Diagnosing and treating adolescent endometriosis

By Anthony M. Propst, MD, and Marc R. Laufer, MD

Not at all rare in teens, endometriosis is sometimes severe even in early adolescence. Accurate and early diagnosis is important so you can start treatment before this disease affects reproductive potential. Family history is one red flag.

Endometriosis in adolescents has been underappreciated. It is, in fact, a common cause of pelvic pain and dysmenorrhea in that age group, affecting as many as 45% to 70% of adolescents with chronic pelvic pain.^1,2 Endometriosis—or the presence of endometrial glands and stroma in aberrant locations outside the normal endometrial cavity—is a major cause of pelvic pain and infertility in women of reproductive age. This review, however, focuses on outlining our current experience with diagnosing and treating the disease in adolescents—a group in which it is often overlooked, yet may be just as widespread.

More common than thought?

Found in all ethnic and social groups, endometriosis predominantly affects patients of reproductive age but occurs in women ranging from 10.5 years to 76 years.^3,4 The frequency of a disease can be expressed as the number of new cases diagnosed per unit of time (incidence) or the number of known cases at any given time (prevalence).⁵ Because endometriosis is a surgically diagnosed disease, estimated prevalence rates vary widely based on the groups of women studied. In a large, uncontrolled clinical series, Wheeler reported endometriosis prevalence rates in women undergoing gynecologic surgery as 2% for laparoscopic tubal ligation, 11% for abdominal hysterectomy, and 31% for operative laparoscopy.⁵

Accurately determining prevalence among adolescents is also difficult, as endometriosis can be diagnosed only in girls undergoing surgery. In 1998, our institution—Children's Hospital, Boston—reported that of 282 adolescents with chronic pelvic pain who underwent laparoscopy between 1974 and 1983, 45% were diagnosed with endometriosis.¹ More recently, we evaluated adolescent girls with chronic pelvic pain that did not respond to medical therapy with oral contraceptives (OCs) and nonsteroidal anti-inflammatory drugs (NSAIDs).² We diagnosed endometriosis in 70% of this selected population. Incidence of endometriosis in adolescents with chronic pelvic pain increases with age, from 12% in the 11- to 13-year-old group to 54% in the 20- to 21-year-old group.¹

Some women may be genetically predisposed to developing endometriosis. Simpson and colleagues reported that 6.9% of the first-degree female relatives of women with endometriosis also had the disease, compared with 1% of their husbands' first-degree relatives.⁶ The most probable mode of inheritance is polygenic and multifactorial. Strongly suspect a diagnosis of endometriosis in symptomatic adolescents with a family history of endometriosis.

Retrograde menstruation, which occurs in about 75% of women, is more common in those with endometriosis.⁷ An increase in retrograde menstruation by obstruction of the uterine outflow tract is associated with a higher incidence of endometriosis in adolescents and women of reproductive age.⁸ Any anomaly that obstructs the genital outflow tract—such as uterine anomalies, cervical agenesis or stenosis, vaginal septum, and imperforate hymen—can be a contributing factor in the formation of endometriosis.⁹ Even the youngest adolescents with congenital obstructing müllerian malformations and functioning endometrium often have severe endometriosis.¹ Unlike endometriosis unrelated to outflow obstruction, the disease in patients with reproductive-tract anomalies usually resolves after a patent outflow tract is established.⁹

Diagnosing adolescents

Endometriosis is the most common pathologic condition of the pelvis in adolescents with chronic pelvic pain. Other common diagnoses in those undergoing laparoscopy are pelvic adhesions, ovarian and paratubal cysts, and uterine malformations (Table 1).

TABLE 1
Laparoscopic findings in adolescents with chronic pelvic pain unresponsive to OCs and NSAIDs

Laparoscopic
findings

Adhesions

   Prior surgery

      With endometriosis

      Without endometriosis

   No prior surgery

      With endometriosis

      Without endometriosis

11/46 (23.9%)

8

3

5

3

3

0

Müllerian anomalies

      With endometriosis

      Without endometriosis

3/46 (6.5%)

1

2

A history of chronic pelvic pain in an adolescent with endometriosis usually reveals cyclic or acyclic pelvic pain. In one study at our institution, 64% of adolescents with endometriosis had cyclic pain and 36% had acyclic pain.³ Recently we reported that 90% of affected teens have some degree of acyclic pain.² Some patients experience an increase in symptoms at midcycle and again with menses. Unlike functional dysmenorrhea, endometriosis-associated pain tends to increase in severity over time and may occur throughout the month. Although NSAIDs and OCs may give some initial relief, the pain usually persists, leading to laparoscopy for diagnosis and treatment. Figure 1 outlines our protocol for the evaluation and treatment of adolescent chronic pelvic pain.

