| disease | Premenstrual Tension Syndrome |
| alias | Premenstrual Tension Syndrome, Premenstrual Tension, Late Luteal Phase Anxiety Disorder, LLPDD, PMS |
Women of childbearing age experience a series of mental, behavioral, and constitutional symptoms repeatedly 7 to 14 days before menstruation (i.e., during the luteal phase of the menstrual cycle), which quickly disappear after the onset of menstruation. Due to the more prominent mental and emotional disturbances of this condition, it was previously referred to as "premenstrual tension" or "premenstrual tension syndrome." In recent years, it has been recognized that the symptoms of this condition are widespread, affecting not only mental and neurological symptoms but also several unrelated organs and systems, including a variety of organic and functional symptoms. Therefore, it is collectively termed "premenstrual syndrome (PMS)." However, some scholars emphasize the symptoms related to emotional abnormalities and propose "late luteal phase dysphoric disorder (LLPDD)" as a subtype of PMS.
bubble_chart Pathogenesis
(1) Fluid retention: Excessive aldosterone hormone causes systemic fluid retention, which is often used to explain the formation of PMS. It is known that progesterone can block the effect of aldosterone on renal tubules, promoting the excretion of sodium in urine. However, progesterone-induced sodium loss leads to compensatory increases in aldosterone. Additionally, the enhanced conversion of progesterone into deoxycorticosterone and other mineralocorticoids in the latter half of menstruation increases aldosterone secretion before menstruation, peaking just before the period. Thus, the increased aldosterone excretion during the luteal phase is physiological, helping to maintain stable plasma sodium levels. Moreover, measurements of plasma aldosterone levels in PMS patients have not shown significant differences compared to control groups, which does not support the above theory.
(3) Increased prolactin (PRL) excretion: In recent years, there has been significant debate over whether increased PRL excretion is a major disease cause factor in PMS. Plasma PRL concentrations follow a circadian rhythm, peaking during sleep, and also show significant daily fluctuations. PRL levels reach their highest point during ovulation, with average levels in the luteal phase being higher than in the follicular phase. Some PMS patients exhibit higher average PRL concentrations throughout the menstrual cycle compared to healthy women, particularly more pronounced premenstrually. Treatment with bromocriptine to suppress PRL secretion has shown significant symptom relief. Elevated PRL levels during the luteal phase may accompany decreased progesterone excretion or reduced FSH/LH levels, theoretically supporting the idea that increased PRL plays a role in PMS formation. However, most studies have not found significant differences in PRL levels between normal individuals and PMS patients. PRL's role in osmotic regulation is more pronounced in animals than in humans, possibly only affecting mammary glands by altering local osmotic balance, leading to breast swelling and tenderness. Additionally, women with hyperprolactinemia rarely exhibit PMS symptoms. Bromocriptine treatment primarily alleviates breast symptoms with limited effects on other symptoms, leaving the theory of increased PRL excretion lacking strong, reliable evidence.
(4) Imbalance in ovarian steroid hormones: For years, the hormone disease cause theory of PMS has focused on estrogen (E) and progesterone (P) imbalance or withdrawal reactions. This is because the characteristic emotional, behavioral, and constitutional symptoms of PMS consistently occur during the luteal phase of the menstrual cycle, aligning with the development of the corpus luteum. Thus, it is hypothesized that certain triggers originate from the corpus luteum, likely due to declining progesterone levels or altered E/P ratios in the mid-to-late luteal phase. However, recent studies have not found abnormalities in ovarian hormone production or metabolism in PMS patients. The average levels of ovarian steroids in PMS patients show no difference from those in healthy individuals. The fact that PMS patients maintain normal reproductive function without impaired fertility further supports the notion that their ovarian hormones remain in normal balance.(5) Neurotransmitter-neuroendocrine system imbalance
1. Endorphin (β-endorphin, β-EP) theory: Experimental studies have confirmed that β-EP participates in the regulation of GnTH secretion during the menstrual cycle in normal women. It indirectly inhibits LH secretion through the hypothalamus. This inhibitory effect is also influenced by ovarian hormones. It is known that the activity level of β-EP in the brain is lowest during the menstrual period and early follicular phase, reaching its peak during the luteal phase.
