| disease | Dysmenorrheal |
| alias | Dysmenorrhea |
Dysmenorrhea refers to cramping pain in the lower abdomen before, during, or after menstruation, accompanied by general discomfort that severely affects daily life. It is classified into two types: primary and secondary. Primary dysmenorrhea, also known as functional dysmenorrhea, is diagnosed when no significant abnormalities in the pelvic organs are found after thorough gynecological clinical examinations. Secondary dysmenorrhea, on the other hand, occurs when there are evident pathological changes in the reproductive organs, such as endometriosis, pelvic inflammatory disease, tumors, etc.
bubble_chart Etiology
Primary dysmenorrhea: It is generally believed to be caused by the following reasons: shedding of the endometrial cast (membranous dysmenorrhea), uterine hypoplasia, uterine flexion, cervical stenosis, poor posture and constitutional factors, allergic states, and psychological factors.
Secondary dysmenorrhea: Dysmenorrhea patients diagnosed with pelvic organ lesions through bimanual examination are considered to have secondary dysmenorrhea. It is often misdiagnosed as primary dysmenorrhea when local abnormal signs are not yet obvious. Therefore, for dysmenorrhea that begins more than three years after menarche, the possibility of secondary dysmenorrhea should be considered, and further examination is necessary.
The common cause of secondary dysmenorrhea in young women is endometriosis, which closely resembles the symptoms of primary dysmenorrhea. If the patient has progressive dysmenorrhea or a family history of endometriosis (mother or sisters with the disease), laparoscopy should be performed early to confirm the diagnosis and initiate conservative surgical treatment promptly to preserve fertility.
Additionally, other causes of secondary dysmenorrhea include: congenital uterine anomalies (such as bicornuate uterus, septate uterus, rudimentary horn uterus, transverse vaginal septum, etc.), pelvic inflammatory disease, adenomyosis, uterine fibroids, uterine polyps, uterine adhesions, cervical stenosis, ovarian cysts, and pelvic congestion syndrome.Apart from dysmenorrhea, if fever accompanies menstruation, pelvic inflammation should be considered. Dysmenorrhea occurs in about 5% of women with intrauterine devices (IUDs). In the absence of infection, the cause of dysmenorrhea may be excessive prostaglandin (PG) release due to IUD-induced endometrial irritation, leading to strong uterine contractions.
Patients with uterine anomalies or complete obstruction of the lower genital tract may experience cyclic lower abdominal pain, absence of menstruation beyond the expected age of menarche, while other secondary sexual characteristics develop normally. Cyclic lower abdominal pain results from hematometra, typically appearing within 2–3 years after breast development begins. Obstruction due to genital tract anomalies, imperforate hymen, or transverse vaginal septum can be easily diagnosed through gynecological examination. However, cases with unilateral obstruction and contralateral patency (e.g., non-separated double uterus, unilateral vaginal blind end, or a rudimentary horn uterus not connected to the vagina) are harder to diagnose. Such patients often have a history of progressively worsening dysmenorrhea, and palpable masses may be mistaken for vaginal cysts or ovarian tumors.
Adenomyosis, endometrial polyps, and uterine fibroids are rare in adolescent girls. Dysmenorrhea caused by these conditions usually appears after the age of 25, with variable pain patterns and prolonged duration.
(1) Molecular Biology of Uterine Muscle Contraction
The basic functional unit of muscle is the myofibril, composed of myosin (or Mosin) and actin (or Actin). The relative movement between these two proteins results in muscle contraction, known as the sliding filament theory. Additionally, an important regulatory protein called calmodulin plays a key role. In the resting state, calmodulin inhibits the interaction between myosin and actin. When a nerve impulse reaches the muscle, the conformation of the membrane protein in the sarcoplasmic reticulum changes, significantly increasing its permeability to calcium ions (Ca++). This leads to the release of large amounts of Ca++ stored in the sarcoplasmic reticulum. When the cytoplasmic Ca++ concentration rises to a certain level, it binds to calmodulin, causing a conformational change in calmodulin itself. This activated calmodulin then binds to inactive myosin light-chain kinase (MLCK), forming an active complex. Through ATP hydrolysis, the myosin light chain is phosphorylated, enabling the binding of myosin to actin. The relative movement between these two proteins manifests as muscle contraction.
