Version May 2024
INTRODUCTION — Endometriosis classically 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 occur in adolescents and 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 in adults: Pathogenesis, epidemiology, and clinical impact".)
●(See "Endometriosis: Clinical features, evaluation, and diagnosis", section on 'Imaging'.)
●(See "Endometriosis: Treatment of pelvic pain".)
●(See "Endometriosis: Management of ovarian endometriomas".)
●(See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists".)
●(See "Endometriosis: Treatment of infertility in females".)
●(See "Female infertility: Reproductive surgery".)
●(See "Clinical features, diagnostic approach, and treatment of adults with thoracic endometriosis".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
EPIDEMIOLOGY
●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 64 percent of those with chronic pelvic pain that undergo laparoscopy [3,4]. The prevalence among adolescents undergoing laparoscopy for pelvic pain not controlled with oral contraceptive pills and nonsteroidal anti-inflammatory drugs is 50 to 70 percent [5-7].
●Timing of onset – Two-thirds of adult women with endometriosis report that their symptoms started before age 20 [8]. Although it had been assumed that endometriosis presented only after many years of menstruation, this was incorrect: symptomatic cases have been documented prior to premenarche in girls who have started breast development (endometriosis is stimulated by estrogen) and in others soon after menarche [9-11].
●Genetic association – 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) [12].
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 in adults: Pathogenesis, epidemiology, and clinical impact", 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 on, pelvic structures [13].
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 menstrual flow, such as vaginal agenesis, imperforate hymen, and transverse vaginal septum, have been associated with endometriosis in the adolescent population [10,14,15].
●Endometriosis in locations outside the pelvis may be secondary to dissemination of endometrial cells or tissue through lymphatics and blood vessels [16].
●The coelomic metaplasia theory proposes that the coelomic (peritoneal) cavity contains undifferentiated cells or cells capable of dedifferentiating into endometrial tissue [17]. This theory is based upon embryologic studies demonstrating that all pelvic organs, including the endometrium, are derived from cells lining the coelomic cavity.
●The direct transplantation theory is the probable explanation for endometriosis that develops in episiotomy after vaginal delivery or the abdominal wall after cesarean section.
●The cellular immunity theory suggests that a deficiency in cellular immunity allows ectopic endometrial tissue to proliferate [18-20]. Alterations in cellular immunity may work in conjunction with retrograde menstruation as a mechanism for endometriosis development.
Several early life risk factors may also contribute to the development of endometriosis in adolescence. Prior studies have postulated breastfeeding in early life, secondhand smoke during childhood [21], and sexual and physical abuse in early life [22] are associated with increased risk of endometriosis. Dietary exposures in adolescence may impact the risk of subsequent endometriosis, such as dairy intake [23]. However, early life and adolescent interventions to reduce risk of endometriosis remain understudied and causality cannot be inferred from the above studies.
CLINICAL MANIFESTATIONS — Heightened awareness 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 [8]. Ideally, early diagnosis and treatment of endometriosis will prevent or slow disease progression [24], and subsequently 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/cramps (severe, progressive dysmenorrhea) (table 1) [25]; isolated cyclic pain is the least common pain presentation [7]. Bowel symptoms (eg, rectal pain, constipation, painful defecation that may be cyclic, rectal bleeding) and bladder symptoms (eg, dysuria, urgency, hematuria) are also common [7]. Most adolescents with endometriosis have superficial disease, while deeply infiltrative endometriosis and ovarian endometriomas and infertility are rare in this age group.
There can be overlap of symptoms that involve pelvic pain and gastrointestinal (GI) symptoms. If the young patient's pain is cyclic in nature and worse with their periods, a gynecologic evaluation may be warranted prior to a GI evaluation. GI symptoms can be common with endometriosis, but GI disorders do not typically have a cyclic relationship to menstrual cycles. Acyclic pelvic pain may be a strong predictor for the likelihood of irritable bowel syndrome (IBS), thus screening for IBS should be considered [26]. If the adolescent has pain and a family history of endometriosis and/or infertility, a gynecologic evaluation may be the best first option for evaluation prior to a GI evaluation.
By contrast, adults with endometriosis commonly have cyclic pain, and present with dysmenorrhea, dyspareunia, a pelvic mass, infertility, or chronic pelvic pain. (See "Endometriosis: Clinical features, evaluation, and diagnosis", section on 'Clinical features'.)
