Menopausal hormone therapy (MHT) remains the cornerstone treatment for vasomotor symptoms (VMS) and genitourinary syndrome of menopause (GSM), and is also indicated for the prevention and management of osteoporosis in younger postmenopausal women. In light of accumulating evidence and evolving clinical practices, the Korean Society of Menopause has updated its MHT guidelines for the first time since 2020 [1]. This revision aims to provide clinicians and patients with accurate, up-to-date information and practical guidance for the appropriate use of MHT.
EXAMINATIONS REQUIRED PRIOR TO MENOPAUSAL HORMONE THERAPY
A thorough evaluation of the indications and contraindications is essential prior to initiating MHT (Fig. 1). This assessment should include a comprehensive medical history, physical examination, and relevant diagnostic investigations. Given the heterogeneity of menopausal symptoms, the evaluation should be personalized based on each patient’s risk profile and integrated with routine age-appropriate health screenings [2,3,4].
Fig. 1. Examinations required prior to MHT. MHT: menopausal hormone therapy.
Key elements of the basic assessment include lifestyle factors (e.g., smoking, alcohol intake), mental health conditions (e.g., depression), and personal or familial history of Alzheimer’s disease, osteoporosis, diabetes, endometrial or breast cancer, thyroid disorders, cardiovascular disease, and venous thromboembolism (VTE). Physical examination should include height, weight, and blood pressure measurements, along with pelvis, breast, and thyroid assessments. Laboratory testing should encompass liver and renal function, hemoglobin levels, fasting glucose, and lipid panels. Imaging and screenings such as mammography, bone mineral density (BMD) assessment, and cervical cancer screening are essential [3]. Considering cost-effectiveness in the Korean clinical context, routine pelvic ultrasonography is also recommended.
Additional tests such as thyroid function tests, breast ultrasonography, and endometrial biopsy may be warranted based on individual risk factors. These assessments—both basic and elective—should be repeated every 1 to 2 years, depending on the patient’s clinical status.
MHT is indicated for alleviating symptoms of estrogen deficiency, including VMS, urogenital atrophy, and postmenopausal bone loss. In women with premature ovarian insufficiency, MHT is recommended until the average age of natural menopause, regardless of symptom presence. Contraindications include unexplained vaginal bleeding, estrogen-dependent malignancies (e.g., breast cancer), active thromboembolic disease, liver dysfunction, and gallbladder disease [2,4]. Given the multifactorial nature of menopausal experiences—encompassing physical, psychological, social, and cultural aspects—clinicians are advised to apply a patient-centered approach while adhering to standard examination protocols [3].
MENOPAUSAL HORMONE THERAPY FOR WOMEN IN MENOPAUSAL TRANSITION
The menopausal transition begins with the onset of menstrual irregularity and concludes with the final menstrual period. This phase is frequently marked by symptoms such as heavy or unpredictable bleeding and VMS, including hot flushes. These symptoms typically start 1 to 3 years prior to menopause, reach their peak around the time of menopause, and may continue for several years—occasionally persisting for up to 10 years after menopause. It is estimated that about 75% of women between the ages of 45 and 55 experience these symptoms, which can substantially affect mood, self-esteem, sleep quality, and overall energy levels [5].
Ovarian reserve assessments, including serum anti-Müllerian hormone, follicle-stimulating hormone, estradiol (E2), and antral follicle count, have limited predictive value in determining the timing of menopause. Due to the variability in ovarian function during this phase, routine hormonal testing is not recommended for the general population [5]. However, in specific conditions such as Turner mosaicism, annual hormone evaluation is advised for ongoing monitoring and management [6].
Management of symptoms during the menopausal transition should be guided by their frequency and severity [7,8]. Even women with regular menstrual cycles who experience significant hot flushes may benefit from medical evaluation and intervention. Lifestyle interventions— such as stress reduction, weight management, and cognitive behavioral therapy (CBT) aimed at improving sleep—have shown efficacy in alleviating symptoms [8]. Some dietary supplements, including soy isoflavones, black cohosh, vitamin E, and omega-3 fatty acids, may provide mild symptom relief, though their effectiveness is often similar to that of placebo [7].
