Diagnosis and Treatment of Endometriosis in Adolescents

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1/17/2016 Diagnosis and treatment of endometriosis in adolescents

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Offi cial reprint from UpToDatewww.uptodate.com 2016 UpToDate

AuthorMarcR Laufer, MD

Section EditorsRobert L Barbieri, MD

Amy B Middleman, MD, MPH, MSEd

Deputy EditorKristen Eckler, MD, FACOG

Diagnosis and treatment of endometriosis in adolescents

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2015. | This topic last updated: May 19, 2015.

INTRODUCTION Endometriosis refers to the presence of endometrial glands and stroma outside the

endometrial cavity and uterine musculature. These ectopic endometrial implants are usually located in the pelvis,

but can occur nearly anywhere in the body. The disease can be associated with many distressing and debilitating

symptoms, or it may be asymptomatic. Despite numerous studies, considerable controversy remains regarding the

incidence, pathogenesis, natural history, and optimal treatment of this disorder.

This topic will discuss endometriosis specifically in adolescents. The disease in adults is reviewed separately:

(See "Endometriosis: Pathogenesis, clinical features, anddiagnosis".)

(See "Overview of the treatment of endometriosis".)

(See "Diagnosis and management of ovarian endometriomas".)

(See "Gonadotropin releasing hormone agonists for long-term treatment of endometriosis" .)

(See "Pathogenesis and treatment of infertility in women with endometriosis".)

(See "Reproductive surgery for female infertility".)

(See "Clinical features, diagnostic approach, and treatment of adults with t horacic endometriosis".)

PREVALENCE The prevalence of endometriosis in the general population is not known estimates vary

depending upon the population studied (symptomatic or asymptomatic) and the method of diagnosis (clinical

versus surgical). The disease has been reported in 25 to 38 percent of adolescents with chronic pelvic pain [ 1,2]

and 47 percent of those with chronic pelvic pain that undergo laparoscopy [3]. The prevalence among adolescents

undergoing laparoscopy for pelvic pain not controlled with oral contraceptive pills (OCs) and nonsteroidal anti-

inflammatory drugs (NSAIDs) is 50 to 70 percent [4-6].

EPIDEMIOLOGY Two-thirds of adult women with endometriosis report that their symptoms started before age

20 [7]. Although it had been assumed that endometriosis presented only after many years of menstruation, this

was incorrect: symptomatic cases have been documentedprior to menarche in girls who have some breast

development, and others soon after menarche [8-10].

Some adolescents may have a genetic predisposition to developing endometriosis. In one study of 123 patients

with histologically proved endometriosis, first degree female relatives of affected patients were significantly more

likely to have been diagnosed with endometriosis than relatives of controls (7 versus 1 percent) [ 11].

PATHOGENESIS Many theories have been proposed to explain the etiology of endometriosis. No single theory

explains all cases, and all of the theories help to explain some aspects of the disease. The types and frequencies

of pathogenetic mechanisms may be different in adolescents and postpubertal/premenarchal endometriosis than in

adult endometriosis. It is likely that the cause of endometriosis is multifactorial, with contributions from several of

the proposed mechanisms. (See "Endometriosis: Pathogenesis, clinical features, and diagnosis", section on

'Pathogenesis'.)

The following theories for the pathogenesis of endometriosis have been proposed:

The implantation or retrograde menstruation theory suggests that endometrial tissue from the uterus is shed

during menstruation and transported through the fallopian tubes, thereby gaining access to, and implanting
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on, pelvic structures [12].

This theory is supported by the observation that endometriosis occurs most commonly in the dependent

portion of the pelvis. In addition, obstructive congenital anomalies of the female genital tract that enhance

retrograde flow have been associated with endometriosis in the adolescent population [ 9,13,14]. As an

example, one series identified six adolescents with mllerian anomalies and endometriosis [13]. The

youngest patient was a 12-year-old with vaginal atresia and bicornuate uterus who developed

hematocolpos, likely followed by retrograde flow leading to her endometriosis. Repair of this type of

obstructive anomaly has been associated with resolution of endometriosis [14], but in our experience, thishas not been true in all cases.

Endometriosis in locations outside the pelvis is explained by dissemination of endometrial cells or tissue

through lymphatics and blood vessels [15].

The coelomic metaplasia theory proposes that the coelomic (peritoneal) cavity contains undifferentiated

cells or cells capable of dedifferentiating into endometrial tissue [16]. This theory is based upon embryologic

studies demonstrating that all pelvic organs, including the endometrium, are derived from cells lining the

coelomic cavity. Support for this theory derives from the observation of endometriosis in premenarchal girls

who have some breast development [8,17,18].

The direct transplantation theory is the probable explanation for endometriosis that develops in episiotomy,

hysterotomy, and other surgical scars.

The cellular immunity theory, which is the most recently proposed hypothesis, suggests that a deficiency in

cellular immunity allows ectopic endometrial tissue to proliferate [19-21].

CLINICAL MANIFESTATIONS Appreciation of the clinical manifestations of endometriosis in the adolescent

may decrease the length of time between patient presentation and clinical diagnosis, which averages nine years

[7]. Ideally, early diagnosis and treatment of endometriosis will retard disease progression [ 22], and decrease the

adverse long-term effects of the disease (chronic pain, endometriomas, infertility), and thus improve the quality of

life of adolescents and women with this disorder.

