Individual treatment of endometriosis should be based on the extent of the disease, the severity of symptoms, the patient’s desire for childbearing, the patient’s age, and other coexisting medical and surgical factors. Available treatment modalities are expectant, hormonal, surgical, and combined medical/surgical. Expectant management of infertile women with mild endometriosis has been previously recommended. More recent data suggest that treatment at the time of laparoscopy maginally improves pregnancy rates.

Medical Treatment

Endometriotic implant growth usually depends on ovarian steroids. Medications that suppress ovarian function appear to be beneficial. Ovarian suppression has not been shown to improve pregnancy rates for infertile women with mild or moderate endometriosis; several studies have reported a decreased pregnancy rate with medical management likely as a result of the period of anovulation associated with use of these agents. Medical therapy should not be used to enhance fertility. Medical therapy has been shown, however, to relieve pain and reduce the amount of endometriosis visible at laparoscopy. Medical therapy may be indicated for women with pain. Analgesics, oral contraceptives, progestins, danazol, and gonadotropin-releasing hormone (GnRH) agonists all seem to be effective in reducing pelvic pain (Table Medications Commonly Used to Treat Endometriosis). Medical therapy also may be effective in reducing the progression of disease, but this benefit is not as well documented. Hormonal therapy is ineffective in resolving endometriomas and has no effect on adhesion formation. Contraindications to medical therapy include hypersensitivity to any of the individual agents and undiagnosed abnormal vaginal bleeding.

Table Medications Commonly Used to Treat Endometriosis

Medication Dose Route
Nonsteroidal anti- inflammatory drugs Varies Oral
Oral contraceptives 1-2 pills daily continuous dosing Oral
Medroxyprogesteone acetate 20-100 mg daily Oral
Depot medroxy progesterone 150 mg (3 mo) Depot injection
Megestrol acetate 40 mg daily Oral
Norethindrone acetate 5-15 mg daily (start at 5 mg daily and increase dose every 2 wk if needed) Oral
Danazol 200-800 mg daily Oral
Leuprolide acetate 3.75 mg (1 mo); 11.25 mg (3 mo) Depot injection
Nafarelin acetate 200 μg twice daily Intranasal

Medical therapy has been employed before and after conservative surgical treatment of endometriosis. There is no good evidence that preoperative treatment reduces operating time or bleeding. It has no benefit over surgery alone for endometriosis-associated pain or infertility. Postoperative treatment may be beneficial for delaying pain recurrence.

Analgesics

Prostaglandin synthesis by ectopic endometrium may be responsible for characteristic symptoms of endometriosis, such as pelvic pain and dysmenorrhea. Nonsteroidal anti-inflammatory drugs inhibit biosynthesis of prostaglandins and alleviate these symptoms. These drugs are well tolerated, safe, and inexpensive and are recommended as first-line treatment in women with mild symptoms.

Oral Contraceptive Pills

Specific contraindications to taking oral contraceptives include being a smoker older than age 35 years and having a history of thromboembolic disease. Treatment usually involves the use of low-dose (20–35 μg of ethinyl estradiol) oral contraceptives continuously for 6 to 9 months. The treatment usually is begun with one tablet daily and increased to two tablets per day only if breakthrough bleeding occurs. The administration of more than two pills is not recommended because of increasing undesirable side effects. The lowest dose of hormone that produces amenorrhea is maintained during the course of therapy. During the initial 2 to 3 months of treatment, many patients experience worsening symptoms referable to the endometriosis.

Progestins

Medroxyprogesterone acetate is the most commonly used progestin to treat endometriosis. Oral medroxyprogesterone acetate, 20 to 100 mg/day, or injection of depot medroxyprogesterone acetate, 150 mg every 3 months, results in significant amelioration of pain symptoms. A drawback to the use of depot medroxyprogesterone acetate is the prolonged interval to resumption of ovulation after cessation of therapy, which may be 1 year. The depot form should not be used in women who desire pregnancy in the near future and should be reserved for patients who do not want to conceive. The most prominent side effects consist of spotting and breakthrough bleeding, depression, weight gain, and bloating. Megestrol acetate and norethindrone acetate may also be used with similar side effects.