Hormonal treatment options during this transitional phase include estrogen-progestogen therapy (EPT), low-dose combined oral contraceptives (COC), and oral or transdermal estrogen administered alongside an levonorgestrel-releasing intrauterine system (LNG-IUS) [9,10,11]. In women who have undergone hysterectomy, estrogen-only therapy (ET) is an appropriate option during the menopausal transition, although it is less frequently indicated in this stage than in postmenopausal stage. EPT is a proven treatment for alleviating menopausal symptoms in both perimenopausal and postmenopausal women. However, because the hormone levels used are generally lower than those in standard premenopausal regimens, breakthrough bleeding can occur more frequently. For women who also require contraception, low-dose COCs are a suitable option, helping to manage both VMS and menstrual irregularities [9,12,13]. Regimens with continuous administration or shorter hormone-free intervals, such as E2/dienogest COC (Qlaira®), may help reduce symptom flares during hormone-free days. Low-dose COCs are generally considered safe for women aged 40–55 in the absence of major risk factors like obesity, smoking, or cardiovascular disease, though individualized risk assessment remains critical.
Combining oral or transdermal estrogen with an LNG-IUS offers an effective strategy not only for symptom relief but also for the prevention of endometrial hyperplasia [14].
The long-term impact of initiating estrogen therapy during the menopausal transition on cardiovascular and breast cancer risk is still not fully understood. Thus, therapy decisions should be tailored based on symptom burden and patient-specific risk factors. Hormone therapy (HT) should be avoided in women with cardiovascular conditions (e.g., coronary artery disease (CAD), stroke, or thromboembolic events such as pulmonary embolism or deep vein thrombosis), estrogen-dependent malignancies (e.g., breast or endometrial cancer), active liver or gallbladder disease, unexplained vaginal bleeding, or suspected pregnancy [7].
VASOMOTOR SYMPTOMS AND QUALITY OF LIFE
Key points
VMS result from declining estrogen levels in the central nervous system.
VMS is the primary indication for MHT.
MHT is the most effective treatment for VMS in healthy postmenopausal women who are 60 years old or younger and within 10 years of menopause.
Symptom recurrence is common after discontinuing MHT.
Hot flushes, a hallmark of VMS, involve sudden waves of heat often accompanied by palpitations, sweating, and disrupted sleep. The global prevalence of VMS shows regional variation, with lower rates reported in Asia (22%–63%) compared to Western countries (36%–74%) [15]. Identified risk factors include smoking, anxiety, depression, and obesity. Symptoms usually peak within 1–2 years following the final menstrual period, but in some women, they may persist for more than a decade [16,17]. VMS has also been linked to elevated risks of cardiovascular disease, decreased bone density, and cognitive decline [18].
MHT remains the most effective intervention for VMS, achieving symptom reduction of approximately 75% with standard-dose therapy and around 65% with low-dose regimens [19]. In contrast, ultra-low-dose transdermal MHT may be less effective in older populations. For women who have undergone hysterectomy, ET is recommended, whereas EPT is advised for those with an intact uterus. Non-hormonal alternatives, including selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, and gabapentin, have been shown to offer moderate symptom relief [20,21,22,23,24].
Recently, neurokinin receptor antagonists such as fezolinetant and elinzanetant have emerged as promising non-hormonal options for managing moderate-to-severe VMS, particularly in women who cannot or prefer not to use HT. Fezolinetant, a selective neurokinin 3 receptor antagonist, has shown significant efficacy in reducing the frequency and severity of hot flushes in clinical trials [25,26].
After discontinuing MHT, symptom recurrence occurs in up to 87% of cases, regardless of the tapering method used [27]. MHT also improves overall quality of life by enhancing sleep, reducing abdominal fat, and lowering the risks of type 2 diabetes and joint replacement surgery [23]. Tibolone is particularly effective for improving sexual function, while low-dose E2/norethindrone acetate (NETA) is preferred for VMS relief [28].
A study on Korean women in 2010 aged 40–60 years reported VMS prevalence rates of 41.6% in perimenopausal women, 53.1% in early postmenopausal women, and 36.5% in late postmenopausal women [29]. Among women under 45, 50% reported experiencing hot flushes alone, whereas 70% of those aged 45–60 experienced both hot flushes and sweating [29]. A 2001 Gallup Korea survey found that 62.7% of postmenopausal women aged 50–59 receiving MHT reported symptom relief [30]. Additionally, low-dose E2 hemihydrate/drospirenone therapy reduced VMS by 84.4%, compared to 48.1% with placebo [31]. Transdermal estrogen therapy significantly improved hot flushes, night sweats, and insomnia within three months [32]. Korean studies have also shown significant improvements in Women’s Health Questionnaire (WHQ) scores and overall quality of life, including better management of physical and depressive symptoms, improved sleep, and enhanced self-perceived attractiveness [33]. 36-Item Short Form Health Survey assessments indicated higher quality-oflife scores among HT users compared to non-users [34].
