Medical Update: Endometriosis - Current Concepts and Treatment

by James H. Liu, MD and Marcelle I. Cedars, MD

The following article was previously published in the RESOLVE NationalNewsletter.

Endometriosis is defined as the presence of both endometrial gland cells andstroma cells located outside of the uterus. This benign disease is often diagnosed in women who delay childbearing, women who have pelvic pain,and in women with infertility; in addition, the incidence of endometriosis inwomen with first-degree relatives (mother, sister) having the disease isincreased by 6%. Although the reported incidence varies, endometriosis is commonly found in 10 to 15% of women between the ages of 25 and 44 years who are actively menstruating. It has been estimated that 25 to 50% of women with infertility have endometriosis. The incidence of infertility can be high in women with severe endometriosis because distortion of normal pelvic anatomy can lead to impaired egg pickup and movement of the egg through the fallopian tubes. However, some women with minimal endometriosis and normal pelvic anatomy also experience infertility and may have an increased incidence of luteal phase dysfunction, luteinized unruptured ovarian follicle syndrome ("trapped oocyte"), increased peritoneal prostaglandin production, and/or increased immune response because of pelvic macrophage activity, which can result in difficulty conceiving for carrying a pregnancy to term.

Symptoms, Signs, and Diagnosis

Some women with severe endometriosis may be asymptomatic while others with minimal disease may have incapacitating pain. Pelvic pain usually results from cyclic bleeding of endometrial glands into the surrounding tissue causing inflammation and scarring. The diagnosis is suspected on the basis of symptoms and/or physical findings on pelvic examination (the diagnosis can be established only by visualizing lesions,usually with laparoscopy). There may be a fixed uterus, enlarged and non-mobile ovaries, or painful nodules behind the uterus. By definition, both endometrial gland cells and stroma cells must be present to diagnose endometriosis. These cells contain estrogen and progesterone receptors that allow for growth and thickening of the uterine lining in response to sequential changes in ovarian steroids during the menstrual cycle. These same changes occur in endometrial and stroma cells that have attached to organs outside of the uterine cavity, causing the bleeding and scarring called "endometrial implants" or chocolate cysts.

Several blood proteins have been reported to be elevated in patients with endometriosis. CA-125 is a blood protein that is found in reproductive tissues including endometriosis. Elevated CA-125 levels result from pelvicinfections, pregnancy, and ovarian cancer. Studies that measure CA -125 in endometriosis patients have shown that it is not consistently elevated in patients with early stage endometriosis and cannot be used to accurately predict the presence of endometriosis. However, in women that have severe endometriosis,

elevations of CA-125 (>35 U/ml) can be used to monitor results of therapy. Blood levels may be drawn every 6 months, or when pelvic pain returns.

Treatment Options

Treatment must be individualized to the woman's age, symptoms,desire for pregnancy, and extent of disease. Treatment options include medically suppressing ovarian function to arrest the growth and activity of endometrial implants, conservative surgical resection of as much of the endometriosis as possible (either via laparoscopy or laparotomy), a combination of the 2 therapies, and extirpative surgery (total abdominal hysterectomy with or without unilateral or bilateral removal of the ovaries).Various drugs are available for suppressing ovarian function and growth ofendometrial tissue. These are listed in Table 1 below.

Table 1. Current medical therapies for endometriosis

Medications Dose/Duration Side Effects

Danocrine400-800 mg/day for 6 months

Weight gain, edema, acne, oily skin, hirsutism, hot flushes, muscle cramps, decreased breast size, adverse blood lipid changes

Gonadotropin-releasing-hormone (GnRH) agonist

Nafarelin

Leuprolide - depot

Goserelin - 1 month

Goserelin - 3 month

400-800 g/day x 6 months

3.75 mg/month x 6 months

3.7 mg/month x 6 months

10.8 mg/3 month x 6 month

Hot flushes, vaginal dryness, loss in bone density, mood changes, decreased sex drive

Progestins

Medroxy-progesterone

20-30 mg /day orally x 6 months 100 mg IM q 2

Breakthrough bleeding, mood swings, depression, dry

acetate

Medroxy-progesterone acetate - depot

wk for 2 mo.; then 200 mg IM monthly for 4 mo.

or irritated vagina

Continuous estrogen-progestin

Birth control pill (30-50g estinyl estradiol ) with progestin for 6 months

Abdominal swelling, breast tenderness, increased appetite, nausea, breakthrough bleeding, blood clotting in veins

Conservative surgical treatment for pelvic pain is primarily directed at removal of endometriosis implants. For some patients with persistent midline pelvic pain, disruption of the sensory nerve fibers that innervate the uterus and fallopian tubes can theoretically reduce pain. These sensory nerves (the presacral nerve plexus) are located in the midline of the pelvis and extend towards the uterosacral ligaments. Presacral neurectomy can be performed as part of a conservative endometriosis-related procedure to relieve painful menstrual cycles. This operation requires a laparotomy; ablation of the uterosacral ligaments is performed via laparoscopy, using either electrocautery or laser. Pain relief with either procedure approaches 70-80% initially. However, pain often returns with regrowth of endometriosis lesions.