Differential diagnosis — Causes of pelvic pain in adolescents include pregnancy (intrauterine or ectopic), appendicitis, pelvic inflammatory disease, müllerian abnormalities with outflow obstruction, hernia, bowel disease, urinary tract disease, and musculoskeletal 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 their 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 [27], but this should not preclude further evaluation for endometriosis. Mental health screening should also be considered as there is an increased risk of anxiety and depression in adolescents with symptoms of pelvic pain [28]. The patient's family may be involved in contributing to the history, but the history, including sexual activity, should be taken in private when appropriate. School absenteeism or decreased engagement in prior work, activities, or relationships should be assessed.
A family history should be obtained, and it should be noted that if a patient has a first-degree relative with endometriosis or suspected disease, such as pelvic pain or infertility. In such situations, the patient is advised of a seven times greater risk of having endometriosis compared with the general population [29].
Associated diseases — It should be noted that there is a higher than expected rate of autoimmune diagnoses in women with endometriosis compared with the general population [30-35]. There is an increased rate of arthritis, inflammatory bowel disease, thyroid disease, migraine headaches, systemic lupus erythematosus, Sjögren's disease, postural orthostatic hypotension, and multiple sclerosis.
Physical examination — The goal of the physical examination is to determine the etiology of the pain and to rule out an ovarian tumor or obstructive 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, particularly those who have not been sexually active or are unable to use tampons. A pelvic exam should not be a barrier to further evaluation, diagnosis, and treatment of endometriosis.
●(See "Congenital uterine anomalies: Clinical manifestations and diagnosis".)
●(See "Congenital anomalies of the hymen and vagina".)
The abdominal examination is usually normal but can be helpful in localizing the pain. Evidence of a reticulated pattern of hyperpigmentation, called erythema ab igne, would suggest chronic exposure to heat for pain relief (eg, heating pad, hot water bottle).
We do not typically perform speculum and bimanual exams on adolescents. These exams will likely be low yield and uncomfortable and generally do not add information that cannot be obtained from imaging studies. On pelvic examination, adolescents rarely have uterosacral nodularity, a common finding in adults with deep or advanced disease. Adnexal enlargement may be palpable if an endometrioma is present, but these masses are also rare in adolescents [36]. Sonographic examination can be performed to augment (or in place of) a limited physical examination and identify/exclude causes of abdominopelvic pain other than endometriosis. (See 'Imaging studies' below.)
Laboratory — Laboratory tests to consider include:
●Complete blood count and erythrocyte sedimentation rate, which may suggest the presence of an acute or chronic inflammatory process but are not elevated due to endometriosis
●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 as it is nonspecific (table 3). It has been used occasionally to follow the progress of disease in patients who have histologically or visually confirmed endometriosis at surgery [37], but we prefer to rely on the patient's report of self-specific symptoms, which is typically pain, to follow endometriosis, and thus do not use CA 125 in clinical management. (See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact".)
Imaging studies — In adult women with endometriosis, sonography and magnetic resonance imaging (MRI) can identify ovarian endometrioma and deeply infiltrative endometriosis, which are signs of more advanced disease. However, these tend to be less useful in diagnosis of endometriosis in adolescents since endometriomas and deep endometriosis are rare and the typical superficial peritoneal lesions of adolescent endometriosis cannot be appreciated with imaging. Still, ultrasound and MRI may be useful to identify/exclude several structural causes of pelvic pain in adolescents, such as ovarian torsion or hemorrhage, tumors, genital tract anomalies.
MRI 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 superficial peritoneal lesions, which is the most common form of endometriosis in adolescents [38-40]. Computed tomography is also an insensitive test in the diagnostic evaluation of endometriosis, unless an endometrioma is identified. (See "Endometriosis: Management of ovarian endometriomas".)
OUR APPROACH — The discussion below on the decisions leading to diagnosis and treatment options are not as straightforward as the headings imply (algorithm 1). While there is a clear statement on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and combined estrogen-progestin contraceptives (or progestin-only therapy for those with a contraindication or who prefer not to use estrogen) for the treatment of dysmenorrhea, the next steps for clinical evaluation and management of persistent pain are less clear. If an adolescent has continued pain on hormonal therapy and NSAID therapy after three months of treatment, there are no data suggesting that a different estrogen-progestin or progestin-only contraceptive will improve their symptoms. Thus, we advise moving to the next step for evaluation rather than opting for an alternative medical treatment.