2.5 Serotonin (serotonin, Sr) theory: It is known that the neurotransmitter Sr plays a mediating role in the occurrence of emotional and behavioral disorders. Administering small doses of Sr-function-reducing drugs to monkeys can induce behavioral changes in experimental animals, suggesting that abnormal Sr metabolism may be linked to the pathogenesis of PMS. Reports indicate that PMS patients exhibit significantly lower levels of Sr in whole blood during the last 10 days of the menstrual cycle, whereas the control group shows elevated Sr levels starting from the mid-luteal phase. This results in marked differences in Sr levels between the two groups during the mid- to late-luteal phase and the premenstrual phase. Tryptophan loading tests (50mg/kg) revealed that both groups exhibited a fixed increase in whole-blood Sr levels during the follicular and mid-luteal phases. However, by the late-luteal and premenstrual phases, the control group continued to show elevated levels, while PMS patients experienced a decline. This indicates that PMS patients exhibit defects in the Sr-related nervous system during the premenstrual phase, leading to altered responsiveness to stimuli.
bubble_chart Clinical Manifestations
There are over 150 symptoms associated with PMS, but not every patient experiences all of them. Each individual has their own prominent symptoms, and the severity varies from person to person and over time, rather than being fixed. However, the onset and resolution of symptoms in relation to menstruation are generally consistent, which is a characteristic feature of this condition. Fertility and the number of pregnancies or deliveries are not associated with PMS. The duration of the condition varies; those with severe symptoms requiring treatment tend to have a longer course, with about 40% of patients experiencing symptoms for 1–5 years, and 10% lasting over 10 years.
Typical symptoms often begin one week before menstruation, gradually worsening and peaking in severity 2–3 days before menstruation, then suddenly disappearing after the period starts. Some patients experience a longer resolution period, with symptoms gradually diminishing and persisting until 3–4 days after menstruation begins. Another less common type is the biphasic pattern, where there are two distinct phases of severe symptoms: one around ovulation, followed by a symptom-free interval, and then the reappearance of typical symptoms one week before menstruation. Previously termed "mid-cycle tension," this pattern shares the same clinical symptoms and pathological mechanisms as PMS and is actually a special subtype of PMS.
(1) Psychological symptoms: These include changes in mood, cognition, and behavior. Initially, patients may feel general lack of strength, fatigue, drowsiness, or sleepiness. Emotional changes manifest in two distinct types: one involves nervousness, restlessness, dysphoria, irritability, and heightened emotional reactions to trivial matters, leading to arguments, crying, or loss of control; the other type involves listlessness, depression, anxiety, sadness, emotional numbness, social withdrawal, difficulty concentrating, impaired judgment, and even paranoid delusions or suicidal thoughts.
(2) Fluid retention symptoms
1. Hand, foot, and eyelid edema: This is relatively common. A few patients experience significant weight gain, making normally well-fitting clothes feel tight and uncomfortable. Some report abdominal bloating, accompanied by nausea, vomiting, or other gastrointestinal disturbances, occasionally with intestinal spasms. Clinically, diarrhea and frequent urination may occur during menstruation. Due to pelvic tissue edema and congestion, symptoms such as pelvic distension and lower back pain may also arise.
2. Premenstrual headache: A common complaint, usually bilateral but sometimes unilateral, with pain occurring in varying locations, often in the temples or occipital region. It may be accompanied by nausea and vomiting, appearing a few days before menstruation and peaking at the onset of menstrual flow. The headache may be continuous or episodic, possibly related to intermittent intracranial edema, and can be confused with menstrual migraines. The latter, however, are typically unilateral and preceded by dizziness, nausea, or other prodromal symptoms minutes to hours before onset, along with visual disturbances (e.g., flashing lights or blind spots) and nausea or vomiting during the attack. Differentiation can be made based on headache location, severity, and accompanying symptoms.
