Dysmenorrhea

Etiology

Since the 1960s, many theories have been proposed to explain the etiology of dysmenorrhea, including psychological, biochemical, and anatomical etiologies. Among these, the biochemical theory has the strongest supporting evidence.[8] 

Associated risk factors for dysmenorrhea include the following:

• Age (commonly 13 to 15 years) up to 30 years
• Smoking [9]
• Attempts to lose weight
• Higher or lower than normal body mass index
• Depression or anxiety
• Longer menstrual cycles
• Younger age at menarche
• Nulliparity
• History of sexual assault
• Previous cesarean section with incomplete uterine scar healing (uterine niche)
• Longer and heavier menstrual flow
• Family history of dysmenorrhea
• Disruption of social networks [7][10]

Primary Dysmenorrhea

Prostaglandins are believed to be the main cause of dysmenorrhea.[11][12] Elevated levels of prostaglandins have been identified in the menstrual fluid and endometrial tissue of women with dysmenorrhea.[6] As hormone levels decline during the menstrual cycle, endometrial shedding begins. At the onset of menstruation, endometrial cells release prostaglandins, which stimulate uterine contractions. The intensity of the cramps is proportionate to the amount of prostaglandins released.[13][14] Uterine contractions cause tissue hypoxia and ischemia, which in turn cause pain and sometimes associated nausea and diarrhea.[6]

Secondary Dysmenorrhea

Secondary dysmenorrhea refers to menstrual pain resulting from an underlying disease, disorder, or structural abnormality within or outside the uterus and affects up to 10% of women worldwide.[3][15] This type of dysmenorrhea may affect women at any time after menarche and may be a new symptom for females in their 30s or 40s. Secondary dysmenorrhea can be associated with varying intensities of pain and, at times, other symptoms such as dyspareunia, heavy menses, intermenstrual bleeding, and postcoital bleeding. Common causes of secondary dysmenorrhea include endometriosis, large cesarean scar niche, fibroids, adenomyosis, endometrial polyps, interstitial cystitis, pelvic inflammatory disease, and possibly the use of an intrauterine contraceptive system.[7][11][16] 

Up to 29% of individuals with dysmenorrhea may have underlying endometriosis. The prevalence is even higher among those with dysmenorrhea that does not respond to nonsteroidal anti-inflammatory drugs (NSAIDs), with studies suggesting that up to 35% of these patients may have endometriosis.[17] Adenomyosis is another common condition associated with secondary dysmenorrhea. In addition, reproductive tract anomalies are present in up to 3.8% of young women, and both obstructive and nonobstructive anomalies may contribute to secondary dysmenorrhea.

Epidemiology

Dysmenorrhea is one of the most common gynecological concerns among menstruating patients, regardless of age or race, and is a frequently identified cause of pelvic pain. The prevalence of dysmenorrhea can vary between 16% and 91% in individuals of reproductive age, with severe pain observed in 2% to 29% of individuals.[10]  Agarwal et al showed the prevalence of dysmenorrhea to be 80% in adolescents. Of those affected adolescents, approximately 40% had severe dysmenorrhea.[18]

Symptoms associated with dysmenorrhea may include gastrointestinal symptoms such as nausea, bloating, diarrhea, constipation, vomiting, and indigestion. Irritability, headache, and lower back pain are prevalent among women presenting with primary dysmenorrhea. Tiredness and dizziness may also be associated.[19] In approximately 16% to 29% of women, dysmenorrhea is associated with significant impairment in quality of life.[10] Furthermore, 12% of school and work activities may be missed each month due to dysmenorrhea-related absenteeism.[20]

Pathophysiology

The pathophysiology of primary dysmenorrhea is not fully understood. Nevertheless, the identified cause is believed to be hypersecretion of prostaglandins from the uterine lining. Prostaglandins cause pain by increasing uterine contractions and uterine pressure. Impaired uterine perfusion, ischemia, hypoxia, and metabolites from anaerobic metabolism may also play a role in the cause of pain.[7] The increase in collagenases, inflammatory cytokines, and matrix metalloproteinases in the endometrium is associated with decreased progesterone and estradiol during menstruation. The subsequent breakdown of endometrial tissue frees phospholipids, which are converted to arachidonic acid. The arachidonic acid is converted to prostacyclins, prostaglandins, and thromboxane-2a via cyclooxygenase.[17] Prostaglandin F2 alpha and prostaglandin E2 increase the uterine tone and cause high-amplitude contractions of the uterus. Ischemia may also be present.[21][22] 