When the nerve impulse ceases, the permeability of the sarcoplasmic reticulum membrane protein to Ca++ decreases. The cytoplasmic Ca++ is pumped back into the sarcoplasmic reticulum for storage via the Ca pump (a protein with ATPase, adenosine triphosphatase activity). Once the Ca++ concentration returns to pre-contraction levels, calmodulin dissociates from myosin light-chain kinase. A phosphatase then removes the phosphate group from the myosin light chain, dephosphorylating it. Meanwhile, myosin light-chain kinase itself is phosphorylated by cAMP-dependent protein kinase, significantly reducing its affinity for calmodulin. As a result, the smooth muscle returns to a relaxed state.
The balance between contraction and relaxation in smooth muscle primarily depends on the level of active myosin light-chain kinase, whose activity is determined by intracellular Ca++ concentration.
ATP hydrolysis by ATPase releases phosphate and energy, serving as the direct source for myosin phosphorylation and the required energy. ATPase requires magnesium ions (Mg++) for activation. Therefore, Mg++ can promote ATP consumption by activating ATPase, leading to uterine muscle relaxation. When Mg++ reaches 1.6–3 mmol/L (3.2–6 mEq/L), the basal tension of the uterine muscle layer significantly decreases, and the amplitude and frequency of contractions markedly reduce.
Prostaglandins (PGs) also play a significant role in smooth muscle contraction. They act as Ca++ carriers, increasing the reflux of Ca++ across the muscle cell membrane and promoting the release of Ca++ stored in the sarcoplasmic reticulum, thereby elevating intracellular Ca++ concentration. PGs can also inhibit adenylate cyclase, blocking the formation of cAMP, which leads to reduced phosphorylation of sarcoplasmic reticulum membrane proteins, decreased binding with Ca++, and ultimately an increase in cytoplasmic Ca++, triggering the contraction of myofibrils.
(II) Cyclic Changes of Prostaglandins (PGs)
Unlike hormones secreted by typical endocrine glands, PGs are not synthesized by a specific endocrine gland and stored for release when needed, acting on target organs through blood circulation. Instead, when the body requires them, PGs are synthesized locally from the precursor arachidonic acid under neural or hormonal influence, released immediately, and exert their effects. Thus, they are considered local hormones. Only PGI2, unlike other PGs, is not rapidly metabolized in the lungs and can function as a circulating hormone.
The PGs in the uterus primarily originate from the endometrium. Lysosomes in endometrial cells release phospholipase A2 (PLA2) in response to various stimuli. Through the catalytic action of PLA2, arachidonic acid bound to cell membrane phospholipids is liberated. As a precursor for PGs synthesis, this initiates the biosynthesis of PGs, primarily PGF2α. Recent studies report that during the menstrual cycle, the concentration of PGF in the endometrium shows a linear correlation with the logarithmic value of 17β-estradiol (E2) in uterine venous blood, while PGE levels remain relatively constant. Experiments indicate that E2 promotes the formation of intracellular lysosomes, especially under the synergistic effect of progesterone (P), leading to abundant lysosome development in endometrial stromal cells. Due to the presence of PLA2 within lysosomes, once lysosomes degrade, PLA2 is released, freeing more arachidonic acid and stimulating PGs synthesis.
In the human endometrium, the levels of PGF2α and PGE2 are similar in the early proliferative phase. As the menstrual cycle progresses, both increase, with PGF2α levels rising continuously after ovulation and peaking during menstruation, reaching six times the early proliferative phase level—significantly higher than PGE2. Thus, PGF2α is the predominant PG in the endometrium during the luteal and menstrual phases.
Although PGs are synthesized in the endometrium, their receptors are mainly located in myocytes. In vitro experiments suggest that the effect of PGs on human uterine muscle depends on the PG dose and varies with the menstrual cycle phase. PGE2 relaxes uterine muscle, while PGF2α induces muscle contraction, increasing amplitude and frequency, with this effect being more pronounced in the premenstrual phase. In vivo trials, intravenous or intrauterine administration of PGF2α to non-pregnant women can cause grade I cramping pain in the lower abdomen. Using a Teflon catheter with a miniature pressure sensor inserted through the cervix into the uterine cavity to measure intrauterine pressure changes reveals increased basal uterine muscle tension (resting pressure), elevated intrauterine pressure, and heightened contraction frequency.
