normal variations of female hormone levels often leads to side effects, including hot flashes (vasomotor symptoms) and mood changes. Stronger anti-estrogens have also been shown to reduce bone mineral density over time, which may lead to an increased risk of osteoporosis.
In addition to hormone-based treatments, various pain-relieving agents are used. The most used painkillers are NSAIDs, which however are associated with well-known side effects and should only be used intermittently. Opioids are sometimes used to relieve pain, but this class of drugs has a high risk of side effects and potential for addiction. Tricyclic antidepressants, antiepileptics and other types of drugs are also sometimes tried as add-on therapy.
As an alternative to drug treatment, surgical removal of endometriotic lesions can be effective, but the recurrence rate is high, and many patients are forced to undergo repeated surgery within a few years. More radical surgery (removal of uterus and ovaries) is sometimes used as a last resort.
The enzyme mPGES-1 plays a key role in the development of endometriosis
Since the treatments currently used do not always provide sufficient results and often lead to undesirable side effects, major scientific efforts have been made to find new, more specific drug targets. Microsomal prostaglandin E synthase (mPGES-1) is an enzyme generally present at low levels in the human body. It stimulates the production of prostaglandin E2 (PGE2), a potent biological messenger that has a pronounced impact on inflammation. During inflammation, the levels of mPGES-1 are upregulated, causing excessive levels of PGE2, which drive inflammatory symptoms. It has been shown that the characteristic lesions found in endometriosis contain high levels of mPGES-1, releasing increased amounts of PGE2 which trigger an immune response in the pelvic cavity and with that the production of even more PGE2 in an attempt to heal the area.
Despite the key role of mPGES-1 in the pathogenesis of endometriosis, there are no pharmaceuticals available that specifically inhibit this enzyme. While there are drugs that exert their mode of action further up in the arachidonic acid cascade, these drugs do not only target mPGES-1 but also affect the synthesis of numerous signaling substances important to many normal functions in the body.
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