Medication Summary
NSAIDs
Dysmenorrhea is strongly associated with high levels of prostaglandins, which can cause severe cramping abdominal pain. Traditional NSAIDs reversibly inhibit COX-1 and COX-2 enzymes, which are necessary for the conversion of arachadonic acid into prostaglandins. NSAIDs are an effective treatment for all causes of dysmenorrhea. [55] NSAIDs are nonselective COX inhibitors; meaning they inhibit both COX-1 and COX-2 enzymes. There is little evidence that selective COX-2 specific inhibitors, such as celecoxib or etoricoxib, show any improved efficacy over NSAIDs in treatment of dysmenorrhea. [55]
Oral contraceptive pills and high dose progestins
Combined oral contraceptive pills, progestin-only oral contraceptive pills, and high-dose progestins, such as Depo-Provera, function by suppressing ovulation through negative feedback to the hypothalamic-pituitary-ovary axis. Suppression of ovarian steroid secretion results in decreased hormonal stimulation of eutopic and ectopic endometrium. Continuous progestins or OCPs can induce regression of adenomyosis; however, longer trials are necessary to understand long-term effects. [40, 56]
Progesterone IUD
Levonorgestrel intrauterine devices (LNG-IUD) were originally approved for contraception but have shown a clear advantage for women with abnormal uterine bleeding. They function by inducing atrophy of endometrial glands and decidualization of the endometrial stroma, [57, 58] resulting in decreased menstrual flow. Additionally, LNG-IUDs are thought to cause downregulation of estrogen receptors diffusely, causing reduction in the size of adenomyotic foci, which then allows more efficient contraction of myometrial tissue and decreased prostaglandin production. [40, 58, 59] Some objective studies have noted significant reduction in the junctional zone when followed by MRI, [60] and one study which obtained myometrial tissue samples noted decreased presence of aberrant lymphangiogenesis in patients with a LNG-IUD. [61] The LNG-IUD has been reported to cause significant reduction in uterine volume, blood loss, and dysmenorrhea. [57, 60, 62, 63, 64, 40, 65, 66]
GnRH agonists
GnRH is a hormone secreted by the hypothalamus into the hypothalamic-pituitary portal system. It then acts through the hypothalamic-pituitary-ovarian axis to induce ovarian function and, subsequently, endometrial response to estrogen and progesterone. Continuous treatment with GnRH agonists causes suppression of gonadotropin secretion, leading to ovarian suppression and a hypoestrogenic state. Additionally, GnRH agonists have been found to significantly reduce inflammatory reaction and angiogenesis in adenomyotic tissues, suggesting it may be effective in inducing regression of adenomyosis. [67] Studies evaluating buserelin acetate and goserelin show significant reduction in uterine and adenomyoma volume, with improvement in chronic pelvic pain. However, improvement in dysmenorrhea and menorrhagia is limited due to vasomotor side effects and decrease in bone mineral density necessitating cessation of the drug. [68, 69, 70, 57] GnRH agonists are considered second-line therapy for adenomyosis due to their significant adverse effects; namely, postmenopausal state and bone loss. [40, 66]
Danazol
A derivative of 17 alpha-etynyl testosterone, danazol suppresses pituitary gonadotropin secretion with subsequent inhibition of ovarian steroids. [56, 40] Systemic treatment has been found to decrease the concentration of estrogen receptors in the uterus, and this is thought to reduce uterine size. However, significant side effects have precluded long-term systemic therapy. [40]
Danazol has also been administered via intracervical injections and intrauterine devices. These methods allow localized delivery of Danazol and circumvent the systemic side effects. One study examined the effect of intracervical danazol injection, noting significant improvement in subjective symptoms (bleeding, pain and dyspareunia) and decrease in uterine size by the 24th week of treatment. [71, 40, 56] In another study, 14 women with adenomyosis noted on either ultrasound or MRI had a danazol-loaded IUD placed and serum danazol levels monitored biweekly. [72] Serum danazol levels remained below the limit of detection and no systemic side effects were observed. Nine of 14 patients showed complete remission of menorrhagia and reduction in thickness of the myometrium. Other studies of danazol-loaded IUDs have had similar results, with the majority of patients finding complete remission of their symptoms of dysmenorrhea and menorrhagia, and minimal systemic side effects. [73]
