R. Wayne Whitted MD, MPH

Paul A. Pietro MD

Marina Santana MMS, PA-C

Rebecca Karousatos MSRD, LD/N

8740 N Kendall Dr. Suite 101

Miami, Florida 33176

Phone: 305-596-3744

www.floridaamigos.com

Diagnosis and Treatment of Endometriosis

Endometriosis is a progressive disease affecting 5 to 10 percent of women. It can cause dyspareunia (pain with

intercourse), dysmenorrhea, low back pain, premenstrual spotting, and infertility. A definitive diagnosis can be

made only by means of laparoscopy, although MRI can often assist (if the radiologist’s training is adequate).

Medical treatment designed to interfere with ovulation generally provides effective pain relief, but the recurrence

rate following cessation of therapy is high, and this type of treatment will not resolve infertility. Minimally Invasive

Surgical treatment improves pregnancy rates (especially in the higher stages) and is the preferred initial treatment

for infertility caused by endometriosis. Surgery also appears to provide better long-term pain relief than medical

treatment. Bilateral oophorectomy and hysterectomy are treatment options for patients with intractable pain, if

childbearing is no longer desired. (Am Fam Physician 1999;60:1753-68.)

Endometriosis is characterized by the presence of endometrial tissue on the ovaries, fallopian tubes or other abnormal sites,

causing pain or infertility. The disease tends to progress under the repetitive influence of the menstrual cycle. Interrupting or

decreasing menstruation is the mainstay of medical therapy. The goal of surgery is to remove endometrial lesions.

Endometriosis is likely to remain problematic as long as menstruation persists. Fortunately, symptoms can be modulated or

alleviated with appropriate treatment.

Epidemiology

Women are usually 25 to 29 years old at the time of diagnosis, which is

frequently delayed in those who present with infertility rather than pain.

familial tendency has been identified.

Endometriosis has been found in 4.1

percent of asymptomatic women undergoing laparoscopy for sterilization;

however, evidence of the disease is present in 20 percent (range: 2 to 78

percent) of women undergoing laparoscopic investigation for infertility.

Approximately 24 percent (range: 4 to 82 percent) of women who complain

of pelvic pain are subsequently found to have endometriosis.

The overall

prevalence, including symptomatic and asymptomatic women, is estimated

to be 5 to 10 percent.

Because surgical confirmation is necessary for the

diagnosis, the true prevalence of the disease is unknown.

Endometriosis should be

considered in women who develop

dysmenorrhea after years of pain-

free cycles.

The Association of Minimally Invasive Gynecologic Surgeons

…dedicated to safe, state-of-the-art surgery and health life-styles for women of all ages

Pathogenesis

Endometriosis is not well understood and is probably multi-factorial in origin. The most widely embraced theory involves

retrograde menstruation

(Figure 1). In endometriosis the refluxed cells may implant in the pelvis, bleed in response to cyclic

hormonal stimulation and increase in size along with progression of symptoms.

Immune alterations may also contribute to the

persistence of implants or endometriosis-associated infertility.

7,8

Two other theories have received support. One holds that peritoneal epithelium can be "transformed" into endometrial tissue,

perhaps because of chronic inflammation or chemical irritation from refluxed menstrual blood. This theory of "coelomic

metaplasia" is based on the observation that coelomic epithelium is the common ancestor of endometrial and peritoneal cells,

thus allowing transformation of one type of cell into another. A final theory hypothesizes that müllerian remnants can

differentiate into endometrial tissue. The circumstances in which this would occur are not clear but, once endometrium is

present, it will cause symptoms in a cyclic fashion.

Although retrograde menstruation seems almost certain to be involved in the pathogenesis of endometriosis, that theory does

not explain the full spectrum of the disease. For example, endometrial implants are occasionally found in such remote sites as

the lung or even the nose. Moreover, endometriosis also occurs, albeit rarely, in men taking large doses of estrogen. The

theories of coelomic metaplasia and müllerian remnant differentiation are better suited than the theory of retrograde

menstruation to explain some of these exceptional circumstances.