Adolescents with endometriosis usually have both acyclic and cyclic pain (severe, progressive dysmenorrhea)

(table 1) isolated cyclic pain is the least common pain presentation [6]. Bowel symptoms (eg, rectal pain,

constipation, painful defecation that may be cyclic, rectal bleeding) and bladder symptoms (eg, dysuria, urgency,

hematuria) are also common [6], while ovarian endometriomas and infertility are rare in adolescents.

In contrast, adults with endometriosis commonly have cyclic pain, and present with dysmenorrhea, dyspareunia, a

pelvic mass, infertility, or chronic pelvic pain. (See "Endometriosis: Pathogenesis, clinical features, and

diagnosis", section on 'Clinical presentation'.)

Differential diagnosis Causes of pelvic pain in adolescents include appendicitis, pelvic inflammatory disease,

mllerian abnormalities with outflow obstruction, hernia, bowel disease, and psychosocial issues. The etiology and

evaluation of chronic pain in this population are discussed in detail separately. (See "Chronic abdominal pain in

children and adolescents: Approach to the evaluation", section on 'Etiology' .)

INITIAL EVALUATION

History Questions that should be addressed by the history are listed in the figure (table 2). Having the patient

keep a diary documenting the frequency and character of her pain will help determine whether the pain is cyclic,

and if it is related to bowel or bladder function. Patients with a history of sexual or physical abuse may be at

increased risk of developing chronic pelvic pain [23], but this should not preclude further evaluation for

endometriosis.

Physical examination The goal of the physical examination is to determine the etiology of the pain and to rule
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out an ovarian tumor or anomaly of the reproductive tract. The approach to abdominopelvic examination depends

on the patient. Although important, it may not be possible to perform a complete pelvic examination in all

adolescents. For adolescents who are not sexually active, rectal-abdominal examination may be better tolerated

than vaginal-abdominal (ie, bimanual) examination a bimanual pelvic examination is not a requirement for

evaluation of adolescent pelvic pain. A Q-tip can be inserted into the vagina to document patency and exclude

obstructive or partially obstructive anomalies such as a transverse vaginal septum, imperforate or microperforate

hymen, vaginal agenesis, or an obstructed hemivagina. Anomalies are present in about 5 percent of these patients

[24].

The abdominal examination is usually normal. On pelvic examination, adolescents rarely have uterosacral

nodularity, a common finding in adults with the disease, but pain in the cul-de-sac is common. Adnexal

enlargement may be palpable if an endometrioma is present, but these masses are also rare in adolescents [ 25].

Sonographic examination should be performed to augment a limited physical examination and identify/exclude

causes of abdominopelvic pain other than endometriosis. (See 'Imaging studies' below.)

Nongynecologic physical findings that are observed more frequently among women with endometriosis are red hair

color, scoliosis, and dysplastic nevi [26-28].

Laboratory Laboratory tests to consider include:

Complete blood count and erythrocyte sedimentation rate, which may suggest the presence of an acute orchronic inflammatory process

Urinalysis and urine culture to identify pain originating in the urinary tract (eg, cystitis, stone)

Pregnancy test and tests for sexually transmitted infections (gonorrhea, chlamydia), when appropriate

CA 125 is most commonly used as a biomarker for ovarian cancer, but can be elevated in other conditions,

including endometriosis. A serum CA 125 level is not a useful screening test due to its high rate of false positives

(table 3). It has been used occasionally to follow the progress of disease in patients who have histologically or

visually confirmed endometriosis at surgery [29], but we prefer to rely on the patient's report of symptoms to follow

endometriosis, and do not use CA 125 in clinical management. (See "Endometriosis: Pathogenesis, clinical

features, and diagnosis".)

Imaging studies In adult women with endometriosis, sonography can identify an endometrioma, which is one

of the presentations of the disease. Imaging is less useful in diagnosis of endometriosis in adolescents since

endometriomas rarely occur and typical lesions of adolescent endometriosis cannot be appreciated with

ultrasound. However, ultrasound may be useful to identify/exclude several structural causes of pelvic pain in

adolescents, such as ovarian torsion or hemorrhage, tumors, genital tract anomalies, and appendicitis. (See

individual topic reviews).

Magnetic resonance imaging can be helpful to better define an abnormality suspected by sonography, but should

not be used as a first-line imaging test because of its expense and poor sensitivity for detecting peritoneal lesions

or staging endometriosis [30-32]. Computed tomography is also an insensitive test in the diagnostic evaluation ofendometriosis, unless an endometrioma is identified. (See "Diagnosis and management of ovarian

endometriomas".)

TRIAL OF MEDICAL THERAPY FOR DYSMENORRHEA

NSAIDs and hormonal therapy Medical treatment of dysmenorrhea is appropriate prior to considering surgical

intervention for diagnosis/treatment of endometriosis in adolescents with dysmenorrhea and/or who have difficulty

participating in normal activities, are missing school, or avoiding extracurricular activities because of pelvic pain. A

three-month trial of nonsteroidal anti-inflammatory agents (NSAIDs) is a reasonable approach when the pain

evaluation suggests a nonacute gynecological source, such as primary dysmenorrhea or endometriosis (table 4)
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[24]. The medication should be started before the expected onset of severe pain, if possible. (See "Primary

dysmenorrhea in adolescents".)