Aromatase inhibitors
The cytochrome aromatase P450 converts androgens to estrogens. It is present in both the eutopic and ectopic endometrium in patients with adenomyosis and endometriosis. [40, 59, 57] Aromatase inhibitors have been used successfully to treat symptoms of severe endometriosis; however, there are very few studies which evaluate aromatase inhibitors as treatment for adenomyosis. When compared to GnRH agonists, aromatase inhibitors have been found to be as effective in reducing adenomyoma volume and improving symptoms [74] and have had an excellent outcome when combined with GnRH agonists. [75]
Nonsteroidal Ant-inflammatory Drugs (NSAIDs)
Class Summary
NSAIDs are most commonly used for the relief of mild to moderate pain. Although the effects of NSAIDs in pain treatment tend to be patient specific, ibuprofen usually is the drug of choice (DOC) for initial therapy. Other options include naproxen, fenoprofen, flurbiprofen, mefenamic acid, ketoprofen, indomethacin, and piroxicam.
Ibuprofen (Advil, Motrin IB, Caldolor, Dyspel, NeoProfen, Provil)
This agent inhibits inflammatory reactions and pain, probably by decreasing the activity of the enzyme cyclooxygenase (COX), in this way inhibiting prostaglandin synthesis. Ibuprofen is usually the DOC for the treatment of mild to moderate pain if no contraindications exist.
Naproxen (Aleve, Anaprox, Anaprox DS)
Naproxen is used for the relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of the enzyme COX.
Ketoprofen
Ketoprofen inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, thereby decreasing prostaglandin synthesis. Smaller initial dosages are particularly indicated in the elderly and in those with renal or liver dysfunction. Doses higher than 75 mg do not improve therapeutic response and may be associated with a higher incidence of adverse effects.
Meclofenamate
Mefenamic acid inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, thereby decreasing prostaglandin synthesis. Compared with other NSAIDs, it is associated with a higher incidence of diarrhea.
Mefenamic acid (Ponstel)
Mefenamic acid inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, thereby decreasing prostaglandin synthesis. Compared with other NSAIDs, it is associated with a higher incidence of diarrhea.
Flurbiprofen
Flurbiprofen may inhibit cyclooxygenase, thereby inhibiting prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.
Fenoprofen (Fenortho, Nalfon)
Decreases formation of prostaglandin precursors by inhibiting cyclooxygenase-1 and 2 (cox-1 and 2) enzymes. May also inhibit neutrophil aggregation/activation, chemotaxis, alter lymphocyte activity, and decrease proinflammatory cytokine levels.
Piroxicam (Feldene)
For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of COX, which is responsible for prostaglandin synthesis.
Progestins
Class Summary
All progestational agents act by decidualization and atrophy of the endometrium. Use of this category of drugs relies on high-dose hormones to suppress the hypothalamus through negative feedback. This results in a hypoestrogenic state. Evidence for direct inhibition of endometrial implants by progestins also exists. These medications provide pain relief equivalent to the gonadotropin-releasing hormone (GnRH) analogues and seem to have a slightly lower recurrence rate.
Norethindrone acetate (Aygestin, Camila, Lyza, Errin, Heather, Norlyroc, Norlyda)
Norethindrone is a common progestin used in many of the oral (PO) contraceptive pills currently available; the dose administered for endometriosis is significantly higher.
Medroxyprogesterone (Provera, Depo-SubQ Provera 104, DepoProvera)
Medroxyprogesterone inhibits secretion of gonadotropins, thereby inhibiting ovulation and decreasing the thickness of the endometrium.