In conclusion, MHT remains the most effective intervention for alleviating VMS. In addition to reducing VMS, MHT has been shown to improve other menopausal symptoms, including joint and muscle discomfort, mood disturbances such as depression, and sleep problems. It also contributes to decreased abdominal fat deposition and improvements in overall quality of life, while positively influencing metabolic and musculoskeletal health indicators [23]. Nevertheless, symptoms often recur after discontinuation, highlighting the importance of individualized treatment strategies that consider both symptom control and long-term health outcomes.
GENITOURINARY SYNDROME OF MENOPAUSE AND SEXUAL DYSFUNCTION
Genitourinary syndrome of menopause
Key points
GSM encompasses all symptoms resulting from atrophic changes in the reproductive organs, vagina, urethra, and bladder due to decreased estrogen levels during menopause, including vulvovaginal atrophy (VVA).
Low-dose vaginal estrogen therapy is both effective and safe, with minimal systemic absorption. Therefore, it is recommended over systemic HT for the treatment of GSM.
Low-dose vaginal estrogen therapy helps prevent recurrent urinary tract infections and alleviates symptoms such as overactive bladder and urgency, effectively improving urinary symptoms. However, systemic MHT does not improve incontinence symptoms and may even increase the risk of developing incontinence.
GSM, formerly known as VVA, refers to a collection of symptoms and signs resulting from estrogen deficiency that affects the external genitalia, vagina, and lower urinary tract, including the urethra and bladder. These changes typically occur during menopause and include vaginal atrophy. Common manifestations include vaginal dryness, a burning sensation, discomfort, and dyspareunia associated with decreased lubrication. Urinary symptoms such as urgency, dysuria, and recurrent urinary tract infections are also frequently reported [35].
Between 40% and 54% of postmenopausal women report bothersome GSM symptoms, and approximately 15% of premenopausal women also experience similar complaints [36]. GSM is particularly prevalent and severe among breast cancer patients treated with aromatase inhibitors [37]. In premenopausal women, VVA-related symptoms are typically linked to transient hypoestrogenic states, including hypothalamic amenorrhea, hyperprolactinemia, contraceptive use, or antiestrogenic medications.
Among GSM-related complaints, vaginal dryness is the most frequently reported and often the most distressing, leading to symptoms such as dyspareunia, burning, itching, and dysuria. Studies have shown that vaginal dryness affects 85% to 93% of women and can contribute to sexual dysfunction, including decreased libido and painful intercourse [38,39]. Regarding urinary symptoms, dysuria and urgency are the most common, reported in 29% and 28% of women with GSM, respectively. Recurrent urinary tract infections and stress incontinence occur less frequently but remain notable concerns [40].
GSM symptoms tend to worsen over time and do not resolve spontaneously, often requiring long-term management. The primary goal of treatment is to restore the physiological environment of the genitourinary tract to alleviate symptoms.
There are no objective diagnostic criteria for GSM; therefore, it is crucial for physicians to actively inquire about genitourinary symptoms and sexual activity even before patients report symptoms. GSM encompasses a range of symptoms affecting the genital, urinary, and sexual systems, primarily due to decreased estrogen levels in postmenopausal women.
Genital symptoms may include vulvar and vaginal dryness, itching, burning, irritation, and abnormal vaginal discharge. Urological symptoms commonly reported by patients include dysuria, increased urinary frequency or urgency, nocturia, and recurrent urinary tract infections.
Sexual symptoms can involve reduced vaginal lubrication and sexual response, pain during penetration (dyspareunia), decreased or delayed orgasm, and postcoital bleeding [35].
Vaginal dryness and dyspareunia during intercourse are the most commonly reported concerns, though postcoital bleeding, pain, or tearing may also occur. Many women perceive these symptoms as a natural part of aging and may hesitate to discuss them, making proactive physician questioning essential.
Even women who are not sexually active may experience genitourinary symptoms during physical activity, while wearing tight clothing, or even at rest. Commonly reported urinary symptoms include urgency, frequency, and incontinence. Some women also report urethral pain, burning, and recurrent urinary tract infections, which are also consequences of estrogen deficiency.