Patients whose pain persists after an initial trial of hormonal contraception with NSAID have several options for continued evaluation and management (algorithm 1). Traditional gynecologic teaching has promoted laparoscopy for surgical diagnosis and surgical management of endometriosis. However, in adult patients with symptoms suggestive of endometriosis, clinical diagnosis followed by medical management and/or surgical management are both viewed as reasonable options. Given the safety of hormonal suppression and similar efficacy to laparoscopy, the thinking has evolved that patients can be given a clinical diagnosis of endometriosis without the need for surgery. For patients who wish to avoid surgery, treatment includes medical suppression with continuous combination estrogen-progestin therapy, progestin alone, GnRH agonist with add-back, or GnRH antagonist. Selection of a specific agent is driven by ease of use, side effects, cost, and availability. In this setting, surgery is reserved for individuals whose pain does not resolve on medical therapy or those who desire a definitive surgical diagnosis before initiating treatment.
As supporting data are limited, the decision to pursue surgical diagnosis versus attempt continued medical treatment based on a clinical diagnosis is guided by patient and family preferences. As part of the shared decision-making process, issues for discussion and consideration include:
●Unknown impact of medical therapy alone on disease progression – It is not known if medical therapy alone suppresses the progression of endometriosis and adhesions. This is an important issue as progression of either can lead to worsened symptoms over a lifetime and impaired fertility. For adolescent patients, there is a small body of data demonstrating that disease progression is suppressed in those who have surgical management followed by medical suppression [24].
●Surgical versus medical risk – Not all adolescent individuals are low risk for surgery or candidates for preferred medical therapy. Complicating factors include prior abdominal surgery, presence of congenital gynecologic anomalies, and underlying medical conditions. Both the World Health Organization Medical Eligibility Criteria for Contraceptive Use and the US Medical Eligibility Criteria for Contraceptive Use maintain evidence-based recommendations for use of contraceptive methods in the context of a range of medical conditions and personal characteristics [41,42]. The benefits and side effects of estrogen-containing contraceptives are discussed in detail separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns".)
●Desire for definitive diagnosis before initiating treatment – Some individuals and/or their families may prefer to avoid hormonal treatment unless there is a demonstrated need. In addition, patients with endometriosis are typically treated with medical suppression until they desire pregnancy, which can be decades later. Not all individuals are comfortable committing to years of therapy based on a clinical diagnosis.
●Hormonal treatment if continued pain – If endometriosis is not identified at time of laparoscopy, hormonal treatment is often still recommended for patients with dysmenorrhea or cyclic exacerbation of pelvic pain.
Regardless of which path is selected, for individuals with continued pain despite treatment with cyclic hormones and NSAIDs, the diagnosis is most likely endometriosis, and the treatment plan that most improves quality of life and functionality should be selected.
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 gynecologic source, such as primary dysmenorrhea or endometriosis (table 4) [43]. 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 [43]. There are no data suggesting one contraceptive pill formulation is better than another for the treatment of dysmenorrhea. 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 or menstrual management, which NSAIDs would not provide. The vaginal ring and transdermal contraceptive patch are other examples of methods of combined hormonal contraception and are acceptable alternatives to OCs. The vaginal ring may not be a desirable choice for some adolescents, such as those who do not utilize tampons. All of these methods are safe and effective if given cyclically, and the oral pill and vaginal ring may be used in an extended or continuous fashion [44-46]. 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 "Endometriosis: Treatment of pelvic pain", section on 'Estrogen-progestin contraceptives' and "Hormonal contraception for menstrual suppression" and "Contraception: Issues specific to adolescents", section on 'Pill, patch, or ring'.)
If the pain does not resolve with NSAIDs and hormonal therapy, then further evaluation is necessary.
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 gonadotropin-releasing hormone (GnRH) agonist is justified provided that there are no other indications for surgery (eg, suspicious adnexal mass, urinary or gastrointestinal tract obstruction) [47]. The empiric utilization of a 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 [48]. The only randomized trial that directly compared use of a GnRH agonist (goserelin) with 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 [49].
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 [50]. Additionally, some guardians 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 [43]. Most bone mass in females has accumulated by age 18 [51].