Danazol

Danazol is a derivative of the synthetic steroid 17α-ethinyl testosterone, which is known to have progestagenic and androgenic effects. It has a mild suppressive effect on gonadotropin secretion, abolishes the luteinizing hormone surge, and has an inhibitory effect on ovarian steroidogenic enzymes and the growth of normal and ectopic endometrium. The drug creates an anovulatory amenorrheic, high-androgen, low-estrogen milieu that is hostile to the growth of endometriotic implants. Specific contraindications to danazol include impaired hepatic, renal, or cardiac function.

A dosage of 600 mg/day for 6 months is recommended and seems to be effective in relieving symptoms and suppressing endometriotic lesions. In practice, the dosage of danazol should be individualized and adjusted to the need of the patient, extent of the disease, and severity of side effects. The medication should be started after the completion of a normal menstruation. Danazol should not be administered to pregnant women because it may cause virilization of the external genitalia of a female fetus. In patients with irregular or abnormal menstrual cycles, the presence of an early pregnancy should be excluded before this medication is given. Patients receiving danazol therapy should use barrier contraceptives during the course of treatment. Menses usually recur within 6 weeks of stopping danazol therapy.

Danazol use results in side effects associated with a hyperandrogenic state, including weight gain, acne, hirsutism, oily skin, a decrease in breast size and, rarely, a deepening of the voice. Other side effects include muscle cramps, flushing, mood changes, depression, and edema. Patients receiving danazol are usually amenorrheic; however, breakthrough bleeding may occur when doses of 400 mg or less are given. Because of the significant side-effect profile, danazol is rarely used today.

Gonadotropin-Releasing Hormone Agonists

Administration of GnRH agonists produces an initial stimulation of pituitary gonadotropes that results in secretion of follicle-stimulating hormone and luteinizing hormone and the expected gonadal response. Continuous or repeated administration of an agonist at supra-physiologic doses produces an inhibition of the pituitary-gonadal axis, however. Functional changes resulting from this inhibition include pituitary GnRH receptor downregulation, gonadal gonadotropin receptor downregulation, attenuated gonadotropin secretion, and decreased steroidogenesis. The inhibitory effects of agonists are fully reversible. The ability of GnRH agonists to produce amenorrhea and anovulation has provided the basis for their use in the management of endometriosis.

Side effects associated with GnRH agonist therapy are those attributable to hypoestrogenism, including hot flashes, vaginal dryness, and some largely reversible loss of bone mineral density. Treatment usually is limited to one 6-month course. Women who develop side effects on GnRH agonists, who require treatment for longer than 6 months, or who require repeat treatments may be candidates for “add-back” therapy. This consists of progestin or combination low-dose estrogen and progestin. Many regimens are commonly used (). Use of oral contraceptive pills for add-back therapy may negate the effect of GnRH agonist treatment because of the supraphysiologic estrogen dose. Add-back therapy usually decreases side effects, but may not completely prevent bone loss. Menses may take 8 to 10 weeks to be re-established after GnRH agonist therapy.

Aromatase Inhibitors

Aromatase is an enzyme involved in the production of estrogen that acts by catalyzing the conversion of testosterone to estradiol. Aromatase is located in estrogen-producing cells in the adrenal glands, ovaries, placenta, testicles, adipose tissue, and brain.

Third-generation aromatase inhibitors act by inhibiting the enzyme aro-matase, which suppresses estrogen production locally and systemically, and are used to treat estrogen-dependent breast cancer. Because GnRH analogue therapy inhibits estrogen production in the ovary, but not locally in the endometriotic lesion, aromatase inhibitors are currently being evaluated for treatment of refractory cases of endometriosis. Letrozole, 2.5 mg daily for 6 months, showed promising results in a small study. Side effects of letrozole include hot flashes and bone pain. Because bone loss is a theoretical risk of prolonged therapy secondary to the hypoestrogenic state induced, add-back therapy with norethindrone acetate may be given.