Laboratory tests are not necessary for diagnosis, which is typically based on clinical findings from a pelvic examination. The physical examination of individuals with GSM may reveal characteristic changes in the vulva, vagina, and urethra, reflecting estrogen deficiency and tissue atrophy. Vulvar changes often include thinning or loss of pubic hair, thinning or fusion of the labia minora, and atrophy of the clitoris.
Vaginal findings may involve retraction or narrowing of the vaginal introitus, pallor or erythema of the vaginal epithelium with possible pinpoint bleeding, and loss of vaginal rugae. In many cases, hymenal remnants are absent. Vaginal secretions may be significantly reduced or absent, though leukorrhea may occasionally be observed. The vaginal pH is typically elevated, often exceeding 5.0. Urethral changes can include prominence or elevation of the urethral meatus or the surrounding urethral ridge, often contributing to urinary symptoms.
Nevertheless, findings from pelvic examinations do not consistently align with the presence or intensity of patient-reported symptoms. Therefore, the diagnosis and initiation of treatment are typically guided by the presence of bothersome symptoms, a vaginal pH exceeding 5.0, or a vaginal maturation index indicating more than 65% parabasal cells, provided there is no evidence of infection or active vaginal bleeding.
Management of GSM includes vaginal lubricants, moisturizers, local estrogen, vaginal dehydroepiandrosterone (DHEA), and oral ospemifene. Among these, DHEA and ospemifene are not currently approved for use in Korea. Lifestyle modifications, vaginal dilators, and pelvic floor physical therapy may also be beneficial for some women. Systemic estrogen or EPT is not used solely for GSM symptoms. Laser and radiofrequency treatments are emerging options; however, further clinical studies are needed to establish them as standard therapies, and they are not yet U.S. Food and Drug Administration (FDA)-approved [41].
Vaginal moisturizers have been shown to improve vaginal dryness and may be recommended for women who prefer to avoid hormone use. Although some studies suggest symptom relief, their efficacy is generally lower than that of local estrogen therapy [42,43] and may be recommended for women who prefer to avoid hormone use. Topical lidocaine can be applied before vaginal insertion to reduce pain, but direct intravaginal use may cause discomfort. Initially, diluted solutions mixed with water-based lubricants are preferred. Care should be taken to avoid affecting a partner’s sensation or causing allergic reactions.
Local estrogen therapy remains the most effective treatment option for GSM, with demonstrated benefits in restoring vaginal pH, promoting the growth of lactobacilli, reducing susceptibility to infections, thickening the vaginal epithelium, enhancing epithelial maturation, and increasing vaginal secretions [44,45]. It has also been shown to lower the recurrence of urinary tract infections and improve urinary symptoms such as urgency, dysuria, nocturia, and symptoms related to overactive bladder and stress incontinence.
Although low-dose local estrogen products carry the same precautionary labeling as systemic HTs—addressing potential risks such as cardiovascular disease, breast and endometrial cancer, and dementia—current evidence suggests these risks are negligible [46]. Serum estrogen concentrations typically remain within the postmenopausal range during treatment. Due to the rapid absorption of estrogen creams, especially in comparison to other formulations, adherence to recommended dosages is essential to avoid systemic exposure.
In patients with pronounced vulvar atrophy or mucosal fissures, initial application to both the vaginal and vulvar areas is advised. Clinical improvement is generally observed within 4 to 6 weeks, and maintenance therapy may be continued beyond symptom resolution. Findings from a 6.2-year follow-up study reported no significant increases in the incidence of stroke, invasive breast or endometrial cancer, colorectal cancer, or thromboembolic events associated with local estrogen use [46]. Therefore, routine endometrial monitoring—such as through transvaginal ultrasonography or biopsy—is unnecessary unless high-risk factors are present or supratherapeutic doses are used. Long-term use is permissible, but any unexpected vaginal bleeding warrants further evaluation.
In women with a history of breast cancer, non-hormonal approaches are generally the preferred option for managing GSM symptoms. When symptoms are particularly severe or do not respond to non-hormonal therapies, the use of low-dose vaginal estrogen may be considered, but only after a thorough risk-benefit discussion with the patient’s oncologist. According to the 2016 guidelines from the American College of Obstetricians and Gynecologists (ACOG), the use of low-dose vaginal estrogen does not appear to elevate the risk of breast cancer recurrence [37].