The expression of COX-2, a cyclooxygenase, is very high during menstruation, and this is what has driven the use of NSAIDs for treatment, as noted below.[17] Vasopressin has also been linked to primary dysmenorrhea. Vasopressin increases uterine contractility and can cause ischemic pain due to its vasoconstrictive effects.[4][23] Leukotrienes C4 and D4 levels are higher in patients with dysmenorrhea and appear to be associated with an increase in uterine contractions as well.[7] Furthermore, uterine contractility is more prominent during the first 2 days of menstruation, which is when dysmenorrhea is most frequent and severe.[24]

The most common causes of secondary dysmenorrhea in premenopausal women include endometriosis and adenomyosis.[24]

History and Physical

Obtaining a detailed history and performing a thorough physical examination are essential to establish the diagnosis of dysmenorrhea. Key historical features include location of pain, timing of onset, characteristics, duration, and associated symptoms such as fatigue, headache, diarrhea, nausea, and vomiting.[19]

In patients with primary dysmenorrhea, the physical examination findings are typically unremarkable. Pelvic examination reveals a normal-sized, nontender, mobile uterus. On examination, individuals with primary dysmenorrhea typically demonstrate the absence of abnormal vaginal discharge, adnexal masses, and uterosacral nodularity.[7]

Common findings that may indicate secondary dysmenorrhea include the following:

• Older age (older than 25) versus younger age, in which primary dysmenorrhea is more common
• Vaginal discharge that is whitish gray, mucopurulent, or has a foul odor (pelvic inflammatory disease concern)
• Friable cervix (a sexually transmitted infection concern)
• Dysuria, dyspareunia, vaginismus, dyschezia, infertility, palpable nodularity, adnexal masses, or tenderness on pelvic examination [25]
• Heavy menstrual bleeding with a mildly enlarged symmetrical uterus (adenomyosis)
• Abnormal bleeding with an enlarged, asymmetrical uterus (leiomyomas possible)
• Obstructive anatomical abnormalities or history of other congenital anomalies (concern for Müllerian anomaly)
• Pelvic masses, such as neoplasms, ovarian cysts, and endometrioma [26][27]

Evaluation

Evaluation of dysmenorrhea begins with a thorough clinical assessment aimed at distinguishing primary dysmenorrhea from pain caused by underlying pelvic pathology. A detailed history and a thorough physical examination guide the need for further diagnostic testing and help identify patients who may require additional evaluation for secondary causes.

Primary Dysmenorrhea

Primary dysmenorrhea may be diagnosed based on the typical history alone.[6] Pain begins just before or at the start of menstrual bleeding. The pain is cyclic and begins with the onset of ovulatory cycles, typically within 2 years of menarche, and peaks at 23 to 48 hours after the onset of bleeding, typically lasting no more than 72 hours.[7]

Secondary Dysmenorrhea

Imaging with ultrasound and magnetic resonance imaging (MRI) is important when considering the underlying cause of secondary dysmenorrhea. Transvaginal ultrasound is the recommended first-line imaging modality for this evaluation. MRI provides excellent soft tissue resolution and allows comprehensive evaluation of structures beyond the uterus, including the bowel, bladder, and peritoneum. This capability is especially valuable for assessing deep-infiltrating endometriosis.[3] 

Computed tomography enables evaluation of both the pelvic organs and the broader abdominal cavity, allowing detection of pelvic inflammatory disease complications, including adhesive bowel obstruction and perihepatic inflammation. When a congenital Müllerian duct anomaly is suspected, three-dimensional transvaginal ultrasound is ideal; however, MRI is frequently used when three-dimensional ultrasound is unavailable.[3]

