Adenomyosis

In a normal uterus, the uterine corpus is composed of a muscular myometrial layer, a smooth outer serosal layer, and an inner endometrial layer which lines the uterine cavity.  The endometrium is composed of two layers. The basalis endometria is a thin, deep layer bordering the myometrium, consisting of ample stroma but rare glands. Overlying this is the functional layer, or functionalis endometria, consisting of abundant glands with less stromal tissue. During a woman’s reproductive years, the functionalis endometria responds to cyclic changes in progesterone and estrogen levels with resulting monthly menses.[1]

Adenomyosis is defined as the presence of ectopic nests of endometrial glands and stroma throughout the myometrium, surrounded by reactive hypertrophic smooth muscle cells.[2] The pathophysiology of adenomyosis development remains poorly understood. Adenomyosis may be present either as diffuse, scattered individual glands, or focal collections of glandular tissue.[3] The most widely accepted theory for the origin of adenomyosis is an abnormal invagination of the basalis layer of the endometrium into the adjacent myometrial layer. The endometrial-myometrial interface is composed of the basalis endometria and the subendometrial myometrium, also known as the myometrial junctional zone.[4] There is no intervening layer between myometrium and endometrium. The absence of any discrete transitional layer is thought to permit abnormal invagination of the basalis endometria directly into the myometrium when endometrial invasion is provoked.[4]

Multiple hypotheses exist regarding the causal factors of endometrial invagination. Likely factors may include mechanical disruption of the endometrial-myometrial interface, hormonal imbalance, and impaired immunity.[4, 5]

Mechanical disruption of the endometrial-myometrial interface has long been thought to predispose women to adenomyosis. This hypothesis is supported by the association of adenomyosis with multiparity and any history of uterine trauma, such as uterine curettage and cesarean section.[5] More recently, the theory of dysfunctional uterine contractility has become popular. This proposes that disordered hyperperistalsis of the uterus can cause mechanical auto-trauma to the endometrial-myometrial junction, causing aberrant dislocation of the basalis endometria into the myometrial layer.[6]

Some studies have suggested that elevated levels of estrogen are necessary for development and maintenance of adenomyosis, just as they are required for ectopic endometrial proliferation and proliferation of endometriotic implants.[7, 4, 5] Some studies have noted elevated estradiol levels in the menstrual blood of women with endometriosis and adenomyosis, and other studies have noted elevated levels of aromatase enzymes in the endometrium of adenomyotic tissue, suggesting elevated estradiol levels are necessary to maintain active adenomyosis.[6, 7] Additionally, symptoms of adenomyosis have been strongly linked to the menstrual cycle. Often, patients will report severely increased abdominal pain during menses. As adenomyotic tissue responds to hormonal changes within the myometrium, it may cause reactive inflammation in the surrounding tissue, with resultant severe menstrual cramping and pain.[8] Supporting this hypothesis is the observation that estrogenic suppression with danazol induces involution of ectopic endometrium and causes remission of symptoms such as dysmenorrhea and menorrhagia.[7, 5]

Adenomyosis has been most strongly associated with middle age, multiparous status, and a history of gynecologic surgery.[9, 10]

Adenomyosis is most frequently diagnosed in women in their fourth and fifth decades[8, 11] , likely because of the increased prevalence of risk factors by that age range and the duration of adenomyotic development.

Increased parity is thought to have a significant role in the development of adenomyosis. Pregnancy may mechanically disrupt the myometrial junctional zone by the action of the trophoblast on the myometrium, favoring infiltration of endometrial cells into the myometrium. As pregnancy progresses, mechanical weakening of the myometrium may occur as the uterus becomes distended, with further resultant infiltration of the endometria basalis. Finally, the tremendous hormonal fluctuations which occur throughout pregnancy may facilitate development of adenomyotic foci.[12, 9]

There is much rationale surrounding the notion that gynecologic surgery may precipitate adenomyosis. In theory, any kind of uterine surgery is thought to mechanically traumatize the uterus. This may cause weaknesses within the myometrium, allowing invasion of the adjacent endometrium.[5, 12] Women with a history of multiple curettage procedures have a well-documented increased risk of adenomyosis; however, the risk associated with cesarean section and other uterine procedures is still debated.[13, 14, 9]

Despite advances in imaging studies, definitive diagnosis still relies on a histologic examination of a surgical specimen, typically at the time of hysterectomy. Prevalence of adenomyosis at the time of hysterectomy has been estimated anywhere between 14% and 66%, dependent upon the pathologist’s diagnostic criteria.[10] A mean frequency of 20-30% has been reported[15, 8] and has been extrapolated to suggest the same incidence in the general population[8] . Risk factors include increased parity, spontaneous abortions, uterine surgery, and middle age.

