Introduction
Primary dysmenorrhea is defined as colic pain in the suprapubic region with irradiation
to the lumbar and thighs that occurs before or during menstruation in the absence
of pelvic illness.[1]
[2]
[3]
[4] Its first manifestation usually appears 6 months after menarche because it occurs
only during ovulatory cycles. The pain typically lasts from 8 to 72 hours and is most
severe on the 1st and 2nd days of menstruation, due to increased release of prostaglandins during this period.
The symptoms are reproducible from one menstrual period to another. It is associated
with nausea, vomiting, diarrhea, low back pain, migraines, dizziness, fatigue, insomnia,
and rarely, syncope and hyperthermia.[1]
[2]
[3]
[4]
[5]
[6] This results of prostaglandins’ action on the smooth muscles of the stomach, intestine,
and blood tissues.[7] Symptom severity is positively correlated with early menarche, increased duration
and amount of menstrual flow.[8]
Epidemiology
Primary dysmenorrhea is the most common gynecological disease in menstruating women.[1]
[2]
[6]
[9] Its prevalence is more significant during the second and third decades of life and
decreases with advancing age, unlike secondary dysmenorrhea.[9] Its prevalence is underestimated and difficult to determine because only a small
number of women seek medical treatment. Contributing to this are the different definitions
of dysmenorrhea that exist and the lack of standard methods for defining its severity.[1]
[2]
[9] According to a systematic review by the World Health Organization in 2006, the prevalence
of dysmenorrhea in menstruating women is between 17 and 81%. Severe dysmenorrhea was
identified in only 12 to 14% of cases.[10]
Impact on Quality of Life
Dysmenorrhea causes high rates of school and work absenteeism, as well as decreasing
quality of life.[5]
[11]
In a study conducted in Portugal, 8.1% of girls reported missing school or work due
to menstrual pain, impacting daily activities in ∼ 65.7% of cases. Only 27.9% sought
medical help.[12] It mainly affects academic performance in terms of concentration, sport, socialization,
and school achievement. It also influences pain tolerance and causes sleep disturbance,
daytime fatigue and drowsiness.[1]
[11] According to the National Sleep Foundation's Women and Sleep Poll, women report
sleep disturbance during the 1st days of menstruation, and 28% report that sleep was disturbed by menstrual pain.[13]
Differential Diagnosis
Before attributing to menstrual pain the diagnosis of primary dysmenorrhea, it is
important to exclude other diseases. Secondary dysmenorrhea is associated with underlying
pelvic disease. It is characterized by later onset of symptoms than primary dysmenorrhea,
usually more than 2 years after menarche. It may be associated with other gynecological
symptoms, such as abnormal uterine bleeding. Pain has different characteristics and
may persist beyond catamenium.[1]
[6]
[9] Endometriosis is the most common cause and, therefore, the most important differential
diagnosis. It is the illness that best mimics the symptoms of primary dysmenorrhea
and is characterized by the presence of endometrial tissue in extrauterine locations.