FIGURE 1. Basic anatomy of retrograde menstruation.

Clinical Features and Diagnostic Evaluation

Endometriosis should be considered in any woman of reproductive age who has pelvic pain (Table 1). The most common

symptoms are dysmenorrhea, dyspareunia and low back pain that worsens during menses.

Depending on the location of the

implants, rectal pain and painful defecation may also occur. The diagnosis of endometriosis should be considered especially if

a patient develops dysmenorrhea after years of pain-free menstrual cycles. Of course, other causes of secondary dysmenorrhea

and chronic

pelvic pain (e.g., upper genital tract infections, adenomyosis, and adhesions) may produce

similar symptoms.

Infertility may also be the presenting complaint. Infertile

patients often have no painful symptoms, and their disease is

only uncovered in the course of the diagnostic work-up for

infertility. The reason for this divergence in clinical

manifestations is unknown.

Physical examination should be performed during early

menses, when implants are likely to be largest and most

tender. The physician should palpate for a fixed, retroverted

uterus, adnexal and uterine tenderness, pelvic masses or

nodularity along the uterosacral ligaments. A rectovaginal

examination is required to identify uterosacral, cul-de-sac or

septal nodules. However, most women with endometriosis

have normal pelvic findings, and laparoscopy is necessary

for definitive diagnosis. Although no single laboratory test

has shown reliable clinical utility, it is possible that

eventually a combination of biochemical markers and

clinical assessment will decrease the need for surgical

confirmation.

10,11

Pelvic ultrasonography, computed tomography and magnetic

resonance imaging are occasionally used to identify

individual lesions, but these modalities are not helpful in

assessing the extent of endometriosis.

Even with direct

visualization, diagnosis of endometriosis can be difficult.

Lesions appear in multiple guises that are at times difficult to

interpret. This diagnostic challenge is compounded by the

unreliable correlation between clinical manifestations and

surgical findings.

A patient who is asymptomatic or has

very mild symptoms may have extensive disease, whereas an

infertile patient may have very few implants. A better

correlation between clinical and surgical disease may be

observed in more severe cases: in at least one study

it has

been found that women with severe, chronic pelvic pain

have a more advanced stage of disease at initial diagnosis.

The American Fertility Society's revised staging instrument

can help standardize findings and document the patient's

baseline condition and subsequent progress.

Staging is

based on location, diameter and depth of lesions, and density

of adhesions. Stages range from minimal to severe disease.

Despite this standardization, the correlation between stage

and extent of disease remains controversial.

Treatment

In most patients, confirmatory laparoscopy is required before

treatment is instituted.

In women with few symptoms, an

empiric trial of oral contraceptives or progestins may be

warranted to assess pain relief. Recently, an empiric three-

month trial of therapy with gonadotropin-releasing hormone

(GnRH) analogs has been a popular strategy.

In severe or

unresponsive cases, or in the investigation of infertility,

exact diagnosis is required to direct management and to justify possibly

unpleasant medical treatments. Patients with

infertility should undergo a thorough basic evaluation for other causes of infertility before diagnostic

laparoscopy is undertaken.

TABLE 1

Differential Diagnosis of Endometriosis

by Symptom

Generalized pelvic pain

Pelvic

inflammatory

disease

Endometritis

Pelvic adhesions

Neoplasms,

benign or

malignant

Ovarian torsion

Sexual or

physical abuse

Nongynecologic

causes

Dysmenorrhea

Primary

Secondary

(adenomyosis,

myomas,

infection,

cervical

stenosis)

Dyspareunia

Musculoskeletal

causes (pelvic

relaxation,

levator spasm)

Gastrointestinal

tract

(constipation,

irritable bowel

syndrome)

Urinary tract

(urethral

syndrome,

interstitial

cystitis)

Infection

Pelvic vascular

congestion

Diminished

lubrication or

vaginal

expansion

because of

insufficient

arousal

Infertility

Male factor

Tubal disease

(infection)

Anovulation

Cervical factors

(mucus, sperm

antibodies,

stenosis)

Luteal phase

deficiency

Adapted with permission from Ryder RM. Chronic pelvic

pain. Am Fam Physician 1996;54:2225.

