Download Adolescent Endometriosis: Diagnosis and

J Pediatr Adolesc Gynecol (2003) 16:S3-S11
Adolescent Endometriosis: Diagnosis and Treatment Approaches
Marc R. Laufer, MDa, Joseph Sanfilippo, MD, MBA b, and Gillian Rose, MD, MBBS, MRCOG c
a
Department of Surgery, Children’s Hospital–Boston; Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and
Reproductive Biology, Brigham and Women’s Hospital; and Harvard Medical School, Boston, Massachusetts, USA; bUniversity of Pittsburgh School of Medicine and Magee-Womens Hospital, Pittsburgh, Pennsylvania, USA; cDirectorate of Women’s and Children’s Services,
Queen Charlotte’s and Chelsea Hospital, London, England
Abstract. Objectives: To review the etiologies, diagnosis,
and treatment options of adolescent endometriosis.
Methods: Review of publications relating to adolescent
endometriosis.
Results: Endometriosis occurs in adolescents as young as
8 years of age; furthermore, there have been documented
cases of endometriosis occurring prior to menarche. Adolescents presenting with pelvic pain are treated with cyclic
combination oral contraceptive pills and nonsteroidal antiinflammatory agents. If the pain does not respond to these
therapies, then in adolescents as in adults, an operative laparoscopy is recommended for the diagnosis and surgical
management of endometriosis. The operating gynecologist
should be familiar with the appearance of the complete
spectrum of various morphologies of endometriosis, as adolescents tend to have clear, red, white, and/or yellow-brown
lesions more frequently than black or blue lesions. Subtle
clear lesions of endometriosis may be better visualized by
filling the pelvis with irrigation fluid so that the clear lesions can be appreciated in a three-dimensional appearance.
Young women who are found to have endometriosis by laparoscopy may present with acyclic, cyclic, and constant pelvic pain. Adolescents with pelvic pain not responding to
conventional medical therapy have approximately a 70%
prevalence of endometriosis. It is known that endometriosis
is a progressive disease and since there is no cure, adolescents with endometriosis require long-term medical management until the time in their lives when they have
completed childbearing. Psychosocial support is extremely
important for this population of young women with endometriosis.
Conclusions: Endometriosis occurs in adolescents, and
presenting symptoms may vary from those seen in adult
women with the disease. All health care providers must be
aware of the existence of adolescent endometriosis. They
should also be aware of the presenting symptoms so that the
adolescent can be appropriately referred to a gynecologist
Address reprint requests to: Marc R. Laufer, MD, Division of Gynecology, Children’s Hospital–Boston, 300 Longwood Ave., Boston,
Massachusetts 02115; E-mail: [email protected]
© 2003 North American Society for Pediatric and Adolescent Gynecology
Published by Elsevier Science Inc.
comfortable with medical and surgical treatment options in
this patient population. If laparoscopy is to be undertaken,
the gynecologist must be prepared not only to diagnose but
to surgically manage endometriosis. In addition, the subtle
laparoscopic findings of endometriosis in adolescents must
be recognized for an appropriate diagnosis. Long-term medical therapy will hopefully decrease pain and the progression of the disease, thus decreasing the risk of advancedstage disease and infertility.