Natural history of adenomyosis is difficult to chart. Typically, patients seek treatment shortly after presentation. Definitive treatment with hysterectomy then precludes any further observation or understanding of symptomatic adenomyosis. However, the presence of adenomyosis has been well documented as an incidental finding in postmenopausal women at time of autopsy, and as an incidental finding at time of hysterectomy.[11] Symptoms of adenomyosis are rarely reported in women older than 60 years, however, presumably due to a postmenopausal hypoestrogenic state.[2]

Some studies suggest that adenomyosis has a negative impact on fertility outcomes; however, limited data exist.[16]  A meta-analysis by Cozzolino et al showed that infertile women with adenomyosis who underwent in vitro fertilization (IVF) had a lower live birth rate, clinical pregnancy rate, and ongoing pregnancy rate than did women without adenomyosis. Additionally, the rate of miscarriage was higher in women who had adenomyosis.[17]  Furthermore, a meta-analysis by Wang et al found that symptomatic and diffuse adenomyosis, but not asymptomatic adenomyosis, was associated with worse IVF outcomes, including live birth and clinical pregnancy rates.[18]

The symptoms of adenomyosis are very common among other gynecologic diseases. During the initial workup, it is important to counsel patients about the diagnostic process, including tests and imaging to rule out malignancy. If adenomyosis is suspected or the diagnosis of adenomyosis is made, discussing the pathophysiology and natural history of the disease should be considered to allow the patient to understand her prognosis and the mechanism of possible treatment.

It is important to obtain a full past medical and past surgical history, including the patient’s gynecologic history, current complaints, medications and previous treatments. Patients with adenomyosis commonly report symptoms similar to those reported by patients with endometriosis. Common complaints include menorrhagia, dysmenorrhea, metrorrhagia, chronic pelvic pain and dyspareunia.[13, 19, 20]  Patients often report a history of multiple pregnancies or uterine surgeries.[12]  Infertility is occasionally reported, but its incidence is inconsistent.[21] However, with more women delaying pregnancy until later in life, infertility may become more frequently associated with adenomyosis.[9, 22, 4, 2]

A full physical examination should be performed. This should include inspection of the perineum, vagina, cervix, and bimanual exam of the uterus and adnexa. The uterine size, shape, mobility and tenderness should be evaluated. A diffusely enlarged, tender, “boggy” uterus is suggestive of adenomyosis. Alternatively, severe endometriosis often presents as a fixed, tender uterus, with palpable nodules within the posterior cul-de-sac and/or lining the uterosacral ligaments and rectovaginal septum.[23, 5]

Although adenomyosis was first characterized in the 1800s,[11]  the diagnostic criteria have differed among pathologists, and prevalence continues to be debated as higher-level imaging modalities have become more common. There is a need for agreed-upon, widespread diagnostic criteria to better understand the incidence and prevalence of adenomyosis.

Currently, adenomyosis remains a largely clinical diagnosis. Definitive diagnosis of adenomyosis requires a histologic examination of uterine tissue.[24] Typically this step is circumvented in women desiring future fertility or who wish to preserve their uterus. Increasing availability and technological advances in imaging such as ultrasound, CT, and MRI scans have improved evaluation for adenomyosis, but it still remains largely under-diagnosed until the time of hysterectomy. It is important both to maintain a high clinical suspicion for adenomyosis throughout the evaluation, as it may shape management options moving forward.

On initial evaluation, laboratory workup should be the same as for any patient who presents for abnormal uterine bleeding. Pregnancy should be ruled out. Patients should be evaluated for anemia, thyroid and/or pituitary dysfunction, bleeding disorders (when indicated), as well as sexually transmitted infections.[25]

Advancement in imaging technology has significantly changed the presumptive diagnosis of adenomyosis. Ultrasound is the most common imaging modality used to evaluate gynecologic symptoms, with a sensitivity between 75% and 88% and a specificity from 67-93%.[22, 26, 27] Unfortunately, accuracy and sensitivity of ultrasound is variable depending on the training of the sonographer. As MRI has become more widely available, it has been reported to be the most reliable diagnostic method for diagnosing adenomyosis, with a reported sensitivity between 70% and 100% and a specificity of 86-93%.[26, 28, 29] However, ultrasonography is often preferred because it is more widely available and significantly more cost-effective for patients.

