Endometriosis

Prof. Dr. Almahdy A, Apt Fakultas Farmasi Unand. 2009

What is endometriosis?
Endometriosis is a common cause of chronic pelvic pain in women and is also associated with infertility. Characterized by the presence of endometrial tissue (Endometrial cells are the same cells that are shed each month during menstruation) outside the uterus, endometriosis is a chronic, recurring disease. Therapy is targeted at relieving symptoms and improving fertility.

The cells of endometriosis attach themselves to tissue outside the uterus and are called endometriosis implants. These implants are most commonly found on the ovaries, the Fallopian tubes, outer surfaces of the uterus or intestines, and on the surface lining of the pelvic cavity.

They can also be found in the vagina, cervix, and bladder, although less commonly than other locations in the pelvis. Rarely, endometriosis implants can occur outside the pelvis, on the liver, in old surgery scars, and even in or around the lung or brain. Endometrial implants, while they can cause problems, are benign (not cancerous)

Who is affected by endometriosis?

Endometriosis affects women in their reproductive years. The exact prevalence of endometriosis is not known, since many women may have the condition and have no symptoms. Endometriosis is estimated to affect over one million women (estimates range from 3% to 18% of women) in the United States. It is one of the leading causes of pelvic pain and reasons for laparoscopic surgery and hysterectomy in this country.

While most cases of endometriosis are diagnosed in women aged around 25-35 years, endometriosis has been reported in girls as young as 11 years of age. Endometriosis is rare in postmenopausal women. Endometriosis is more commonly found in white women as compared with African American and Asian women. Studies further suggest that endometriosis is most common in taller, thin women with a low body mass index (BMI). Delaying pregnancy until an older age is also believed to increase the risk of developing endometriosis.

What causes endometriosis?

The cause of endometriosis is unknown. One theory is that the endometrial tissue is deposited in unusual locations by the backing up of menstrual flow into the Fallopian tubes and the pelvic and abdominal cavity during menstruation (termed retrograde menstruation). The cause of retrograde menstruation is not clearly understood. But retrograde menstruation cannot be the sole cause of endometriosis. Many women have retrograde menstruation in varying degrees, yet not all of them develop endometriosis.

Another possibility is that areas lining the pelvic organs possess primitive cells that are able to grow into other forms of tissue, such as endometrial cells. (This process is termed coelomic metaplasia.)
It is also likely that direct transfer of endometrial tissues during surgery may be responsible for the endometriosis implants sometimes seen in surgical scars (for example, episiotomy or Cesarean section scars). Transfer of endometrial cells via the bloodstream or lymphatic system is the most likely explanation for the rare cases of endometriosis that develop in the brain and other organs distant from the pelvis.

Finally, some studies have shown alternations in the immune response in women with endometriosis, which may affect the body's natural ability to recognize and destroy any misdirected growth of endometrial tissue.

Normal Pelvic Structures

Endometriosis

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What are endometriosis symptoms?

Most women who have endometriosis, in fact, do not have symptoms. Of those who do experience symptoms, the common symptoms are pain (usually pelvic) and infertility. Pelvic pain usually occurs during or just before menstruation and lessens after menstruation.

Some women experience pain or cramping with intercourse, bowel movements and/or urination. Even pelvic examination by a doctor can be painful. The pain intensity can change from month to month, and vary greatly among women. Some women experience progressive worsening of symptoms, while others can have resolution of pain without treatment.
Pelvic pain in women with endometriosis depends partly on where the implants of endometriosis are located. Deeper implants and implants in areas with many painsensing nerves may be more likely to produce pain. The implants may also produce substances that circulate in the bloodstream and cause pain.

Other symptoms related to endometriosis include: lower abdominal pain, diarrhea and/or constipation, low back pain, irregular or heavy menstrual bleeding, or blood in the urine.

Rare symptoms of endometriosis include chest pain or coughing blood due to endometriosis in the lungs and headache and/or seizures due to endometriosis in the brain.

Endometriosis and cancer risk

Women with endometriosis have a mildly increased risk for development of certain types of cancer of the ovary, known as epithelial ovarian cancer (EOC). This risk seems to be highest in women with endometriosis and primary infertility (those who have never borne a child), but the use of oral contraceptive pills (OCPs), which are sometimes used in the treatment of endometriosis, appears to significantly reduce this risk. The reasons for the association between endometriosis and ovarian epithelial cancer are not clearly understood. One theory is that the endometriosis implants themselves undergo transformation to cancer. Another possibility is that the presence of endometriosis may be related to other genetic or environmental factors that also increase a women's risk of developing ovarian cancer

How is endometriosis diagnosed?

Endometriosis can be suspected based on symptoms of pelvic pain and findings during physical examinations in the doctor's office. Occasionally, during a rectovaginal exam (one finger in the vagina and one finger in the rectum), the doctor can feel nodules (endometrial implants) behind the uterus and along the ligaments that attach to the pelvic wall. At other times, no nodules are felt, but the examination itself causes unusual pain or discomfort.

Unfortunately, neither the symptoms nor the physical examinations can be relied upon to conclusively establish the diagnosis of endometriosis. Imaging studies, such as ultrasound, can be helpful in ruling out other pelvic diseases and may suggest the presence of endometriosis in the vaginal and bladder areas, but still cannot definitively diagnose endometriosis. For an accurate diagnosis, a direct visual inspection inside of the pelvis and abdomen, as well as tissue biopsy of the implants are necessary.

As a result, the only accurate way of diagnosing endometriosis is at the time of surgery, either by opening the belly with large-incision laparotomy or smallincision laparoscopy.

How is endometriosis treated?