PATIENTS WHO FAIL THERAPY FOR DYSMENORRHEA — A definitive diagnosis of endometriosis should be established for adolescents who have persistent pain after three to six months of hormonal therapy and nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of dysmenorrhea [43]. Laparoscopy is the gold standard for diagnosis of endometriosis, although there has been a movement to increase the use of clinical diagnosis and treat endometriosis-associated pain without the need for a surgical diagnosis [52,53].
When pain persists despite dysmenorrhea therapy, we talk with the adolescent and family to determine the amount of pain that is being experienced. We suggest that if the pain interferes with activities of daily life or places them at a disadvantage in academics, sports, or social activities compared with others, then we, and the American College of Obstetricians and Gynecologists, have classically recommended that the patient undergo laparoscopy for definitive diagnosis [43]. Typically, laparoscopy is performed after three to six months of pain [43], but waiting this long may result in pain continuing to 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 oral contraceptive pills are found to have endometriosis [7]. 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.
Diagnostic (and therapeutic) laparoscopy — The gynecologic surgeon should have experience operating on patients in this age range or consult with an appropriate pediatric gynecologist or pediatric surgeon. In addition to diagnosis, surgical management of the endometriosis should be part of the primary surgery. Purely diagnostic laparoscopy followed by referral for definitive surgery should be avoided whenever possible.
Endometriotic implants can have a variable appearance in this age group and differ from findings commonly seen in adults (picture 1) [54].
●Common findings – The only series that objectively compared endometriosis lesions in adolescents with those in adults found red flame lesions were more common and powder burn lesions less common in adolescents than in adult patients [55]. This is consistent with the theory that powder burn lesions represent older, more advanced implants. Clear and red lesions may be the more painful lesions of endometriosis (table 5) [56]. Peritoneal windows or defects are also common in adolescents and should be recognized as suggestive of endometriosis.
●Identification of clear lesions – Care must be taken to identify subtle endometriotic lesions that often appear as clear, shiny peritoneal vesicles. Some surgeons have reported that visualization through a liquid medium, such as saline, may facilitate identification [57]. After all the lesions have been located, the fluid is removed so that the lesions can be ablated or excised.
●Role of biopsy if no lesions – 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 [58], while another reported a significant rate in adults [59]. Our experience at Boston Children's Hospital 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 [7].
●Endometriosis documentation – Endometriosis operative findings should be documented in a standardized fashion using a surgical staging system. There are several staging systems reported, and the most commonly used is the revised ASRM Classification of Endometriosis (figure 1). Standardized staging will facilitate follow-up and comparison if future surgery is performed [54]. Although most adolescents present with Stage I to II disease, in one series, 11 of 36 adolescents with endometriosis had stage IV disease [55]. 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) [60].
Surgical treatment — Most adult women experience a reduction in pain after surgical treatment [61,62]. There are no large studies in adolescents. One retrospective cohort study of 85 adolescents (mean age 16.3±2.4 years) reported that pain had disappeared in 42 percent and improved in 38 percent at mean follow-up of 56 months after surgery [63]. Twenty percent reported no change or worsened pain.
●Surgical treatment of lesions – Excision or destruction of superficial peritoneal endometriosis should be performed at the time of laparoscopy [53,64,65]. In adults with stage I or II disease, there is no difference in outcome with excision versus ablation of endometriosis, but surgical excision should be performed for deeply infiltrative lesions [66-71].
●Endometrioma – While ovarian endometriomas are an uncommon presentation in adolescents, first-line treatment in adolescents should be cystectomy versus oophorectomy. Conservative surgical treatments should be considered as opposed to definitive (ie, hysterectomy with or without oophorectomy) to preserve fertility and hormonal production.
Radical excisional surgery or peritoneal stripping has not been shown to be more effective than ablation or excision in adolescents and may be associated with increased risk of adhesion formation [43,72]. 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".)
It should be noted that no surgical procedure or medical therapy results in a cure for endometriosis. Surgery alone is not adequate treatment for endometriosis as there can be microscopic residual disease that must be suppressed with medical therapy [47]. Symptoms will return within one year in approximately 50 percent of adult women who receive only surgical therapy [47,61,66,73]. Thus, medical treatment is typically initiated postoperatively. (See 'Postoperative medical treatment' below.)
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 that will progress to more advanced disease if left untreated.