Equally incapacitating. Endometriosis-associated pelvic pain may incapacitate patients with minimal as well as extensive disease. Fedele and colleagues found no relation between the stage of endometriosis and site of lesions and the severity of pain.¹⁰ Cornillie and colleagues reported that deeply infiltrating endometriotic lesions were more common in patients with pelvic pain whereas superficial implants were found more frequently in infertile women.¹¹

Different from adults. Unlike most adults with endometriosis, adolescents usually present with pelvic pain that is cyclic and noncyclic (Table 2), vs. older women's predominantly cyclic pain.² Endometriomas are rare in this age group. The physical exam may show cul-de-sac tenderness or cul-de-sac nodularity.¹² It may be difficult to physically examine an adolescent, especially one who is not sexually active. Perform either a vaginal- or rectal-abdominal exam in an adolescent with abdominal or pelvic pain.

TABLE 2
Characteristics of subjects with and without endometriosis

Age (years)

<14 7

15­17

>18

(21.8%)

20 (62.5%)

5 (15.6%)

1 (7.2%)

10 (71.4%)

3 (21.4%)

Mean time (months) at menarche

Duration of OCs (months)

<3 17

4­11

>12

(53.1%)

9 (28.1%)

5 (35.7%)

6 (42.9%)

3 (21.4%)

Presenting symptoms

    Acyclic and cyclic pain

    Acyclic pain

    Cyclic pain

    Gastrointestinal pain

    Urinary symptoms

    Irregular menses

    Vaginal discharge

20 (62.5%)

9 (28.1%)

3 (9.4%)

11 (34.3%)

4 (12.5%)

3 (9.4%)

2 (6.3%)

8 (57.1%)

3 (21.4%)

3 (21.4%)

6 (42.9%)

4 (33.3%)

6 (42.9%)*

2 (14.3%)

*P <0.05

Adapted from Laufer MR, et al.²

The definitive diagnosis of endometriosis must be established by laparoscopy, with or without pathologic identification of biopsy specimens. Endometriosis is staged using the revised criteria of the American Society for Reproductive Medicine (ASRM) point-based classification system.¹³

An adolescent's atypical endometriotic lesions may naturally progress to the classic lesions seen in adults. Disease stage may change as well, suggesting that endometriosis probably progresses with age.

Treatment options

Accurate and early diagnosis is important to relieve symptoms and to suppress natural disease progression that could affect your patient's reproductive potential. Once the diagnosis is made, however, the optimal therapy is still debatable. Make sure that your patients and their parents understand the pros and cons of each surgical and medical option and are aware that endometriosis commonly recurs. Treatment most often includes hormonal suppression or surgery.

Surgical therapy first

In our practice, treatment of persistent dysmenorrhea in adolescents unresponsive to NSAIDs and OCs begins with laparoscopic diagnosis, surgical resection, and destruction of all visible lesions of endometriosis. Surgical therapy involves many different techniques to maximally remove or destroy visible endometriotic lesions. These include excision of lesions, laser vaporization, endocoagulation, and unipolar or bipolar electrocoagulation. Whatever surgical approach is chosen, the surgeon's goal should be to remove or destroy all visible endometriotic lesions and adhesions and to restore the patient's normal pelvic anatomy.

Surgical treatment of endometriosis has a high success rate in reducing pain symptoms. Studies evaluating endometriosis-associated pain in adults show improvement rates between 70% and 100% immediately after surgery and 82% one year later.¹⁴ Long-term follow-up five years after laparoscopic surgery showed pelvic pain reduced by 66%.¹⁴ Reportedly, endometriosis implants reappear in 28% of patients within 18 months and 40% within nine years of surgical treatment.¹⁵ Moreover, lysed adhesions re-form in 40% to 50% of patients.¹⁶

Medical treatment

Medical therapy is initiated after optimal surgical resection or destruction of endometriosis. Medical therapy usually involves OCs, the progestins, danazol, and—most frequently—gonadotropin-releasing hormone (GnRH) agonists. It can achieve two goals: pain control and hormonal suppression of the disease to minimize progression. In selecting medical therapy, the physician must consider the patient's age, severity and duration of symptoms, and extent of disease.