• A pelvic examination is important for evaluating dysmenorrhea if the history of onset and duration of lower abdominal pain suggests secondary dysmenorrhea or if the dysmenorrhea is not responding to medical treatment.[27] A pelvic examination is not necessary for an adolescent who is not sexually active and has a typical presentation of primary dysmenorrhea without additional symptoms.[6]                               
• Ultrasound has little benefit in the evaluation of primary dysmenorrhea. However, it can be useful in differentiating the cause of secondary dysmenorrhea, including endometriosis, leiomyomas, Müllerian anomalies, and adenomyosis.[6][11][27] Ultrasound is the preferred initial evaluation of the cause of secondary dysmenorrhea.                          
• Patients who are at risk of sexually transmitted infections or when pelvic inflammatory disease is suspected may need endocervical or vaginal swabs.[11][27]
• If indicated, cervical cytology or HPV testing may be considered to rule out a suspected cervical malignancy.
• MRI or Doppler ultrasonography may be useful when torsion of the adnexa, adenomyosis, or deep pelvic endometriosis is suspected or when ultrasound findings are inconclusive.[27] MRI is particularly helpful in diagnosing Müllerian anomalies, but it is not cost-effective as an initial screening tool.
• Laparoscopy is typically reserved for women who desire fertility and have suspected endometriosis as a cause of secondary dysmenorrhea.

Treatment / Management

Treatment of dysmenorrhea is aimed at providing adequate pain relief to allow patients to perform their daily activities. Initial management of both primary and secondary dysmenorrhea is similar and includes patient education, reassurance, supportive therapy, and medical therapy. If symptoms do not respond to initial treatments, an evaluation for potential causes of secondary dysmenorrhea may be warranted. Treatment strategies are divided into pharmacological and nonpharmacological treatments. Opioids and tramadol should not be regularly used to treat dysmenorrhea.

Nonpharmacological Treatment

Heat application, exercise, and diet: Baseline intervention starts with heat application and exercise. Heat applied to the lower abdomen may be quite soothing with no associated adverse effects. This regime is the preferred initial therapy option for many patients.[28][29] Regular exercise appears to reduce pain in primary dysmenorrhea, but the optimal type, intensity, and frequency remain uncertain. More recent network meta-analyses support the benefit, but heterogeneity remains high. Moderate exercise is recommended for all affected patients.[30](A1)

Maintaining an active lifestyle and consuming a balanced diet rich in vitamins and minerals are generally recommended for better health outcomes. Such lifestyle and dietary modifications may help reduce the severity of dysmenorrhea.[31][32][33] Food supplements, as well as complementary or alternative medicine, including plant-based therapies and Chinese medicine, are used to treat dysmenorrhea. However, they are not regulated by the US Food and Drug Administration (FDA). Current evidence remains insufficient to support the routine use of herbal or dietary therapies for dysmenorrhea.[34](A1)

Spinal manipulation has shown no benefit in prostaglandin levels or pain associated with primary dysmenorrhea in at least 1 high-quality randomized controlled trial.[35] Evidence is limited and insufficient to recommend spinal manipulation routinely. Dietary supplements and herbal/traditional therapies may help some patients, but the quality of the evidence is variable, and they should not replace first-line evidence-based therapy.(A1)

Acupuncture, transcutaneous electrical nerve stimulation, and behavioral counseling: The effectiveness of acupuncture is supported by a few studies.[36][37][38] Transcutaneous electrical nerve stimulation (TENS) and behavioral counseling may be used as second-line nonpharmacological treatments.[17] TENS has more recently gained supportive evidence, with systematic reviews indicating it may reduce pain compared with placebo or no treatment, though certainty is not high. Behavioral counseling may help with coping and quality of life, but it is not as established for direct pain reduction as NSAIDs, heat, exercise, or hormonal therapy.(A1)

Pharmacological Treatment

Nonsteroidal anti-inflammatory drugs: NSAIDs are considered to be the first-line pharmacological treatment for dysmenorrhea and are more effective than a placebo.[39] NSAIDs exert their benefit by inhibiting cyclooxygenase enzymes, thereby blocking prostaglandin production.[40] Use of an NSAID on a scheduled basis starting 1 to 2 days before the onset of pain has been shown to work better than when an NSAID is used on an as-needed basis.[7] 

