Dysmenorrhea refers to a person's abdominal spasmodic pain before and after menstruation or menstrual period, which seriously affects daily life. There are two kinds: primary and secondary. After detailed gynecological clinical examination, those who fail to find obvious abnormalities in pelvic organs are called primary dysmenorrhea, also known as functional dysmenorrhea. Secondary dysmenorrhea refers to obvious pathological changes in reproductive organs, such as endometriosis, pelvic inflammatory disease, tumors and so on.
diagnose
The diagnosis of primary dysmenorrhea mainly lies in excluding the possibility of secondary dysmenorrhea. The medical history should be inquired in detail, and the time, type and characteristics of pain should be paid attention to. According to: ① onset after menarche 1 ~ 2 years; ② Pain begins several hours before or after menstrual blood appears, and lasts for no more than 48 ~ 72 hours; ③ The nature of pain is spastic or similar to labor pain; ④ Gynecological diagnosis of Shuanghe Town or anus was negative. The diagnosis of primary dysmenorrhea can be obtained.
Diagnosis of secondary dysmenorrhea The history of recurrent pelvic inflammatory disease, irregular menstrual cycle, menorrhagia, intrauterine device placement and infertility is helpful for the diagnosis of secondary dysmenorrhea.
Through the diagnosis of Shuanghe Town and Sanlian, we can find some causes of dysmenorrhea, such as uterine malformation, hysteromyoma, ovarian tumor and pelvic inflammatory disease. Nodular thickening of uterosacral ligament diagnosed by anal examination is particularly important for early diagnosis of endometriosis.
Other examinations: erythrocyte sedimentation rate, leucorrhea bacterial culture, B-ultrasound pelvic scanning, hysterosalpingography, diagnosis of curettage, and finally hysteroscopy and laparoscopy can identify the cause of dysmenorrhea as soon as possible. Hysteroscopy can find small lesions missed during curettage, such as small fibroids, polyps, ulcers, etc., and provide valuable diagnostic basis, which can be performed after curettage.
Treatment measures
Primary dysmenorrhea
(1) General treatment: physical exercise to enhance physical fitness. Pay attention to the law of life on weekdays, combine work and rest, have proper nutrition and get enough sleep. Pay attention to the publicity and education of menstrual physiology, and eliminate the fear, anxiety and mental burden of patients through explanation and persuasion. Strengthen menstrual hygiene, avoid strenuous exercise and overwork, and prevent colds.
(2) Inhibition of ovulation: If the patient is willing to control fertility, oral contraceptive tablets (compound norethindrone tablets or compound progesterone tablets) are the first choice for the treatment of primary dysmenorrhea. Oral contraceptives can relieve more than 90% of the symptoms, which may be due to the inhibition of endometrial growth, the decrease of menstrual flow and the decrease of PG below the normal level, which leads to the weakening of uterine activity. The treatment can be tried for 3 ~ 4 cycles, and if the curative effect is satisfactory, you can continue to take it; If the symptoms are not improved obviously, PGs synthesis inhibitor can be added appropriately. Because the drug should be used throughout the menstrual cycle, and the effect is only 1 ~ 2 days at the end of the cycle, unless contraception is needed at the same time, it is generally unpopular with patients.
(3) Prostaglandin synthesis inhibitor (PGsI): PGSI should be selected for patients who are unwilling to use contraception. It inhibits the synthesis of PGS in endometrium, significantly reduces the amplitude and frequency of uterine contraction, but does not affect the function of pituitary-ovarian axis, nor does it cause metabolic side effects like oral contraceptives. As long as it is taken before the onset of pain, it can last for 2 ~ 3 days, which is its greatest advantage. But we need to try a stage to determine the most satisfactory drug type and the most suitable dose for everyone. The trial adjustment period can sometimes be as long as half a year.
According to its chemical structure, commonly used PGSI can be divided into: ① Indole indazoles (such as indomethacin and benzazine): 25mg, 3-6 times a day or 50mg, 3 times a day; (2) Acetic acid: methyl formate (trade name ponstan), initial dosage 500mg, later period 250mg, within 6-8 hours 1 time, chloranilic acid, trade name Xiaoyan Ling, flumizinic acid, initial dosage 400mg, later period 200mg, within 6-8 hours 1 time; (3) phenylpropionic acid derivative: p-isobutyl propionic acid, trade name ibuprofen, 400mg, 4 times a day, methoxynaproxen sodium, trade name naproxen, 500mg for the first dose, 250mg for the second time, 65438+6-8 hours, 0 times; ④ Patasone: Patasone or oxybupropion, the first dose is 200mg, then 100mg, within 6-8 hours 1 time.
