Menopause refers to the permanent cessation of menstruation and is considered a retrospective clinical diagnosis. In women over the age of 40, if menstruation has ceased for 12 months or more and pregnancy or other pathological causes of amenorrhea have been excluded, menopause can be clinically diagnosed. The essence of menopause lies in ovarian failure, rather than simply the absence of menstruation.
The perimenopausal period refers to the transitional stage from a woman's reproductive years to menopause, beginning with the decline in ovarian function and extending to one year after the final menstrual period.
Menopausal syndrome (MPS) refers to a range of physical and psychological symptoms experienced by women before and after menopause, primarily resulting from fluctuations or reductions in sex hormones.
Menopause can be classified as either natural or induced. Natural menopause occurs due to follicular depletion or a lack of responsiveness of residual follicles to gonadotropins, leading to the cessation of estrogen production and follicular development. Induced menopause results from bilateral oophorectomy or damage to the ovaries caused by radiation or chemotherapy. Women with induced menopause are more likely to experience menopausal syndrome.
Pathophysiological Changes
The stages of reproductive aging can be broadly divided into the reproductive phase, the menopausal transition, and the postmenopausal stage. Both the menopausal transition and the postmenopausal stage are further divided into early and late phases. The perimenopausal period encompasses the menopausal transition and the first year of early postmenopause.
During the transition from the reproductive phase to the postmenopausal stage, ovarian function gradually declines. There is a reduction in the number and quality of follicles, leading to changes in menstrual cycles and endocrine patterns. These changes eventually result in menopause and affect multiple organ systems, contributing to the development of various related disorders.
The major pathophysiological changes during menopause are characterized by the concurrent decline in both the quantity and quality of follicles, as well as alterations in the activity of the hypothalamic-pituitary-ovarian (HPO) axis and the hormones it regulates. The hormones involved and their mechanisms of action are described below:
Estrogen
During the menopausal transition, estrogen levels fluctuate significantly rather than decline steadily. Estradiol (E2) is the dominant form. In the postmenopausal stage, estrogen secretion from the ovaries becomes minimal. Circulating low levels of estrogen mainly originate from the aromatization of adrenal and ovarian androstenedione to estrone (E1) in peripheral tissues. The ratio of E2/E1 is typically less than 1.
Progesterone
During the menopausal transition, the ovaries may still ovulate and produce progesterone. However, due to declining follicular quality and luteal insufficiency, progesterone production decreases. After menopause, progesterone secretion ceases.
Androgens
The primary androgens include testosterone and androstenedione. During the menopausal transition, androgen levels remain relatively stable. After menopause, androgens are mainly produced by ovarian stromal cells and the adrenal glands, with an overall decline in levels. Androstenedione, primarily derived from the adrenal glands, drops to about half the premenopausal level. Ovarian production of testosterone may increase due to heightened LH stimulation of stromal cells.
Gonadotropins
During the menopausal transition, follicle-stimulating hormone (FSH) levels begin to fluctuate and gradually rise, while luteinizing hormone (LH) levels remain relatively stable. A serum FSH level ≥25 IU/L indicates entry into the late menopausal transition. Postmenopause, both FSH and LH levels rise significantly, with FSH increasing more prominently (FSH/LH > 1). Two to three years after menopause, FSH and LH reach their peak levels and then gradually decline with age, although they remain elevated.
Anti-Müllerian Hormone (AMH)
Secreted by granulosa cells of preantral and small antral follicles, AMH levels drop significantly in the early menopausal transition—earlier and more noticeably than estradiol. In the late menopausal transition, AMH typically falls below the detectable threshold.
Inhibin B
This is mainly produced by granulosa cells of small and medium antral follicles, and the trend of change in inhibin B mirrors that of AMH. It may serve as a more sensitive marker for declining ovarian function.
Clinical Manifestations
The majority of women experience symptoms related to menopause. Common physical symptoms include menstrual irregularities, hot flashes with sweating, fatigue, musculoskeletal and joint pain, and vaginal dryness. Neuropsychiatric symptoms include mood disturbances, sleep disorders, and cognitive changes. Women in the perimenopausal period are more prone to developing new metabolic disorders, such as altered lipid profiles, impaired glucose metabolism, and bone loss, which may have long-term health implications.