Introduction
Adolescents frequently complain of dysmenorrhea
and pelvic pain. Studies have shown that 25% to
38.3% of adolescents with chronic pelvic pain have
endometriosis.1,2 Traditionally, nonsteroidal anti-inflammatory drugs (NSAIDs) and oral contraceptive pills
(OCPs) are the first line of treatment; however, many
adolescents continue to describe pelvic pain despite
these medications. For these young women, it is important to include endometriosis in the differential diagnosis. Endometriosis in adult women is commonly
associated with cyclic pelvic pain; however, the
symptoms in adolescents may demonstrate acyclic
and cyclic pain. It is estimated that 4% to 17% of postmenarchal females have endometriosis.3 Although in
the past it was assumed that endometriosis presented
only after many years of menstruation, studies have
described endometriosis prior to menarche,4 and 15
and 56 months after menarche. Numerous series have
shown rates of endometriosis at 50% to 70% of adolescents undergoing laparoscopy for pelvic pain who
did not have control of pelvic pain with OCPs and
NSAIDs.7–9
With education of young women, their families,
pediatricians, nurse practitioners, family practitioners,
gynecologists, and pediatric surgeons, we may be able
to decrease the length of time from the onset of symptoms to presentation, and from the time of presenta1083-3188/03/$22.00
doi:10.1016/S1083-3188(03)00066-4
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Laufer et al: Endo Diagnosis and Treatment
tion to diagnosis. In addition, with early diagnosis of
endometriosis it may be possible to decrease the longterm effects of the disease (pain, masses, and infertility), and thus improve affected young women’s quality of life.
The Origin of Endometriosis
It is important to note that some patients may have a
genetic predisposition towards developing endometriosis. This is suggested by the observation that 6.9% of
first-degree female relatives of patients with endometriosis are affected, as compared to 1% or less of
controls.10 We commonly see young women in consultation who are brought in by their mothers, who
have suffered with endometriosis symptoms since adolescence but were not diagnosed until later in life.
Although a tendency to develop endometriosis may be
inherited, the source of endometrial tissue outside the
uterus is still debated.
There are many proposed theories to explain the origin of endometriosis, and no one theory accounts for
all presentations of endometriosis. In a classic 1927
article, Sampson suggested that retrograde menstruation through the fallopian tubes results in seeding the
pelvis with endometrial tissue.11 This theory is supported by the observation that endometriosis occurs
most commonly in the dependent portion of the pelvis. Furthermore, obstructive anomalies of the female
genital tract that enhance retrograde flow have been
associated with endometriosis in the adolescent population.5,12,13 Schifrin and colleagues12 identified 6 adolescents with müllerian anomalies associated with
endometriosis, the youngest being a 12-yr-old with
vaginal atresia and bicornuate uterus leading to a hematocolpos.12 Furthermore, repair of this type of obstructive anomaly has been associated with resolution
of endometriosis.13
Other theories seeking to explain the origin of
endometriosis have proposed that metaplastic cells
transform into endometrial cells,14 and endometrial
cells metastasize through lymphatic and vascular channels, resulting in endometriosis.15 This last theory
helps to explain the finding of endometriosis in tissue
remote from the pelvis such as the lung, brain, and
skin. The most recent theories implicate an immune
mechanism and suggest that a deficiency in cellular
immunity allows the ectopic endometrial tissue to proliferate.16–18 Additionally, environmental exposures
have been hypothesized to influence the development
of endometriosis.
All these theories help explain some aspects of endometriosis. No single theory explains all cases of endometriosis, especially when relating to adolescents.
One very challenging scenario is that of postpubertal/
premenarcheal endometriosis.4 Most likely the cause
of endometriosis is multifactorial, and all proposed
mechanisms may contribute to the etiology of this disease process.
Diagnosis of Endometriosis
Evaluation of Pelvic Pain
In adult women endometriosis is suspected when a patient presents with chronic pelvic pain, dysmenorrhea,
dyspareunia, a pelvic mass, or infertility. In adults the
pain of endometriosis is most often cyclic pain. In the
adolescent endometriosis population, the presenting
pelvic pain is often both acyclic and/or cyclic (see Table 1).9 In addition, bowel and bladder symptoms may
be common in adolescents found to have endometriosis.9 Ovarian endometriomas are rare prior to the age
range of the mid-twenties.
Initial evaluation of an adolescent with pelvic pain
should include a thorough history (see Fig. 1). A
pain diary documenting frequency and character of
pain will help the adolescent and her caregiver to determine whether pain is cyclic, and if it is related to
bowel or bladder function. Complaints of difficulty
participating in normal activities, missing school, or
avoiding extracurricular activities secondary to pain
suggest that medical intervention is appropriate. A
family history of endometriosis is correlated with a
higher likelihood of endometriosis in the patient.10 A
history of sexual abuse or physical abuse may also be
associated with chronic pelvic pain19 but should not
preclude further evaluation.