The above four drugs are absorbed quickly and can be taken within 48 hours before menstruation. However, due to the frequent differences in the onset time of menstruation, it is generally appropriate to give drugs three days before menstruation to ensure the curative effect, and the remission rate is about 70%. If the above drugs are substituted, the effective rate can reach 9%. Gastrointestinal ulcer and allergic to the above drugs are prohibited. The side effects are mild and most of them can be tolerated. Among them, only indomethacin has a high incidence of intestinal reaction, and symptoms such as dizziness, fatigue and headache appear. It can also happen, so that many people stop taking drugs during treatment. A class of drugs such as deacidification or phenylpropionic acid derivatives, especially methoxynapropionic acid, have a long duration of action, and its sodium salt quickly reaches a high value in the blood, so it takes effect quickly and has little side effects, and is the most widely used drug in clinic at present.
When the dosage of PGSI is large, serious side effects will occasionally occur, which should be paid attention to and stopped when necessary. The known side effects are: ① gastrointestinal symptoms: indigestion, heartburn, nausea, abdominal pain, constipation, vomiting, diarrhea and melena caused by gastrointestinal bleeding; ② Central nervous system symptoms: headache, dizziness, dizziness, blurred vision, hearing impairment, irritability, depression, burnout and lethargy; ③ Other symptoms: rash, edema, bronchospasm, fluid retention, liver and kidney dysfunction (elevated transaminase, jaundice, proteinuria, hematuria).
(4) Beta receptor agonist: By exciting the beta receptor on the muscle cell membrane, the adenylate cyclase is activated, and then the intracellular cAMP content is increased. On the one hand, it promotes phosphorylation of sarcoplasmic reticulum membrane protein and strengthens Ca++ binding; On the other hand, it inhibits the activity of myosin light chain kinase, relaxes uterine muscles and relieves dysmenorrhea quickly, but at the same time it has the side effects of increasing heart rate and hypertension.
In recent years, the clinical application of drugs that stimulate uterine β2 receptor alone has obviously reduced the side effects. Commonly used β _ 2 receptor stimulants are: hydroxyisobutyrine, trade names are sulbactam and m-hydroxyisobutyrine, and terbutaline. Administration methods include oral administration, aerosol inhalation, subcutaneous injection, intramuscular injection and intravenous administration.
In severe pain, injection method should be adopted: salbutamol 0. 1 ~ 0.3 mg, intravenous injection or m-hydroxysalbutamol 0.25 ~ 0.5 mg, subcutaneous injection, 1 time, lasting 4 ~ 8 hours. Moderate and mild pain can be taken orally, with salbutamol 2 ~ 4 mg/6h or m-hydroxysalbutamol 2.5 ~ 5 mg/8h, or 0.2 ~ 0.25 mg atomized inhalation, 2 ~ 4 hours 1 time. Atomization inhalation has better effect, because the dosage is small and the effect is quick. Attention should be paid to atomization inhalation: ① Breathe out the air with your big mouth first; ② Inhale liquid medicine at the beginning of deep inhalation; ③ Hold your breath for 3 ~ 4 seconds after inhaling; (4) Then curl your lips and exhale slowly. Usually the dosage is inhaled twice each time, which can last for 4 ~ 6 hours. However, it is generally reflected that the efficacy of β -receptor stimulants is not satisfactory, and there are still side effects such as palpitation and trembling, so they have not been widely used. However, the aerosol method is easy to use and quick to take effect, and it can still be tried.
(5) Calcium channel blockers: These drugs interfere with the permeation of Ca++ through the cell membrane and prevent Ca++ from being released from the intracellular inventory and releasing smooth muscle contraction, which is an important progress in the treatment of cardiovascular diseases. Nifedipine (Nifedipine, trade name: Xintongding, Li Xinping 20 ~ 40 mg) is used to treat primary dysmenorrhea. 10 ~ 30 minutes later, the uterine contraction weakened or disappeared, the amplitude, frequency and duration of muscle contraction decreased, the basal tension decreased, and the pain was relieved for 5 hours without special side effects.
(6) Vitamin B6 and magnesium amino acid chelate: Vitamin B6 can promote magnesium ion (Mg++) to penetrate cell membrane, increase the concentration of Mg++ in cytoplasm, and treat primary dysmenorrhea. 200mg daily, after 4 weeks, the content of magnesium in red blood cells increased obviously. It can also be combined with amino acid chelated magnesium, each time 100mg, twice a day for 4 ~ 6 months. The severity and duration of dysmenorrhea are gradually decreasing.