Hormonal therapy, such as a cyclic low-dose combination estrogen/progestin oral contraceptive pill (OC), or

progestin only therapy (oral, injectable, or implantable), should be given with the NSAIDs [24]. Use of hormonal

therapy leads to decidualization and subsequent atrophy of ectopic and eutopic endometrial tissue, thereby

decreasing bleeding and, in turn, reducing bleeding-related pain. These agents are particularly useful in

adolescents also needing contraception. The vaginal ring and transdermal contraceptive patch are other examples

of methods of combined hormonal contraception and are acceptable alternatives to OCs. All of these methods are

safe and effective if given cyclically or in an extended or continuous cycle [ 33-35]. The extended cycle regimen

has been successful in women whose pain did not respond to cyclic therapy, but is associated with more

unscheduled bleeding. (See "Overview of the treatment of endometriosis", section on 'Estrogen-progestin oral

contraceptives' and "Overview of the treatment of endometriosis", section on 'Initial approach' and "Hormonal

contraception for suppression of menstruation" and "Contraception: Overview of issues specific to adolescents",

section on 'Extended-cycle or continuous pill use'.)

If the pain does not resolve with NSAIDs and hormonal therapy, then further evaluation is necessary to determine

whether endometriosis is the etiology of the pain.

Gonadotropin releasing hormone agonists For adult women in whom endometriosis is the suspected cause

of the pain, an expert panel opined that a trial of medical therapy with a GnRH agonist is justified provided thatthere are no other indications for surgery (eg, suspicious adnexal mass) [ 36]. The empiric utilization of a

gonadotropin releasing hormone (GnRH) agonist allows patients with chronic pelvic pain and a high probability of

endometriosis to avoid a diagnostic surgical procedure before beginning this therapy. Doses are described below

(see 'GnRH agonists' below).

Placebo controlled randomized trials have confirmed the efficacy of this approach [ 37]. The only randomized trial

that directly compared use of a GnRH agonist (goserelin) to low-dose cyclic OCs in adult women with pelvic pain

associated with endometriosis showed that both drugs provided significant relief of pain, but goserelin was

superior for treatment of dyspareunia [38].

We do not utilize empiric GnRH agonists for adolescents 18 years of age or younger because we have concerns

about potential adverse long-term effects on bone formation and bone mineral density [39]. Additionally, some

parents are not comfortable with a trial of empiric therapy due to worries about using a medication with adverse

side effects without a definitive diagnosis. The American College of Obstetricians and Gynecologists does not

endorse the use of empiric GnRH agonist therapy for treatment of presumed endometriosis in young women under

age 18, but considers it an option for consenting women age 18 or over [24]. Most bone mass in females has

accumulated by age 18 [40].

PATIENTS WHO FAIL THERAPY FOR DYSMENORRHEA A definitive diagnosis should be established

before administering further treatment to adolescents who have persistent pain after three to six months of

hormonal therapy and NSAIDS for the treatment of dysmenorrhea [24]. Laparoscopy is the gold standard for

diagnosis of endometriosis.

When pain persists despite dysmenorrhea therapy, we talk with the adolescent and her family to determine the

amount of pain that she is experiencing. We suggest that if her pain interferes with her daily life's activities or

places her at a disadvantage in academics, sports, or social activities compared with others, then she should

undergo laparoscopy for definitive diagnosis. Typically, laparoscopy is performed after three to six months of pain

[24], but waiting this long may interfere with school and social activities. Therefore, it may be necessary to

proceed with laparoscopic evaluation sooner. At surgery, up to 70 percent of adolescents with chronic pelvic pain

that has not responded to a trial of NSAIDs and cyclic OCs are found to have endometriosis [6]. These data are

from studies in the early 1990s. Based on advances in laparoscopic imaging with high definition digital technology,

the current rate is likely higher.
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Diagnostic (and therapeutic) laparoscopy If a gynecologist performs the laparoscopy, he or she must have

experience operating on patients in this age range, otherwise a pediatric gynecologist or pediatric surgeon should

be consulted. A diagnostic laparoscopy with subsequent referral to a specialist for definitive surgery places the

patient at undue risk from two anesthesias. Therefore, the surgical procedure should be both diagnostic and

therapeutic, with surgical management of the endometriosis.

It is especially important to achieve a good cosmetic result in adolescents. To minimize visible scarring, the

laparoscope trocar can be placed through a vertical incision directly in the umbilicus. Additional operative ports

should be placed symmetrically 1 to 2 cm above the pubic symphysis so that the pubic hair will grow over the

incision site(s).

The gynecologist operating on an adolescent with pelvic pain must be familiar with the appearance of

endometriosis implants in this age group. The implants have variable morphology (picture 1), which has been

described in the revised American Society of Reproductive Medicine (ASRM) Classification of Endometriosis [41].

The only series that objectively compared endometriosis lesions in adolescents to those in adults found red flame

lesions were more common and powder burn lesions less common in adolescents than in adult patients [42]. This

is consistent with the presumption that powder burn lesions represent older, more advanced implants. Clear and

red lesions may be the more painful lesions of endometriosis (table 5) [43]. Peritoneal windows or defects are also

common in adolescents and should be recognized as diagnostic of endometriosis.

Care must be taken to identify subtle endometriotic lesions that often appear as clear, shiny peritoneal vesicles.

Visualization through a liquid medium, such as saline, may facilitate identification [44]. After all the lesions have

been located, the fluid is removed so that the lesions can be ablated or excised.

If no evidence of endometriosis is identified, a posterior cul-de-sac biopsy to exclude the presence of microscopic

disease should be performed and may identify lesions not visualized on laparoscopy. One study of nondirected

biopsies found a low prevalence of microscopic endometriosis [45], while another reported a significant rate in

adults [46]. Our experience at Children's Hospital, Boston, is that we find microscopic endometriosis in 3 percent

of adolescent girls with chronic pelvic pain unresponsive to conventional therapy and with a visually normal pelvis

[6].