Endometrium and endometriotic implants contain estrogen, progesterone, and androgen receptors. Estrogens stimulate the growth of endometriotic tissue, whereas androgens cause endometriotic tissue to atrophy. High doses of synthetic progestins produce an anti-estrogenic effect that inhibits endometriotic implant growth.¹⁷ Medical therapy for endometriosis works by taking advantage of the endometrial tissue's reliance on steroid hormones for growth and function and suppressing these properties. As such, hormonal alteration is used to create states of chronic anovulation, pseudopregnancy, or pseudomenopause.¹⁸

Oral contraceptives. OCs for ovarian suppression have long been the mainstay of endometriosis treatment. In 1958, Kistner reported the use of continuous OCs to create a "pseudopregnancy."¹⁹ This term describes the amenorrhea and decidualization of endometrial tissue that is induced by continuous combined estrogen and progestin. This regimen relieves associated pain more than 80% of the time, researchers find, albeit sometimes transiently.²⁰ Patients and parents should be aware that bleeding may be irregular for up to three months before amenorrhea is induced. We recommend a progestin-dominant OC, such as norgestrel, norethindrone, and ethynodiol diacetate. Triphasic OCs are not usually effective. If breakthrough bleeding occurs, double the pill dose or add estrogen or progestin. Besides irregular bleeding, the principal side effects of continuous OCs are headaches, fluid retention, nausea, weight gain, emotional lability, and hypertension.

Progestins. Effectiveness of progestin-only regimens varies. Typical regimens include medroxyprogesterone acetate, 30 mg to 50 mg orally per day, or 150 mg IM every one to three months.²¹ High doses of progestins are required for pain relief and the side effects are not well tolerated. Because of the high rate of side effects—such as weight gain, bloating, acne, headaches, fluid retention, emotional lability, and irregular bleeding—we do not recommend a progestin-only regimen as first-line medical therapy.

Danazol. A derivative of 17a-ethinyl testosterone, danazol is effective in treating endometriosis-associated pain.^22,23 Usually given in divided doses of 800 mg per day, it induces a hyperandrogenic-hypoestrogenic state by interrupting ovarian follicular development and inhibiting the growth and function of endometriotic lesions. Danazol therapy has been shown to improve endometriosis-associated pain in 85% to 100% of patients, although for a quarter of patients, symptoms recur within a year of discontinuing this drug. Despite its efficacy, we do not prescribe danazol for adolescents because of its unacceptable side effects, such as weight gain, acne, oily skin, irregular bleeding, hirsutism, and voice deepening. Side effects such as hirsutism and voice deepening are not completely reversible after treatment is stopped.

GnRH agonists. Currently, the first-line and most widely used medical therapy for endometriosis is gonadotropin-releasing hormone agonists, which create a "pseudomenopausal" state by downregulating gonadotropin release from the pituitary gland and establishing a hypoestrogenic environment.²³ This acyclic, low-estrogen environment suppresses growth and bleeding in the endometriotic implants and prevents additional pelvic seeding from retrograde menstruation. GnRH agonists are available in nasal spray, subcutaneous injection, and IM injection. As adolescent compliance is a major issue, the physician should discuss it with the patient before selecting a GnRH agonist. The nasal spray nafarelin is given as one puff twice daily in alternating nostrils. Depot-leuprolide 3.75 mg is given as an IM injection every four weeks and will induce amenorrhea and hypoestrogenism in more than 90% of women.¹⁷ Depot-leuprolide is also available in an 11.25-mg dosage given every three months. A large comparative study of depot leuprolide vs. danazol reported that both regimens significantly improved the revised ASRM endometriosis scores and endometriosis-related pain.^24,25

Side effects of GnRH-agonist therapy include hypoestrogenic symptoms such as hot flashes, vaginal dryness, headaches, and decreased libido.²⁵ Its most worrying long-term side effect is decreased bone mineral density (BMD).²⁵ Reviewing impact on bone mass, Dawood reported a mean loss of 5.9% to 13.8% of the pretreatment vertebral-body bone mass after six months of treatment with various GnRH agonists.²⁶ Recovery of bone loss is slow, with a significant deficit even six months after GnRH- agonist cessation. Bone loss may not be completely recovered even at one year posttreatment.²⁶ On the other hand, cyclical OCs do not cause bone loss and may enhance spinal bone mass with prolonged use.²⁶

The use of GnRH agonists may have long-term effects on the acquisition of normal BMD in adolescents. Most of the increase in bone size and density occurs during puberty.²⁷ Matkovic and colleagues correlated BMD with Tanner stage in 83 girls between ages 8 and 17 and found that 37% of the total skeletal mass was accumulated between Tanner stages II (mean age, 11 years) and V (mean age, 15 years).²⁸ In addition, the Food and Drug Administration has not approved GnRH agonists for treatment beyond six consecutive months. Even though "add-back" therapy with estrogen and progestins partially averts GnRH agonists' deleterious effects on BMD, it has not been specifically studied in adolescents.²⁷

Our current practice is to offer all adolescents with endometriosis who are over 16 years of age and have completed pubertal maturation a six-month course of Gn-RH-agonist therapy following surgical diagnosis and resection/destruction of endometriotic lesions.¹ After this initial medical therapy concludes, we prescribe continuous OCs. Patients who do well with this therapy can remain on continuous OCs or switch to cyclic pills until they desire fertility. Those who have pain during menses while on cyclic OCs can return to continuous ones. Continuous OCs are our first-line medical therapy for adolescents younger than 16 years, to avoid possible adverse effects of GnRH agonists on bone formation. If these therapies fail, we offer our patients additional surgery followed by medical therapy.