In a systematic review comparing various NSAIDs to placebo for the treatment of dysmenorrhoea, Marjoribanks et al concluded that no single NSAID is safer or more effective than others.[41] A meta-analysis of 70 studies showed that flurbiprofen and tiaprofenic acid were superior for treating dysmenorrhea; however, tiaprofenic acid is not available in the United States.[7] Approximately 20% of patients with dysmenorrhea do not respond to treatment with NSAIDs, a condition referred to as NSAID-resistant dysmenorrhea.[17][42](A1)

Fenamates, such as mefenamic acid, may have slightly greater efficacy than the phenylpropionic acid derivatives, such as ibuprofen and naproxen, because they have a dual action: blocking prostaglandin production and inhibiting prostaglandin actions.[43][44] Mefenamic acid 500 mg at the start of menses or at the onset of pain, followed by 250 mg every 6 hours for up to 3 days, may be helpful. A study recommended ibuprofen and fenamates as preferred for safety and efficacy.[45] Ibuprofen 800 mg every 8 hours or naproxen 440 mg to 550 mg as an initial dose, followed by 220 mg to 550 mg every 12 hours on a scheduled basis, has been recommended. NSAIDs are more effective than paracetamol (acetaminophen). However, paracetamol is still a valid alternative when NSAIDs are contraindicated. Ibuprofen and naproxen remain standard first-choice options because of their familiarity, accessibility, cost, and safety profile. Celecoxib, a COX-2 selective NSAID, was used for the treatment of dysmenorrhea in the past and remains FDA-approved for primary dysmenorrhea, although, like other NSAIDs, it carries boxed cardiovascular and gastrointestinal warnings and is not usually preferred over standard nonselective NSAIDs for routine first-line use. Black box warnings regarding the risk of serious adverse events must be heeded for all NSAIDs.[46] COX-2 selective NSAIDs have also been linked to delayed ovulation since prostaglandins are needed for ovulation.[47][48](A1)

Acetaminophen: Acetaminophen is a pain reliever that may be an alternative for patients who cannot take or cannot tolerate NSAIDs; however, acetaminophen overall is less effective than NSAIDs. Combination formulations of acetaminophen with pamabrom or caffeine (both diuretics) have been shown to reduce pain associated with dysmenorrhea, but they are not central to modern guideline-based treatment.[49][50][51](A1)

Hormonal contraception: Hormonal contraception with estrogen and progesterone in the form of pills, patches, or vaginal rings is reportedly effective in reducing dysmenorrheic pain compared to a placebo in patients who also desire contraception.[52][53][54][55] Most available combination pills provide comparable pain relief, with no significant differences in efficacy. Other studies have argued against the effectiveness of combined hormonal contraceptives as a treatment for dysmenorrhea due to small sample sizes and limited comparative data.[56][57] A combination estrogen and progesterone contraceptive limits endometrial growth as well as inhibits ovulation. Over time, as the endometrium thins, menses become lighter, and fewer uterine contractions occur with menses. These effects, in turn, decrease pain during menses.(A1)

Combination birth control pills also work by decreasing the production of prostaglandins and leukotrienes.[39] Low levels of prostaglandins are noted in the menstrual fluid of women on combined oral contraceptive pills. Contraceptive pill users appear to have significantly lower rates of dysmenorrhea and need fewer additional analgesics for treatment.[13] Continuous regimens of hormonal contraception, wherein the placebo pills are not taken, are even more beneficial in treating dysmenorrhea than cyclic therapy.[17]

Progestin-only contraception, including pills, implants, intrauterine devices, or intramuscular injections, is suitable for the treatment of dysmenorrhea, particularly for patients with secondary dysmenorrhea related to endometriosis.[58][59][60] Progesterone works by causing atrophy of the endometrial lining and by inhibiting ovulation. Dienogest and norethindrone acetate are oral formulations of progesterone that are specifically recommended as primary treatment for secondary dysmenorrhea due to endometriosis.[17](A1)

Gonadotropin-releasing hormone agonists and antagonists: Gonadotropin-releasing hormone (GnRH) agonists, such as nafarelin, leuprolide acetate, and goserelin, may be used as second-line pharmacological treatment options. The GnRH antagonist elagolix is another available therapy. These medications are effective treatment options for dysmenorrhea associated with endometriosis. However, cost and adverse effects may limit the use of these therapies, especially without the use of add-back estrogen and progesterone therapy. The American Society of Reproductive Medicine recommends the use of gonadotropin-releasing hormone agonists to treat dysmenorrhea after the laparoscopic diagnosis of endometriosis. However, these medications are not considered long-term therapies.[17] Modern management does not always require laparoscopic diagnosis before using these agents; rather, it depends on the clinical context.