Gossypol and Chinese patent medicine: gossypol acetate 20mg, taken/kloc-0 once a day for 3 ~ 6 months, has a curative effect on primary dysmenorrhea of over 95%. But there may be obvious side effects, such as fatigue, palpitation, nausea, edema, dizziness, hot flashes, anorexia, osmotic diarrhea and so on. Severe thrombocytopenia and hypokalemia may also occur. Chinese patent medicines include Guizhi Fuling Pill or Ren Tao Chengqi Decoction, with a daily dose of 5g, taken 30 minutes before breakfast and dinner for 30 days. It has been reported that the remission rate can reach 80%, and no side effects such as digestive tract symptoms and rash have been found.
Secondary dysmenorrhea
The treatment principle of secondary dysmenorrhea is targeted treatment for the lesions that cause dysmenorrhea.
Dysmenorrhea caused by intrauterine device can be treated with PGs synthesis inhibitor, which can relieve dysmenorrhea and reduce menstrual flow. In recent years, there are contraceptives containing progesterone, which can reduce the content of PGs in menstrual blood to alleviate the severity of dysmenorrhea; For patients whose curative effect is still not significant, IUD can be removed and other contraceptive measures can be used.
etiology
Primary dysmenorrhea is generally attributed to the following reasons: endometrial tube shedding (membranous dysmenorrhea), uterine hypoplasia, uterine flexion, cervical canal stenosis, bad posture and physical factors, allergic state and mental factors.
Patients with secondary dysmenorrhea are diagnosed as secondary dysmenorrhea if pelvic organ lesions are found in Shuanghe town. It is often misdiagnosed as primary dysmenorrhea when the local abnormal signs are not obvious, so if dysmenorrhea begins more than 3 years after menarche, the possibility of secondary dysmenorrhea should be considered and further examination should be made.
The common cause of secondary dysmenorrhea in young women is endometriosis, which is very similar to the symptoms of primary dysmenorrhea. If the patient has a family history of progressive dysmenorrhea or endometriosis (one of the mother or sister has this disease), laparoscopic examination should be performed as soon as possible to make a definite diagnosis, and conservative surgery should be performed as soon as possible to preserve fertility.
In addition, the causes of secondary dysmenorrhea are: congenital uterine malformation (including biconical uterus, mediastinal uterus, residual horn uterus, vaginal septum, etc. ), pelvic inflammatory disease, adenomyosis, hysteromyoma, uterine polyp, uterine adhesion, cervical canal stenosis, ovarian cyst, pelvic blood stasis syndrome.
Patients with elevated body temperature during menstruation should consider pelvic inflammatory disease in addition to dysmenorrhea. About 5% of women with intrauterine devices suffer from dysmenorrhea. If there is no infection, the cause of dysmenorrhea may be that the intrauterine device stimulates the endometrium and PGs is released too much, resulting in excessive contraction of uterine muscles.
Patients with uterine malformation and complete obstruction of lower reproductive tract may have periodic lower abdominal pain, no menstrual cramps after menarche, and other secondary sexual characteristics are normal. Periodic lower abdominal pain is secondary to reproductive tract hematocele, which usually occurs within 2 ~ 3 years after breast development. Genital tract malformation, hymen atresia and obstruction of vaginal septum can be easily diagnosed by gynecological examination. However, if one side of the reproductive tract is blocked and the other side is unobstructed due to fusion defects, such as undivided double uterus, blind end of one side of vagina or residual angle of uterus that is not connected with vagina, it is difficult to diagnose. These patients have a history of aggravated dysmenorrhea, and they can touch the lump when they are diagnosed, which is easy to be misdiagnosed as vaginal cyst's or ovarian tumor.
Adenomyosis, endometrial polyps and hysteromyoma are relatively rare among adolescent girls. Dysmenorrhea induced by this lesion mostly occurs after the age of 25, and the type of pain is uncertain and the pain lasts for a long time.
pathogenesis
(1) Molecular biology of uterine muscle contraction: The basic functional unit of muscle is myofibril, which consists of myosin (or myosin) and actin (or actin). The relative activity of the two forms muscle contraction, which is the gliding theory of muscle contraction. In addition, there is an important regulatory protein called calmodulin, which blocks the connection between myosin and actin during muscle rest. When nerve impulses are transmitted to muscles, the membrane protein of sarcoplasmic reticulum changes in configuration, and the permeability to calcium ions (Ca++) is greatly increased, and Ca++ stored in sarcoplasmic reticulum is released in large quantities. When the concentration of Ca++ in cytoplasm rises to a certain extent, it will combine with calmodulin, which will change its configuration and combine with inactive myosin light chain kinase to form an active complex. Through ATP hydrolysis, myosin light chain is phosphorylated, which leads to the combination of myosin and actin, and their relative activity is muscle contraction.