The physical exam is very important, but it may not
be able to be performed for all adolescents. The goal
of the physical exam should be to try to determine the
etiology of the pain and to rule out an ovarian tumor
or anomaly of the reproductive tract. For an adolescent who is not sexually active, a rectal-abdominal
exam may be better tolerated than a vaginal-abdominal exam. A Q-tip can be inserted into the vagina to
document a patent vagina without an obstructive or
partially obstructive anomaly such as a transverse
vaginal septum, an imperforate or microperforate hymen, or an obstructed hemi-vagina. An ultrasound
should be utilized to exclude the possible existence of
a pelvic mass or structural anomaly. A common finding on pelvic exam in the setting of endometriosis inTable 1. Symptoms of Adolescents with Endometriosis9
Presenting Symptoms
Acyclic and cyclic pain
Acyclic pain
Cyclic pain
Gastrointestinal pain
Urinary symptoms
Irregular menses
Vaginal discharge
Percent
62.5
28.1
9.4
34.3
12.5
9.4
6.3
Laufer et al: Endo Diagnosis and Treatment
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Fig. 1. Management algorithm for the evaluation and treatment of pelvic pain/endometriosis.7,25
cludes cul-de-sac tenderness.20 If an exam is declined
by the young adolescent then a “Q-tip” evaluation to
document a patent lower reproductive tract and a pelvic ultrasound may be adequate.
Laboratory studies should include a pregnancy test.
A CBC (complete blood count) and erythrocyte sedimentation rate will help to rule out an acute or chronic
inflammatory process. Urinalysis and urine culture
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help identify a urinary tract source of pain. Sexually
transmitted disease testing should be obtained when
appropriate. In patients with a known diagnosis of endometriosis, CA-125 may be used to follow the
progress of disease, but this assay is not a useful
screening test due to its high rate of false positives.21
We prefer to rely on reporting of symptoms to follow
endometriosis and do not use CA-125 in clinical management.
Ultrasound evaluation of the pelvis is the most
helpful radiological study in the setting of pelvic pain.
In adults endometriomas may often be identified on
ultrasound; however, endometriomas are rarely seen
in adolescents. Ultrasound can identify other causes of
pelvic pain such as ovarian cysts, torsion, tumors,
genital tract anomalies, and appendicitis. CT scan
with contrast may help rule out appendicitis in cases
of acute pain, but is otherwise not helpful. MRI is an
excellent but expensive modality for evaluation of
genital tract anomalies.
Empiric Treatment
The differential diagnosis of chronic pelvic pain is extensive.22 When the evaluation of pain suggests a
nonacute gynecological source such as primary dysmenorrhea, endometriosis, or adhesions, a trial of
NSAIDs is recommended. The patient should begin
the medication before the expected onset of severe
pain if possible. A low-dose oral contraceptive may
also improve symptoms of dysmenorrhea by suppressing hormonal stimulation associated with ovulation
and decreasing menstrual flow.
In cases where disabling pain persists, laparoscopy
to diagnose endometriosis is essential. Chronic pelvic
pain is usually defined as 3 to 6 months of pelvic pain.
When working with adolescents, it is important to realize that 3 to 6 months of debilitating pain may interfere
with school and social activities. It may be necessary to
proceed with a surgical laparoscopic evaluation prior to
the full 3 to 6 months. Upon laparoscopic evaluation,
we have found that 69% of adolescents with chronic
pelvic pain not responding to a trial of NSAIDs and cyclic OCPs have endometriosis.9
Empiric depot leuprolide has been utilized in adult
women with chronic pelvic pain and clinically suspected endometriosis.23,24 Although controversial, the
utilization of empiric GnRH agonist therapy alleviates
the need for a surgical procedure. We, however, do
not routinely utilize gonadotropin-releasing hormone
(GnRH) agonists for women age 16 yrs or younger
due to concerns of adverse effects on final bone density formation.25 Additionally, some parents are not
interested in utilizing empiric therapy due to concerns
of using a medication with adverse side effects without a definitive diagnosis. We thus do not routinely
recommend empiric GnRH agonist therapy for treat-
ment of presumed endometriosis for young women
under age 18, but it is an option for consenting women
over age 18.