These symptoms often appear in distinct phases. Vasomotor symptoms (VMS) are most frequently observed in the late menopausal transition and early postmenopause. The incidence of genitourinary syndrome of menopause (GSM) increases in the postmenopausal stage.
Menstrual Changes
Irregular menstruation is a common feature during the menopausal transition. It results from infrequent or absent ovulation and is characterized by irregular cycles, prolonged bleeding duration, and changes in menstrual volume. The appearance of symptoms during this period is closely related to fluctuations in ovarian function.
Vasomotor Symptoms
These primarily manifest as hot flashes and excessive sweating, which are due to instability in thermoregulatory control and are considered hallmark symptoms of estrogen decline. Hot flashes typically begin in the chest and spread to the head and neck, sometimes affecting the entire body. In some cases, they remain localized to the head, neck, and breasts. Affected areas may feel hot and appear flushed, with episodes lasting from seconds to several minutes and occurring multiple times per day. Triggers include nighttime or stress. These symptoms may last one to two years, occasionally extending to five years or more. Severe hot flashes can interfere with daily activities, work, and sleep. Hormone therapy remains the most effective treatment.
Psychological and Cognitive Symptoms
These often include difficulty concentrating and marked emotional fluctuations, such as irritability, anxiety, depression, and loss of emotional control. Memory decline, difficulty falling asleep, frequent awakenings, and vivid dreams are common. Some women also present with somatic symptoms alongside anxiety and depression, including cardiopulmonary complaints (e.g., chest tightness, shortness of breath, palpitations), gastrointestinal symptoms (e.g., a sensation of a lump in the throat, constipation), limb pain, and pseudoneurological symptoms. It is essential to rule out organic diseases before attributing somatic symptoms to menopause.
Osteoporosis
Rapid bone loss and degenerative changes in joints during early menopause can lead to skeletal pain in the back, limbs, and joints. The risk of postmenopausal osteoporosis increases significantly, particularly affecting the vertebrae. Compression fractures, reduced height, and kyphotic spinal deformities may occur. Osteoporotic fractures at sites such as the distal radius and femoral neck may result from minor trauma during daily activities.
Genitourinary Syndrome of Menopause (GSM)
GSM encompasses a collection of symptoms and signs resulting from decreased estrogen and other sex hormones, leading to atrophy of the genital and urinary tracts and sexual dysfunction. Over 50% of postmenopausal women may experience GSM. Symptoms include vulvovaginal atrophy, dryness, burning, irritation, itching, abnormal discharge, decreased libido, dyspareunia, and discomfort during intercourse. Urinary symptoms may include increased frequency, urgency, difficulty urinating, recurrent lower urinary tract infections, and urinary incontinence.
Cardiovascular Symptoms and Metabolic Abnormalities
A decline in basal metabolic rate and redistribution of body fat toward abdominal visceral areas may result in weight gain and disturbances in glucose and lipid metabolism. The risk of atherosclerosis and coronary artery disease increases postmenopause, likely associated with decreased estrogen levels.
Diagnosis
Diagnosis is generally based on medical history and clinical manifestations, with the exclusion of organic and psychiatric conditions. Laboratory evaluation of ovarian function and referrals to specialists may support diagnosis.
Medical History and Symptom Assessment
Information should be collected regarding symptoms, age, past medical history (e.g., cardiovascular disease, malignancy), hysterectomy or oophorectomy status, menstrual history, reproductive history, family history, and previous treatments including hormone or medication use. Menopausal symptoms can be assessed and quantified using standardized scoring systems.
Physical Examination
A general and gynecological examination should include measurements of height, weight, waist and hip circumference, blood pressure, and systemic evaluations. A gynecological exam may aid in differentiating causes of menstrual irregularities and exclude gynecological inflammation or tumors that may lead to abnormal bleeding.
Supplementary Examinations
Serum Hormone Assays
Selective hormone measurements can help assess ovarian function.
Serum FSH and estradiol (E2)
FSH >10 IU/L during the menopausal transition suggests diminished ovarian reserve; amenorrhea with FSH >40 IU/L and E2 <10–20 pg/mL indicates ovarian failure.