Endometriosis should be staged according to the revised ASRM Classification of Endometriosis (figure 1) tofacilitate follow-up and comparison if future surgery is performed [41]. Although most adolescents present with

Stage I to II disease, in one series, 11 of 36 adolescents with endometriosis had stage IV disease [42]. In general,

the stage of disease does not correlate with degree of pain. When counseling patients postoperatively, it is

important to remember that the severity of symptoms does not correlate with the extent or location of lesions

(table 6) [47].

Surgical treatment Most adult women experience a reduction in pain after surgical treatment [48,49]. There are

no large studies in adolescents.

Electrocautery, endocoagulation, or laser ablation or resection of implants should be performed at the time of

diagnostic laparoscopy [50]. In adults with Stage I or II disease, there is no difference in outcome with excision

versus ablation of endometriosis [51]. Lysis of adhesions is also performed at the time of surgery. Laparotomy is

rarely required. Any large endometriotic cysts should be removed, with preservation of as much ovarian tissue as

possible. Care must be taken to avoid damage to the ureters, major blood vessels, bowel, and bladder. (See

"Endometriosis: Surgical management of pelvic pain", section on 'Laparoscopic excision or ablation'.)

However, surgery alone is not adequate treatment for endometriosis as there can be microscopic residual disease

that must be suppressed with medical therapy [36]. Symptoms will return within one year in approximately 50

percent of adult women who receive only surgical therapy [36,48,52,53].

POSTOPERATIVE MEDICAL TREATMENT There are no long-term follow-up data describing the natural

history of untreated endometriosis first detected in adolescents we do not know the proportion of endometriosis
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that will progress to more advanced disease if left untreated.

The general consensus is that adolescents with histologically confirmed endometriosis should receive medical

treatment after surgical ablation/resection until they have completed childbearing [24]. Compared to eutopic

endometrium, endometriotic implants are characterized by overproduction of prostaglandins and local production of

estrogens and cytokines, which synergize the activities of each other, promote implantation of ectopic

endometrium, and cause the pain associated with endometriosis. The rationale for medical therapy is inhibition of

prostaglandin synthesis, decidualization and subsequent atrophy of residual ectopic endometrial tissue, and

reduction of ovarian estrogen production, thereby inhibiting the growth and activity of the ectopic endometrium.

The goal of medical therapy is to manage pain due to residual disease, allow the patient to function comfortably in

her daily activities, and suppress disease progression, which could impair fertility. Long-term follow-up data in

adolescents show that endometriosis that is surgically identified and destroyed and then followed by medical

therapy tends not to progress [22,54]. There are limited data on the course of adolescents who undergo complete

excision of visible endometriosis but do not undertake postoperative hormonal suppression [ 55].

Treatment efficacy should be assessed regularly by asking the patient to rate her pain on a scale of 0 to 10 at

each visit. She should be aware that she may not become pain free, but her medications can be adjusted to

maximize pain relief and promote participation in school and social activities. Support groups for adolescents with

endometriosis are available and can be useful (www.youngwomenshealth.org).

Several medical therapies are available, each with differing risks, benefits, and side effect profiles [56]. The choice

of treatment depends upon the severity of the patient's symptoms, the extent of disease, and compliance.

Although numerous options have been described for the treatment of endometriosis [4,39], combination hormonal

therapy or GnRH agonists are usually used for first-line therapy. For adolescents with confirmed endometriosis,

we offer both therapies to those ages 16 or over, but use only continuous combination hormonal therapy in those

under 16 years of age out of concern about the effects of GnRH agonists on the formation of normal bones and

bone density [57].

Continuous hormonal therapy Use of continuous hormonal therapy after surgery may retard progression of

disease and control any remaining pain [34]. (See 'NSAIDs and hormonal therapy'above.)

Combination estrogen/progestins Combination therapy can be used to suppress menstruation and inducea pseudo-pregnancy state for suppression of endometriosis and endometriosis associated pain. A monophasic

progestin dominant pill is most effective for the suppression of menses. It is important for adolescents to be

reminded that, for this treatment to be successful, the pill must be taken at the same time daily. We typically

recommend 6:00 pm, 7:00 pm, or 8:00 pm. We recommend that the pill not be taken upon wakening, as most

adolescents do not get up at the same time on weekdays and weekends. If the pill is taken late, there appears to

be an increased risk of breakthrough bleeding.

Progestins Progestins inhibit endometriotic tissue growth by causing initial decidualization and eventual

atrophy. They also inhibit pituitary gonadotropin secretion and ovarian hormone production, resulting in a mildly

hypoestrogenic state relative to normal.

The most commonly used progestational agents are:

Norethindroneacetate (5 to 15 mg daily by mouth)

Medroxyprogesterone acetate (30 to 50 mg daily by mouth)

Depot medroxyprogesterone acetate (150 mg intramuscularly every one to three months)

Each of these therapies improves symptoms in approximately 80 to 100 percent of patients with endometriosis

[58-61]. The etonogestrel subdermal implant has also been used successfully but experience is limited [ 62-65].

(See "Overview of the treatment of endometriosis".)

Potential bothersome side effects of progestins include weight gain, bloating, depression, and unscheduled
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bleeding [7] however, many patients tolerate this therapy very well [ 61]. Oral progestin therapy should be

considered prior to long-term intramuscular injections so that side effects can be identified and addressed or the

medication easily discontinued.