PGs also have important effects on the blood vessels of the uterine membrane. PGF2α can cause the spiral arteries of the uterine membrane to contract, leading to changes in the membrane during menstruation, ultimately resulting in the shedding and expulsion of the membrane. In contrast, PGE2 acts as a vasodilator. PGI2 is a potent inhibitor of platelet aggregation and a vasodilator, suggesting its involvement in the regulation of uterine hemodynamics. It can also control the spontaneous contractions of the pregnant uterine muscle strips and reduce the muscle tension induced by PGF2α. Thromboxane (TXA2) is primarily derived from platelets and has a strong uterine contraction effect. During menstruation, the levels of TXA2 are extremely high to enhance uterine contractions and prevent hypermenorrhea. Therefore, the balance between PGF2α, PGE2, PGI2, and TXA2 during menstruation determines the amount of menstrual flow and the severity of dysmenorrhea.
(3) The relationship between dysmenorrheal and prostaglandins (PGs)
By using a miniature pressure sensor to measure the intrauterine pressure in dysmenorrheal patients and simultaneously determining local uterine blood flow, four major abnormalities were identified: ① Under resting conditions of the uterine myometrium, the baseline intrauterine pressure was >1.33～6.67kPa (>15～50mmHg), whereas under normal circumstances it is <1.33kPa; ② During uterine contractions, the intrauterine pressure increased to >16～20kPa (>120～150mmHg); ③ The contraction frequency increased, with >5 contractions within 10 minutes; ④ The contractions were uncoordinated and rhythmically disordered, leading to reduced uterine blood flow and O2 deficiency, resulting in severe pain for the patient. Between contractions, blood flow increased and pain diminished. Intravenous administration of 250mg of the β2 receptor agonist—terbutaline (metaproterenol) to the patient eliminated uterine contractions, significantly improved local blood flow, and completely relieved the pain. It is evident that the common feature of primary dysmenorrheal is excessive uterine myometrial activity, which causes local uterine ischemia due to over-contraction.
bubble_chart Clinical Manifestations
Primary dysmenorrheal often occurs in ovulatory menstruation, so there are usually no symptoms or only grade I discomfort in the first 1-2 years after menarche. Severe spasmodic pain mostly occurs in young women 1-2 years after menarche. If regular dysmenorrheal appears from the beginning or spasmodic dysmenorrheal occurs as late as after the age of 25, other abnormal conditions should be considered.
Dysmenorrheal mostly begins at the onset of menstruation or a few hours before vaginal bleeding, often presenting as spasmodic colicky pain lasting 1/2 to 2 hours. After the onset of severe abdominal pain, it transitions to moderate paroxysmal pain, lasting about 12-24 hours. The pain gradually disappears once menstrual flow becomes smooth, though occasionally some may need to stay in bed for 2-3 days. The pain is mostly located in the lower abdomen, and in severe cases, it may radiate to the lumbosacral region or the inner front of the thighs. Over 50% of patients are accompanied by gastrointestinal and cardiovascular symptoms, such as nausea, vomiting (89%), diarrhea (60%), dizziness (60%), headache (45%), and fatigue (85%). Occasionally, syncope and collapse may occur.
Primary dysmenorrheal often disappears spontaneously after childbirth or gradually fades with age after marriage.
The diagnosis of primary dysmenorrhea primarily involves ruling out the possibility of secondary dysmenorrhea. A detailed medical history should be taken, paying attention to the timing, type, and characteristics of the pain. Based on the following criteria: ① onset within 1–2 years after menarche; ② pain starting at the onset of menstruation or a few hours before, lasting no more than 48–72 hours; ③ pain characterized as spasmodic or resembling childbirth labor pain; ④ negative findings on gynecological bimanual or rectal examination—a diagnosis of primary dysmenorrhea can be made.
Diagnosis of secondary dysmenorrhea A history of recurrent pelvic inflammatory disease, irregular menstruation cycles, hypermenorrhea, intrauterine device placement, or infertility can aid in the diagnosis of secondary dysmenorrhea.
Through bimanual and rectovaginal examinations, some disease causes leading to dysmenorrhea can be identified, such as uterine malformations, uterine fibroids, ovarian tumors, or pelvic inflammatory masses. Palpation of nodular thickening of the uterosacral ligaments during rectal examination is particularly important for the early diagnosis of endometriosis.
