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Treatment of Endometriosis-Associated Pain

 

An article was published this month in Fertility and Sterility which focused on new developments in the medical treatment of endometriosis1. Before understanding the new developments, let’s discuss some of the traditional treatment strategies and their limitations. As discussed in the blog reviewing endometriosis causes, we know that it is an estrogen-dependent disease and pain is caused by the associated inflammation. It is no surprise that most treatments aim at decreasing estrogen production or interrupting the inflammatory pathways.  The new article focuses on “up and coming” treatment strategies for pain, citing that current approaches are temporary treatments (not curative) and many suppress ovulation, which is not ideal for those wishing to conceive. Below is a review of commonly used treatments in addition to newer potential developments for endometriosis-associated pain. Most authorities recommend a stepwise approach to the use of these interventions (Table 1), but tailor their treatment strategy for each patient individually. Currently, the only medical treatment for pain that does not affect ovulation, are NSAIDS (Motrin, Advil, Aspirin, Naprosyn).

First Line Therapy

In the United States, almost all women with chronic pelvic pain suggestive of endometriosis are initially treated with a combination of cyclic oral contraceptives and NSAIDs, such as ibuprofen. NSAIDs act by decreasing prostaglandin production, which are responsible for aspects of inflammatory pain and uterine cramping. Although no trials have shown benefit of NSAIDS compared to placebo, the quality of studies are poor, and they remain one of the few treatment strategies for endometriosis that do not suppress ovulation2. Oral contraceptives, are another first line treatment of pelvic pain caused by endometriosis, because progestins can block the growth of endometrial tissue in endometriosis lesions. They can be used in monthly cycles or given continuously. Although they all contain estrogen, the doses are so low that they do not appear to stimulate endometriosis implants.

Additional Medical Therapies

Additional medical treatment strategies that are currently approved include medications classified as GnRH agonists, high dose progestins, androgens, and aromatase inhibitors.

GnRH agonists are one of the most effective treatments for endometriosis-associated pain. Endometriosis lesions grow when serum estradiol concentrations are in the premenopausal range (30 to 300 pg/mL) and regress when estradiol levels are in the menopausal range (<20 pg/mL). These medications act centrally, inhibiting the brain’s signals to the ovaries to make estrogen, decreasing the circulating estrogen concentration to menopausal levels and shutting down growth of endometriosis.  Numerous clinical trials have demonstrated that approximately 85% of women with endometriosis and pelvic pain who are treated with GnRH agonist analogues experience relief of their pain, but not without side effects. The most common side effects are related to menopausal symptoms such as vasomotor symptoms (hot flashes), decreased libido, vaginal dryness, and decreased bone density. For this reason, it is recommended that “hormonal add-back therapy” be given with GnRH analogs (such as norethindrone 5mg daily with a very low dose estrogen component) to minimize the hypoestrogenic vasomotor symptoms and protect against bone loss, without affecting the pain control3.

High-dose progestins have also been demonstrated in multiple clinical trials to be effective in the treatment of pelvic pain caused by endometriosis. They act by both suppressing the signal from the brain to the ovaries, as well as by acting directly against endometriosis implants. A problem with progestin treatment is that some women gain weight or experience symptoms typical of the premenstrual period, such as mood changes and bloating, which are not desirable side effects.

One of the first hormonal treatments of endometriosis was testosterone, which worked well but had a serious side of masculinization. Research has shown that a synthetic oral androgen, Danazol, can be very effective in treating endometriosis associated pain, but its side-effects are dose related and can masculinize both patient and child if she were to get pregnant while taking the medication. For this reason, it is not often prescribed.

Lastly, aromatase inhibitors, which can block estrogen production in both the ovary and in endometriosis lesions, have been demonstrated to reduce pain symptoms in women with endometriosis4. They should not be used without ovarian suppressive agents in pre-menopausal women as the decrease in estrogen production will result in loss of feedback inhibition to the pituitary and hypothalamus and subsequent stimulation of ovarian estrogen production.

Developmental Medical Treatment Strategies

One of the more promising medical treatments is a “GnRH antagonist”. Similar to the above-mentioned GnRH agonists, antagonists will shut down the brains signal to the ovaries, but in a dose-dependent manner. This means that the estrogen production could be suppressed enough to treat the endometriosis, but not so much as to cause menopausal symptoms1. More studies are needed, but they have shown great potential.

            Many other types of medical therapy have been studied but none have shown safety or efficacy required to obtain approval for use. Some of these are hormonally targeted including progesterone receptor modulators (PRMs) and selective estrogen receptor modulators (SERMs), while others target inflammation, such as anti-tumor necrosis factor-alpha and pentoxifylline and may help treat endometriosis pain without inhibiting ovulation.  However, according to recent Cochrane reviews and publications, there is still not enough evidence to support these agents in the treatment of endometriosis related pelvic pain1,5.