Levonorgestrel intrauterine (Kyleena, Liletta, Mirena, Skyla)
The levonorgestrel-releasing intrauterine device inhibits secretion of gonadotropins, thereby inhibiting ovulation and decreasing the thickness of the endometrium.
Contraceptives, Oral
Class Summary
In some patients, oral contraceptives (OCs) can prevent dysmenorrhea altogether, though these agents are not approved by the FDA for this indication. Use of OCs in a manner that reduces the number of menstrual cycles may be beneficial for some patients. Combination OCs provide effective pain relief and are associated with a reduced menstrual flow.
Norgestrel/ethinyl estradiol (Cryselle 28, Elinest, Low-Ogestrel, Ogestrel)
This drug combination reduces secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary by decreasing the amount of gonadotropin-releasing hormones.
Levonorgestrel oral/ethinyl estradiol (Levora, Altavera, AmethiaChateal, Delyla, Levora)
This drug combination reduces secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary by decreasing the amount of gonadotropin-releasing hormones.
Norgestimate/ethinyl estradiol (Estarylla, Previfem, Sprintec, TriNessa, Ortho-Cyclen)
This drug combination reduces secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary by decreasing the amount of gonadotropin-releasing hormones.
Etynodiol/ethinyl estradiol (Zovia, Kelnor)
This drug combination reduces secretion of LH and FSH from the pituitary by decreasing the amount of gonadotropin-releasing hormones
Drospirenone/ethinyl estradiol (Ocella, Yaz, Gianvi, Zarah)
Reduces secretion of LH and FSH from the pituitary by decreasing the amount of gonadotropin-releasing hormones.
Androgens
Class Summary
Agents from this class may suppress pituitary secretion of follicle stimulating hormone and luteinizing hormone.
Danazol
Danazol causes atrophy of normal and ectopic endometrial tissue by suppressing pituitary output of luteinizing hormone and follicle stimulating hormone. Pretreatment with danazol or GnRH agonists before resectoscopic endometrial ablation (REA) results in higher amenorrhea rates at 12 months, shorter procedures, greater reported ease of surgery, and lower postoperative dysmenorrhea rates.
GNRH Agonists
Class Summary
These agents stimulate the release of luteinizing hormone and follicle stimulating hormone from the anterior pituitary. In large doses can cause down regulation of receptors in the pituitary gland, which in turn decreases secretion of luteinizing hormone and follicle stimulating hormone. These agents produce more consistent endometrial thinning. Pretreatment with GnRH agonists or danazol before resectoscopic endometrial ablation (REA) results in higher amenorrhea rates at 12 months, shorter procedures, greater reported ease of surgery, and lower postoperative dysmenorrhea rates.
Leuprolide (Eligard, Lupron Depot)
Leuprolide suppresses ovarian and testicular steroidogenesis by decreasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. This agent is available in a daily subcutaneous (SC) dosing regimen and the much more convenient monthly intramuscular (IM) depo formulation.
Goserelin (Zoladex)
Goserelin suppresses ovarian and testicular steroidogenesis by decreasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. This agent is administered monthly as a subcutaneous (SC) implant in the upper abdominal wall; it is otherwise similar to the drugs in this class.
Nafarelin (Synarel)
Nafarelin is an analogue of gonadotropin-releasing hormone (GnRH) that is approximately 200 times more potent than natural endogenous GnRH. Upon long-term administration, this agent suppresses gonadotrope responsiveness to endogenous GnRH, thereby reducing secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn reduces ovarian and testicular steroid production.
Nafarelin is available as a nasal solution (2 mg/mL). Administration of this agent is delivered via a nasal spray, which requires twice daily (bid) dosing; it is otherwise similar to the other drugs in this category.
-
MRI of fundal adenomyoma.
-
Photo of an adenomyoma dissecting through the uterine wall.
-
Ultrasound of an adenomyoma dissecting through the anterior uterine wall separate from the endometrial cavity.
-
Adenomyosis noted within thickened myometrium.