Adenomyosis is another cause of secondary dysmenorrhea and is defined as a benign
invasion of the myometrium by endometrial tissue.[1]
[14] When menarche occurs associated with pain, flow obstruction should be suspected
as in Müllerian anomalies: imperforate hymen, transverse vaginal septum, or vaginal
agenesis.[2]
[6]
[8]
[15] Abortion and ectopic pregnancy may present with severe pelvic pain and bleeding
and should be the primary suspect in sexually active adolescents and young women.[8] Pelvic inflammatory disease should be suspected in the presence of sexually transmitted
infection's history or abnormal vaginal discharge associated with dyspareunia.[4] Non-gynecological disorders include: gastrointestinal causes (irritable bowel syndrome,
inflammatory bowel disease, chronic constipation and lactose intolerance), genitourinary
causes (cystitis, renal lithiasis) and psychogenic causes (trauma, history of sexual
abuse).[2]
[9]
[15]
Diagnosis
The evaluation of menstrual pain should include a detailed clinical history and physical
examination, and it is important to exclude pelvic disease. Clinical history should
include: menstrual history (age at menarche, regularity, and duration of cycles, amount
of flow, time between menarche and onset of dysmenorrhea), pain characterization (type,
location, irradiation, associated symptoms, chronology), treatments used, family history
of dysmenorrhea, sexual history, system review (gastrointestinal, genitourinary, musculoskeletal,
and psychosocial).[2]
[15] Pelvic examination should be performed in sexually active adolescents, women with
severe pain or activity limitation, and in cases that do not respond to first and
second-line treatments. In non-sexually active adolescents with no history of a systemic
disease but typical of primary dysmenorrhea, a pelvic examination is not necessary,
but abdominal examination should be performed to exclude other diseases.[2]
[4]
[6]
[7]
[8]
[15] Pelvic examination consists of: inspection of the external genital area (important
for determining sexual maturity, visualization of the hymen [signs of trauma]), speculum
examination (allows assessment of anatomical diseases such as flow obstruction or
the presence of vaginal discharge suggestive of infection), bimanual examination (allows
the uterus to be evaluated for its mobility, size, texture, and presence of masses
such as fibroids and it also allows uterosacral attachments and ligaments to be evaluated
for masses and nodules suggestive of endometriosis).[14] In primary dysmenorrhea, the pelvic examination shows no changes.[4] When history and physical examination suggest pelvic disease, further investigation
should be undertaken to determine the causes of secondary dysmenorrhea using transvaginal
ultrasound, magnetic resonance imaging, and, possibly, laparoscopy.[2]
[4]
[6]
[7]
[8]
[14]
Pathophysiology
The etiology of primary dysmenorrhea is characterized by increased synthesis and release
of prostaglandins, which cause hypercontractility of the myometrium, resulting in
uterine muscle ischemia and hypoxia and, subsequently, pain.[1]
[3]
[5]
[11] This statement is supported by: similarity between symptoms of primary dysmenorrhea
and prostaglandin-induced uterine contractility in labor or abortion; prostaglandins
in the menstrual fluid of women with primary dysmenorrhea and by demonstrating the
efficacy of cyclooxygenase (COX) inhibitors in pain relief by inhibiting prostaglandin
synthesis.[3]
[9] Prostaglandins are synthesized through long-chain polyunsaturated fatty acids such
as arachidonic acid, a common component of cell membrane phospholipids. Its synthesis
is limited by the availability of free fatty acid precursors, which are regulated
by cyclic adenosine monophosphate (cAMP). Thus, through the cAMP pathway, prostaglandin
production can be stimulated by adrenaline, peptide, and steroid hormones, but also
by mechanical stimuli and tissue trauma.[1]
Arachidonic acid is derived from phospholipids through the lysosomal enzyme phospholipase
A2 ([Fig. 1]). The stability of lysosomal activity is regulated by several factors, one of which
is progesterone. High progesterone levels stabilize lysosome activity. Decreased progesterone
levels, which occur when the corpus luteum regresses in the late luteal phase, results
in a decrease in this stabilizing effect on endometrial lysosomes, leading to the
release of phospholipase A2 and hydrolysis of cell membrane phospholipids for arachidonic
acid synthesis and of eicosatetraenoic acid. These compounds serve as precursors of
the COX and lipoxygenase pathways. Thus, during menstruation, increased availability
of arachidonic acid, intracellular destruction, and tissue trauma favor prostaglandin
production. It was also possible to conclude that dysmenorrhea occurs only in ovulatory
cycles.[1]
[3]
[5]
[11]
[15]
Fig. 1 Prostaglandin synthesis pathway. Abbreviations: 5-HPETE, arachidonic acid 5-hydroperoxide;
PGF2a, prostaglandin F2a; PGE2, prostaglandin E2; PGG2, prostaglandin G2; PGH2, prostaglandin H2.