Surgical Diagnosis
Operative laparoscopy can be undertaken to make a
definitive diagnosis of endometriosis. If a gynecologist is going to perform the surgical procedure, he or
she must feel comfortable operating on patients in this
age range and be able to perform the required surgery.
A diagnostic laparoscopy with subsequent referral to a
“specialist” for definitive surgery places the patient at
undue risk from two anesthesias. In the adolescent
population it is especially important to achieve a good
cosmetic result with laparoscopy. 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. Endometriotic
implants have variable morphology, which has been described in the revised American Society of Reproductive Medicine (ASRM) Classification of Endometriosis
(see Fig. 2).26 Only one series has objectively compared
lesions in adolescents to those found in adults.27 This
series suggests red flame lesions are more common in
adolescents with endometriosis than in adult patients.
Powder-burn lesions are less common in adolescents,
which is consistent with the presumption that these lesions represent older, more advanced implants. It has
been suggested that the clear and red lesions are the
more painful lesions of endometriosis (see Table 2).28
Peritoneal Alan-Masters windows are also common in
adolescents and should be recognized by the operating
gynecologist. Care must be taken to identify subtle lesions of endometriosis that often appear as clear, shiny
peritoneal vesicles. Visualization of lesions through a
liquid distention medium may facilitate identification
of clear vesicular lesions.29 If no evidence of endometriosis is identified, a cul-de-sac biopsy to rule out microscopic disease should be performed as endometriosis
may be identified without visualization on laparoscopy.
Although one study suggests a low prevalence of microscopic endometriosis,20 another report shows a significant rate of microscopic endometriosis in adults.30
Recent experience at Children’s Hospital, Boston suggests a significant amount (3%) of microscopic endometriosis in adolescents with a visually normal pelvis.9
At the time of laparoscopy, endometriosis should be
staged according to the revised ASRM Classification of
Endometriosis26 in order to facilitate follow-up and comparison if future surgery is performed. Interestingly, although most adolescents present with Stage I–II disease,
Laufer et al: Endo Diagnosis and Treatment
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Fig. 2. ASRM classification of endometriotic lesions.26
in one reported series of 36 adolescents with endometriosis, 31% had stage IV disease.27 When counseling patients postoperatively, it is important to remember that
the severity of symptoms has not been found to correlate
with the extent or location of lesions (see Table 3).31
Treatment of Endometriosis
Surgical Treatment
Operative laparoscopy is performed for definitive diagnosis, coagulation, ablation, or resection of endometrioTable 2. Type of Lesion and Pain28
Type of Lesion
Clear
Red
White
Black
Pain perception 1–27 mm from lesion
Association with Pain
76%
84%
44%
22%
sis in the least invasive and most cost-effective fashion.
Laparotomy is rarely indicated. Removal of lesions of
endometriosis may be performed with electrocautery,
endocoagulation, or laser.32 Surgery has been shown to
reduce pain from endometriosis in rates of 38% to 100%
of adult women.33,34 Regardless of the technique, care
must be taken to avoid damage to the ureters, major vessels, bowel, and bladder. Lysis and resection of adhesions is also performed at the time of surgery. As noted
previously, endometriomas are rare in adolescents; however, large ovarian cysts should be removed, taking care
to preserve ovarian tissue. Surgery alone is not adequate
treatment for endometriosis as there can be microscopic
residual disease that must be suppressed with medical
therapy.24 With surgery alone, studies have shown that
symptoms will return in approximately 50% of adult
women within 1 year.24,34–36
Medical Treatment Options
Endometriosis is a chronic disease that has been
shown to be progressive. Adolescent patients with en-
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Table 3. Staging and Pain are Unrelated31
Stage of Disease
Stage I
Stage II
Stage III
Stage IV
Percent of Patients with Pain
40
24
24
12
dometriosis confirmed by laparoscopy should receive
medical treatment of their disease. The goal of medical therapy is to treat pain from postoperative residual
disease and suppress progression. The choice of treatment depends on the severity of the patient’s symptoms, the extent of disease, and compliance. The
patient and the health care provider can follow success
or failure of medical therapy. Adolescents should be
asked to rate their pain on a scale of 0 to 10 at the time
of each visit. Medical therapy should be utilized to decrease pain and permit the adolescent to function. The
patient should be aware that she may not be pain free
but her medications should be adjusted to maximize
pain relief and promote school and social function and
participation.
