Long-term management of endometriosis: Medical therapy and treatment of infertility

Clinical Fellow, Department of Obstetrics and Gynecology, University Hospitals Case Medical Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio

Chair, Department of Obstetrics and Gynecology, University Hospitals Case Medical Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio

Endometriosis is a chronic and recurrent reproductive disorder with variable clinical presentations. Management varies depending on the patient’s age, symptoms, extent of the disease, reproductive goals, treatment risks, side effects, and cost considerations. This article reviews the agents used in the medical management of endometriosis and discusses the use of assisted reproduction techniques (ART) for patients with endometriosis who desire pregnancy.

Medical treatment of endometriosis incorporates two goals: pain control and suppression of estrogen production. The rationale for hormone therapy (HT) is to induce amenorrhea, thereby creating a relatively hypoestrogenic environment that will inhibit endometrial growth and promote regression of the disease.¹ The main disadvantage of this approach is that symptoms recur once therapy is discontinued. Selection of HT for the individual patient depends on therapeutic effectiveness, tolerability, drug cost, the physician’s experience, and expected patient compliance. Currently available hormonal therapies have similar clinical effectiveness in treating chronic pelvic pain. The therapeutic objectives are to prevent disease recurrence, preserve fertility, and reduce operative intervention.

For decades, nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to manage endometriosis-associated pain. NSAIDs target COX-1 and COX-2 enzymes that reduce production of prostaglandins, purported to cause dysmenorrhea and bowel irritability. Although studies that focus solely on use of NSAIDs are lacking, these agents are widely used because of their acceptable side effects, reasonable cost, and ready availability. A recent Cochrane review showed that limited data support routine use of NSAIDs in patients with endometriosis.²

Typically, combined oral contraceptives (COCs) are used for women who are not currently interested in fertility and have minimal or mild disease. COCs induce decidualization followed by atrophy of endometriotic tissue. In a placebo-controlled, double-blind, randomized trial, Harada et al found that low-dose COCs over 4 cycles relieve pain in patients with mild dysmenorrhea and may also delay the progression of disease.³

In a 6-month randomized trial comparing low-dose COC treatment with the gonadotropin-releasing hormone (GnRH) agonist goserelin, both drugs provided significant pain relief, with goserelin slightly better for treatment of dyspareunia.^2,4 Pain recurrence was similar in both groups 6 months after treatment.

Several studies have evaluated elimination of the pill-free interval, but there is insufficient evidence to demonstrate superiority of either cyclic or continuous COC therapy.⁵

COCs can be used long term for patients with endometriosis or until pregnancy is attempted. It is the most affordable long-term medical therapy, and any COCs can be used. A common problem for all long-term continuous COC regimens is breakthrough bleeding, which is commonly treated by discontinuing COCs for a few days and then restarting.

A variety of oral, parenteral, and implantable progestins have been used in the management of endometriosis (TABLE). Progestins inhibit the growth of endometriotic tissue by inducing decidualization followed by atrophy of uterine-type tissue.

Progestins in the medical management of endometriosis

Depot medroxyprogesterone acetate (DMPA) given subcutaneously every 12 weeks has been approved by the FDA for treatment of endometrosis pain. Medroxyprogesterone 30 mg orally per day, norethindrone 5 mg, or DMPA 150 mg IM every 3 months can also induce amenorrhea.

The most prominent side effect associated with progestins is breakthrough bleeding, which can be managed with a 10- to 14-day course of low-dose estrogen. Higher doses of progestins are associated with weight gain, mood changes, depression, and irritability.⁶ Clinical responses with progestin-only therapy are similar to those with continuous oral contraceptives.⁷

The effectiveness of progestins in the treatment of endometriosis-associated pain was shown in a multicenter randomized trial where use of DMPA was comparable to a GnRH agonist in reducing dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, and pelvic induration.⁸

In comparing progestins to other treatment modalities, the main concern is transient bone loss. Recent data have shown that the use of the levonorgestrel-releasing intrauterine system (LNG-IUS) provides symptom relief in patients even with advanced endometriosis.⁹ Compared with other long-term progestins, the LNG-IUS does not negatively affect bone mineral density.¹⁰

Finally, a randomized trial showed that the subdermal implantable contraceptive etonogestrel effectively decreased the intensity of endometriosis-related pain (dyspareunia, dysmenorrhea, nonmenstrual pelvic pain) with a side effect profile similar to that of DMPA.¹¹ Collectively, when administered as a stand-alone therapy, progestins cost less and appear to demonstrate similar efficacy to GnRH agonists for the inital management of pelvic pain.

GnRH agonists have emerged as a first-line medical therapy for endometriosis-associated pain in moderate to severe disease. Randomized trials have shown that GnRH agonists are as effective as other medical therapies in relieving pain and reducing the progression of endometriotic implants.¹²

With adequate steroid “add-back” therapy, GnRH agonists have a better side effect profile than other hormonal therapies. Prolonged therapy with GnRH agonists suppresses gonadotropin secretion and secondarily suppresses endogenous ovarian steroidogenesis. Major disadvantages of long-term use include the high cost of medication ($400 to $600 a month) and the side effects of hypoestrogenism, such as hot flushes, bone loss, and vaginal dryness.

