Management
Endometriosis is a chronic disease. As in primary dysmenorrhea, first-line treatment includes analgesia and hormonal therapy. Endometriosis is an estrogen-dependent disease; most therapies are aimed at supressing ovarian function (20). Most hormonal options are equivalent at reducing pelvic pain; factors such as cost and contraception should be considered in decision-making (20,22,39). CHC or progestin-only options can be offered with anticipated improvement in two thirds of women (24,39). The adolescent should keep a pain journal that logs pain, response to treatment, and other symptoms (19).
Non-steroidal anti-inflammatories: NSAIDS can be used prior to expected onset of menses. In endometriosis, there is no clear evidence of a benefit for relief of symptoms compared to placebo (49).
CHC: CHC are an ideal first choice due to documented safety, efficacy, low side effect profile and low cost (39). Adolescents with suspected or confirmed endometriosis should be counselled on menstrual suppression to prevent further endometrial proliferation (19,21,22,50). Endometrioma formation and recurrence are reduced through CHC-associated anovulation (50,51). No COC preparation has demonstrated superiority (50). Adolescents who experience ongoing dysmenorrhea with cyclic use can be transitioned to extended cycle. An randomized controlled trial (RCT) demonstrated reduced post-operative dysmenorrhea recurrence in cyclic versus non-cyclic users (52). Another RCT demonstrated improvement in pain scores for both cyclic and extended use, however discontinuation rates were higher in the continuous use group due to unspecified side-effects (53).
Progestins: These include oral, intramuscular and LNG-IUS. Progestins demonstrate 80-100% improvement in symptoms due to anti-angiogenic, immunomodulatory and anti-inflammatory effects (22). Side effects include unscheduled bleeding, bloating, breast tenderness, weight gain, and mood changes (24,54). Depot medroxyprogesterone acetate (DMPA) and LNG-IUS are more effective at achieving menstrual suppression compared to oral regimens (28).
Oral progestins can be used to achieve menstrual suppression (Table 3) (28). Medication should be started at lowest dose and increased until menstrual suppression is achieved. Dosage adjustment and compliance is required (28). Progestin-related side effects may be more common in oral regimens (28,54). Norethindrone acetate (NETA) has demonstrated effectiveness for menstrual suppression in adolescents (55). In a Cochrane review, medroxyprogesterone was superior to danazol and equivalent to gonadotropin releasing agonists (GnRHa) at 12 months (54). Dieonogest has selective 19-nortestosterone and progesterone activity (9,56). In the adult population, it has been shown to be equivalent to GnRHa in reduction of dysmenorrhea, dyspareunia, physical symptoms and signs of endometriosis and improvement in daily activities (57). Adolescents requiring contraception should be prescribed oral progestins that are indicated for contraception.
Table 3
Dosage regimens for progestin only options are seen in Table 3.
Table 3
LNG is a 19-nortestosterone progestin with anti-estrogen effects on the endometrial lining, thereby inducing endometrial decidualization with resulting endometrial atrophy (58). Ovulation may not always be suppressed. When comparing LNG-IUS and GnRHa (leuprolide acetate), both demonstrate improvement in pain (20,58). Reduced recurrence of pain post-surgery is seen with LNG-IUS (19,58). It is safe to use in adolescent and nulliparous women with 96% success at insertion (30). Higher-dose LNG-IUS is associated with more effective menstrual suppression (28). Adolescents should be counselled on pain with insertion, and cramping/unscheduled bleeding that improves by three months (30).
DMPA can be used safely in adolescents. Users experience improvement in endometriosis and CPP symptoms (56). DMPA suppresses ovulation and leads to amenorrhea by inducing endometrial atrophy. Amenorrhea rates are 55% at one year, and 68% at two years (11). Unscheduled bleeding and weight gain are the most common reasons for discontinuation (59). Use beyond two years is associated with reversible decrease in bone mineral density (BMD) (8,59). At two years post-discontinuation, the BMD was similar to non-users. Further, there is no evidence to support increased risk of fractures and/or osteoporosis (59). Well-counselled adolescents may choose the benefit of symptom control over risk (60). Women using DMPA should be recommended calcium and vitamin D supplementation.