Although numerous options have been described
for the treatment of endometriosis,7,25 at the Children’s Hospitals in Boston and Pittsburgh, continuous
oral contraceptives or gonadotropin-releasing hormone
agonists are usually first-line therapy. We offer either
therapy to women over age 16, and only continuous
oral contraceptives to women less than 16 yrs for concern of the effects of the GnRH agonist on the formation of normal bones and bone density.
Nonsteroidal Anti-inflammatory Agents. As noted
earlier in this report, NSAIDs are appropriate empiric
treatment for dysmenorrhea. NSAIDs are also helpful
adjuvant agents for the treatment of pelvic pain associated with endometriosis.
Hormonal Suppression. Clearly, not all patients
with endometriosis find relief from symptoms with
NSAIDs alone.37 Suppression of menses, ovulation,
and endometriosis generally achieves superior pain
control. By hormonally decreasing stimulus to endometriotic tissue, regression of disease and improved
pain control may be achieved. There are differing modalities for suppression of menses, ovulation, and endometriosis, each with differing risks, benefits, and
side-effect profiles.
Combination Estrogen and Progestin Therapy. Oral
contraceptives, contraceptive patch, and the vaginal
ring all contain both estrogen and progestin. Continuous low-dose combination estrogen/progestin therapy
diminishes pain from endometriosis by creating a hormonal “pseudopregnancy” state in which endometrial
implants are relatively inactive.38 Gynecologists and
pediatricians have extensive experience with OCP ad-
ministration in adolescents. OCPs are generally well
tolerated and may be safely used for at least 10 years
without an associated increase in mortality.39 There is
a lack of data on the long-term utilization of continuous hormonal therapy, although this has been a widely
utilized treatment modality. There has been a recent
small study showing benefits of long-term hormonal
therapy.40 In a similar fashion to the continuous pills,
the contraceptive patch (OrthoEvra) or the vaginal
ring (NuvaRing) can be used in a continuous fashion
without breaks to attempt to suppress menses, pain,
and endometriosis.
Danazol. Danazol is a 17--ethinyltestosterone
derivative that creates an acyclic environment, and
multiple studies show its efficacy in treating endometriosis to be equivalent to a variety of GnRH agonists.41–47 Danazol has significant androgenic side
effects secondary to affecting sex-hormone-bindingglobulin levels, resulting in an increase of free testosterone. For example, in a series by Buttram of 220 patients, complaints included weight gain, depression,
muscle cramps, decreased breast size, flushing, oily
skin and hair, acne, hirsutism, irreversible deepening
of the voice, and skin rash.48 In this particular series
7% of patients discontinued the drug secondary to intolerable side effects. Compared with patients using
danazol, patients using GnRH agonists reported a better quality of life.49 Given the side effects, this medication would likely be poorly tolerated by adolescents
and is not widely utilized in management of endometriosis.