Treatment may be expectant, or a patient may choose either medical or surgical options. Infertile patients may increase the

likelihood of subsequent conception by undergoing surgery, but medical treatment has not been shown to help these patients

conceive.

17,18

Furthermore, pregnancy is contraindicated in patients receiving medical treatment and is in fact unlikely, because

the drugs that are used interfere with ovulation. Medical and surgical approaches have been successful in reducing the pain

associated with endometriosis.

Medical Treatment

Medical treatment should be reserved for use in patients with pain or dyspareunia, because no pharmacologic method appears

to restore fertility.

Danazol. Danazol (Danocrine) has been highly effective in relieving the

symptoms of endometriosis, but adverse effects may preclude its use.

(There are now other treatments that may be better tolerated.) Danazol is a

synthetic androgen that inhibits leuteinizing hormone (LH) and follicle-

stimulating hormone (FSH), resulting in a relatively hypoestrogenic state.

Endometrial atrophy is the likely mechanism in the relief of pain from

endometriosis. Adverse effects related to estrogen defiency include

headache, flushing, sweating and atrophic vaginitis. Androgenic side effects

include acne, edema, hirsutism, deepening of the voice and weight gain.

Danazol therapy should be started when the patient is menstruating. The initial dosage should be 800 mg per day, given in two

divided oral doses, but this dosage can be titrated down as long as amenorrhea persists and pain symptoms are controlled.

Patients with less severe symptoms may be given 200 to 400 mg per day, in two divided oral doses. Treatment duration is six

months but can be extended to nine months in responsive patients with severe disease. The overall response rate is 84 to 92

percent, with beneficial effects lasting up to six months after treatment has stopped.

TABLE 2

Medical Treatment of Endometriosis

Drug

Dosage Adverse effects

Cost*

Danazol (Danocrine) 800 mg per day in 2 divided doses Estrogen deficiency,

androgenic side

effects

$410,

brand

367,

generic

Oral contraceptives 1 pill per day (continuous or cyclic) Headache, nausea,

hypertension

brand†

24 to

27‡,

generic

Medroxyprogesterone

suspension (Depo-Provera)

100 mg IM every 2 weeks for 2

months; then 200 mg IM every

month for 4 months or 150 mg IM

every 3 months

Weight gain,

depression, irregular

menses or

amenorrhea

22, brand

13,

generic

Medroxyprogesterone

(Provera)

5 to 20 mg orally per day Same as with other

oral progestins

Norethindrone acetate

(Aygestin)

5 mg per day orally for 2 weeks;

then increase by 2.5 mg per day

every 2 weeks up to 15 mg per day

Same as with other

oral progestins

113§

Because no pharmacologic method

appears to restore fertility, medical

treatment for endometriosis should be

reserved for use in patients with pain or

dyspareunia.

Leuprolide (Lupron) 3.75 mg IM every month for 6

months

Decrease in bone

density, estrogen

deficiency

371,

brand

318,

generic

Gosarelin (Zoladex) 3.6 mg SC (in upper abdominal

wall) every 28 days

Estrogen deficiency 470

Nafarelin (Synarel) 431 400 mg per day: 1 spray in 1 nostril

in a.m.; 1 spray in other nostril in

p.m.; start treatment on day 2 to 4

of menstrual cycle

Estrogen deficiency,

bone density changes,

nasal irritation

IM = intramuscularly; SC = subcutaneously.

*--Estimated cost to the pharmacist based on average wholesale prices (rounded to the nearest dollar) for one

month of treatment at the lowest dosage level in Red book. Montvale, N.J.: Medical Economics Data, 1999.

Cost to patient will be greater, depending on prescription filling fee.

†--Cost based on prices of Lo-Ovral 28 and Ortho-Novum.

‡--Cost based on generic versions of Lo-Ovral 28 and Ortho-Novum.

§--For one month's therapy at 15 mg per day.

GnRH Agonists. These agents (e.g., leuprolide [Lupron], gosarelin [Zoladex]) inhibit the secretion of gonadotropin and are

comparable to danazol in relieving pain.