Surgical Treatment

Surgical treatment usually can be accomplished at the initial laparoscopy undertaken to diagnose the disease. Conservative or limited surgery is appropriate for women desiring future fertility and for women with pelvic pain. Conservative procedures include excision, vaporization, and coagulation of endometrial implants; excision of ovarian endometriomas; and lysis of adhesions. These can be accomplished at laparoscopy with surgical excision, laser (carbon dioxide, argon, potassium titanyl phosphate [KTP], or neodymium: yttrium-aluminum-garnet [Nd:YAG]), and monopolar or bipolar electrocautery. Treatment outcomes using sharp excision, carbon dioxide laser, argon laser, KTP laser, and electrosurgery during laparoscopy seem to be comparable. Conservative surgery is most often performed through the laparoscope; however, in the case of extensive disease with cul-de-sac obliteration and dense scarring of the ovaries to the pelvic sidewalls, or when removal of large endometriomas, enterostomy, extensive enterolysis, bowel resection, or other situations deemed too complex for the laparoscope are required, laparotomy may be necessary. Adjunct procedures, including presacral neurectomy and uterosacral nerve ablation, have been recommended for relief of central pelvic pain. The long-term benefit of these procedures has not been conclusively shown. Uterosacral plication, uterine suspension, and oophoropexy have even less clearly defined benefits. Patients with significant bowel involvement may require resection of the affected segment and anastomosis.

Pregnancy rates are acceptable after laparoscopic surgery for endometriosis (). Two randomized, controlled studies on the effectiveness of laparoscopic conservative surgery report conflicting results in women with less severe stages of endometriosis. The effectiveness of surgery for minimal or mild endometriosis has been difficult to show. The Canadian Collaborative Group on Endometriosis reported a randomized trial of laparoscopy with and without treatment in 341 women with minimal or mild disease. The fecundity rate in treated patients was 4.7 versus 2.4 per 100 person-months in controls (95% confidence interval 1.2–3.1). The Gruppo Italiano per lo Studio dell’ Endometriosis conducted a similar study in 111 patients with stage I or stage II endometriosis. One year after surgery, the pregnancy rate was 29% in the no treatment group and 24% in the ablation/resection group. These conflicting studies show the controversy regarding the value of surgery for patients with mild disease. If lesions are observed at the time of laparoscopy, however, destruction or excision of these lesions may improve fecundity and is unlikely to cause significant morbidity.

Definitive therapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy are indicated for patients who have completed childbearing or have significant persistent pelvic pain after conservative treatment. One or both ovaries may be spared if they are completely uninvolved and the endometriosis can be resected completely. Approximately one third of women treated conservatively have recurrent endometriosis and require additional surgery within 5 years. After bilateral oophorectomy, estrogen replacement therapy may be initiated immediately with little risk of reactivating residual disease. There is no reason to delay replacement therapy after surgery.

Assisted Reproduction

In patients with persistent infertility associated with endometriosis, super-ovulation (with and without intrauterine inseminations) and assisted reproductive technologies offer some promise. Spontaneous monthly fecundity rates of 0.10 for stage I, 0.09 for stage II, 0.18 for stage III, and 0.0 for stage IV endometriosis have been reported.

A significant increase in cycle fecundity was seen with four cycles of clo-miphene citrate and intrauterine insemination compared with controls having intercourse (0.095 versus 0.033). Cycle fecundity for gonadotropins and intrauterine insemination also compare favorably with no treatment for women with stage I or stage II endometriosis and infertility (0.15 and 0.045). A report on the effects of expectant management, clomiphene citrate and intrauterine insemination, gonadotropins and intrauterine insemination, or in vitro fertilization and embryo transfer (IVF/ET) on cycle fecundity in women with infertility and minimal or mild endometriosis showed improved cycle fecundity rates with treatment ().

The effect of endometriosis on the outcome of IVF is controversial. Overall, the diagnosis of endometriosis (especially previously treated disease) does not seem to decrease pregnancy rates in patients with less severe stages of disease. Some investigators have suggested, however, that patients with endometriosis undergoing IVF have a reduced implantation rate, possibly secondary to endometrial dysfunction or an embryotoxic environment. Women with advanced endometriosis and a history of a previous oophorectomy and a contralateral ovarian cystectomy seem to do poorly in IVF/ET programs. It is possible that the previous ovarian surgery has depleted the available oocyte pool, making the women perimenopausal. Women with large endometriomas at the start of an IVF/ET cycle also may be at risk for a poor cycle outcome. Resection of an endometrioma should be considered before initiation of an IVF/ET cycle.

 

Selections from the book: “Reproductive endocrinology and infertility : the requisites in obstetrics and gynecology”. Edited by Ruben Alvero and William D. Schlaff, 2007.

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