Progestins. Progestational agents include norethindrone acetate (15 mg daily by mouth), medroxyprogesterone acetate (30–50 mg daily by mouth), and
depot medroxyprogesterone acetate (150 mg intramuscularly every 1 to 3 months), each of which will improve symptoms in approximately 80% to 100% of
patients with endometriosis.50–52 At therapeutic doses,
progestins may be associated with side effects such as
weight gain, bloating, depression, and irregular bleeding. However, many patients tolerate this therapy very
well. Oral progestin therapy should be considered
prior to long-term intramuscular injections so that side
effects can be identified and addressed or the medication discontinued. The long-term utilization of depot
medroxyprogesterone acetate has been shown to result
in loss of bone density in some patients, and therefore
monitoring of serum estradiol and/or bone density is advised.53,54 In at-risk patients, low-dose estrogen therapy
can be used. The cardiovascular effects of long-term
therapy remain unknown and warrant investigation.
Gonadotropin-Releasing Hormone Agonists. GnRH
agonists may also be prescribed for adolescents who
are over age 16. We generally prescribe depot leuprolide acetate 11.25 mg intramuscularly every 3 months.
Side effects include: hot flashes, headaches, difficulty
Laufer et al: Endo Diagnosis and Treatment
sleeping, mood swings, depression, and vaginal dryness. With this dose more than 90% of patients will
become amenorrheic and hypoestrogenic.55 We do
not routinely utilize GnRH agonists for individuals
younger than 16 due to concerns of adverse affects on
permanent bone density. Upon completion of this
therapy the patient begins continuous OCPs. Nafarelin
(nasal spray), one puff twice daily intranasally, is an
alternative GnRH agonist; however, compliance is often unpredictable in the adolescent population. The
utilization of add-back therapy can help to alleviate
the side effects of GnRH agonists. Add-back therapy
is based on the “estrogen threshold hypothesis” and
the concept is demonstrated in Figure 3.56
(OCP, patch, or ring) then prolonged utilization of
GnRH agonist with add-back therapy can be initiated.
We have had patients with surgically diagnosed disease refractory to other medication on this prolonged
GnRH agonist with add-back for over 10 years. Prior
to the initiation of “retreatment” with a GnRH agonist
or if therapy is to be prolonged greater than 9 months,
a baseline bone density evaluation should be obtained,
then repeated 6 months later and, if stable, repeated
every 2 years. As noted above, the long-term utilization of GnRH agonist with add-back therapy has not
been studied in the adolescent population.61
If pain does not respond to aggressive medical therapy, it may be resulting from recurrent endometriosis
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, lasered, or resected.
We utilize adhesion preventive agents laparoscopically following surgical lysis of adhesions.
Issues for Future Consideration
Early diagnosis of endometriosis and treatment will
hopefully suppress progression and advancement of
disease. This is an area that needs future investigation.
Fig. 3. Estrogen threshold hypothesis.56
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Additionally, there are some areas that are particularly
challenging. For instance, how should we treat the adolescent daughter of a woman who had no pelvic pain
but who had Stage IV endometriosis and infertility?
Should she have an evaluation and treatment even
though she has no pelvic pain, in an attempt to avert
the silent development of Stage IV endometriosis and
future infertility? These areas should be addressed in
future investigations.
Conclusions
Evaluation of pelvic pain in adolescents begins
with a history and physical exam, pain calendar, laboratory evaluation, and possible ultrasound. Empiric
treatment of chronic pelvic pain and dysmenorrhea in
adolescents may include nonsteroidal anti-inflammatory agents and hormonal therapy. A definitive diagnosis of endometriosis can only be made by laparoscopy.
Forty-five to seventy percent of adolescents with
chronic pelvic pain have endometriosis diagnosed at
the time of laparoscopy. A gynecologist familiar with
the appearance of endometriosis in adolescents should
perform the surgical laparoscopic procedure. In adolescents, the laparoscopic appearance of endometriosis may be subtle, with red flame lesions and clear,
shiny peritoneal vesicles. Surgical management involves diagnosis of endometriosis and ablation of
lesions. Medical management of endometriosis in adolescents is achieved with hormonal suppression
using continuous hormonal therapy, gonadotropinreleasing hormone agonists, or other medications. A
multidisciplinary approach to pelvic pain with the assistance of pain treatment services and complementary and alternative therapies are also helpful for some
adolescents.
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