Aromatase inhibitors: These inhibitors may be used to treat secondary dysmenorrhea as they induce amenorrhea. However, adverse effects, including loss of bone mineral density, may prohibit use, especially without concomitant estrogen and progesterone add-back therapy. Thus, these inhibitors are reserved for second or third-line therapy.

Vasodilators: Investigational and adjunctive agents such as sildenafil citrate promote smooth muscle relaxation in the uterus. Nitric oxide donor drugs, such as transdermal nitroglycerin or glyceryl trinitrate patches (0.1 mg), similarly relax smooth muscle. Adverse effects of vasodilators include headaches and feeling light-headed. These medications are typically not used for first-line treatment of dysmenorrhea.[7] Further research is required to clarify the therapeutic role of vasodilators in the management of dysmenorrhea.[17]

Calcium channel blockers: These agents, such as nifedipine 20 to 40 mg, inhibit uterine contractions and reduce dysmenorrhea-related pain. However, headache, tachycardia, and flushing may limit use.[17] These agents are currently considered investigational and not first-line therapies.

Vasopressin/oxytocin receptor agonists: These investigational agents have been studied for the treatment of dysmenorrhea, as these hormones stimulate myometrial contractions. Atosiban and SR49059 have both been studied for NSAID-resistant dysmenorrhea; however, no conclusions on the timing, effectiveness, or method of administration have yet been made.[17]

Antispasmodics: Antispasmodics have been studied for the treatment of dysmenorrhea, as muscle spasm has been implicated as a cause of dysmenorrhea. Globally, hyoscine butylbromide has been used to treat dysmenorrhea for its anticholinergic effects at muscarinic receptors, which lead to smooth muscle relaxation. A similar medication, hyoscyamine sulfate, is available in the United States, but it is not Food and Drug Administration–approved for use for dysmenorrhea. In a randomized controlled trial, the use of an antispasmodic medication along with an NSAID gave better results than the use of an NSAID alone.[17]

Magnesium: Magnesium has both muscle-relaxing effects and vasodilator properties and has thus been shown to reduce pain from dysmenorrhea. Lack of formulation and dosage recommendations has resulted in the conclusion that magnesium should be used in combination with other therapies, not alone, in the treatment of dysmenorrhea.[7]

Surgical Options

Surgical options should be considered only when medical management has failed to provide satisfactory relief.

Laparoscopy: Laparoscopy is the next step in the evaluation and treatment of dysmenorrhea if the patient has a high likelihood of underlying pathology and if relief has not been achieved within 3 to 6 months of initial pharmacological treatment. When symptoms persist despite an adequate trial of NSAIDs and hormonal therapy, clinicians should reassess adherence, reconsider the diagnosis, and evaluate for secondary causes such as endometriosis; laparoscopy is considered when symptoms persist, imaging is unrevealing, or pathology is strongly suspected. Current endometriosis guidance supports empiric medical treatment before diagnostic laparoscopy in many patients. The goal of surgery is to resect endometriotic implants. Postoperative suppression of any residual or microscopic endometriosis is recommended with either progesterone alone, combination birth control, or GnRH agonist therapy.

Endometrial ablation: Endometrial ablation may be considered for patients with heavy menstrual bleeding who have completed childbearing, particularly when medical management has not provided adequate relief. It is not appropriate for those desiring future childbearing.