Conclusion

Although often overlooked, endometriosis is a common cause of chronic pelvic pain in adolescents. Adolescents with chronic pelvic pain unresponsive to NSAIDS and OCs should undergo laparoscopy to diagnose and treat endometriosis, if present. Initial surgical management consists of resecting or destroying all visible lesions. Subsequent management of hormonal suppression uses OCs in a continuous or cyclical manner for the younger teenager and GnRH agonists for the older adolescent patient.

REFERENCES

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6. Simpson JL, Elias S, Malinak LR: Heritable aspects of endometriosis: I. Genetic studies. Am J Obstet Gynecol 1980;137:327

7. Liu DT, Hitchcock A: Endometriosis: Its association with retrograde menstruation, dysmenorrhea, and tubal pathology. Br J Obstet Gynaecol 1986;93:859

8. Olive DL, Henderson DY: Endometriosis and müllerian anomalies. Obstet Gynecol 1987;69:412

9. Sanfilippo JS: Endometriosis in adolescents, in Wilson EA (ed): Endometriosis. New York, AR Liss; 1987, pp 161-172

10. Fedele L, Parazzini F, Bianchi S, et al: Stage and localization of pelvic endometriosis and pain. Fertil Steril 1990;53:155

11. Cornillie FJ, Oosterlynck D, Lauweryns JM, et al: Deeply infiltrating pelvic endometriosis: Histology and clinical significance. Fertil Steril 1990;53:978

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13. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997;67:817

14. Redwine DB: Treatment of endometriosis-associated pain. Infertil Reprod Med Clin North Am 1993;3:697

15. Olive DL: Conservative surgery, in Schenken RS (ed): Endometriosis: Contemporary Concept in Clinical Management. Philadelphia, PA, Lippincott, 1989, pp 213-247

16. Vancaillie T, Schenken RS: Endoscopic surgery, in Schenken RS (ed): Endometriosis: Contemporary Concepts in Clinical Management. Philadelphia, PA, Lippincott, 1989, pp 249-266

17. Barbieri RL: Treatment of endometriosis with the GnRH-agonists, in Barbieri RL, Friedman AJ (eds): Gonadotropin Releasing Hormone Analogs: Applications in Gynecology. New York, Elsevier, 1991, pp 63-76

18. Olive DL, Schwartz LB: Endometriosis. N Engl J Med 1993;328:1759

19. Kistner RW: The treatment of endometriosis by inducing pseudopregnancy with ovarian hormones: A report of 58 cases. Fertil Steril 1959;10:539

20. Luciano AA, Pitkin RM: Endometriosis: approaches to diagnosis and treatment. Surg Ann 1984;16:297

21. Vercellini P, De Giorgio, Oldani S, et al: Depot medroxyprogesterone acetate vs. an oral contraceptive combined with very low-dose danazol for long-term treatment of pelvic pain associated with endometriosis. Am J Obstet Gynecol 1996;175:396

22. Barbieri RL, Hornstein MD: Medical therapy for endometriosis, in Wilson EA (ed): Endometriosis. New York, AR Liss, 1987,pp 111-140

23. Barbieri RL: New therapy for endometriosis. N Engl J Med 1988;318:512

24. Wheeler JM, Knittle JD, Miller JD: Depot leuprolide acetate vs. danazol in the treatment of women with symptomatic endometriosis: I. Efficacy results. Am J Obstet Gynecol 1992;167:1367

25. Wheeler JM, Knittle JD, Miller JD: Depot leuprolide acetate vs. danazol in the treatment of women with symptomatic endometriosis: A multicenter double-blind randomized clinical trial: II. Assessment of safety. The Lupron Endometriosis Study Group. Am J Obstet Gynecol 1993;169:26

26. Dawood MY: Impact of medical treatment of endometriosis on bone mass. Am J Obstet Gynecol 1993;168:674

27. Lubianca JN, Gordon CM, Laufer MR: "Add-back" therapy for endometriosis in adolescents. J Reprod Med 1998;43:164

28. Matkovic V, Jelic T, Wardlaw GM, et al: Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis: Inference from a cross-sectional model. J Clin Invest 1994;93:799

DR. PROPST is a Clinical Fellow in Reproductive Endocrinology and Infertility, Brigham and Women's Hospital, and a Clinical Fellow in Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston. He is also a Major in the United States Air Force.

DR. LAUFER is Chief of Gynecology, Children's Hospital; Associate Obstetrician/Gynecologist, Brigham and Women's Hospital; and Assistant Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston.

 

Mark Laufer, Anthony Propst. Diagnosing and treating adolescent endometriosis. Contemporary Pediatrics 2000;9:71.