12-19

Like danazol, GnRH agonists are contraindicated in pregnancy and have

hypoestrogenic side effects. In particular, they have been shown to produce a mild degree of bone loss, although this condition

reverses after the medication is discontinued. Because of concerns about osteopenia, "add-back" therapy with low-dose

estrogen has been recommended but is not currently an FDA-labeled indication for estrogen replacement therapy.

20,21

The dosage of leuprolide is a single monthly 3.75-mg depot injection given intramuscularly. Gosarelin, in a dosage of 3.6 mg,

is administered subcutaneously every 28 days. A nasal spray (nafarelin [Synarel]) is also available and is used twice daily. The

response rate is similar to that with danazol; about 90 percent of patients experience pain relief. The pregnancy rate after the

use of these agents is no different from that in untreated patients.

Oral Contraceptive Pills. Oral contraceptive pills (OCPs) suppress LH and FSH and prevent ovulation. They also have direct

effects on endometrial tissue, rendering it thin and compact. The decidualization of endometrial implants, coupled with reduced

reflux related to lower menstrual volume, is the probable mechanism of pain relief with OCPs, making them comparable to

other treatments in effect.

Combination OCPs alleviate symptoms in about three quarters of patients. No hormonal

combination appears to be more effective than another. They can be taken continuously (with no placebos) or cyclically, with a

week of placebo pills between cycles. The OCPs can be discontinued after six to 12 months or continued indefinitely,

depending on such factors as patient satisfaction and the desirability of pregnancy.

Progestational Agents. Progestins are similar to combination OCPs

in their effects on FSH, LH and endometrial tissue. They may be

associated with more bothersome adverse effects than OCPs and, if a

depot form (i.e., medroxyprogesterone suspension [Depo-Provera]) is

used, return to fertility may be delayed. Nonetheless, progestins are

effective in reducing the symptoms of endometriosis. One study that

pooled data from 14 investigations found no significant difference

between the efficacy of progestins and that of any other medical

treatment.

Although this conclusion was based on analysis of the

combined results of a handful of small, heterogeneous studies, it is

important because progestins are much cheaper than either danazol or

GnRH analogs.

TABLE 3

Surgical vs. Medical Treatment of

Endometriosis

Advantages Disadvantages Treatment

Given the likelihood of comparable efficacy, as well as the certainty

of a high rate of recurrence regardless of the agent used, physicians

may elect to prescribe OCPs or progestins as first-line agents on the

basis of cost alone. If effective, these agents can be used safely for

long periods of time. Progestins can be given orally on a daily basis

or delivered by injection. Oral regimens may include once-daily

administration of medroxyprogesterone at the lowest effective dosage

(5 to 20 mg). Depot medroxyprogesterone has been given

intramuscularly every two weeks for two months at 100 mg per dose

and then once a month for four months at 200 mg per dose. Medical

treatments are reviewed in Table 2.

Surgical Treatment

Surgical treatment is the preferred approach to infertile patients with

advanced endometriosis.

The benefit of surgery in these patients

may be due entirely to the mechanical clearance of adhesions and

obstructive lesions (Figure 2). Some of the endometrial lesions are

cystic or nodular and can be excised (Figures 3, 4 and 5), while some

are hemorrhagic or petechial and amenable to laser obliteration

(Figures 6 and 7). Until recently, surgery in infertile patients with limited disease was thought to be no better than expectant

management. However, a recent randomized, controlled study involving 341 infertile women with minimal or mild

endometriosis demonstrated a 13 percent absolute increase in the probability of pregnancy in a 36-week period.

Infertile

patients with documented endometriosis can benefit from the same reproductive techniques (e.g., superovulation, in vitro

fertilization) that are used in other infertile patients.

24,25

FIGURE 2. Laparoscopic excision of nodular

endometrial lesions ov rlying the rectum.

FIGURE 4. Nodular endometrial lesions in

the posterior cul-de-sac.