When the nerve impulse stops, the permeability of sarcoplasmic reticulum membrane protein to Ca++ decreases, and Ca++ in cytoplasm is transported back to sarcoplasmic reticulum for storage by CA pump (protein with ATPase and adenosine triphosphatase activity). When the concentration of Ca++ returned to pre-contraction, calmodulin was separated from myosin light chain kinase. Another phosphatase separates phosphoric acid from myosin light chain to dephosphorize myosin light chain; However, myosin light chain kinase itself is phosphorylated under the action of camp-dependent protein kinase, which obviously reduces the affinity for calmodulin and makes smooth muscle return to a relaxed state.
Besides Ca++ and calmodulin, cAMP also regulates the function of myosin light chain kinase at the cellular level. On the one hand, cAMP promotes the phosphorylation of the former kinase itself, thus inhibiting its activity; on the other hand, it promotes the phosphorylation of sarcoplasmic reticulum membrane proteins, strengthens the binding and storage with Ca++, and reduces the concentration of Ca++ in cytoplasm. By exciting β -adrenergic receptor and activating adenylate cyclase, the content of cAMP in cells increases, so adrenergic nerves participate in the relaxation mechanism of smooth muscle.
The balance between contraction and relaxation of smooth muscle mainly depends on the level of active myosin light chain kinase, and the activity of this enzyme is determined by the intracellular Ca++ concentration.
ATP is hydrolyzed by ATPase to release phosphoric acid and energy, which is the direct source of myosin phosphorylation and energy needed. Atpase needs the activation of magnesium ion (Mg++), so Mg++ can consume ATP by activating ATPase, and relax uterine muscles. When Mg++ reaches 1.6 ~ 3 mmol/L (3.2 ~ 6 meq/L), the basic tension of myometrium decreases obviously, and the contraction amplitude and frequency decrease obviously.
Prostaglandins (PGs) also play an important role in smooth muscle contraction. As a carrier of Ca++, PGs can increase the backflow of Ca++ through the sarcoplasmic membrane, promote the release of Ca++ stored in sarcoplasmic reticulum, and increase the intracellular concentration of Ca++. PGs can also inhibit adenylate cyclase, block the formation of cAMP, reduce the phosphorylation of sarcoplasmic reticulum membrane protein, reduce the binding with Ca++, and finally lead to the increase of cytoplasmic Ca++, triggering myofibril contraction.
(2) Periodic change of prostaglandin (PGs): PGs is different from the hormone of general endocrine gland, it is not synthesized by a specific endocrine gland, but stored in inventory, released when necessary, and acts on target organs through blood circulation; It releases the precursor arachidonic acid locally through the influence of nerves or hormones when the body needs it, and can be synthesized, released and played a role immediately. Therefore, it is a local hormone. Only PGI2, unlike other PGs, metabolizes rapidly in the lungs. It can be used as a circulating hormone.
PGs in uterus mainly comes from endometrium. Lysosomes in endometrial cells are stimulated to release phospholipase A2(PLA2). Through the catalysis of PLA2, arachidonic acid combined with phospholipids on cell membrane was released. As the precursor of PGs synthesis, the biosynthesis of PGs was initiated, mainly the formation of PGF2α. In recent years, it has been reported that the concentration of PGF in endometrium is linearly related to the logarithmic value of 17β- estradiol (E2) concentration in uterine venous blood, while the concentration of PGE in menstrual cycle is basically constant. It is known from the experiment that E2 can promote the formation of lysosomes in cells, especially with the cooperation of progesterone (P), a large number of lysosomes are developed in endometrial stromal cells. Due to the accumulation of PLA2 in lysosomes, once lysosomes degenerate, PLA2 is released and more arachidonic acid is released, which promotes the synthesis of PGs.
The content of PGFs in human endometrium is close to that in the early stage of hyperplasia, and gradually increases with the progress of menstrual cycle. After ovulation, PGFs continued to increase, reaching the peak in menstrual period, which was 6 times that of the initial stage of hyperplasia and significantly higher than PGE2. Therefore, PGF is the most important PGF in luteal phase and menstrual period.