The long-term utilization of depot medroxyprogesterone acetatehas been shown to result in loss of bone density,

which is reversible after discontinuation of the progestin. (See "Depot medroxyprogesterone acetate for

contraception", section on 'Reduction in bone mineral density'.)

GnRH agonists GnRH agonists can be prescribed for adolescents, with laparoscopically confirmed

endometriosis, who are at least 16 years old. Our preference is depot leuprolideacetate (11.25 mg intramuscularlyevery three months) it is alwaysgiven with add-back therapy. We use the three-month formulation to improve

compliance with therapy. Some patients who receive a one-month formulation experience the expected flare

effect (increased pain and bleeding) and then do not return for their second one-month injection. With the three-

month formulation, patients who have increased pain and bleeding with the flare effect will have the GnRH agonist

in their system for three months and thus continue to benefit from the subsequent suppression. Nafarelin nasal

spray (one puff twice daily intranasally) is an alternative GnRH agonist however, compliance is often

unpredictable in the adolescent population. (See "Gonadotropin releasing hormone agonists for long-term treatment

of endometriosis".)

Over 90 percent of patients will become amenorrheic and hypoestrogenic on this dose of leuprolide [66]. Side

effects include hot flashes, headaches, difficulty sleeping, mood swings, depression, and vaginal drynesstherefore, we do not utilize GnRH agonist therapy without add-back therapy. Menses typically return 60 to 90 days

after cessation of intramuscular leuprolide therapy.

Generally, initial treatment with a GnRH agonist is continued for six months. Upon completion of this initial six-

month course of GnRH agonist therapy, the patient must then choose a treatment course. She can return to a

continuous combined hormonal contraceptive, as described above. If she is not able to tolerate continuous

combination hormonal or progesteroneonly therapy, then long-term utilization of a GnRH agonist with add-back

can be prescribed (see below). A baseline bone density assessment is obtained after the initial six to nine months

of therapy and is then repeated every two years. If bone density remains stable, then the assessment is repeated

every two years while the patient is receiving GnRH agonists.

Add-back therapy The utilization of add-back therapy can help alleviate the side effects of GnRH agonists

without reducing their efficacy, as long as the add-back regimen does not involve high doses of estrogen [67].

Add-back therapy is based upon the "estrogen threshold hypothesis," which is demonstrated in the f igure (figure 2)

[68]. Basically, adequate sex steroid (estrogen plus progestin, or progestin alone) is provided to prevent significant

bone demineralization, but not enough to stimulate growth of endometriotic tissue.

Options for sex steroid add-back therapy used in adult women include [69,70]:

Norethindrone acetate (5 mg daily) alone, or

Conjugated estrogen (0.625 mg) plus either norethindrone acetate (5 mg) or medroxyprogesterone acetate (5

mg daily)

Patient satisfaction is higher with use of norethindronecompared with the other options (table 7) [69].

Safety The safety of long-term use of a GnRH agonist with add-back therapy in adolescents is under

investigation [57]. One study performed serial bone mineral density examinations in 36 adolescents receiving a

GnRH agonist with norethindroneacetate add-back [71]. Bone density was preserved with this treatment over an

11-month mean treatment period, but preservation of bone density was better at the hip than at the spine. At the

hip, 6 subjects had a BMD Z-score between -1.0 and -2.0 SD, while 2 had a Z-score -2.0 SD. At the spine, 11

subjects had a BMD Z-score between -1.0 and -2.0 SD, while 3 had a Z-score -2.0 SD.

Danazol Danazol is a 17-alpha-ethinyltestosterone derivative that creates an acyclic environment. Its

mechanisms of action include inhibition of pituitary gonadotropin secretion, direct inhibition of endometriotic implant
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growth, and direct inhibition of ovarian enzymes responsible for estrogen production. (See "Overview of the

treatment of endometriosis", section on 'Danazol'.)

Danazol's efficacy in treating mild to moderate endometriosis is equivalent to that of a variety of GnRH agonists

[72-78]. Over 80 percent of patients experience relief or improvement of pain symptoms within two months of

treatment [79]. Large endometriotic cysts and adhesions do not respond well surgery is the preferred therapy for

these lesions.

Most women taking danazol have side effects that are dose-dependent. Side effects include weight gain, muscle

cramps, decreased breast size, acne, hirsutism, oily skin, decreased high density lipoprotein levels, irreversibledeepening of the voice, increased liver enzymes, hot flashes, mood changes, and depression [ 80]. Androgenic

side effects are related to decreased sex-hormone-binding-globulin levels, resulting in an increase of free

testosterone.

Bothersome to intolerable side effects are a common reason for discontinuation of the drug [80]. Although GnRH

agonists are also associated with side effects, patients using these drugs report a better quality of life than those

taking danazol [81]. Given the side effect profile, danazol would likely be poorly tolerated by adolescents, and thus

is not utilized in the management of endometriosis in the adolescent population.

Nonsteroidal antiinflammatory agents NSAIDs are helpful adjuvant agents for the treatment of pelvic pain

associated with endometriosis. In animal models of surgically induced abdominal/peritoneal endometriosis,

NSAIDs differentially inhibited lesion establishment and growth, resulting in significantly reduced disease burden

[82,83]. This effect may also occur in humans [84,85]. Nonsteroidal therapies, such as antiinflammatory and

antiangiogenic drugs, are an emerging area of investigation in treatment of endometriosis [86]. (See "Overview of

the treatment of endometriosis", section on 'Analgesics'.)