Etonogestrel, an active metabolite of desogestrel, is available as a subdermal implant. Its primary mechanism is anovulation. Improved dysmenorrhea has been reported (59). It is safe for use in adolescents. However, discontinuation may occur due to increase in unscheduled bleeding (30). Counselling young women on common side effects prior to insertion may improve retention rates.
Anti-progestogens: Gestrinone, an anti-progestogen, inhibits production and use of progesterone (54). When compared to GnRHa, gestrinone was not as effective at six months, but more effective at 12 months (54). Small studies indicate improvement in pain. Side effects include unscheduled bleeding, acne, weight gain, and fluid retention (54).
GnRHa: GnRHa improve endometriosis-related pain by inducing a hypogonadic-state via suppression of the hypothalamic-pituitary-ovarian axis (61). Approximately 90% of users are amenorrheic (43). GnRHa may also improve pain by reducing inflammation, angiogenesis, and inducing apoptosis in endometrial cells (61). In adults, pain can be reduced by 80%, similar to DMPA and LNG-IUD (61). Side effects include hot flushes, vaginal dryness, sleep disturbance, headaches, mood changes and bone loss (21,61). Studies in the adult population suggest addition of letrozole or tamoxifen may reduce these symptoms. GnRHa use in adolescents should be considered second line, after inadequate response to hormonal treatment. For empiric treatment of pelvic pain, initiation of GnRHa should be delayed to 18 years (9). With surgically confirmed endometriosis, the initiation of GnRHa should be delayed until 16 yrs to ensure the majority of bone accrual has occurred (7,9). Intramuscular, intranasal and subcutaneous forms are available, with equivalent treatment outcomes (20). A “GnRHa flare” can occur due to an initial surge of LH and FSH, resulting in increased pain and unscheduled bleeding. To prevent flare, the initial dose should be timed with the late luteal phase (61). Flare symptoms can also be avoided by allowing three-weeks crossover when transitioning from CHC to GnRHa.
Spine BMD can be reduced by 5-8% after 3-6 months of GnRHa use; BMD may not return to baseline once treatment is complete (61,62,63). Based on the threshold theory, “add-back treatment” allows for low estrogen levels to protect bone and reduce vasomotor symptoms without activating endometriotic tissue (20). An RCT demonstrated stability in BMD at 12 months of add-back (64). Adolescence is a time of bone accrual and add-back treatment should be initiated simultaneously with GnRHa (20). This differs from the adult population, whereby add-back treatment is offered after six months. Add-back treatment does not reduce effectiveness (20,24,62). Options include conjugated equine estrogen 0.625 mg with NETA 5 mg, or NETA 5 mg alone (38,61). NETA is converted to ethinyl estradiol and was approved by the Food and Drug Administration for add-back treatment in adults (35,64). Both options have demonstrated improvement in adolescent quality of life, including improved pain, physical symptoms, and social functioning (38).
There is limited research on prolonged use of GnRHa in the adolescent population, and no current guidelines for BMD monitoring (57). Baseline BMD is not required unless there are additional risk factors for osteoporosis (61). Expert opinion suggests that for young women without additional risk factors, a dual-energy X-ray absorptiometry of hip and lumbar spine should be completed after nine months of treatment (7,8,61). BMD should be monitored every two years with ongoing treatment (8). Adolescents should be counselled on calcium and vitamin D supplementation.
Androgens: Androgens, such as Danazol, have been previously described to improve dysmenorrhea, but are often avoided due to androgen-related side effects including acne, hirsutism, weight gain, edema, muscle cramping, and worsening lipid profile (20,21,39). Danazol induces endometrial atrophy and has immunosuppressive effects (60). The European Society of Human Reproduction and Endocrinology (ESHRE) advises against the use of Danazol for treatment of endometriosis in adult women (20).