Complementary therapies

There are no large clinical trials that evaluate the use of complementary therapies for the treatment of pelvic pain in women with endometriosis. However, many women with endometriosis report that nutritional interventions such as avoiding red meat, as well as trans-saturated and saturated fats, reduce pain symptoms6. Exercise and structured relaxation programs may also reduce pain symptoms. And, although more rigorous research is required, the efficacy of Chinese herbal medicine and Japanese-style acupuncture may have value in select patient populations.

 

Surgical treatment

Surgical treatment of endometriosis-associated pain is either conservative or definitive. In conservative surgery, the intent is to remove the endometriosis lesions and scar tissue while preserving the pelvic organs. In definitive surgery, both ovaries and often the uterus (unless future childbearing is desired) are removed.

Conservative Surgery

A Cochrane review of multiple randomized controlled trials showed that in patients with mild-moderate endometriosis, laparoscopic surgery has proven to improve pain7. In cases of more severe disease, the surgical approach should be individualized.  Endometriomas should be surgical excised if they cause pain refractory to medical management, become enlarged and risk torsion, or require histology to exclude malignancy. Surgical removal of endometriomas resulted in better long-term results than aspiration, although ovarian reserve can be compromised if care is not taken in their resection. Unfortunately, conservative surgery typically fails to provide permanent relief of pain from endometriosis, In fact, the cumulative probability of pain recurrence is estimated to be between 20 and 40%, and the probability of requiring a further surgical procedure between 15-20%8.

Definitive Surgery

Definitive surgery for endometriosis involves removal of both ovaries and, typically, the uterus. Many studies report that about 90% of women with endometriosis and pelvic pain experience long-term relief of their pain after removal of both ovaries. The risk of endometriosis-associated pain recurrence is most related to whether any ovarian tissue was left at the time of the surgery, because the estrogen produced by the ovary stimulates the endometriosis lesions.

After definitive surgery, patients are typically started on low-dose estrogen replacement to prevent vasomotor symptoms and vaginal dryness. The use of low-dose estrogen after bilateral oophorectomy has not been proven to cause recurrence of pelvic pain.

 

Summary

            If hormonal therapy and conservative surgery can be used to treat painful symptoms until menopause, the disease will ultimately regress with loss of estrogen production. Until then, we have many different types of medical and surgical treatments for endometriosis associated pain, but none are without limitations, and other than definitive surgery, none are curative. In the recently published article by Bedaiway et al, they proposed excellent criteria for the ideal medical treatment1. In general, the treatment would be curative rather than suppressive, able to treat pain while not preventing fertility, and have minimal side effects. It is important for patients to understand the difficulty in treatment and allow physicians to individualize their care based on symptoms and desire for fertility. As for fertility, please see our blog on treatment for endometriosis-associated infertility.

Table 1: Stepwise Treatment of Endometriosis Pelvic Pain

*Macer M. Women’s Health-Endometriosis. ACP Medicine 2014

Step Description Recommendation
1 Thorough history and physical examination Detailed history and physical examination.

 

2 Noninvasive laboratory testing Pelvic ultrasonography, complete blood count, urinalysis, endocervical cultures for sexually transmitted disease

 

3 Empirical therapy Oral contraceptives plus nonsteroidal anti-inflammatory medication

 

4 Surgical diagnostic procedure Laparoscopy to determine the cause of pain if empirical therapy does not result in sufficient relief of pain. Excision of implant or endometrioma (endometriosis cyst) if present.

 

5 GnRH agonist (with add back therapy if >6 months) Leuprolide in depot form given monthly or every three months as an injection. Oral norethindrone add back treatment.
6 Progestin only agents If GnRH agonists cannot be tolerated due to side effects
7 Definitive surgery Removal of uterus and both ovaries
8 Alternative medical therapies still in research Aromatase inhibitors, anti-TNFa, acupuncture, Chinese herbal medications

 

References

1 –Bedaiway M, Alfaraj S, Yong P, Casper R. New developments in the medical

treatment of endometriosis. Fertil Steril 2017. In press.

2 – Brown J, Crawford TJ, Allen C, Hopewell S, Prentice A. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database of Systematic Reviews2017, Issue 1. Art. No.: CD004753.

  1. Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstetrics and gynecology 1998;91:16-24.
  2. Committee opinion no. 663 summary: aromatase inhibitors in gynecologic

practice. Obstet Gynecol 2016;127:1187–8.

  1. Lu D, Song H, Li Y, Clarke J, Shi G. Pentoxifylline versus medical therapies

for subfertile women with endometriosis. Cochrane Database Syst Rev

2009:CD007677.

  1. Macer M, Taylor HS. Women’s Health-Endometriosis. ACP Medicine 2014, Ch. 10.
  2. Duffy JMN, Arambage K, Correa FJS, Olive D, Farquhar C, Garry R, Barlow DH, Jacobson TZ. Laparoscopic surgery for endometriosis. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011031.
  3. Vercellini P, Barbara G, Abbiati A, Somigliana E, Vigano P, Fedele L. Repetitive surgery for recurrent symptomatic endometriosis: what to do? European journal of obstetrics, gynecology, and reproductive biology 2009;146:15-21.