Other examinations: Such as erythrocyte sedimentation rate, leucorrhea bacterial culture, pelvic ultrasound, hysterosalpingography, and diagnostic curettage. Finally, hysteroscopy and laparoscopy can help clarify the cause of dysmenorrhea early. Hysteroscopy can detect small lesions missed during curettage, such as small fibroids, polyps, or ulcers, providing valuable diagnostic evidence and can be performed after diagnostic curettage.
bubble_chart Treatment Measures
Primary dysmenorrhea
(1) General treatment: Engage in physical exercise to enhance constitution. Pay attention to daily routines, balance work and rest, maintain proper nutrition, and ensure adequate sleep. Emphasize education on menstrual physiology to alleviate patients' fear, anxiety, and psychological burdens through explanation and persuasion. Strengthen menstrual hygiene, avoid strenuous exercise, excessive fatigue, and prevent exposure to cold.
(2) Ovulation suppression: If the patient is willing to control fertility, oral contraceptive pills (compound formula norethisterone tablets or compound formula megestrol tablets) are the first-choice treatment for primary dysmenorrhea. Over 90% of symptoms can be relieved with oral contraceptives, likely due to inhibited endometrial growth, reduced menstrual flow, and prostaglandin (PG) levels dropping below normal, leading to decreased uterine activity. Treatment can be tried for 3–4 cycles; if the results are satisfactory, it can be continued. If symptom improvement is minimal, PGs synthesis inhibitors may be added. Since medication is required throughout the menstrual cycle while effects only appear in the last 1–2 days, this method is generally unpopular unless contraception is also needed.
(3) Prostaglandin synthesis inhibitors (PGSI): For patients unwilling to use contraception, PGSI is preferred. It inhibits endometrial PGs synthesis, significantly reducing the amplitude and frequency of uterine contractions without affecting the pituitary-ovarian axis or causing metabolic side effects like oral contraceptives. The greatest advantage is that it only needs to be taken 2–3 days before pain onset. However, a trial period is required to determine the most effective drug type and optimal dose for each individual, which may sometimes take up to six months.
Common PGSIs can be categorized by chemical structure: ① Indole and indazole derivatives: e.g., indomethacin, benzydamine (benzyrin): 25mg, 3–6 times daily, or 50mg, 3 times daily; ② Fenamates: mefenamic acid (brand name Ponstan), initial dose 500mg, then 250mg every 6–8 hours; clofenamic acid (brand name Anti-inflammatory Spirit), flufenamic acid, initial dose 400mg, then 200mg every 6–8 hours; ③ Phenylpropionic acid derivatives: ibuprofen, 400mg, 4 times daily; sodium naproxen (brand name Naproxan), initial dose 500mg, then 250mg every 6–8 hours; ④ Phenylbutazone derivatives: phenylbutazone or oxyphenbutazone, initial dose 200mg, then 100mg every 6–8 hours.
All four categories of drugs are rapidly absorbed and can be taken within the first 48 hours of menstruation. However, since menstrual onset timing varies, it is generally advisable to administer the medication 3 days before the expected menstruation to ensure efficacy, with a relief rate of around 70%. If these drugs are alternated, the effectiveness rate can reach 90%. Contraindications include gastrointestinal ulcers and allergies to the above drugs. Side effects are mild and mostly tolerable. Indomethacin has a higher incidence of gastrointestinal reactions and may cause dizziness, fatigue, weakness, headache, etc., leading to many discontinuing treatment. Fenamates or phenylpropionic acid derivatives, especially naproxen due to its prolonged action and rapid peak blood levels of its sodium salt, act quickly with minimal side effects, making them the most commonly used drugs in clinical practice.
When the dosage of PGSI is large, severe adverse reactions may occasionally occur, so caution is advised, and discontinuation of the medication should be considered if necessary. Known adverse reactions include: ①Gastrointestinal symptoms: dyspepsia, heartburn, nausea, abdominal pain, constipation, vomiting, diarrhea, and melena due to gastrointestinal bleeding; ②Central nervous system symptoms: headache, dizziness, vertigo, blurred vision, hearing impairment, dysphoria, depression, fatigue, and drowsiness; ③Other symptoms: rash, edema, bronchospasm, fluid retention, and impairment of liver and kidney function (elevated transaminases, jaundice, proteinuria, hematuria).