The American Society of Clinical Oncology recommends non-hormonal agents as the first-line treatment for GSM in breast cancer survivors. If symptoms persist, low-dose vaginal estrogen may be offered as a second-line option, with the exception of patients taking aromatase inhibitors. In these individuals, vaginal DHEA is suggested as an alternative; however, data on its safety profile in this specific group remain insufficient [37].
Vaginal DHEA was approved in 2016 for the treatment of dyspareunia associated with genitourinary atrophy. DHEA is converted intracellularly into androgens and estrogens via aromatase. A 12-week clinical study demonstrated that serum levels of DHEA, DHEA-S, testosterone, and E2 remained within the normal postmenopausal range, with minimal effects on the endometrium [47]. Although no definitive relationship between DHEA and breast cancer has been established, the FDA has issued warnings regarding its use in breast cancer patients, though it is not contraindicated. However, vaginal DHEA is not approved for use in Korea as of 2025.
Ospemifene (60 mg), a selective estrogen receptor modulator (SERM), has demonstrated estrogenic activity on vaginal tissues without adversely affecting the endometrium or breast in a 52-week clinical trial [48]. It is administered orally and may be a suitable option for women who prefer not to use local vaginal therapies. However, its safety in breast cancer survivors remains uncertain. Although some studies indicate that ospemifene does not significantly increase the risk of breast cancer recurrence, the FDA currently does not support its use in this population. Reported adverse effects include hot flushes in approximately 7% of users and a slight elevation in thrombotic risk [49].
Laser and radiofrequency energy-based therapies have gained global attention as potential treatments for GSM by promoting tissue regeneration through controlled epithelial injury [50]. Despite their popularity, these interventions have not been approved by the FDA, which issued warnings in 2018 regarding their safety. Major professional organizations, including ACOG, the American Urogynecologic Society, and the North American Menopause Society, advise against their routine use due to insufficient evidence regarding long-term safety and effectiveness [51].
Engaging in sexual activity—either with a partner or through masturbation—can enhance vaginal tissue health by improving blood flow and elasticity. Women who have abstained from sexual activity for a prolonged period may benefit from symptom relief prior to resuming intercourse. For those with a history of dyspareunia, secondary vaginismus may be present. In such cases, vaginal dilators may be used to gradually desensitize and relax the pelvic muscles through progressive mechanical dilation. Starting with the smallest diameter and advancing slowly is recommended. The incorporation of mindfulness techniques during dilator use may also help reduce anxiety and discomfort during vaginal insertion.
Pelvic floor physical therapy, including techniques such as biofeedback, has been shown to aid in identifying and alleviating painful trigger points. It is widely recognized as a valuable intervention for managing urinary symptoms and incontinence associated with menopause [52].
Sexual dysfunction
Key points
Advancing age and declining estrogen levels negatively affect sexual function, leading to vaginal dryness, dyspareunia, and decreased sexual desire and response.
Measuring sex hormone levels is not particularly useful for diagnosing or treating sexual dysfunction, and androgen testing is not recommended for assessing androgen deficiency in healthy women.
The role of GSM in sexual dysfunction should always be considered.
Vaginal estrogen therapy effectively improves sexual function in women with GSM.
Systemic HT and low-dose vaginal estrogen therapy are effective treatments for GSM, enhancing vaginal lubrication, blood flow, and sensory function, thereby improving sexual function, particularly by alleviating dyspareunia.
For women experiencing decreased sexual desire, systemic HT with transdermal estrogen is preferred over oral estrogen. Additionally, tibolone has been shown to effectively improve female sexual dysfunction by enhancing sexual desire and arousal.
Advancing age and declining estrogen levels are key contributors to sexual dysfunction in women, manifesting as vaginal dryness, dyspareunia, diminished libido, and reduced sexual responsiveness. These effects are often more pronounced in women who experience surgical menopause, which is associated with abrupt hormonal changes that can markedly increase the incidence of hypoactive sexual desire disorder [53,54,55,56,57].
In clinical practice, measuring serum androgen levels is not a reliable diagnostic tool for identifying androgen deficiency in healthy women, as hormone levels do not consistently align with the severity or presence of symptoms. When evaluating sexual dysfunction, it is essential to consider the role of GSM, particularly vaginal atrophy. Symptoms such as vaginal dryness and dyspareunia not only cause discomfort but also negatively affect other aspects of sexual response, including desire, arousal, and orgasm, thereby reducing overall sexual satisfaction [58].