MANAGEMENT OF RECURRENT PAIN Endometriosis is a chronic and progressive disease, thus pain can

recur despite therapy. Management options for recurrent pain include:

Changing to a different treatment modality. If girls less than 16 years of age have persistent pain while

taking continuous combination hormonal therapy, then utilization of GnRH agonists with add-back therapy

may be needed. One course of six to nine months of therapy may be adequate, followed by return to

combination continuous hormonal therapy.

Prolonged utilization of a GnRH agonist with add-back therapy. We have treated patients with surgically

diagnosed disease refractory to other medications with prolonged GnRH agonist treatment plus add-back

for over 10 years. A baseline bone density evaluation should be obtained prior to starting retreatment with a

GnRH agonist or if therapy is to be continued for over six to nine months.

We obtain a baseline bone mineral density assessment after the initial six months of therapy and then

repeat it two years later. If bone density is stable on GnRH agonist with add-back therapy, then the test is

repeated every two years as long as the patient continues on this regimen. If bone density is decreasing

despite add-back therapy, then either surgical ablation/excision or continuous combination hormonal therapy

are options. As noted above, the long-term utilization of a GnRH agonist with add-back therapy has not

been studied in the adolescent population [57].

Pain that does not respond to aggressive medical therapy may be due to recurrent endometriosis, endometriomas,

and/or pelvic adhesions from endometriosis or prior surgery. A repeat laparoscopic procedure should be considered

in this clinical situation. If surgery is to be undertaken, then lysis of adhesions should be performed

laparoscopically. All visible lesions of endometriosis should be cauterized, laser ablated, or resected. We utilize

adhesion preventive agents laparoscopically following surgical lysis of adhesions. (See "Postoperative peritoneal

adhesions in adults and their prevention".)

A multi-disciplinary approach to pelvic pain, with the assistance of pain treatment services and complementary
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and alternative therapies, is also helpful for some adolescents.

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and

Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond

the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written

at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable

with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

patient info and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient information: Endometriosis (Beyond the Basics)")

In addition, there is adolescent endometriosis specific downloadable information handouts at

www.youngwomenshealth.org listed below:

Endometriosis:

http://www.youngwomenshealth.org/endoinfo.html

Continuous Hormonal Treatment for Endometriosis:

http://www.youngwomenshealth.org/endo_cont_horm.html

Hormonal Treatment Options for Adolescent Endometriosis:

http://www.youngwomenshealth.org/hormone-therapy.html

Monthly Live Monitored Chat Rooms for Adolescent with Endometriosis:

http://www.youngwomenshealth.org/chat.html

Parents Guide to Adolescent Endometriosis:

http://www.youngwomenshealth.org/endo_parent.html

SUMMARY AND RECOMMENDATIONS The goals of therapy are to relieve pain, prevent disease

progression, and preserve fertility. An algorithm for evaluation and management of adolescents with chronic pelvic

pain is shown in the figure (figure 3).

Symptomatic endometriosis occurs in adolescents, in rare cases before menarche. (See 'Prevalence' above

and 'Epidemiology'above.)

Adolescents with endometriosis usually have both acyclic and cyclic pain. Bowel symptoms (eg, rectalpain, constipation, painful defecation that may be cyclic, rectal bleeding) and bladder symptoms (eg,

dysuria, urgency, hematuria) are also common, but uterosacral nodularity and ovarian endometriomas are

rare. (See 'Clinical manifestations'above.)

For evaluation of pelvic pain in adolescents, we suggest history and physical examination, pain diary,

laboratory evaluation (eg, pregnancy test, complete blood count, erythrocyte sedimentation rate, urinalysis,

urine culture, testing for gonorrhea and chlamydia), and ultrasonography to exclude other anatomic causes.

However, a bimanual pelvic examination should not be considered a requirement for evaluation of

adolescent pelvic pain. (See 'Initial evaluation'above.)

When the pain evaluation suggests a nonacute gynecological source, we suggest medical treatment of

th th

th th
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http://www.uptodate.com/contents/diagnosis-and-treatment-of-endometriosis-in-adolescents?topicKey=OBGYN%2F7415&elapsedTimeMs=9&source=sear 10

dysmenorrhea/endometriosis rather than laparoscopy for diagnosis and therapy (Grade 2C). We suggest

nonsteroidal anti-inflammatory agents and cyclic hormonal therapy for first-line therapy (Grade 2C). (See

'Trial of medical therapy for dysmenorrhea'above.)

Patients who do not respond to medical therapy within three months should undergo laparoscopy to make a

definitive diagnosis and undergo ablation/resection of lesions and/or adhesions. Fifty to 70 percent of

adolescents with chronic pelvic pain have endometriosis diagnosed at the time of laparoscopy. A

gynecologist familiar with the appearance and treatment of endometriosis in adolescents should perform the

surgical laparoscopic procedure. The laparoscopic appearance of endometriosis may be subtle, with red

flame lesions and clear shiny peritoneal vesicles rather than powder burns. (See 'Patients who fail therapy

for dysmenorrhea'above.)

For medical management of confirmed endometriosis in adolescents 16 years of age, we suggest

continuous hormonal therapy with either a combination estrogen/progestin or progestin therapy alone for

first-line therapy (Grade 2C). Gonadotropin-releasing hormone agonists (with add-back therapy) are a

second-line approach. For adolescents >16 years of age, we suggest either continuous combined hormonal

contraception or gonadotropin-releasing hormone agonists with add-back therapy as first-line therapy (Grade

2C). (See "Overview of the treatment of endometriosis" and 'Postoperative medical treatment'above.)