Anti-Müllerian Hormone (AMH)
AMH ≤1.1 ng/mL suggests diminished ovarian reserve; AMH <0.2 ng/mL indicates approaching menopause; postmenopause, AMH is typically undetectable.
Ultrasound Examination
A reduction in antral follicle count, decreased ovarian volume, and thinning of the endometrium may be observed in the baseline state.
Bone Mineral Density (BMD) Assessment
Dual-energy X-ray absorptiometry (DEXA) of the lumbar spine and proximal femur can confirm osteoporosis or low bone mass. In postmenopausal women, a BMD T-score ≤ -2.5 SD below the peak value of healthy adults of the same sex and ethnicity indicates osteoporosis. A T-score between -2.5 and -1 SD suggests low bone mass, while a T-score ≥ -1 SD is considered normal.
Differential Diagnosis
In women presenting with irregular vaginal bleeding and thickened endometrium during the menopausal transition, endometrial biopsy may be indicated to rule out endometrial pathology. Hot flashes, mood changes, and sleep disturbances should be differentiated from psychiatric disorders and hyperthyroidism.
Treatment
The health management strategy for postmenopausal women includes enhancing education and awareness regarding menopause and its management. A healthy lifestyle should begin during the menopausal transition, accompanied by annual health check-ups and necessary medical interventions (hormonal and/or non-hormonal treatment), supported by multidisciplinary care.
Treatment goals include alleviating menopause-related symptoms and effectively preventing, detecting early, and addressing age-related diseases such as osteoporosis and atherosclerosis.
Health Guidance
Educational outreach should be reinforced for women in the menopausal transition and postmenopausal stages, offering comprehensive health management guidance.
Psychological Adjustment and Education
Scientific education and psychological counseling may assist postmenopausal women in adjusting their mental state, fostering accurate understanding of menopausal syndrome as a normal physiological process.
Healthy Lifestyle
A balanced diet, regular moderate exercise and outdoor activities, maintenance of a healthy weight, increased social and cognitive engagement, and avoidance of unhealthy habits such as smoking and excessive alcohol consumption may help most women transition smoothly through perimenopause.
Adequate Nutrient Intake
The daily calcium requirement for postmenopausal women is 1500 mg/day. Calcium supplementation may be considered when dietary intake is insufficient to reduce bone loss. Vitamin D is appropriate for perimenopausal women with limited outdoor activity, at 400–500 IU/day orally. When combined with calcium, it enhances calcium absorption.
Pharmacological Treatment
Menopausal Hormone Therapy (MHT)
MIT is considered the most effective treatment for menopause-related symptoms. MHT should be initiated when indications are clear, contraindications are absent, and the woman has a subjective willingness to proceed. Women under the age of 60 or within 10 years of menopause without contraindications typically benefit the most.
Indications include:
- Menopausal symptoms such as vasomotor and neuropsychological disturbances;
- Urogenital symptoms, including vaginal dryness, burning sensation, recurrent urinary tract infections;
- Low bone mass, osteoporosis, and fracture risk;
- Premature estrogen deficiency, such as in premature ovarian insufficiency (POI), hypothalamic-pituitary amenorrhea, or surgical menopause.
Contraindications include:
- Known or suspected pregnancy;
- Unexplained vaginal bleeding, which may be due to tumors, inflammation, iatrogenic factors, trauma, or ovarian dysfunction—differential diagnosis is needed before MHT;
- Known or suspected breast cancer or other hormone-related malignancies;
- Active venous or arterial thromboembolic disease within the last six months;
- Severe hepatic or renal dysfunction—transdermal administration is recommended for patients with liver or kidney abnormalities.
Conditions requiring caution:
- Uterine fibroids, endometriosis, adenomyosis, history of endometrial hyperplasia, thrombophilia, gallstone disease, autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis), benign breast disease or family history of breast cancer, epilepsy, migraines, asthma, porphyria, otosclerosis, and meningioma (progestogens are contraindicated in current meningioma regardless of estrogen dependence).
Common Medications
Oral Estrogens:
- Natural estrogens: 17β-estradiol, estradiol valerate, conjugated estrogens;
- Synthetic estrogens: ethinyl estradiol.