There are 9 classes of prostaglandins, those implicated in the pathogenesis of primary
dysmenorrhea are prostaglandin F(2α) PGF2α and prostaglandin E2 (PGE2). Prostaglandin F(2α) is more important in dysmenorrhea because it causes uterine
vasoconstriction and contraction of the myometrium, while PGE2 causes either relaxation
or contraction of the myometrium. Prostaglandins have several effects, including pain,
inflammation, body temperature change, and sleep regulation. The larger the amount
of prostaglandins, the greater the severity of menstrual pain and associated symptoms.[1] In addition to elevated prostaglandin levels, dysmenorrhea is also characterized
by increased: uterine contractions, resting tone (> 10 mm Hg), active intrauterine
pressure (> 120 mm Hg), frequency of contractions, and uncoordinated contractions.
These anomalies lead to poor uterine perfusion, causing pain.[1]
[3]
The role of prostanoids such as thromboxane A2, prostacyclins, and leukotrienes is
not yet well established. Prostacyclins are a potent uterine vasodilator and relaxant
and are thought to be decreased in dysmenorrhea. Leukotrienes, produced by the 5-lipoxygenase
pathway, may be responsible for some forms of nonsteroidal anti-inflammatory drug
(NSAID)-resistant dysmenorrhea. In women with dysmenorrhea, there is a greater number
of leukotrienes in the menstrual fluid, especially C4 and D4 leukotrienes. Also, there
are specific binding sites on myometrial cells for C4 leukotrienes, so leukotrienes
are also thought to contribute to uterine hypercontractility. The involvement of vasopressin
in the pathogenesis of dysmenorrhea is also controversial, but it is thought that
high levels of circulation may produce dysrhythmic uterine contractions, leading to
reduced uterine flow, hypoxia and, consequently, pain.[3]
[9]
[11] Recent evidence has shown that nitric oxide may also be involved, because it was
found to be responsible for uterine quiescence during pregnancy.[11]
Some studies have shown that women with dysmenorrhea have hypersensitivity to pain,
but there is still no consensus on the subject.[1] It is thought that, in these cases, there is variation in the way pain is processed;
the peripheral nociceptive information generated by the sexual organs during menstruation
is amplified, causing increased excitability of the somatovisceral convergent neurons
in the spinal cord and, consequently, increased pain perception.[16]
[17] Changes in brain structure were also observed in women with dysmenorrhea, such as
lower gray matter volume in brain regions involved in pain transmission and sensory
processing, and a larger volume of gray matter in regions involved in pain modeling
and regulation of endocrine functions. These changes support the amplification of
pain facilitation.[18]
Risk Factors
There are two types of risk factors for primary dysmenorrhea: non-modifiable and behavioral.
Non-modifiable risk factors include: family history of dysmenorrhea, age under 20
years (symptoms are more pronounced during adolescence), menarche before age 12 (due
to early establishment of ovulatory cycles), menstrual flow lasting longer than 7
days and nuliparity.[1]
[2]
[7]
[14]
[15]
[19] The association between multiparity and decreased risk of dysmenorrhea can be explained
by several assumptions such as: lower release of prostaglandins by the endometrium
after term delivery, neuronal degeneration that occurs in the uterus after a term
delivery, and decreased uterine norepinephrine in the third trimester of pregnancy.[20] Behavioral risk factors include: body mass index (BMI) < 20 or > 30, low intake
of omega 3 (fish), smoking (nicotine induces vasoconstriction), caffeine consumption
(also induces vasoconstriction), and psychosocial symptoms such as depression and
anxiety. Also, a stressful relationship with the parents may favor primary dysmenorrhea.[21] It is important to identify these behavioral factors as they are subject to intervention.[1]
[2]
[7]
[14]
[15]
[19] Stress inhibits the release of luteinizing and follicle-stimulating hormones, which
leads to impaired follicular development with alteration in progesterone synthesis
and release that influences prostaglandin activity. Besides, stress-related hormones,
such as adrenaline and cortisol, also, influence prostaglandin synthesis and myometrial
binding.[20] Some studies have shown an association between the occurrence of primary dysmenorrhea
and other conditions that cause chronic pain, such as irritable bowel syndrome, migraines,
and fibromyalgia. Women with primary dysmenorrhea are twice more likely to develop
irritable bowel syndrome than women without dysmenorrhea. In addition, this condition
may exacerbate symptoms of other diseases with the increased pain sensitivity.[22]
Treatment
The goal of the treatment is to provide adequate relief from menstrual pain. General
measures for pain control include educating the patient about the physiology of menstruation
and the pathophysiology of menstrual pain, reassurance and support.[9]
[23] There are three types of treatment for primary dysmenorrhea control: pharmacological,
non-pharmacological, and surgical, with pharmacological treatment being the most effective
([Fig. 2]).[3]
Fig. 2 Flowchart on the treatment of dysmenorrhea. Abbreviations: NSAIDs, non-steroidal
anti-inflammatory; IUS-intrauterine system; LUNA, laparoscopic uterosacral nerve ablation;
PSN, presacral neurectomy.