The general consensus is that adolescents with histologically confirmed endometriosis should receive hormonal medical treatment after surgical ablation/resection until they are ready to attempt pregnancy [43]. Compared with 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 their daily activities, and suppress disease recurrence or 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 [24,74]. The follow-up study reported that while disease can persist following surgical resection, it does not tend to progress with surgical management followed by medical suppression. This study also reported no increase in the rates of adhesion formation from the initial surgical procedure [24]. There are limited data on the course of adolescents who undergo complete excision of visible endometriosis but do not undertake postoperative hormonal suppression [75]. It is notable that radical excisional surgery for Stage I or II superficial disease also has the risk of subsequent adhesion formation [76].
Treatment efficacy should be assessed regularly, and we do this by asking the patient to rate their pain on a scale of 0 to 10 at each visit. We educate patients that they may not become pain free, but the 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 [72,77]. The choice of treatment depends upon the severity of the patient's symptoms, the extent of disease, compliance, and need for contraception. Although numerous options have been described for the treatment of endometriosis [5,50], combination hormonal therapy or gonadotropin-releasing hormone (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 and progestin-only therapies 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 [78].
Continuous hormonal therapy — Use of continuous hormonal therapy after surgery may retard progression of disease and control any remaining pain [45]. (See 'NSAIDs and hormonal therapy' above.)
Combination estrogen-progestins — Combination therapy can be used to suppress menstruation and induce a "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. For many adolescents, the time they take their medication may be in the evening, as most adolescents do not get up at the same time on weekdays and weekends. If the pill is delayed or missed, 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:
●Norethindrone (0.35 mg daily by mouth)
●Norethindrone acetate (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)
Families should be reassured that contraception may be used for noncontraceptive benefits (eg, for endometriosis) and contraception does not increase the likelihood of riskier sexual behavior [79]. However, some families of younger patients may be more interested in use of oral norethindrone acetate or medroxyprogesterone acetate, as they are not approved as contraceptive agents.
It should be noted that although a progestin only, norethindrone acetate has been shown to be converted to a low amount of ethinyl estradiol [80].
Each of these therapies improves symptoms in approximately 80 to 100 percent of patients with endometriosis [81-85]. Norethindrone acetate alone has been shown to be effective and well tolerated in adolescents [85]. With higher doses of norethindrone acetate (15 mg per day), liver adenomas have been reported as with combination estrogen-progestin pills, and thus, we typically use doses less than 10 mg per day [86]. The etonogestrel subdermal implant has also been used successfully, but experience is limited [87-90]. (See "Endometriosis: Treatment of pelvic pain", section on 'Progestins'.)
Potential bothersome side effects of progestins include weight gain, bloating, depression, and unscheduled bleeding [8]; however, many patients tolerate this therapy very well [84]. 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.
Drospirenone (commercial name Slynd) is a progestin-only contraceptive pill that may also be considered, although its use for endometriosis has not been studied.
The long-term utilization of depot medroxyprogesterone acetate has been shown to result in loss of bone density, which is reversible after discontinuation of the progestin.
Progestin intrauterine devices (IUDs) deliver the progestin levonorgestrel (LNG) to the local uterine environment. Many use LNG IUDs for the treatment of dysmenorrhea and endometriosis-associated pain. No LNG IUD is approved by the US Food and Drug Administration for treatment of endometriosis-associated pain. We commonly offer LNG IUD placement at the time of anesthesia for endometriosis, such as the time of laparoscopy, to potentially minimize the discomfort of pelvic examination for the adolescent. We consider the simultaneous use of systemic hormonal therapy with the IUD as patients may continue to experience bleeding and pain with the IUD is used alone for endometriosis management [91]. This is expected to inhibit ovulation more consistently, and thus reduce the risk of hemorrhagic ovarian cysts and ovarian endometriomas. The types of LNG IUDs, patient selection, insertion, and management of complications are presented separately.
●(See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)
●(See "Intrauterine contraception: Candidates and device selection".)
●(See "Intrauterine contraception: Insertion and removal".)
●(See "Intrauterine contraception: Management of side effects and complications".)