Due to the multifactorial nature of female sexuality, the impact of HT on sexual dysfunction remains complex and somewhat inconsistent. Nevertheless, ET and EPT have been shown to improve sexual function in women who experience menopausal symptoms or enter menopause prematurely, primarily by relieving vaginal discomfort such as dyspareunia [59,60,61,62].
Tibolone has demonstrated superior effects compared to EPT in enhancing sexual desire, arousal, frequency of sexual activity, and vaginal lubrication, making it a favorable option for women experiencing sexual dysfunction [28]. Systemic MHT and low-dose vaginal estrogen both help restore vaginal lubrication, increase blood flow, and improve sensation, thereby supporting sexual function. Although estrogen therapy is effective in alleviating dyspareunia, it has limited benefits for improving libido, arousal, or orgasmic function. In cases where systemic HT is needed and the patient reports decreased libido, transdermal estrogen is preferred over oral formulations, since oral estrogen increases sex hormone-binding globulin (SHBG) levels, which can reduce free testosterone [63].
For women whose primary complaint is decreased libido, testosterone therapy may enhance sexual desire, satisfaction, arousal, and orgasmic response, in both natural and surgically-induced menopause. This benefit appears to be independent of concurrent estrogen therapy and is also observed in cases where libido is diminished due to antidepressant use. When appropriately dosed and formulated for female patients, testosterone therapy generally carries a low risk of masculinizing side effects [64]. However, such formulations are not currently available in Korea.
Intravaginal testosterone is another treatment modality under investigation for GSM. The female genitourinary tract expresses androgen receptors as well as enzymes such as aromatase and 5α-reductase. Clinical studies have shown that intravaginal testosterone, used alone or alongside vaginal estrogen three times per week, can significantly improve dyspareunia, libido, lubrication, and overall sexual satisfaction when compared to placebo [65]. Despite these findings, no testosterone products are approved for intravaginal use in Korea.
In addition, combination therapy using bazedoxifene (BZA) and conjugated equine estrogen (CEE) has shown potential in improving specific aspects of sexual function, alongside alleviating genitourinary symptoms and dyspareunia in menopausal women [66].
CORONARY ARTERY DISEASE
Key points
Initiating MHT in healthy early postmenopausal women within 10 years of menopause and/or before the age of 60 could be expected to provide preventive effects against CAD.
The effects of MHT on CAD may vary depending on the timing of initiation, the use of progestogens, and the type of progestogen used.
MHT is not currently recommended solely for the primary or secondary prevention of CAD.
A meta-analysis of observational studies revealed that current users of MHT experienced a 28% reduction in the risk of CAD and a 38% reduction in overall mortality [67]. In contrast, randomized controlled trials (RCTs) have yielded differing results. The Heart and Estrogen/progestin Replacement Study trial, which evaluated the efficacy of combined CEE/medroxyprogesterone acetate (MPA) therapy for secondary CAD prevention, showed no protective effect and even reported a 50% increased risk during the first year of therapy, which diminished over time [68]. Similarly, the Women’s Health Initiative (WHI) trial, which focused on primary prevention, found no benefit with CEE/MPA and observed an 80% increase in CAD risk during the first year, followed by a decline in subsequent years [69]. Notably, CEE monotherapy in the WHI study did not show either an increase of initial risk or a significant preventive effect [70].
These discrepancies between observational studies and randomized trials may stem from differences in study populations. Clinical trials like WHI enrolled older postmenopausal women (mean age 63.2 years), many of whom likely had subclinical atherosclerosis, whereas observational cohorts typically included healthier women closer to menopause onset. In such older populations, the vascular environment may have been less responsive to the potential benefits of HT.
Further analyses from the WHI study indicated that the timing of MHT initiation influenced CAD risk. Women who began therapy within 10 years of menopause showed a trend toward reduced CAD risk, whereas initiating treatment more than 20 years after menopause was associated with a significantly increased risk [71]. A meta-analysis of 23 clinical trials supported this, showing a 32% risk reduction in CAD when HT was started before age 60 or within 10 years of menopause, with no protective effect observed in older women [72]. Another meta-analysis of 19 RCTs found that early initiation of HT reduced all-cause mortality by 30% and cardiovascular mortality by 48% [73]. In the WHI study, women in their 50s receiving CEE exhibited significantly lower coronary artery calcium scores, an indicator of reduced CAD risk [74].