Oral Progestogens:
- Natural progestogen: micronized progesterone;
- Synthetic progestogens: dydrogesterone;
17α-Hydroxyprogesterone Derivatives:
- Medroxyprogesterone acetate;
19-Nortestosterone Derivatives (with varying degrees of androgenic activity):
17α-Spironolactone Derivative:
- Drospirenone, which has strong antimineralocorticoid and some antiandrogenic effects.
Oral Sequential Estrogen-Progestogen Combinations:
- 17β-estradiol tablets/dydrogesterone tablets: 28 tablets per box, the first 14 containing only estradiol, the latter 14 containing estradiol and 10 mg dydrogesterone. Two dosage forms are available: 1/10 and 2/10 (1 mg or 2 mg estradiol per tablet, respectively);
- Estradiol valerate/cyproterone acetate tablets: 21 tablets per box; the first 11 contain 2 mg estradiol valerate, the remaining 10 contain 2 mg estradiol valerate and 1 mg cyproterone acetate.
Oral Continuous Combined Estrogen-Progestogen Formulation:
- Estradiol/drospirenone tablets: 28 tablets per box, each containing 1 mg estradiol and 2 mg drospirenone.
Oral Selective Estrogen Receptor Modulator:
- Tibolone: its three metabolites exhibit estrogenic, progestogenic, and weak androgenic activities in different target tissues. There is no need to add a progestogen during use.
Transdermal Estrogens:
- Estradiol gel, estradiol hemihydrate patches, estradiol benzoate cream. Transdermal estrogen delivery minimizes hepatic effects on protein synthesis and coagulation factors. Compared with oral administration, transdermal estrogen presents a significantly reduced risk of venous thrombosis, cardiovascular events, and gallbladder disease.
Vaginal Estrogen Preparations:
- Prasterone vaginal capsules, prasterone cream, chlorquinaldol-prasterone vaginal tablets, estriol cream, conjugated estrogen cream, prasterone vaginal suppositories.
Prasterone acts strictly locally without stimulating endometrial hyperplasia;
Estriol causes minimal endometrial stimulation and does not significantly affect plasma estradiol levels;
Conjugated estrogens slightly raise plasma estradiol levels and may mildly affect the endometrium.
Injectable Estrogens:
- Estradiol benzoate injection.
Levonorgestrel-Releasing Intrauterine System (LNG-IUS):
- Contains 52 mg levonorgestrel, releasing 20 µg per day into the uterine cavity, effective for 5 to 7 years.
Treatment Regimens
Progestogen-only regimen: Suitable for women in the early menopausal transition without symptoms of estrogen deficiency, aiming to regulate menstrual cycles.
- In the second half of the cycle, progestogen may be administered from day 14 of menstruation or withdrawal bleeding for 10–14 days, using dydrogesterone 10–20 mg/day or micronized progesterone 200–300 mg/day.
- Long-cycle or continuous progestogen therapy may be considered for women with a history of endometrial hyperplasia or heavy menstrual bleeding. LNG-IUS may be preferred.
Estrogen-only regimen: Appropriate for women who have undergone hysterectomy. Continuous use is common.
- Oral options include estradiol valerate 0.5–2 mg/day, 17β-estradiol 1–2 mg/day, or conjugated estrogens 0.3–0.625 mg/day.
- Transdermal options include estradiol gel (0.5–1 measured dose daily) applied to areas such as the arms, thighs, or buttocks (avoiding the breasts and perineum), or estradiol hemihydrate patches changed every 7 days.
Sequential estrogen-progestogen regimen: Suitable for women with an intact uterus who are perimenopausal or postmenopausal and prefer withdrawal bleeding.
- In the continuous sequential regimen, estrogen is administered daily, and progestogen is added cyclically. Sequential preparations (e.g., 17β-estradiol tablets/dydrogesterone tablets) may be used continuously in a 28-day cycle, or estrogen may be applied transdermally for 28 days with progestogen added in the second half of the cycle for 10–14 days.
- In the cyclical sequential regimen, treatment is interrupted for 3–7 days each cycle. A typical schedule may use estradiol valerate/cyproterone acetate tablets for 21 days followed by a 7-day break. Alternatively, oral or transdermal estrogen may be used for 21–25 days, with progestogen added for 10–14 days, followed by a 3–7 day drug-free interval before starting the next cycle.