Endometriosis and Assisted Reproductive Technologies

In vitro fertilization (IVF) would seem to be an effective treatment for many of the proposed defects in endometriosis-related infertility. Ovarian hyperstimulation and luteal phase support may correct ovulatory orendocrinologic dysfunction. Oocyte aspiration and embryo transfer to the uterus may correct defects in ovum capture or transport and may remove the oocyte, sperm, and early embryo from a potentially toxic environment. Early studies when IVF was performed primarily after laparoscopic oocyte retrieval demonstrated a decreased pregnancy rate related mainly to a reduced number of oocytes retrieved. Clearly, adhesions or poor surgical access to the ovaries played a role. The introduction of ultrasound-guided oocyte aspiration would be expected to normalize this pregnancy rate. Data,however, remain conflicting, with some studies showing no change while other studies show no decrease in number of oocytes retrieved or the percentage fertilized but a decrease in pregnancy rates. Some of these discrepancies may be due to the varying severity of the endometriosis in the women studied.

Some studies have shown that fertilization rates improve after either medical or surgical treatment of the endometriosis. Additional studies have suggested a decrease in embryo quality suggesting an intrinsic oocyte abnormality in women with endometriosis. The presence of endometriosis cysts (endometriomas) has been shown to be associated with decreased response to ovarian stimulation, lower oocyte fertilization rates, decreased number of embryos available for transfer, and decreased pregnancy rates.

A recent study focusing on oocyte quality noted a decreased pregnancy rate in

endometriosis patients using either their own oocytes or donated oocytes from women with endometriosis. No decrease inimplantation rate or on-going pregnancy rate was seen when these patients received oocytes from patients without endometriosis. These observations suggest that the decreased implantation and pregnancy rate in women with endometriosis was due to poor oocyte quality and not to a defect in the endometrium.

Pre-treatment with GnRH agonist (Lupron, Synarel) has been shown to result in increased numbers of oocytes retrieved, an increase in the fertilization rate, and improved embryo quality for women with endometriosis undergoing IVF. In vitro studies also have shown a decrease in embryotoxicity of peritoneal fluid after such pre-treatment.

Many IVF programs continue to use the woman's blood serum for embryo culture or sperm processing. Blood serum from women with endometriosis has been shown to decrease fertilization rates and early embryo development. This effect increases with the severity of the endometriosis and decreases after treatment of the endometriosis.

Treatment of endometriosis with removal of endometriomas prior toan IVF cycle is advantageous. For select patients, pre-treatment with a prolonged course of GnRH agonist (6-16 weeks) appears to be advantageous. Further, serum from patients with endometriosis should not be utilized in the in vitro culture process.

The concern about the possible toxicity of peritoneal fluid has raised questions about using GIFT in women with endometriosis. Results in the literature are unclear regarding pregnancy rates in women with endometriosis using GIFT. Because GIFT uses ovulatory stimulating drugs,oocyte aspiration and progesterone for luteal support, some but not all of the problems associated with endometriosis are overcome. However, toxic factors within the peritoneal cavity may decrease sperm motility and survival, decrease fertilization and affect early embryo development,suggesting that GIFT will not be effective for a certain subgroup of women with endometriosis.

Endometriosis and Altered Immune Factors

An increase in the level of natural killer cells and other changes in the immune system have been associated with endometriosis. Auto-antibodies directed against ectopic endometrium (i.e. endometriosis) may affect normal uterine endometrium and can lead to early implantation failure and increased early pregnancy loss. In response to the inflammation associated with endometriosis implants, increased numbers of macrophages in peritoneal fluid may result in secretion of cytokines, growth factors, and prostaglandins that may interfere with sperm function, embryo development and implantation. In unaffected women, lymphocytes are activated in the presence of endometrium, whereas in some women with endometriosis,lymphocytes do not proliferate in the presence of autologous endometrium,which suggests a defect in cellular immunity. Other autoimmune responses include increased levels of lupus anticoagulant and antiphospholipid antibodies in blood serum. However, not all patients with endometriosis have these autoantibodies and many women without endometriosis have been found to have these same immune alterations.

Treatment for these autoantibodies remains controversial. Some studies suggest treatment specifically for endometriosis while others suggest that glucocorticoids (steroids) may be effective.

Future Directions

Integrins represent a new area of research in endometriosis and infertility. A specific integrin appears in the endometrium during the time of implantation. This receptor protein is measured by special staining in an endometrial biopsy, and appears to play a role in the normal implantation process. Absence of this integrin has been associated with endometriosis while treatment with high doses of progesterone and treatment of the endometriosis itself appears to correct this defect. In the future the presence of integrins may be a critical marker to follow in treatment of infertile patients with endometriosis.

The cornerstone of medical treatment of endometriosis has been based on the key observation that sex hormones, namely estrogen and progesterone, regulate the growth, proliferation and activity of endometriosis lesions. GnRH agonists are very effective in suppressing sex hormones and thus endometriosis, but their side effects preclude long-term use. New drug combinations that have antiestrogen and antiprogesterone activities are being tested for treatment of endometriosis in animal models. These new combinations include an antiestrogen (raloxifene) which has the ability to suppress hot flushes, prevent calcium loss from bone, and does not stimulate endometrial tissue growth. Goals for future drug development will be directed towards reducing the side effects of low estrogen levels while still suppressing endometriosis.

James H. Liu, MD is Professor and Head, Division of Reproductive Endocrinology and Infertility at the University of Cincinnati, Department of Obstetrics and Gynecology.

Marcelle I. Cedars, MD is an Associate Professor and Director of the Centerfor Reproductive Health at the University of Cincinnati Medical Center.

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