Hysterectomy: Hysterectomy may be offered as a last resort to women who have failed all other possible treatment modalities. Removal of the ovaries may be considered based on the etiology of the dysmenorrhea, the patient's age, and the risk of future need for additional surgery to remove the ovaries. Hysterectomy is reserved for the treatment of selected refractory secondary causes, not routine dysmenorrhea management, because it does not guarantee pain resolution, especially in patients with endometriosis.

Nerve transection procedures: Nerve transection procedures, including laparoscopic uterine nerve ablation and presacral neurectomy, are not recommended except possibly in select cases of patients with refractory midline pelvic pain. Further research is warranted regarding these procedures.[17] Pain has been noted to recur during postoperative nerve regeneration. Adverse effects are significant and may include pelvic organ prolapse, constipation, and urinary dysfunction.[7] Evidence for presacral neurectomy is limited and must be weighed against the morbidity of this procedure. 

Differential Diagnosis

The differential diagnosis of dysmenorrhea is broad and can be categorized into gynecological conditions and non-gynecological conditions as follows: 

Gynecologic Conditions

• Endometriosis
• Obstruction of the reproductive tract, including imperforate hymen, transverse vaginal septum, vaginal agenesis, OHVIRA syndrome (uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis), and cervical stenosis
• Functional and nonfunctional adnexal cysts
• Adnexal torsion (typically does not present with cyclic pain with menses)
• Adenomyosis
• Pelvic inflammatory disease or sexually transmitted infections
• Endometrial polyps
• Asherman syndrome
• Obstructive Müllerian duct anomalies, such as uterus didelphys, unicornuate uterus, bicornuate uterus, septate uterus, and uterine agenesis
• Leiomyomas
• Ectopic pregnancy
• Chronic pelvic pain
• Membranous dysmenorrhea, a rare condition characterized by colicky pain due to uterine contractions with resultant shedding of the endometrium in a single piece, retaining the shape of the uterus [61]

Non-Gynecologic Conditions

• Irritable bowel syndrome
• Urinary tract infections
• Interstitial cystitis
• Musculoskeletal causes, including abdominal wall muscles, abdominal wall fascia, pelvic and hip muscles, sacroiliac joints, and lumbosacral muscles [62] 

Pertinent Studies and Ongoing Trials

Various phenotypes of dysmenorrhea likely exist, each with its distinct underlying causes. The use of breakthrough pain management in the treatment of dysmenorrhea may be helpful in the future as pertinent studies of NSAID-resistant treatment of dysmenorrhea evolve.[17]

Prognosis

An initial medical treatment regimen is initiated and continued for 2 to 3 months before symptoms are reassessed. If symptoms improve but are still present, a second treatment method may be added. If minimal or no response is noted, a change in treatment, including discontinuation of the initial treatment, may be offered. Patients are continued on treatment for an additional 3 months and then reassessed. If an adequate response is not obtained, evaluation for an underlying cause of secondary dysmenorrhea may be initiated. A multidisciplinary pelvic pain evaluation with physical therapy input and treatment may also be considered.

Dysmenorrhea can have a significant impact on patients' day-to-day lives. Such impact is reflected in absenteeism rates from school or work. Dysmenorrhea may also limit a patient's participation in sports or social events. Furthermore, dysmenorrhea is often accompanied by emotional stressors. In the United States alone, dysmenorrhea is estimated to account for approximately 140 million lost work hours annually, representing a substantial public health and economic burden.[63] 

With the use of recommended treatment options, the prognosis for primary dysmenorrhea is generally good. Mild-to-moderate dysmenorrhea typically responds well to NSAIDs, whereas severe dysmenorrhea may still respond to NSAIDs but require higher doses or combination/adjuvant therapy. In the case of persistent dysmenorrhea, secondary causes of dysmenorrhea should be investigated. The prognosis of secondary dysmenorrhea depends on the etiology, type, location, and severity of the specific cause.

Complications

The complications of primary dysmenorrhea can be described based on the severity of the pain and its impact on the patient's overall well-being and ability to carry out daily activities. As primary dysmenorrhea is not associated with any specific pathology or disease, no additional known complications are observed.

In contrast, the complications of secondary dysmenorrhea vary depending on the underlying cause and may include, but are not limited to, infertility, pelvic organ prolapse, heavy bleeding, and anemia.[24][64]