Upon completion of GnRH agonist with add-back therapy for six to nine months, the patient begins a

continuous combined hormonal contraceptive. If she is not able to tolerate continuous combination

hormonal therapy, then we suggest long-term utilization of a GnRH agonist with add-back (Grade 2C). (See

'GnRH agonists'above.)

We have treated patients with surgically diagnosed disease refractory to other medications with prolonged

GnRH agonist treatment plus add-back for over 10 years. A baseline bone density evaluation should be

obtained prior to starting retreatment with a GnRH agonist or if therapy is to be continued for over six

months. If the patient remains on GnRH agonist with add-back therapy, a bone density test should be

obtained every two years. Pain that does not respond to aggressive medical therapy may be due to

recurrent endometriosis, endometriomas, pelvic adhesions from endometriosis or prior surgery, or a new

and different disease process. A repeat laparoscopic procedure should be considered for diagnosis and

therapy in this clinical situation. (See 'Management of recurrent pain'above.)

Use of UpToDate is subject to the Subscription and License Agreement.

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GRAPHICS

Frequency of presenting symptoms in adolescents with

endometriosis

Both acyclic and cyclic pain 63 percent

Acyclic pain only 28 percent

Cyclic pain only 9 percent

Gastrointestinal pain 34 percent

Urinary symptoms 13 percent

Irregular menses 9 percent

Vaginal discharge 6 percent

Adapted from Laufer, MR, Goitein, L, Bush, M, et al. J Pediatr Adolesc Gynecol 1997 10:199.

Graphic 72066 Version 1.0


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Initial history

Characteristics of the pain: Location (diffuse or localized, if so where?), onset sudden or gradual,

constant or intermittent, magnitude, timing, duration, quality (sharp or dull), radiation,

relationship to various activities (physical, sexual, physiologic, menses)

Is pain associated with symptoms such as dysuria, urinary frequency, nausea, vomiting, chills,

fever, backache or other musculoskeletal pain, or change in bowel habits?

Past medical/surgical history with attention to symptoms suspicious for, diagnosis of, and therapy

for endometriosis or pelvic inflammatory disease (PID), gastrointestinal (GI) or genitourinary (GU)

problems, infection, musculoskeletal problems, or psychiatric conditions. Any previous diagnostic

tests or treatments for pain?

Menstrual, contraceptive, sexual, and gynecologic history

Is there a history of sexual or substance abuse?

Family history of relevant clinical conditions

How does pain interfere with daily activities?

Does anything make the pain better or worse?

Adapted from Gambone, JC, Mittman, BS, Mun ro, MG, et al. Fertil Steril 2002 78:961.



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Conditions associated with an elevated serum CA 125 concentration

Gynecologic malignancies

Epithelial ovarian, fallopian tube, and

primary peritoneal cancers

Endometrial cancer

Benign gynecologic conditions

Benign ovarian neoplasms

Functional ovarian cysts

Endometriosis

Meig syndrome

Adenomyosis

Uterine leiomyomas

Pelvic inflammatory disease

Ovarian hyperstimulation

Pregnancy

Menstruation

Nongynecologic conditions

Cirrhosis and other liver disease

Ascites

Colitis

Diverticulitis

Appendicular abscess

Tuberculosis peritonitis

Pancreatitis

Pleural effusion

Pulmonary embolism

Pneumonia

Cystic fibrosis

Heart failure

Myocardiopathy

Myocardial infarction

Pericardial disease

Renal insufficiency

Urinary tract infection

Recent surgery

Systemic lupus erythematosus

Sarcoidosis

Nongynecologic cancers

Breast

Colon

Liver

Gallbladder

Pancreas

Lung

Hematologic malignancies

Data from:

1. Buamah P. J Surg Oncol 2000 75:264.

2. Miralles C, et. al. Ann Surg Oncol 2003 10:150.

3. Moss EL, et al. J Clin Pathol 2005 58:308.



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Suggested nonsteroidal antiinflammatory drug (NSAID) doses in

primary dysmenorrhea

Drug Initial dose Subsequent

dose, as needed

Maximum dose

per day in

short-term use

(3 days)

Propionic (phenylpropionic) acids

Ibuprofen* 400 to 600 mg 400 to 600 mg every

4 to 6 hours

2400 mg

Naproxen base* 500 mg 250 mg every 6 to 8

hours

1250 mg

Naproxen sodium* 550 mg 275 every 6 to 8

hours

1375 mg

Fenoprofen 200 mg 200 mg every 4 to 6

hours

3200 mg

Ketoprofen 50 mg 25 to 50 mg every 6

to 8 hours

300 mg

Fenamates

Mefenamic acid 500 mg 250 mg every 6 hours 1000 mg

Meclofenamate 100 mg 50 mg every 4 to 6

hours

400 mg

Acetic acids

Indomethacin 25 mg 25 mg three times

daily

150 mg

Tolmetin 400 mg 400 mg three times

daily

1800 mg

Diclofenac 75 to 100 mg 50 mg three times

daily

150 mg (100 mg

beginning on day 2 in

some countries)

Etodolac 400 mg 200 to 400 mg every

6 to 8 hours

(immediate release)

1000 mg (immediate

release)

Salicylates (nonacetylated)

Diflunisal 1000 mg 500 mg twice daily 1500 mg

Oxicams

Meloxicam 7.5 mg 7.5 mg once daily 15 mg

Piroxicam 20 mg 10 to 20 mg once

daily

20 mg

NSAIDs are taken at the first onset of menses and continued for one to three days or usual


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duration of painful symptoms. Patients with severe symptoms may begin taking an NSAID

one to two days prior to onset of menses. All doses shown are for oral administration in

adult or adolescent women. Patients should be well hydrated and without significant kidney

disease (CrCl >60 mL/minute).