Anti-androgens: Cyproterone acetate (CPA) has anti-androgenic and anti-gonadotropic effects. It is available with estrogen in a CHC. CPA has been compared to COC, and both demonstrate improvement in pain at six months (50,56). As CPA can be associated with liver toxicity; liver function should be monitored (54). This may be an option for young women with contraindications to estrogen. Contraception is recommended in sexually active patients due to teratogenicity.
Aromatase inhibitors (AI): Over expression of aromatase has been identified in endometriotic implants (39). AI has been studied as part of combination treatment (with a progestin, CHC, or Danazol) to induce ovarian suppression (21,22). Side effects include vaginal dryness, hot flushes, and decreased BMD (20). Long term studies are needed. ESHRE suggests that AI should only be considered after hormonal treatment failure (20).
Surgery: Surgery should be considered after treatment failure extending to 3-6 months. For an adolescent, missing school/activities beyond this time can be particularly detrimental (43).
As the appearance of endometriotic lesions differs significantly in adolescents compared to adults, the operating gynaecologist should be familiar with diagnosis and treatment of endometriosis in this population (7,24,43). There is currently no evidence in adolescents suggesting that surgical treatment halts disease progression or prevents infertility (8). The American College of Obstetricians and Gynecologists recommends consideration of LNG-IUS placement at the time of laparoscopy for any patient with dysmenorrhea, chronic pain, or both (23).
Post-operative considerations: Patients should be counseled to continue hormonal treatment, as menstrual suppression reduces dysmenorrhea and endometrioma recurrence (7,20). There is no benefit to short post-operative courses of hormone treatment on pain, recurrence and fertility, thus ongoing medical treatment post-surgery is recommended unless fertility is imminently desired (19,24,50). An RCT in adults demonstrated a cure rate of 50% with surgery and 60% with combination of surgery and GnRH treatment, with reduced recurrence in combined treatment (65). Combination treatment demonstrated stability of endometriosis in 70% of adolescents after a mean interval of 29 months (1). A Cochrane Review demonstrated improved dysmenorrhea with post-operative medical treatment, however there was no effect on preventing pain recurrence when compared with surgery alone (66). Another review recommended post-operative long-term treatment with an emphasis on extended cycle, rather than cyclic use, of CHC to prevent recurrent retrograde menstruation and ovulation (50). Adolescents should be counselled on the possibility of recurrence as 30-50% of young women require repeat surgery within five years (19). Repeat surgery should be reserved for adolescents with pain more than two years post initial surgery despite ongoing medical treatment (7).
Complementary medicine: Women should be encouraged to disclose the use of complementary medicine to ensure there are no interactions with concurrent medications. Most of the adult studies described involve small sample sizes (67). Studies have examined Vitamins B1, E, and D, Omega 3 fatty acids, magnesium and ginger with modest or no effect (11,67). A recent Cochrane review demonstrated limited effectiveness for fenugreek, fish oil, fish oil plus vitamin B1, ginger, valerian, Vitamin B1, sataria, and zinc sulfate (31). A small RCT demonstrated improvement in sleep quality, daily pain, dysmenorrhea, dyspareunia, dyschezia and dysuria with the use of melatonin (68). A Cochrane review demonstrated improvement in dysmenorrhea, reduction in associated symptoms and reduced use of additional medications with the use of traditional Chinese medicine compared to placebo (27). A small randomized-controlled sham study of Japanese acupuncture in adolescents demonstrated initial improvement in pelvic pain at four weeks, although this difference waned at six months (69). Some patients with chronic pain may find an anti-inflammatory diet improves their daily pain, provided adequate nutrient intake is achieved.
Support: Adolescents with endometriosis experience significant effects on school, work and relationships (20). Young women with chronic pain should be screened for mental health illness and offered support (38). Collaborative care encompassing pain management, behavior modification, menstrual suppression and emotional support should be encouraged (9,38). More research is needed on psychological treatment for adolescents with CPP.