(4) β-receptor agonists: By stimulating the β-receptors on the muscle cell membrane, they activate adenylate cyclase, thereby increasing intracellular cAMP levels. On one hand, this promotes the phosphorylation of membrane proteins in the sarcoplasmic reticulum, enhancing the binding of Ca++; on the other hand, it inhibits the activity of myosin light-chain kinase, leading to relaxation of the uterine muscles and rapid relief of dysmenorrhea. However, it also has side effects such as increased heart rate and elevated blood pressure.
In recent years, drugs that selectively stimulate uterine β2 receptors have been clinically applied, significantly reducing side effects. Commonly used β2 receptor agonists include salbutamol (brand name Ventolin) and terbutaline (brand name Bricanyl). Administration methods include oral, aerosol inhalation, subcutaneous, intramuscular, and intravenous routes.
For severe pain, injection is preferred: salbutamol 0.1–0.3 mg intravenously or terbutaline 0.25–0.5 mg subcutaneously, every 4–8 hours. For moderate to grade I pain, oral administration is suitable: salbutamol 2–4 mg every 6 hours or terbutaline 2.5–5 mg every 8 hours. Aerosol inhalation of 0.2–0.25 mg every 2–4 hours is also an option. Aerosol inhalation is preferable due to its rapid onset and lower dosage. When using aerosol inhalation, note the following: ① First exhale completely; ② Inhale the medication deeply at the start of inhalation; ③ Hold the breath for 3–4 seconds after inhalation; ④ Then exhale slowly through pursed lips. The usual dose is two inhalations per session, lasting 4–6 hours. However, the efficacy of β-receptor agonists is generally considered unsatisfactory, and side effects such as palpitations and tremors persist, limiting their widespread use. Nonetheless, the convenience and rapid action of aerosol administration make it worth trying.
(5) Calcium channel blockers: These drugs interfere with Ca++ transport across the cell membrane and prevent Ca++ release from intracellular stores, relaxing smooth muscle contractions. This represents a significant advancement in the treatment of cardiovascular diseases. Nifedipine (brand names Adalat, Procardia), 20–40 mg, is used to treat primary dysmenorrhea. Within 10–30 minutes of administration, uterine contractions weaken or cease, with reductions in amplitude, frequency, and duration of muscle contractions, along with decreased basal tension and pain relief lasting up to 5 hours, without significant side effects.
(6) Vitamin B6 and magnesium-amino acid chelates: Vitamin B6 promotes Mg++ transport across the cell membrane, increasing intracellular Mg++ concentration, which is used to treat primary dysmenorrhea. A daily dose of 200 mg for 4 weeks significantly increases red blood cell magnesium levels. It can also be combined with magnesium-amino acid chelates, 100 mg each, taken twice daily for 4–6 months, progressively reducing the severity and duration of dysmenorrhea. (7) Gossypol and Chinese patent drugs: Gossypol acetic acid, 20 mg daily for 3–6 months, achieves over 95% efficacy in treating primary dysmenorrhea. However, it may cause significant side effects such as fatigue, palpitations, nausea, edema, dizziness, hot flashes, anorexia, osmotic diarrhea, and even severe conditions like thrombocytopenia and hypokalemia. Chinese patent drugs like Cinnamon Twig and Poria Pill or Peach Kernel Chengqi Decoction, 5 g daily, divided into doses taken 30 minutes before breakfast and dinner for 30 days, have been reported to achieve an 80% relief rate without gastrointestinal symptoms or rashes. Secondary dysmenorrhea The treatment principle for secondary dysmenorrhea is to address the underlying cause of the condition with targeted therapy. Dysmenorrhea caused by intrauterine devices can be treated with PGs synthesis inhibitors, which not only relieve dysmenorrhea but also reduce menstrual volume. In recent years, progesterone-releasing intrauterine devices have been developed, which can decrease the PGs content in menstrual blood and alleviate the severity of dysmenorrhea. For patients with unsatisfactory therapeutic effects, it is advisable to remove the intrauterine device and switch to other contraceptive methods. For patients with atypical medical history or unsatisfactory pelvic examination, an ultrasound scan is recommended. If the pelvic examination shows no positive signs and the use of contraceptive drugs or PGs synthesis inhibitors is effective, a diagnosis of primary dysmenorrhea can be made. If there is no improvement after 5-6 treatment cycles, further examinations such as laparoscopy or hysteroscopy should be performed to rule out organic sexually transmitted diseases such as endometriosis or submucous fibroids.
