By Rebecca Bowers

EXECUTIVE SUMMARY

Researchers are exploring the use of metronidazole for the treatment of endometriosis, which affects up to 10% of U.S. women between the ages of 25 and 40. The current treatment options include hormone therapy and surgery, but these approaches involve significant side effects and recurrence of the condition after treatment.

  • The Food and Drug Administration has approved elagolix, an oral gonadotropin-releasing hormone antagonist, for treating women with moderate to severe endometriosis pain. Initial pain management options begin with nonsteroidal anti-inflammatory drugs, such as ibuprofen, naproxen sodium, and mefenamic acid.
  • Hormonal contraceptives, such as combined oral contraceptives, a contraceptive patch or vaginal ring, a single-rod contraceptive progestin implant, intramuscular or subcutaneous depot medroxyprogesterone acetate, or a levonorgestrel intrauterine device, also are options for treatment of the estrogen-dependent condition.

Researchers are exploring the use of metronidazole for treatment of endometriosis, which affects up to 10% of U.S. women between the ages of 25 and 40.1 The current options for treatment include hormone therapy and surgery, but these approaches involve significant side effects and recurrence of the condition after treatment.

Most of the time, endometriosis results from retrograde menstruation, where endometrial tissue flows back into the pelvic cavity, instead of out through the cervix. The endometrial tissue enters the abdominal cavity and attaches to organs in the abdominal and pelvic cavities. These areas include the outside of the uterus, the ovaries, the intestines, and other organs or tissues. The endometrial tissue follows the monthly menstrual cycle, resulting in bleeding and inflammation, scarring, and pain. Up to 30% to 50% of women with endometriosis may experience infertility.2

Using mice with surgically induced endometriosis, the researchers found that treatment with metronidazole reduced the size of lesions related to endometriosis in the gut of the animals. This finding held true when the treatment was begun before the lesions started forming and after endometriosis already was established.1

Previous research has suggested that gut microbes linked to bowel problems such as inflammatory bowel disease also feature prominently in endometriosis. In the current study, when investigators treated mice with metronidazole, endometrial lesions became smaller and inflammation was reduced.

“Our initial goal was to understand how these gut bacteria, or microbiota, might be connected to endometriosis, but in the process, we may have found a cost-effective treatment,” notes Ramakrishna Kommagani, PhD, assistant professor of obstetrics and gynecology at Washington University School of Medicine in St. Louis’s Center for Reproductive Health Sciences and principal investigator of the study.

Ampicillin, neomycin, and vancomycin, which also were tested in the study, did not lessen inflammation or shrink lesions. Since findings indicated very low levels of a protective type of gut bacteria in the mice with endometriosis, scientists surmise it may be possible to use probiotics in addition to antibiotics to increase levels of protective bacteria.

“This study is exciting as it opens new frontiers in identifying bacterial candidates that can promote endometriosis in reproductive-age women, and it enables us to conduct future studies aimed at developing simpler ways to diagnose endometriosis,” notes paper coauthor Indira Mysorekar, PhD, the James P. Crane professor of obstetrics and gynecology and professor of pathology and immunology at Washington University School of Medicine in St. Louis. Mysorekar also serves as director of the Center for Reproductive Health Sciences at the university.

New Drug Available for Pain Treatment

Clinicians now have a new drug option in treating women with moderate to severe endometriosis pain. In July 2018, the Food and Drug Administration approved elagolix (Orilissa), an oral gonadotropin-releasing hormone receptor antagonist specifically developed for such an indication.

Patients with endometriosis pain have been treated with various forms of pain management, such as nonsteroidal anti-inflammatory drugs including ibuprofen, naproxen sodium, and mefenamic acid. Clinicians also may have used hormonal contraceptives, such as combined oral contraceptives, a contraceptive patch or vaginal ring, a single-rod contraceptive progestin implant, intramuscular or subcutaneous depot medroxyprogesterone acetate, or a levonorgestrel intrauterine device, for treatment of the estrogen-dependent condition.

Elagolix is available in tablet form in two strengths. The lower-strength tablet is taken once per day for no more than 24 months, while the
higher-strength dosage is taken twice per day for no more than six months. Using the medication for a longer period is not recommended because of the potential for bone loss. In clinical trials, both dose strengths decreased pain during and between menstrual periods after three months of treatment.3

Endometriosis is the most common cause of secondary dysmenorrhea in adolescents.4 It is not known whether elagolix is safe and effective in children younger than 18 years of age. The current treatment recommended for endometriosis in adolescents is conservative surgical therapy for diagnosis and treatment, with suppressive medical therapies for preventing endometrial proliferation.4

The most common side effects associated with the use of elagolix are hot flashes and night sweats, headache, nausea, difficulty sleeping, absence of periods, anxiety, joint pain, depression, and mood changes. In addition to bone loss, potential serious side effects include suicidal thoughts or behaviors; worsening mood, including depression and anxiety; changes in menstrual bleeding that could make it difficult to detect pregnancy; and abnormal liver tests. The drug also may increase the risk of early pregnancy loss.

“Endometriosis is often characterized by chronic pelvic pain that can impact women’s daily activities,” says Hugh Taylor, MD, a study investigator and chair of the Department of Obstetrics, Gynecology and Reproductive Sciences at the Yale School of Medicine. “Women with endometriosis may undergo multiple medical treatments and surgical procedures seeking pain relief and this approval gives physicians another option for treatment based on a woman’s specific type and severity of endometriosis pain.”

REFERENCES

  1. Chadchan SB, Cheng M, Parnell LA, et al. Antibiotic therapy with metronidazole reduces endometriosis disease progression in mice: A potential role for gut microbiota. Hum Reprod 2019. doi: 10.1093/humrep/dez041.
  2. Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet 2010;27:441-447.
  3. Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med 2017;377:28-40.
  4. ACOG Committee Opinion No. 760 Summary: Dysmenorrhea and endometriosis in the adolescent. Obstet Gynecol 2018;132:1517-1518.