GnRH agonists may be administered via intramuscular, subcutaneous, or intranasal routes. Leuprolide acetate (parenteral), nafarelin acetate (intranasal), and goserelin acetate (subcutaneous implant) are the most commonly used compounds. The majority of clinical trials showed adequate pain relief ranging between 70% and 90%.

Clinicians have explored the use of add-back hormone replacement therapy with long-term GnRH agonist regimens to reduce vasomotor symptoms, vaginal atrophy, and bone demineralization. Many series have demonstrated that add-back therapy does not interfere with the GnRH agonist’s ability to relieve pelvic pain.¹³

Add-back therapy has been attempted with progestins and a combination estrogen/progestin in a dose used for hormone replacement therapy. All patients treated with a GnRH agonist should ensure adequate calcium intake. Add-back regimens reduce adverse clinical and metabolic side effects associated with hypoestrogenism. Moreover, extended GnRH agonist therapy can be safe for up to 1 year, provided that the appropriate add-back preparation is used concomitantly. High-dose norethindrone acetate (5 mg orally daily) is the most widely used agent for add-back therapy, and it is FDA approved for treatment of endometriosis-associated pelvic pain in conjunction with leuprolide.¹⁴

Initial treatment with a GnRH agonist is continued for 6 months and could be extended for 1 year. Interestingly, there are reports about the use of a GnRH agonist with add-back therapy for up to 10 years with excellent pain relief and bone sparing.¹⁵ The high cost of GnRH agonists, side effect profile, and need for add-back therapy make this treatment approach less attractive long term.

Danazol is a 17-ethinyl testosterone derivative that effectively suppresses endometriosis-related pain symptoms within 2 months of use. It has multiple levels of action, including inhibition of pituitary gonadotropin secretion, direct inhibition of endometriotic implant growth, and direct inhibition of ovarian enzymes responsible for estrogen production. Danazol is given orally in divided doses ranging from 400 to 800 mg daily, generally for 6 months.

The major drawback to danazol use is its undesired androgen side effects. These include acne, oily skin, facial hair and deepening of the voice, menopausal hot flushes, atrophic vaginitis, emotional lability, weight gain, fluid retention, migraine headaches, altered lipid profile, dizziness, fatigue, and depression.¹⁶ Because of its side effects, danazol is rarely used, but recent data suggest that it may have a role as a vaginal agent.¹⁷

In contrast to hormonal interventions that target ovarian estrogen production, aromatase inhibitors (AIs) inhibit local estrogen production in endometriotic implants. Additionally, AIs inhibit estrogen production in the ovary, brain, and adipose tissue.¹⁸ The aromatase enzyme converts testosterone and androstenedione to estradiol and estrone. Endometriotic implants express aromatase and consequently can generate their own estrogen, which can maintain their viability and growth. Animal studies have shown that AIs can effectively eradicate endometriotic implants. Limited clinical experience with AIs testified to the feasibility of their use in the treatment of endometriosis.^19,20

A recent systematic review showed that AIs significantly reduced endometriosis- associated pain compared with GnRH agonists alone.²¹ AIs are administered in various doses, such as 2.5 mg daily for letrozole and 1 mg daily for anastrazole. AIs given to reproductive-aged women will cause increased follicle-stimulating hormone (FSH) levels and subsequent superovulation. Other concerns about prolonged AI therapy are associated bone loss and multifollicular ovarian cyst development due to the initial FSH rise. For this reason, AIs are combined with an FSH suppression agent, such as COCs, progestins, or GnRH agonists. The off-label nature of its use for such purpose should be carefully reviewed with patients.

When treating infertility associated with endometriosis, a stepwise approach is routinely used. Management of endometriosis-associated infertility involves a combination of expectant management, surgery, controlled ovarian stimulation (COS), intrauterine insemination, and advanced assisted reproduction techniques (ART).

The use of COS with or without intrauterine insemination may be beneficial for a short course of therapy in patients with endometriosis with tubal patency. If COS does not result in a pregnancy, in vitro fertilization (IVF) is a prudent next step. If initial surgery fails to restore fertility in patients with moderate (stage III) or severe (stage IV) endometriosis-related infertility, IVF is an effective alternative. Reoperation for asymptomatic patients offers little added benefit when it comes to infertility.²² Patients with endometriosis appear to have reduced ovarian response to gonadotropins and need a higher dose of gonadotropins for IVF.²³ It remains unclear whether the presence or degree of endometriosis is associated with impaired oocyte quality or the fertilization and implantation rate.²⁴ The effect of endometriosis surgery on the outcome of subsequent IVF cycles has been studied, and regression analyses have showed that the time interval between surgery and oocyte retrieval does not affect implantation rates in endometriosis patients undergoing IVF.²⁵

Numerous medical treatments are available to treat endometriosis. Current evidence is insufficient to support the superiority of one therapy over another. It is important to consider the patient’s preference in the treatment approach and to provide appropriate counseling on the risks, side effects, and cost, because endometriosis is a chronic disease that will require long-term treatment.

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