Surgical Beneficial for

infertility

Possibly better

long-term

results

Definitive

diagnosis

Option for

definitive

treatment

Expensive

Invasive

Medical Decreased

initial cost

Empiric

treatment

Effective for

pain relief

Adverse effects

common

Unlikely to

improve fertility

FIGURE 3. Cystic implants

adjacent to the right ovary; note

bluish appearance.

FIGURE 5. Ovary with

endometrioma.

The usefulness of conservative surgery for pain relief is unclear, but it appears that immediate postoperative efficacy is at least

as high as with medical treatment, and long-term outcomes may be considerably higher.

Laparoscopy is much more

expensive than medical treatment, however, causing some physicians to argue that overall costs can be reduced by aggressive

use of empiric treatments before surgery is considered.

Table 3 summarizes the advantages and disadvantages of medical and

surgical treatments.

Definitive surgery, which includes hysterectomy and oophorectomy, is reserved for use in women with intractable pain who no

longer desire pregnancy.

In less severe cases, one ovary may be retained to preserve ovarian function, although improvement

will be less definitive. Women who have undergone oophorectomy should be treated with estrogen replacement, even at the

risk of some recurrence.

FIGURE 7. Extensive endometriosis in the

ovarian fossa. Lesions have a petechial

appearance.

FIGURE 6. Hemorrhagic lesions overlying the

right ureter.

In practical terms, when the diagnosis of endometriosis is made at laparoscopy, surgical ablation of lesions is frequently

performed. Thus, because laparoscopic diagnosis is usually recommended before instituting treatment, most women with

endometriosis undergo surgical therapy initially. It is generally agreed that an expert surgeon who is extensively trained in

ablation procedures will have the best outcomes

(Figure 8).

Recurrence Rates

Perhaps the strongest reason for beginning with surgical treatment is the apparently lower recurrence rate compared with

medical treatment.

Early studies of conservative surgical therapy showed a laparoscopically defined cumulative five-year

recurrence rate of about 19 percent.

28,29

The long-term benefit of surgical intervention for pain is enhanced by definitive

surgery, including bilateral oophorectomy, with a 10 percent cumulative recurrence after 10 years.

This rate is considerably

lower than those following medical therapy. In one study of recurrence after medical treatment, cumulative five-year rates of

recurrence were 53.4 percent.

Unfortunately, patients whose presenting complaint was pain and those seeking treatment for

infertility were grouped together in the analysis. Other studies show similar recurrence rates, regardless of the medical therapy

used.

At least one study noted higher recurrence rates in patients with more advanced stages of disease.

Combining or repeating treatments may result in better long-term outcomes, but studies of combined treatments are

inconclusive because of lack of randomization, small sample size or insufficient follow-up time. One randomized, double-blind

study

showed additional pain relief and objective improvement with immediate postoperative treatment with danazol or

medroxyprogesterone, but the study ended with a second laparoscopy after six months, too soon to identify longer-term

benefits. In a more recent investigation, it was found that the best and only statistically significant long-term outcomes were

achieved with surgery followed by danazol treatment; however, the study was limited by a small sample size.

Although few

studies have been conducted to evaluate retreatment with danazol or GnRH analogs, repeated administrations of these drugs are

theoretically an option and are probably safe at appropriate intervals.

Algorithm for treating endometriosis

Treatment of Endometriosis

FIGURE 9.Algorithm for treating endometriosis based on presenting symptom of either pain or

infertility. (Broken arrow = optional consideration; OCPs = oral contraceptive pills; GnRH =

gonadotropin-releasing hormone)

The Author

CAROLINE WELLBERY, M.D.,

is an assistant professor in the Department of Family Medicine at Georgetown University School of

Medicine, Washington, D.C. Dr. Wellbery graduated from the University of California, San Francisco,

School of Medicine, and completed a residency in family practice at the Santa Rosa (Calif.) Community

Hospital. She serves as assistant deputy editor for American Family Physician.

Address correspondence to Caroline Wellbery, M.D., Department of Family Medicine, Georgetown University

Medical Center, 3800 Reservoir Rd., Washington, DC 20007. Reprints are not available from the author.

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