3. Breast distending pain: Before menstruation, the breasts often feel full, swollen, and painful, particularly along the outer edges and nipple areas. In severe cases, pain may radiate to the armpits and shoulders, disrupting sleep. On palpation, the breasts are tender and diffusely firm or thickened, sometimes with granular nodules but no localized lumps. Symptoms completely resolve after menstruation and reappear in the next cycle, though their severity is not fixed. Generally, symptoms resolve on their own within 2–3 years without treatment. If lobular hyperplasia occurs, persistent pain may be present throughout the menstrual cycle, worsening premenstrually. Palpation may reveal flat, granular, dense areas with indistinct borders that do not resolve post-menstruation. Comparing examinations before and after menstruation may reveal significant changes in lump size.
(3) Other symptoms
1. Appetite changes: Increased appetite is common, often with cravings for sweets or salty foods. Some patients develop aversions to specific foods or experience anorexia.
2. Symptoms of autonomic nervous system dysfunction: Manifestations include tidal fever, sweating, dizziness, vertigo, and palpitations due to unstable vasomotor activity.
3. Oily skin, acne, changes in libido.
The diagnosis primarily relies on understanding the patient's medical history, as well as family and household history. Since many patients exhibit emotional disturbances and psychiatric symptoms, special attention must be paid to these aspects. Currently, clinical diagnosis is mainly based on the following three key criteria: ① The cyclical appearance of at least one psychoneurotic symptom, such as fatigue, irritability, depression, anxiety, sadness, hypersensitivity, suspicion, emotional instability, etc., and one constitutional symptom, such as breast distending pain, limb swelling, abdominal distension and fullness discomfort, headache, etc., during the first three menstrual cycles; ② Symptoms recur during the luteal phase of the menstrual cycle, and there must be an asymptomatic interval during the late follicular phase, meaning the symptoms disappear no later than four days after the onset of menstruation and do not recur before the twelfth day of the next cycle; ③ The severity of the symptoms is sufficient to affect the patient's normal life and work. Only those who meet all three criteria can be diagnosed with PMS.
Mortola (1992) proposed a quantitative diagnostic standard based on symptom scoring. Over three years, he prospectively analyzed 170 women with PMS and an asymptomatic control group, identifying the 12 most common emotional, behavioral, and conduct symptoms and the 10 most common constitutional symptoms of PMS, listed in order as: fatigue (apathy), irritability, abdominal distension and fullness with limb swelling, anxiety/tension, breast distending pain, emotional instability, depression, food cravings, acne, increased appetite, hypersensitivity, edema, dysphoria (irritability), tearfulness, preference for solitude, headache, forgetfulness, gastrointestinal symptoms, difficulty concentrating, tidal fever, palpitations, and vertigo. Each symptom is scored based on severity: mild symptoms that do not interfere with daily life score 1 point; grade II symptoms that affect daily life but do not incapacitate or prevent work score 2 points; and grade III symptoms that severely impact daily life and render the patient unable to work score 3 points. The total scores for the follicular phase (days 3–9 of the cycle) and the luteal phase (the last 7 days of the cycle) are calculated separately. The diagnostic criteria for PMS are: ① The total luteal phase score must be at least twice the follicular phase score; ② The total luteal phase score must exceed 42 points; ③ The total follicular phase score must be below 40 points—if it exceeds 40, other conditions should be considered. Although this method is cumbersome, it minimizes misdiagnosis. In summary, pure PMS must include an asymptomatic interval before ovulation; otherwise, it must be differentiated from other conditions (where symptoms only worsen before menstruation).