The Danish Osteoporosis Prevention Study also provided compelling evidence for early MHT initiation. In this trial, approximately 1,000 younger postmenopausal women (mean age 50 years) who received MHT for 10 years experienced a 52% reduction in a composite outcome of death, heart failure, and myocardial infarction [75]. However, the Kronos Early Estrogen Prevention Study (KEEPS) trial, which enrolled younger postmenopausal women (mean age 52 years, within three years of menopause), did not demonstrate changes in carotid intima-media thickness after four years of therapy, though the progression of coronary artery calcification was slower in the treatment group than in placebo [76].
Findings from the Early versus Late Intervention Trial with Estradiol study further reinforced the “timing hypothesis” or “window of opportunity” concept. In this study, MHT significantly reduced carotid intimamedia thickness in women who were within six years of menopause, whereas no such benefit was observed in women who were more than 10 years postmenopause [77]. This supports the notion that the cardiovascular outcomes of MHT depend critically on the timing of its initiation.
Finally, data from the WHI suggest that the cardiovascular effects of HT may differ between CEE monotherapy and CEE/MPA combination therapy, highlighting the potential influence of progestogen type on CAD outcomes [72].
The Menopause Society (TMS) suggested that discrepancies in CAD outcomes between observational and randomized controlled studies may be due to differences in study populations and that the effectiveness of HT is influenced by age and the duration since menopause [27]. Meanwhile, the International Menopause Society (IMS) noted that HT is associated with a reduced risk of diabetes and has beneficial effects on cardiovascular risk factors such as dyslipidemia and metabolic syndrome [23]. Strong evidence suggests that initiating standard-dose estrogen monotherapy within 10 years of menopause in women under 60 years reduces the incidence and mortality of CAD, with combined progestin therapy showing similar trends. However, in women with existing CAD, HT does not appear to offer significant benefits [78]. Currently, MHT is not recommended when used solely for the primary or secondary prevention of CAD.
Further research is warranted to elucidate how variables such as HT dosage, formulation, administration route, treatment duration, and ethnic or racial differences among populations influence cardiovascular outcomes.
In South Korea, heart disease was the second leading cause of death among women in 2022. The mortality rate from ischemic heart disease—comprising conditions such as myocardial infarction and angina— stood at 24.3 per 100,000 individuals. Importantly, while many Organisation for Economic Co-operation and Development countries have witnessed declining rates of myocardial infarction, South Korea has seen a substantial increase. Between 1990 and 2015, the incidence of myocardial infarction rose by 43% nationally, contributing to an increased overall burden of ischemic heart disease. From 2018 to 2022, the number of patients treated for ischemic heart disease increased from 910,000 to over 1.03 million, marking a 12.9% rise. During the same period, national healthcare expenditures for the condition grew by 25.7%, from approximately 988.3 billion to 1.2425 trillion KRW.
STROKE
Key points
Meta-analyses including data from the WHI study found that MHT does not increase stroke risk in women under 60 years of age or within 10 years of menopause.
The risk of stroke varies depending on age, and MHT increases the risk of ischemic stroke in women over 60 years of age.
MHT therapy does not specifically increase stroke risk in postmenopausal women with preexisting cardiovascular disease.
Lower-dose oral HT or transdermal HT may further reduce stroke risk.
Multiple meta-analyses and findings from the WHI study indicate that MHT does not elevate the risk of stroke in women younger than 60 years or within 10 years of menopause onset [71,73,78,79,80]. For EPT users in this group, the incidence of stroke was rare (< 1 per 1,000 person-years) and not statistically significant. ET was associated with a slight reduction in stroke risk—approximately 1 per 10,000 person-years—in women aged 50–59, while a non-significant increase of 13 per 10,000 person-years was observed in women within 10 years of menopause [78,80].
Conversely, women over 60 or more than 10 years postmenopause experienced a heightened risk of ischemic stroke with HT use. In this cohort, EPT was linked to a hazard ratio (HR) of 1.45, and ET to an HR of 1.55, without any notable influence on hemorrhagic stroke [71].
Longitudinal data from the WHI, spanning 13 years of follow-up, revealed no significant differences in stroke risk between MHT and placebo groups, irrespective of age [78]. Furthermore, meta-analyses suggest that MHT does not increase stroke risk in postmenopausal women with established cardiovascular disease [74]. Observational studies also propose that low-dose oral MHT and transdermal estrogen formulations may be associated with a lower stroke risk compared to higherdose oral preparations [81].