Endometriosis can be treated with medications and/or surgery. The goals of endometriosis treatment may include pain relief and/or enhancement of fertility.

Medical treatment of endometriosis

Nonsteroidal anti-inflammatory drugs or NSAIDs (such as ibuprofen or naproxen sodium) are commonly prescribed to help relieve pelvic pain and menstrual cramping. These pain-relieving medications have no effect on the endometrial implants.

Since endometriosis occurs during the reproductive years, many of the available medical treatments for endometriosis rely on interruption of the normal cyclical hormone production by the ovaries. These medications include GnRH analogs, oral contraceptive pills, and progestins.

Gonadotropin-releasing hormone analogs (GnRH analogs) Gonadotropin-releasing hormone analogs (GnRH analogs) have been effectively used to relieve pain and reduce the size of endometriosis implants. These drugs suppress estrogen production by the ovaries by inhibiting the secretion of regulatory hormones from the pituitary gland. As a result, menstrual periods stop, mimicking menopause. Nasal and injection forms of GnRH agonists are available.

The side effects are a result of the lack of estrogen, and include:

hot flashes, vaginal dryness, irregular vaginal bleeding, mood changes, fatigue, and loss of bone density (osteoporosis). Fortunately, by adding back small amounts of estrogen and progesterone in pill form (similar to treatments sometimes used for symptom relief in menopause) many of the annoying side effects due to estrogen deficiency can be avoided. "Add back therapy" is the term that refers to this modern way of administering GnRH agonists along with estrogen and progesterone in a way to keep the treatment successful, but avoid most of the unwanted side effects.

Oral contraceptive pills

Oral contraceptive pills (estrogen and progesterone in combination) are also sometimes used to treat endometriosis. The most common combination used is in the form of the oral contraceptive pill (OCP). Sometimes women who have severe menstrual pain are asked to take the OCP continuously, meaning skipping the placebo (sugar pill) portion of the cycle. Continuous use in this manner will free a woman of having any menstrual periods at all. Occasionally, weight gain, breast tenderness, nausea, and irregular bleeding are mild side effects. Oral contraceptive pills are usually well-tolerated in women with endometriosis.

Progestins
Progestins [for example, medroxyprogesterone acetate (Provera, Cycrin, Amen), norethindrone acetate, norgestrel acetate (Ovrette)] are more potent than birth control pills and are recommended for women who do not obtain pain relief from or cannot take a birth control pill. Side effects are more common and include: breast tenderness, bloating, weight gain, irregular uterine bleeding, and depression. Since the absence of menstruation (amenorrhea) induced by high doses of progestins can last many months after cessation of therapy, these drugs are not recommended for women planning pregnancy.

Other drugs used to treat endometriosis

Danazol (Danocrine) Danazol (Danocrine) is a synthetic drug that creates a high androgen (male type hormone) and low estrogen hormonal environment by interfering with ovulation and ovarian production of estrogen. Eighty percent of women who take this drug will have pain relief and shrinkage of endometriosis implants, but up to 75% of women develop side effects from the drug.

Side effects can include:

weight gain, edema, decreased breast size, acne, oily skin, hirsutism (male pattern hair growth), deepening of the voice, headache, hot flashes, changes in libido, and mood changes.

All of these changes are reversible, except for voice changes; but the return to normal may take many months. Danazol should not be taken by women with certain types of liver, kidney, and heart conditions

Aromatase inhibitors

A newer approach to the treatment of endometriosis has involved the adminis tration of drugs known as aromatase inhibi tors [for example, anastrozole (Arimidex) and letrozole (Femara)]. These drugs act by interrupting local estrogen formation with in the endometriosis implants themselves. They also inhibit estrogen production in the ovary, brain, and other sources, such as adipose tissue.

Medical Treatment
Progestin Ovary

Estrogen
Endometriosis Tissue

Oral contraceptives Danazol GnRH agonists

Role of Estrogen in Endometriosis

Estrogen

Role of Estrogen in Endometriosis

Estrogen

Cell growth

Role of Estrogen in Endometriosis

Aromatase

Estrogen

Cell growth

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PGE2 Cytokines

Aromatase

Estrogen

Cell growth

Aromatase In Endometriosis
Aromatase is key for the biosynthesis of estrogen In patients aromatase expression is higher in endometriosis tissue than in normal endometrium In endometriosis tissue aromatase activity is stimulated by prostaglandin Estrogen synthesized by endometriotic tissue stimulates growth of lesions

Role of Estrogen in Endometriosis

Aromatase Inhibitors
PGE2 Cytokines Letrozole Exemestane Anastrozole

Aromatase

Estrogen

Cell growth

Role of Estrogen in Endometriosis

Aromatase Inhibitors
PGE2 Cytokines Letrozole Exemestane Anastrozole Danazol

Aromatase

Estrogen

Cell growth

Research is still ongoing to characterize the effectiveness of aromatase inhibitors in the management of endometriosis. Aromatase inhibitors cause significant bone loss with prolonged use and cannot be used alone without other medications in premenopausal women because they stimulate development of multiple follicles at ovulation

Endometriosis At A Glance
Endometriosis is the growth of endometrial tissue but in a location outside of the uterus. Endometriosis is most commonly found on other organs of the pelvis. The exact cause of endometriosis has not been identified.

Endometriosis is more common in women who are experiencing infertility than in fertile women, but the condition does not fully prevent conception. Pelvic pain during menstruation or ovulation can be a symptom of endometriosis, but may also occur in normal women.

Endometriosis can be suspected by definite diagnosis: by surgery, usually laparoscopy.

Treatment of endometriosis includes medication and surgery for both pain relief and treatment of infertility if pregnancy is desired.