Ultrasonography

On transvaginal ultrasonography, common features include the following:

• Diffusely enlarged, globular, asymmetric uterus[27]

• Distorted, heterogenous myometrium[27] with increased or decreased areas of echogenicity[26, 30]

• Presence of myometrial cysts: poorly defined areas with abnormal echotexture

• Diffuse or focal thickening of the uterine junctional zone[31]

• Myometrial mass with ill-defined borders[31]

Ultrasound features of adenomyosis have been categorized as direct (ie, those that indicate ectopic endometrial tissue in the myometrium) or indirect (ie, those that reflect changes in the myometrium secondary to endometrial tissue in the myometrium). A European consensus on definitions of these features classified myometrial cysts, hyperechogenic islands, and echogenic subendometrial lines and buds as direct features of adenomyosis, and globular uterus, asymmetric myometrial thickening, fan-shaped shadowing, translesional vascularity, irregular junctional zone, and interrupted junctional zone as indirect features.[32]

MRI

On T2-weighted MRI, the junctional zone is more easily visualized as a low signal intensity zone adjacent to the endometrium. Although exact diagnostic criteria vary, a junctional zone thickness greater than 12mm is generally considered diagnostic for adenomyosis, with a sensitivity of 63% and specificity of 96%, based on studies correlating junctional zone measurement on MRI and histologic confirmation of adenomyosis.[33]  Additionally, heterotopic endometrial tissue appears as small foci of increased high signal intensity within the junctional zone.[26]

Other procedures, such as diagnostic hysteroscopy, myometrial biopsy, and endometrial biopsy, have occasionally been found to be useful in identifying suspected adenomyosis.

Although hysteroscopy cannot definitively prove or exclude the presence of adenomyosis due to its limited visualization, examination and biopsy of the endometrial surface can demonstrate features which would support adenomyosis. These may include the following[34, 35] :

• Irregular endometrium with superficial openings

• Irregular subendometrial myometrium (junctional zone) on histologic exam

• Irregular myometrial architecture on histologic exam

• Intramural endometriomas

Myometrial biopsy has long been considered as a possible means for obtaining a specimen for histologic diagnosis without requiring hysterectomy. Myometrial core needle biopsy can be performed under direct visualization during diagnostic laparoscopy for the evaluation for chronic pelvic pain or infertility.[36, 37] Core needle biopsy obtained under direct visualization from an area that has been evaluated with ultrasound and suspected to have adenomyosis, has a sensitivity of 98% and a specificity of 100%.[37]

Some physicians have performed transvaginal myometrial core needle biopsy under ultrasound guidance, which is less invasive but requires physician training.  Additionally, there is currently no protocol on the number of needle biopsies required. Uterine tissue specimen for histologic analysis may also be obtained via transcervical punch biopsy.[29]

The definitive diagnosis of adenomyosis depends on histologic examination identifying endometrial glands remote from the endomyometrial junction. Traditionally, diagnosis is made when endometrial glands and stroma are found at least 1 low-power field beneath the endomyometrial junction (greater than or equal to 4 mm).[24]  However, looser diagnostic criteria have been proposed and adopted. Some pathologists have accepted a distance of greater than or equal to 2.5 mm between endomyometrial junction and ectopic endometrial glands acceptable for diagnosis. Further, other pathologists have suggested diagnosing adenomyosis only if a certain percentage of myometrium is involved.[24, 5]

On gross examination, adenomyotic uteri typically appear as diffusely enlarged and globular. Adenomyotic foci are surrounded by disordered, hypertrophied smooth muscle cells, sometimes containing hemolyzed blood and hemosiderin pigments.[5] Adenomyotic glands and stroma typically resemble proliferative endometrium, but occasionally may have secretory appearance.[2]

Occasionally, adenomyosis is present as a focal collection of endometrial glands and stroma within the myometrium remote from the endomyometrial junction, and this is termed adenomyoma. Adenomyomas are distinct from leiomyoma because of their poorly defined margins, which subtly merge with surrounding myometrium.  In contrast, leiomyoma have discrete borders that can be easily separated from adjacent myometrium and enucleated at the time of myomectomy.[5]

Adenomyosis can be classified according to degree of endometrial penetration. Some experts suggest numeric grading—grades 1, 2 and 3, respectively—to adenomyotic involvement of the inner third, two thirds and entire myometrium.[38] Other clinicians suggest using the term “mild” to describe when only microscopic foci are present, or when only the inner third of myometrium is involved; severe or diffuse disease is diagnosed when disease extended to the outer two thirds of myometrium or there was involvement of the entire uterus.[39]

A universal grading system should be utilized to avoid over- and under-diagnosis of adenomyosis, and to provide better understanding of prevalence and response to treatment.