GnRH agonists — GnRH agonists can be prescribed for adolescents with laparoscopically confirmed endometriosis who are at least 16 years old. While GnRH agonists are used in adolescents younger than 16 with precocious puberty, treatment duration is shorter for precocious puberty, and therefore, the outcomes and risks cannot be extrapolated to young postpubertal women with endometriosis. For GnRH therapy, our preference is depot leuprolide acetate (11.25 mg intramuscularly every three months); it is always given with add-back therapy. We use the three month formulation to improve compliance with therapy. Occasionally, 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, especially in younger adolescents, since the suppression appears to be less than with the intramuscular formulation. Due to the typical twice daily dosing, compliance is often unpredictable in the adolescent population. The dose can thus be titrated to less than twice daily dosing as long as estradiol levels and menses are suppressed. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists".)
Over 90 percent of patients will become amenorrheic and hypoestrogenic on this dose of leuprolide [92]. Side effects of GnRH analogs without add-back therapy include hot flashes, headaches, difficulty sleeping, mood swings, depression, and vaginal dryness; therefore, 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 [93]. Upon completion of this initial six month course of GnRH agonist therapy, the patient must then choose a treatment course. One common option is a return to a continuous combined hormonal contraceptive, as described above. GnRH-agonist therapy with add-back has not been approved for use beyond 12 months by the U.S. Food and Drug Administration (FDA) [93], but if the patient is not able to tolerate continuous combination hormonal or progesterone only therapy, then long-term utilization of a GnRH agonist with add-back can be prescribed. 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. (See 'Add-back therapy' below.)
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 [94]. Add-back therapy is based upon the "estrogen threshold hypothesis," which is demonstrated in the figure (figure 2) [95]. 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 [96,97]:
●Norethindrone acetate (5 mg daily) alone, or
●Conjugated estrogen (0.625 mg) plus either norethindrone acetate (2.5 or 5 mg) or medroxyprogesterone acetate (5 mg daily)
Patient satisfaction is higher in adult women with use of norethindrone compared with the other options (table 7) [96]. Patient satisfaction and bone density were higher in adolescent women with the use of norethindrone acetate plus conjugated equine estrogens as compared with norethindrone plus placebos [77,98,99].
Safety — The safety of long-term use of a GnRH agonist with add-back therapy in adolescents is under investigation [78]. One study performed serial bone mineral density examinations in 36 adolescents receiving a GnRH agonist with norethindrone acetate add-back [100]. 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.
GnRH antagonists — To date, there are no studies of the use of GnRH antagonists in adolescents. Use of GnRH antagonists in adult patients is reviewed elsewhere. (See "Endometriosis: Treatment of pelvic pain", section on 'Antagonists'.)
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 growth, and direct inhibition of ovarian enzymes responsible for estrogen production. (See "Endometriosis: Treatment of pelvic pain", section on 'Danazol'.)
Danazol's efficacy in treating mild to moderate endometriosis is equivalent to that of a variety of GnRH agonists [101-107]. Over 80 percent of patients experience relief or improvement of pain symptoms within two months of treatment [108]. Large endometriotic cysts and adhesions do not respond well; surgery is the preferred therapy for these lesions.
Those 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, irreversible deepening of the voice, increased liver enzymes, hot flashes, mood changes, and depression [109]. 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 [109]. Although GnRH agonists are also associated with side effects, patients using these drugs report a better quality of life than those taking danazol [110]. Given the side effect profile, danazol may be a desirable and well-tolerated option by gender-diverse individuals, including transgender men. Endometriosis has been laparoscopically diagnosed in transmasculine adolescents with pelvic pain while receiving testosterone therapy for gender affirmation [111].
Nonsteroidal anti-inflammatory agents — Nonsteroidal anti-inflammatory 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 [112,113]. This effect may also occur in humans [114,115]. Nonsteroidal therapies, such as antiinflammatory and antiangiogenic drugs, are an emerging area of investigation in treatment of endometriosis [116]. (See "Endometriosis: Treatment of pelvic pain", section on 'Nonsteroidal anti-inflammatory drugs'.)
MANAGEMENT OF RECURRENT PAIN — Endometriosis is a chronic and inflammatory disease, which can be progressive, thus pain can recur despite therapy. Management options for recurrent pain include:
●Change treatment modality – If adolescents less than 16 years of age have persistent pain associated with endometriosis while taking continuous combination hormonal therapy, then utilization of gonadotropin-releasing hormone (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. Alternatively, for those who do not do well off of GnRH agonist long-term, a GnRH agonist with add-back can be reutilized.
●Prolong 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 14 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.
●Monitor bone mineral density – 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 [78].