Continuous combined estrogen-progestogen regimen: Suitable for women more than one year postmenopause who wish to avoid withdrawal bleeding. Estrogen (oral or transdermal, same dosage as monotherapy) may be combined with oral dydrogesterone (5–10 mg/day) or micronized progesterone (100–200 mg/day). A combined preparation such as estradiol/drospirenone tablets may be used continuously. Women with LNG-IUS in place may take oral or transdermal estrogen.
Tibolone regimen: With fewer instances of unexpected bleeding, tibolone is suitable for postmenopausal women more than one year into menopause who do not desire withdrawal bleeding. The dose is 1.25–2.5 mg/day orally.
Local vaginal estrogen regimen: This is the preferred choice for women with genitourinary syndrome of menopause (GSM) and is mainly used to treat local urogenital symptoms of estrogen deficiency. It may be used alone or with systemic MHT (oral or transdermal). Options include prasterone vaginal capsules or cream, estriol cream, and conjugated estrogen cream. A typical dose includes one capsule/day or 0.5–1 g/day of cream, used continuously for 2–3 weeks. After symptom relief, frequency may be reduced to 2–3 times/week or further adjusted depending on response. Short-term local therapy does not require additional progestogen, but for long-term use (more than six months), endometrial monitoring is necessary.
Adverse Effects and Risks
Uterine Bleeding
Unexpected bleeding during hormone therapy is often breakthrough bleeding but warrants thorough investigation to exclude endometrial pathology, including hysteroscopy if necessary.
Sex Hormone-related Side Effects
Initial use of estrogen may cause breast tenderness, increased vaginal discharge, and headaches. Dose reduction may help, and target doses can be resumed once symptoms improve. Progestogen may cause depression, irritability, mastalgia, and edema, typically mild. Androgens may increase the risk of hyperlipidemia, atherosclerosis, and thromboembolic events.
Tumors
Long-term estrogen monotherapy in women with a uterus increases the risk of endometrial hyperplasia and cancer. This risk may be reduced by sufficient and appropriately timed progestogen co-therapy. The association between MHT and breast cancer is complex; estrogen-only regimens generally do not significantly increase the risk. Breast cancer risk depends on the type of progestogen used, with natural progesterone or dydrogesterone posing a lower risk than other synthetic progestins.
Thrombotic Disease
The risk of venous thromboembolism (VTE) increases with age and is positively correlated with obesity. Oral MHT increases this risk, whereas transdermal estrogen does not. Risk also varies by progestogen type; natural progestogens carry a lower VTE risk than synthetic ones.
Individualization Principle
Hormone therapy regimens should be tailored according to the woman’s age, uterine and ovarian function (e.g., perimenopause, early or late postmenopause), menopause-related symptoms, and additional risk factors. Estrogen dose and administration route should be adjusted with advancing age and menopausal duration. The goal is to achieve maximum benefit with minimal risk by using the lowest effective dose.
Follow-up
There is currently no fixed duration limit for MHT use. Follow-up should be standardized, including regular history updates and evaluations of efficacy, adverse effects, and individualized risk-benefit profiles. Reassessment should be conducted at 1, 3, 6, and 12 months after initiation, and at least once annually thereafter to determine whether to continue or adjust the MHT regimen.
Non-Hormonal Medications
These are mainly considered for women with therapeutic needs who have contraindications to MHT, are temporarily unsuitable, or decline hormone therapy.
- Selective serotonin reuptake inhibitors (SSRIs): Paroxetine hydrochloride 20 mg once daily in the morning may improve vasomotor and neuropsychological symptoms.
- Sedatives: May be used when sleep disorders significantly affect quality of life.
- Vaginal moisturizers and lubricants: May help improve sexual function.
Other Therapies
Acupuncture, cognitive behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), stellate ganglion block, and hypnotherapy may offer supportive benefits.
Menopause is an inevitable physiological stage in a woman’s life, and the late postmenopausal period is the longest phase of the female life cycle. Through proactive psychological adjustment, enhanced self-care, comprehensive lifestyle changes beginning in the menopausal transition, and appropriate medical consultation when needed, including MHT in suitable candidates, women may relieve menopausal symptoms and improve quality of life.