Pharmacological
NSAIDs: These are considered the first line of treatment. They act by inhibiting COX, which
results in decreased prostaglandin production and, consequently, decreased prostaglandin
concentration in menstrual fluid, decreased uterine contractility, and menstrual volume.
Its adverse effects are uncommon and well tolerated but mainly consist of gastrointestinal
symptoms such as nausea, vomiting, and heartburn. Other less common adverse effects
include nephrotoxicity, hepatotoxicity, hematological abnormalities, bronchospasm,
fluid retention, and edema. There is still little evidence on which NSAID is more
effective or safer, but, currently, the most widely used ones are ibuprofen, naproxen,
mefenamic acid, and ketoprofen.[3]
[6]
[9]
[14]
[15] They are most effective when they start before the onset of symptoms and need to
be continued for 3 days.[2]
[7] Cyclooxygenase II inhibitors are more specific and are less likely to induce duodenal
ulcers. Because they cause serious adverse effects, they are no longer used for the
treatment of primary dysmenorrhea.[3]
[8]
[15]
[23]
[24]
Hormonal Contraceptives
-
Combined oral contraceptive (estrogen-progestin): This is the second line of treatment,
acting to suppress ovulation and endometrial growth by causing a decrease in menstrual
volume and prostaglandin secretion, with a subsequent decrease in intrauterine pressure
and uterine contractility.[2]
[3]
[8]
[11] Continuous use is more effective than cyclic use because it decreases the frequency
of menstrual periods leading to a decrease in dysmenorrhea.[2]
[9] They are effective in both primary and secondary dysmenorrhea, so their use should
be initiated without waiting for the definitive diagnosis.[2]
[15]
-
Progestin-only methods: These drugs may be effective in treatment, as the progestin
component is responsible for inducing endometrial atrophy, leading to pain relief,
but has not yet been studied as well as combined oral contraceptives.[23] Progestin-only pill (desogestrel) decreases menstrual flow and ∼ 10% of women get
amenorrheic. It can be used as an alternative to combined oral contraceptives, causing
fewer adverse effects.[2]
[23]
[25] Long-acting injectable medroxyprogesterone acetate causes amenorrhea in 50% of women
due to endometrial atrophy; however, due to effects on bone mineral density, it is
not used currently.[2]
[7]
[8]
[9]
[23] The intrauterine levonorgestrel-releasing device (IUS) has been shown to reduce
menstrual flow and endometrial thickness, reducing pain.[1]
[7]
[9]
[23] The non-hormonal intrauterine copper device is associated with increased menstrual
flow and pain and is, therefore, not used.[9]
-
Transdermal and vaginal contraceptives: their use has not been well studied in primary
dysmenorrhea but the effects of estrogen-progestin contraceptives on the endometrium
are similar regardless of their methods of administration and should not affect their
effectiveness.[23]
[26]
-
Subdermal implant with etonogestrel release: allows contraception for 3 years. Several
studies have shown an improvement in symptoms of dysmenorrhea after use.[8]
Others
-
Tocolytics: Since primary dysmenorrhea is caused by uterine hypercontractility, these
drugs, by blocking contractility, maybe effective in treatment. Thus, nitric oxide,
nitroglycerine and calcium channel blockers are being investigated as potential drugs
for the treatment of dysmenorrhea, but they are not yet used for it.[23] Transdermal nitroglycerin is less effective than NSAIDs and has more adverse effects,
such as migraines; therefore, due to their low tolerability, they are not used for
treatment.[3]
[7]
[27] Calcium channel blockers such as nifedipine inhibit myometrium contractility by
blocking calcium entry into cells of the smooth muscle, decreasing the pain. They