bubble_chart Treatment Measures
Since the disease cause and mechanism of disease are still unclear, there is currently no specific or standardized treatment method, and symptomatic treatment is primarily employed. Therefore, the first step is to clearly identify the main aspects of the symptoms, tailor the treatment to the individual, and address the symptoms accordingly. This includes two aspects: ① Addressing the patient's psychopathological factors through health education, helping the patient understand the physiological basis of the symptoms to improve their response to them. This is supplemented by adjusting daily routines, strengthening physical exercise, improving nutrition, and reducing environmental stress reactions to alleviate symptoms. ② Pharmacotherapy, using drugs that modulate the activity of neurotransmitters in the central nervous system to alleviate psychological and emotional disturbances, or using hormones to suppress ovulation to eliminate severe PMS symptoms such as breast distending pain. For clinical reference, the treatment plans targeting the main symptoms are outlined as follows:
(1) Strengthening health education: Help patients recognize that PMS is a common phenomenon among women of childbearing age. Through a series of lifestyle adjustments and simple drug treatments, symptoms can be alleviated, thereby eliminating the patient's concerns and unnecessary psychological burdens. This prepares them psychologically before symptoms appear and encourages preventive measures in daily life and nutrition.
(2) Supplementing minerals and vitamins: These have been widely used to treat PMS. Reports suggest that daily intake of 1000mg Ca and 360mg Mg can improve negative emotions, water retention, and pain during the luteal phase. However, the mechanism of action is not understood, and treatment outcomes vary significantly. Some patients experience marked improvement, while others see no effect at all.
(3) Correcting typical edema retention: Since there is no experimental confirmation of actual fluid retention in PMS patients, diuretics are not immediately necessary. If symptoms do not improve after reducing salt intake and supplementing calcium and magnesium, or if weight gain exceeds 2500g during the luteal phase, a diuretic—spironolactone (25mg, four times daily)—can be administered from days 18 to 26 of the cycle. Potassium excretion is minimal, so potassium supplementation is unnecessary, and dependency is unlikely. Besides reducing swelling and weight, this can also alleviate psychiatric symptoms, including lethargy, drowsiness, depression, and sadness.
(4) Breast distending pain: Wearing a supportive bra, reducing intake of coffee bean-containing beverages, and oral contraceptives can help alleviate symptoms. The most economical option with fewer side effects is oral gestrinone, a synthetic 19-norsteroid with androgen and anti-E/P properties. By blocking E receptors in the terminating lactation gland, it eliminates cyclical changes in the breast, effectively reducing distending pain and tenderness, and can dissolve or shrink breast nodules. Side effects, mainly acne, are due to its androgen properties. Severe cases may require danazol.
Bromocriptine can reduce and inhibit promoting lactation secretion, effectively alleviating cyclical breast pain and dissolving breast nodules. However, 40% of patients experience side effects such as dizziness, nausea, and headache. To minimize the frequency and severity of side effects, treatment should start with a low dose. Begin with 1.25mg/d, gradually increasing to a maximum of 5mg/d, starting 14 days before menstruation and stopping when menstruation begins.
(5) Managing neuropsychiatric symptoms: PMS diagnosis and treatment often involve psychiatry. Patients with severe affective disorders require collaboration with psychiatrists. Drug treatment can only alleviate symptoms, making patients feel better and improving functional status, but cannot completely eliminate symptoms. Due to significant individual variability in drug responses, it is impossible to predict which regimen will work best for a specific patient beforehand. Therefore, experimental treatment is necessary before finalizing a plan, and each regimen should ideally be tested for three cycles to determine its efficacy.
1. Premenstrual Dysphoric Disorder: For symptoms lasting less than 1 week, self-help therapies such as physical exercise, dietary adjustments, and vitamin and mineral supplementation should be emphasized. If necessary, tranquilizers can be taken during the luteal phase, such as meprobamate 200–400mg, chlordiazepoxide 5–10mg, or diazepam 5mg, three times daily. For prominent symptoms like headache, muscle pain, or pelvic/abdominal pain, naproxen can be taken—500mg initially, followed by 250mg twice daily; or mefenamic acid 250–500mg, 2–3 times daily. For sleep disturbances (easy to fall asleep but often waking up in the middle of the night with racing thoughts and unable to fall back asleep), where insomnia leads to daytime fatigue and mood changes, doxepin can be prescribed—starting with a dose of 10mg, which can be increased to 25mg if needed, taken 1–2 hours before bedtime.