Avoid NSAID use in women with a history of gastrointestinal bleeding, coagulopathy,

ischemic heart disease, stroke, heart failure, liver disease, or aspirin sensitive asthma.

Use with caution or avoid in patients receiving co-medication with anticoagulants, systemic

glucocorticoids, lithium, loop diuretics, and other interacting drugs. Specific interactions

may be checked by using Lexi-Interact program included with UpToDate.

* Available without a prescription in United States and other countries. Naproxen sodium is more rapidly

absorbed than naproxen base.

Minimal or no effect on platelet functioning and generally tolerated by adults with asthma at daily dose

of 1000 mg.

Relatively COX-2 selective and minimal effect on platelet functioning at daily dose of 7.5 mg. Rarely

associated with serious cutaneous allergic reactions (eg, Stevens-Johnson syndrome).

Risk of serious gastrointestinal complications may be elevated in doses 20 mg per day consider

concurrent pharmacologic gastroprotection. Rarely associated with serious cutaneous allergic reactions

(eg, Stevens-Johnson syndrome).

Prepared with data from:

1. Anon. Drugs for pain. Treatment guidelines from the Medical Letter 201 3. 11:31.

2. Majoribanks J, Proctor M, Farquhar C, et al. Nonsteroidal anti-inflammatory drugs for

dysmenorrhoea (review). Cochrane Database Systematic Rev (2010). 20:1.

3. Lexicomp Online. Copyright 1978-2016 Lexicomp, Inc. All Rights Reserved.



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The top, middle, and bottom series are representative of red,

white, and black implants, respectively

Reproduced with permission from: Revised American Society for Reproductive Medicine

classification of endometriosis: 1996. Fertil Steril 1997 67:817. Copyright 1997 AmericanSociety for Reproductive Medicine.



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Association between lesion type and pain

Lesion type Pain, percent

Red 84

Clear 76

White 44

Black 22

Adapted from Demco, L. J Am Assoc Gynecol Laparosc 1998 5:241.



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Examples of the classification of endometriosis

Modified from the American Society for Reproductive Medicine.



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Percentage of endometriosis patients with pain according to stage of

disease

Stage Occurrence of pain, percent

I 40

II 24

III 24

IV 12

Adapted from Fedele, L, Parazzini, F, Bianchi, S, et al. Fertil Steril 1990 53:155.



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Estrogen threshold hypothesis

Reproduced with permission from: Barbieri, RL. Hormone treatment of endometriosis:

the estrogen threshold hypothesis. Am J Obstet Gynecol 1992 166:740. Copyright

1992 Elsevier.



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GnRH agonists combined with steroid "add-back"

Low dose steroid

hormone regimen Comment Investigator

Transdermal estradiol patch 25

mcg/day, plus

medroxyprogesterone acetate 2.5mg daily

This regimen did not completely prevent

bone loss. The estradiol concentration

achieved is in the range of 30 pg/ml.

Howell, 1995

Norethindrone acetate 5 mg daily This is a very high dose of progestin,

which is associated with a decrease in

HDL-cholesterol.

Hornstein, 1997

Conjugated equine estrogen

0.625 mg plus norethindrone

acetate 5 mg daily

This regimen prevented bone loss and

markedly reduces the vasomotor

symptoms reported. Pain relief was

excellent.

Hornstein, 1997

Conjugated equine estrogen

0.625 mg plus

medroxyprogesterone acetate 5

mg daily


bone loss.

Moghissi, 1998

Conjugated equine estrogen 0.3

mg plus medroxyprogesterone

acetate 2.5 mg daily


bone loss.

Moghissi, 1998

Transdermal estradiol 25

mcg/day, plus norethindrone

acetate 5 mg daily


bone loss.

Zupi, 2004

GnRH agonist treatment combined with low dose steroid "add-back" causes atrophy in

endometriosis, improves pelvic pain and minimizes vasomotor symptoms and bone loss. The

low dose steroid hormone regimens that have been documented to be effective in randomized

clinical trials when used in combination with a GnRH agonist are listed above.

GnRH: gonadotropin-releasing hormone HDL: high-density lipoprotein.

Courtesy of Robert L. Barbieri, MD.



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Protocol for evaluation and treatment of adolescent pelvic

pain/endometriosis

NSAIDS: Nonsteroidal anti-inflammatory drugs CHT: combination hormonal therapy (oral

contraceptive pills, estrogen/progestin patch, estrogen/progestin vaginal ring) Progestins:

norethindrone acetate, medroxyprogesterone acetate GnRH: gonadotropin-releasing

hormone agonist add-back: estrogen + progestin or norethindrone acetate alone.

Adapted with permission from: Laufer, MR, Sanfilippo, J, Rose, G. Adolescent

endometriosis: diagnosis and treatment approaches. J Pediatr Adolesc Gynecol 2003 16(3

Suppl):S3-11. Copyright 2003 North American Society for Pediatric and Adolescent

Gynecology.


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Diagnosis and Treatment of Endometriosis in Adolescents

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