Histologic description of adenomyosis should include four parameters[10] :

1. Presence of ectopic endometrial tissue >2.5mm from endomyometrial junction

2. Depth of penetration within the myometrium

   1. One third- mild

   2. Between ⅓ and ⅔- moderate

   3. More than ⅔- severe

3. Degree of spread (number of foci per low-power field)

   1. 1-3 islets - Grade 1

   2. 4-10 islets- Grade 2

   3. >10 islets- Grade 3

4. Configuration of lesions

   1. Diffuse

   2. Nodular

The most important factor when considering treatment of a patient with adenomyosis is her desire for future fertility. The only definitive treatment for symptoms associated with adenomyosis is hysterectomy; however, this is not an option for patients who desire future fertility and may not be an option for patients who are poor surgical candidates. Additionally, because adenomyosis is still rarely definitively diagnosed before hysterectomy, treatment relies on a presumptive diagnosis. Surveillance for improvement is based on clinical presentation, with little ability for surveillance through imaging studies.

The medications most commonly used to treat symptoms of adenomyosis are anti-inflammatory medications and hormonal therapies. The most common class of anti-inflammatory medications used to treat menorrhagia are nonsteroidal anti-inflammatory drugs. These inhibit formation of prostaglandins, which are considered the primary mechanism of action in uterine pain. Hormonal therapies cause ovarian suppression, mainly through negative feedback on the hypothalamic-pituitary-ovarian axis. By suppressing ovarian function, hormonal stimualtion of adenomyotic tissue is suppressed.

High intensity focused ultrasound

High intensity focused ultrasound (HIFU) is a conservative surgical method that allows patients to preserve their uterus. MRI or ultrasound imaging is used to visualize the uterus and direct high-intensity ultrasound beams at a targeted area within the myometrial tissue. These targeted ultrasound beams cause thermal ablation and necrosis. HIFU can be used on both focal and diffuse adenomyosis.[40, 41] Patients treated with MRI-guided FUS have shown improvement in menorrhagia and dysmenorrhea, with a decrease in uterine size.[42, 43, 44]

Uterine artery embolization

Uterine artery embolization (UAE) has long been used as conservative treatment for women with symptomatic uterine fibroids. More recently, it has been considered as a treatment for symptomatic adenomyosis for women who are not candidates for surgical management. After UAE, patients with adenomyosis have reported significant improvement in dysmenorrhea, pelvic heaviness and urinary frequency.[45] Mean uterine volume has consistently been shown to have a significant decrease after UAE.[46, 45] Resolution of symptoms may last from 17 months to >4 years; however, the overall efficacy of UAE for adenomyosis remains unknown.[47, 46, 48]

Adenomyomectomy

Although adenomyomas are focal areas of adenomyosis surrounded by myometrial hypertrophy, there is no well-defined plane between an adenomyoma and normal myometrium. Adenomyomectomy is a surgical option for adenomyomas and is performed in the same manner as a myomectomy. After the location of the adenomyoma has been identified as well as possible using imaging techniques, the adenomyoma can be removed via laparotomy or laparoscopy.[49, 50, 51] For larger, more severe cases of adenomyoma and adenomyosis, wedge resection of the uterus can be performed.[52] Multiple different techniques exist for uterine reconstruction after resection of diffuse adenomyosis or adenomyoma[53] ; however, few studies have been performed evaluating fertility after reconstruction.

Hysterectomy

Hysterectomy is currently considered the only definitive management for adenomyosis and is still the recommended method if desired future fertility is not a factor. In many instances, adenomyosis is incidentally noted on histologic examination.

Typically, because adenomyosis is confined to the uterus, diagnosis and management can be managed by an OB/GYN. For patients desiring surgical management, a gynecologist adept in hysterectomy should be involved. If a patient prefers management with a uterine artery embolization, interventional radiology must be consulted for evaluation and management. If a patient desires future fertility, she should be referred to a reproductive endocrinologist for counseling regarding expectations of future fertility and for discussion of fertility options.

Diet

Although a healthy diet is always recommended, no diet has been found to cause or prevent the development of adenomyosis. However, obesity has been identified as an independent risk factor associated with the presence of adenomyosis and endometriosis, possibly due to exposure to elevated estrogen levels.[54]  A healthy diet, therefore, may reduce the risk of obesity.

Activity

There are no known physical activities that may cause or prevent the development of adenomyosis. However, as mentioned previously, obesity has been identified as an independent risk factor associated with adenomyosis[54]  and may be prevented with appropriate diet and physical activity.

By avoiding potential risk factors, the risk of developing adenomyosis may be reduced. Minimizing unnecessary estrogen exposure and uterine trauma may prevent the occurrence of inciting events. Suppression of ovulation may additionally prevent further maturation of existent adenomyotic implants and may prevent the initial development of adenomyosis.

Long-term monitoring is not typically indicated. Conservative management can be continued without scheduled surveillance, and future management can be dictated by the patient's symptoms.

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]

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.

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.

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.

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.

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.