2. Premenstrual exacerbation of depressive affective disorder: Antidepressants can be taken throughout the cycle, such as tricyclic antidepressants, or nortriptyline 25mg at bedtime, with the dose increased as needed up to 125mg; or clomipramine 25mg/d, increased to 75mg/d if necessary. Alternatively, fluoxetine 20mg can be taken every morning, but it should be avoided initially in patients with prominent insomnia.
3. Cyclothymic behavior: For patients with alternating manic mood and grade I depressive mood, antimanic drugs such as buspirone can be administered. It can be started 12 days before menstruation at 25mg/d; or alprazolam (triazolam) 0.25–5mg/d, taken 6–14 days before menstruation. For those with longer-lasting symptoms, it can be taken from 14 days before menstruation until the second day of menstruation, 0.25mg three times daily, with the dose increased based on the patient's response up to 4mg/d. After menstruation begins, the dose should be tapered by 25% daily until the follicular phase to avoid withdrawal anxiety. Atenolol, which crosses the blood-brain barrier, blocks CNS and peripheral β-receptors, producing sympathetic blockade, and also reduces plasma renin activity and inhibits aldosterone excretion, can alleviate irritable mood at a dose of 50mg/d.
(6) Hormone therapy and ovulation suppression:
1. Progesterone therapy: Although it is not clear whether PMS is associated with progesterone deficiency, the use of progesterone during the luteal phase is widely supported by clinicians. Common methods include progesterone suppositories vaginally at 200–400mg/d or oral micronized progesterone 200mg twice daily.
2. Ovulation suppression: This is only suitable for patients with poor response to multiple drug therapies or those with severe symptoms that impair normal life and work. ① The use of GnRHa (leuprolide 3.75mg/month intramuscularly or buserelin 200mg 2–3 times daily intranasally) has the highest success rate but is expensive and requires hormone replacement therapy to avoid the consequences of hypoestrogenemia. ② Danazol 200mg/d for 3 months creates a pseudo-menopausal state with anovulation, low estrogen, and androgenic effects. Many PMS symptoms, such as depression, irritability, tension, breast pain, and swelling, are significantly alleviated. However, the incidence of androgenic side effects is high, and there are serious long-term metabolic side effects, such as decreased HDL and increased LDL concentrations, accelerating cardiovascular disease. ③ Long-term E2 therapy, commonly 0.2mg E2 transdermal patch daily, supplemented with norethisterone 5mg from days 19–26 of the menstrual cycle. ④ Medroxyprogesterone 30mg/d orally is the most economical and convenient option with fewer side effects, but its efficacy is inferior to the above three drugs. Some patients may develop depression, and the drug should be discontinued immediately if detected. If the treatment proves reliable after several months, long-acting medroxyprogesterone 150mg can be administered intramuscularly every 3 months.
In summary, although there is currently no specific drug to cure PMS, symptom control can generally achieve satisfactory results. The total treatment duration varies for each individual, with most women requiring about 2 years, and some even needing treatment until menopause.
The symptoms of PMS are not unique to PMS itself, and thus often require differentiation from other diseases, especially psychiatric disorders. First, attention should be paid to whether the symptoms appear cyclically. If the cyclical nature and the timing of symptom onset before menstruation are overlooked, PMS can easily be confused with general anxiety or depression. The latter conditions exhibit the same symptoms across all three phases of the menstrual cycle (follicular, ovulatory, and luteal phases), with no regular changes in severity. Second, differentiation should be made from chronic conditions that worsen cyclically by assessing whether symptoms are present during the follicular phase. For example, idiopathic cyclical edema, a condition of unknown cause that predominantly affects women, is characterized by periodic swelling and episodes of anxiety, indicating disturbances in water-electrolyte balance (increased aldosterone secretion). The basis for distinguishing it from PMS is that symptoms can occur throughout the menstrual cycle but worsen before menstruation. Excessive use of diuretics may exacerbate symptoms, and referral to internal medicine for treatment is advisable. Another example is recurrent major depressive disorder, which worsens before menstruation, making it difficult to distinguish from PMS. Therefore, patients with psychiatric disorders that coincide with PMS should first be evaluated by a psychiatric specialist to rule out mental illness before being treated for PMS.