Although PGs is synthesized in intima, PGs receptor is mainly in muscle cells. In vitro experiments show that the effect of PGs on human uterine muscles is related to the dose of PGs and changes with the time of menstrual cycle. PGE2 relaxes uterine muscles, while PGF2α promotes muscle contraction, increasing the amplitude and frequency, especially in premenstrual period. In vivo, intravenous injection or intrauterine injection of PGF2α to normal non-pregnant women can cause mild spasmodic pain in the lower abdomen. A PTFE catheter with a miniature pressure sensor was put into the uterine cavity through the cervix, and the contraction of uterine myometrium was recorded by measuring the pressure change in the uterine cavity. It can be seen that the basic tension (static pressure) of uterine muscle increases, the intrauterine pressure increases and the contraction frequency increases.
PGs also has an important effect on endometrial blood vessels. PGF2α can cause the contraction of endometrial spiral artery, which leads to the change of endometrial menstrual period, and finally the endometrium is exfoliated and discharged. However, PGE2 plays a role in vasodilation. PGI _ 2 _ 2 is a powerful platelet aggregation inhibitor and vasodilator, suggesting that PGI _ 2 _ 2 may be involved in the regulation of uterine hemodynamics, and can control the spontaneous contraction of pregnant uterine muscle strips and reduce the muscle tension caused by PGF _ 2α. Thromboxane (TXA2) mainly comes from platelets and has a strong uterine contraction. During menstruation, TXA2 content is extremely high to strengthen uterine contraction and prevent menorrhagia. Therefore, the balance of PGF2α, PGE2, PGI2 and TXA2 during menstruation determines the amount of menstrual flow and the severity of dysmenorrhea.
(3) Relationship between dysmenorrhea and prostaglandin (PGs): The uterine cavity pressure and local uterine blood flow of patients with dysmenorrhea were measured by micro-pressure sensor, and four main abnormalities were found: ① When the myometrium was at rest, the uterine cavity basic pressure was >1.33 ~ 6.67 kPa (>15 ~ 50 mHg), and the normal situation was < 65443. ② During uterine contraction, uterine pressure increased, >16 ~ 20kpa (>120 ~150mmhg); (3) The contraction frequency increased by more than 5 times within 65438 00 minutes; (4) The uncoordinated uterine contraction and disordered rhythm lead to the decrease of uterine blood flow and the lack of O2, resulting in severe pain. The blood flow in the contraction gap increases and the pain is relieved. Intravenous injection of 250 mg β _ 2 receptor stimulant-m-hydroxyshuchuanning (m-hydroxytert-butylepinephrine) to the patient, the uterine contraction disappeared, the local blood flow was obviously improved, and the pain was completely relieved. It can be seen that the common feature of primary dysmenorrhea is that the myometrium of uterus is too active, which leads to uterine ischemia due to excessive contraction.
clinical picture
Primary pain often occurs in ovulation menstruation, so it is generally asymptomatic or only mildly uncomfortable after menarche 1 ~ 2 years. Severe spasmodic pain mostly occurs in young women after menarche in 1 ~ 2 years. If you have regular dysmenorrhea at the beginning or spasmodic dysmenorrhea after the age of 25, you should consider other abnormal conditions.
Dysmenorrhea usually begins a few hours before menstrual cramps or vaginal bleeding, and it is often spasmodic colic and lasts for 1/2 ~ 2 hours. Severe abdominal pain turned into moderate paroxysmal pain after the attack, lasting about 12 ~ 24 hours. After the menstrual blood flow is smooth, it gradually disappears, and occasionally it is necessary to stay in bed for 2 to 3 days. The pain is mostly in the lower abdomen, and in severe cases, it can radiate to the lumbosacral part or the inner front side of the thigh. About 50% patients have gastrointestinal and cardiovascular symptoms. Such as nausea, vomiting (89%), diarrhea (60%), dizziness (60%), headache (45%) and fatigue (85%). Occasionally syncope and collapse.
Primary dysmenorrhea often disappears spontaneously after delivery or gradually disappears with age after marriage.
differential diagnosis
Those with atypical medical history and unsatisfactory pelvic examination should be scanned by B-ultrasound. There are no positive signs in pelvic examination, and primary dysmenorrhea can be diagnosed by contraceptive drugs or PGs synthesis inhibitors. If the drug is ineffective in 5 ~ 6 cycles, further laparoscopy or hysteroscopy should be performed to rule out organic diseases such as endometriosis and submucosal myoma.