are associated with several adverse effects: transient facial flushing, increased
heart rate, palpitations, and migraines.[3]
[23]
[28]
-
Vitamins: Vitamin E relieves primary dysmenorrhea because it suppresses phospholipase
A2 and COX activity, thus inhibiting prostaglandin production and promoting prostacyclin
action, with consequent vasodilation and muscle relaxation.[3]
[5] Vitamin B1 supplementation can improve dysmenorrhea by reversing common symptoms
of B1 deficiency, such as muscle cramps, fatigue, and decreased pain tolerance.[5]
-
Omega 3: Dysmenorrhea is associated with diets rich in omega 6 and low in omega 3
fatty acids. Increased incorporation of omega 3 into membrane phospholipids through
ingestion of fish oil leads to lower production of prostaglandins and leukotrienes.
Adverse effects include: nausea and acne exacerbation.[3]
[5]
[7]
Non-Pharmacological
Lifestyle changes: The role of arachidonic acid as a precursor to prostaglandin production led to the
thought of the role of diet in controlling dysmenorrhea. Thus, changes in diet such
as low-fat diet, ingestion of beans, seeds, fruits and vegetables allow a decrease
in arachidonic acid production. Besides, physical exercise seems to decrease the symptoms
of dysmenorrhea. A general benefit of exercise is reported in women younger than 25
years of age who exercise at least 45 to 60 minutes, 3 times a week.[29] Implementing a healthy lifestyle with proper nutrition, exercise, smoking cessation,
and low alcohol consumption alleviates the symptoms of dysmenorrhea and minimizes
its discomfort and inconvenience.[2]
[7]
[9] Some studies show lack of evidence of any dietary supplement to reduce dysmenorrhea
and also the lack of safety data of these products.[30]
Topical heat: consists of the direct application of heat in the suprapubic region; it is an effective
and low-cost natural method.[2]
[3]
[9]
Transcutaneous Electrical Nerve Stimulation (TENS): It allows pain relief through two mechanisms. The first is to raise the threshold
for pain signals caused by uterine hypoxia and hypercontractility by sending a series
of afferent impulses through the large-diameter sensory fibers of the same nerve root,
resulting in less pain perception. The second mechanism is the stimulation of endorphin
release by the peripheral nerves and spinal cord thus providing another partial pain
attenuation pathway.[3]
[5] It may be an alternative in women with contraindications to the use of NSAIDs and
its effects. Adverse effects include: muscle stiffness, migraines, nausea, skin redness
or burn.[2]
[5]
Acupuncture and acupressure: The mechanism of acupuncture involves stimulation of nerve fibers and receptors in
a complex interaction with endorphins and serotonins.[5]
[9] Some evidence suggests their use as a treatment, but it is still insufficient for
their recommendation, and further studies are needed to prove their effectiveness.[31]
[32] They may be an alternative in women not interested in pharmacological treatment.[2]
[3]
Surgical
Only indicated in rare cases of women with severe and treatment-refractory dysmenorrhea,
requiring re-evaluation of the diagnosis and investigation of secondary causes;[33] however, there are very few studies on this topic and the ones that exist are old
reports that have not been replicated enough to safely recommend these methods.
Laparoscopic uterosacral nerve ablation (LUNA): involves the transection of afferent pain fibers in the uterosacral ligaments.[9]
[33]
Presacral neurectomy (PSN): direct transection of nerve fibers in the pelvis.[9]
[33]
Hysterectomy: this method can be considered as the last resort in cases refractory to conventional
therapy and in which laparoscopy reveals normal anatomy and absence of deep infiltration
by endometriosis.[2]
[7]