●Role of repeat laparoscopic surgery – 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. However, coexisting pain conditions are common in adolescents with endometriosis and should be thoroughly investigated and treated when present [117]. A repeat laparoscopic procedure should be considered in select patients whose persistent pain and all other potential sources of pelvic pain have been maximally treated. 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 long-term follow-up study reported that adolescents with early stage superficial peritoneal disease do not tend to have disease progression after surgical management followed by medical suppression [24]. That study also reported no increase in adhesion development with that technique. Radical excisional surgery for early-stage superficial peritoneal disease has been questioned to result in adhesions without proven benefit over destruction and excisional surgery [76].
A multi-disciplinary approach to pelvic pain, with the assistance of pain treatment services and complementary and alternative therapies, should be considered in all adolescents with endometriosis. (See "Chronic pelvic pain in adult females: Treatment", section on 'Nonpharmacologic therapies'.)
Social work or similar counselor involvement may be helpful and patients with significant school absenteeism may benefit from academic accommodations. Complementary therapies that may be helpful include acupuncture [118] and pelvic floor physical therapy [119]. Physical therapy may need to be tailored to the adolescent as teens uncomfortable with vaginal insertion may need therapy techniques performed on pelvic floor musculature externally.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Endometriosis".)
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 5th to 6th 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 10th to 12th 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 education: Endometriosis (Beyond the Basics)")
In addition, there is adolescent endometriosis-specific downloadable information as handouts from the Center for Young Women's Health at Boston Children's Hospital and www.youngwomenshealth.org listed below:
●Continuous Hormonal Treatment for Endometriosis
●Hormonal Treatment Options for Adolescent Endometriosis
●Monthly Live Monitored Chat Rooms for Adolescent with Endometriosis
●Parents' Guide to Adolescent Endometriosis
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: von Willebrand disease".)
SUMMARY AND RECOMMENDATIONS
●Treatment goals – The goals of therapy are to relieve pain, prevent disease progression, and preserve fertility. An approach for the evaluation and management of adolescents with chronic pelvic pain is shown in the algorithm (algorithm 1).
●Clinical presentation
•Timing of symptom onset – Symptomatic endometriosis commonly occurs in adolescents, in rare cases before menarche. (See 'Epidemiology' above.)
•Common symptoms – Adolescents with endometriosis usually have both acyclic and cyclic pain. Bowel symptoms (eg, rectal pain, 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.)
●Initial evaluation – 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.)
●Trial of medical therapy – Medical treatment of dysmenorrhea is appropriate prior to considering surgical intervention for diagnosis/treatment of endometriosis in adolescents with dysmenorrhea and/or those who have difficulty participating in normal activities, are missing school, or avoiding extracurricular activities because of pelvic pain. (See 'Trial of medical therapy for dysmenorrhea' above.)
•When the pain evaluation suggests a nonacute gynecologic source, we suggest medical treatment of dysmenorrhea/endometriosis rather than laparoscopy for diagnosis and therapy (Grade 2C). (See 'NSAIDs and hormonal therapy' above.)
•We suggest nonsteroidal anti-inflammatory agents and cyclic hormonal therapy for first-line therapy (Grade 2C). A three-month trial is a reasonable approach. (See 'NSAIDs and hormonal therapy' above.)
●Role of laparoscopy – 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.)
●Postoperative medical treatment
•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 (GnRH) agonists (with add-back therapy) are a second-line approach. (See 'Postoperative medical treatment' above.)
•For adolescents >16 years of age, we suggest either continuous combined hormonal contraception, progestin-only therapy, or GnRH agonists with add-back therapy as first-line therapy (Grade 2C). (See "Endometriosis: Treatment of pelvic pain" 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 the patient 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.)
●Management of recurrent pain
•Prolonged GnRH agonist treatment – We have treated patients with surgically diagnosed disease refractory to other medications with prolonged GnRH agonist treatment plus add-back for over 14 years. (See 'Management of recurrent pain' above.)
•Monitor bone mineral density – 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 a GnRH agonist with add-back therapy, a bone density test should be obtained every two years. (See 'Management of recurrent pain' above.)
•Role of repeat surgery – 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. The majority of our patients have a single surgical procedure, but a repeat laparoscopic procedure can be considered for therapy in this clinical situation. (See 'Management of recurrent pain' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc R Laufer, MD, who contributed to earlier versions of this topic review.
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