According to the 2024 Korean Stroke Registry, ischemic stroke accounted for 89.4% of all strokes reported between 2012 and 2022. Among female patients, 40.7% had ischemic strokes, with a mean age at onset of 72.5 years. The proportion of ischemic strokes occurring in women younger than 55 years declined to 8.8% in 2022, reflecting a consistent downward trend over the past decade [82]. In the same year, the in-hospital mortality rate for ischemic stroke was 2.6%. Upon discharge, 44.1% of patients were functionally independent, while 38.8% required assistance, indicating progressive improvements in clinical outcomes [83].
VENOUS THROMBOEMBOLISM
Key points
MHT increases the risk of VTE, particularly in older women and those more than 10 years postmenopause.
The risk of VTE is highest during the first year of MHT initiation and decreases thereafter.
ET has a lower VTE risk than EPT, and does not increase the risk in early postmenopausal women.
Oral estrogen therapy is contraindicated in women with a history of VTE or high-risk profiles. In high-risk women, transdermal estrogen may be a safer alternative. For combined HT, transdermal estrogen with micronized progesterone or dydrogesterone may be a better option.
The incidence of VTE is very low in Asian women, and no cases of the factor V Leiden mutation have been reported in Korea.
In Western populations, the incidence of VTE is approximately 5.4 cases per 10,000 individuals annually, with known risk factors including advancing age, obesity, a personal history of thrombotic events, and underlying thrombophilia [84]. Use of MHT is associated with approximately a twofold increase in VTE risk, particularly during the first year of initiation. This risk is further elevated in older women and those initiating therapy more than 10 years after menopause [85].
The thrombogenic potential of oral estrogen is greater than that of transdermal formulations, largely due to first-pass hepatic metabolism. Oral estrogen enhances thrombin generation and reduces fibrinolytic activity by decreasing plasmin levels. In contrast, transdermal estrogen avoids hepatic metabolism and is thus considered safer for women at increased risk of thromboembolic or cardiovascular events.
The choice of estrogen and progestogen components also impacts VTE risk. Oral CEE is associated with a higher thrombotic risk compared to E2 [86]. Among progestogens, MPA appears to increase VTE risk more than micronized progesterone or pregnane derivatives such as dydrogesterone, which are considered more favorable options in terms of thrombotic safety [87,88,89,90]. Moreover, combination therapy with EPT has been shown to carry a higher VTE risk than ET alone, with particularly high risk observed in women who have the factor V Leiden mutation or a body mass index ≥25 kg/m2 [91,92].
In contrast to Western populations, the incidence of VTE in East Asian populations is substantially lower [93]. In Korea specifically, no cases of factor V Leiden mutation have been reported, and only one documented instance of VTE associated with MHT exists—this case did not involve the mutation [94].
BREAST CANCER
Key points
The risk of breast cancer associated with MHT depends on factors such as type of hormones (particularly progestogens), method of administration, timing of initiation, duration of use, past usage, and individual characteristics.
According to the WHI study, in the EPT group, fewer than 1 additional case of breast cancer occurred per 1,000 women per year. In contrast, the ET group demonstrated a reduction of 7 cases per 10,000 women annually over a 7.2-year treatment period, with this effect persisting for 20 years.
MHT does not increase the relative risk (RR) of breast cancer in women with a family history of breast cancer or in those with breast cancer gene (BRCA) 1 or BRCA2 mutations who have undergone oophorectomy.
Systemic MHT is not recommended for women with a history of breast cancer.
Given the differences in the incidence, age distribution, and clinical characteristics of breast cancer between Korean women and Western populations, there are inherent limitations in directly extrapolating findings from studies conducted in Western women to the Korean population.
The association between MHT and breast cancer risk is influenced by multiple factors, including the type of therapy (ET, EPT, or CEE-BZA), the timing of therapy initiation, duration of use, hormone formulation, and individual patient characteristics.
In the WHI study, women receiving combined CEE and MPA showed a modestly elevated breast cancer risk, with 9 additional cases per 10,000 person-years (HR 1.28, 95% CI 1.13–1.45) over a 20-year period [95]. Conversely, those treated with CEE alone experienced a reduced risk, with 7 fewer cases per 10,000 person-years over 7.2 years of treatment (HR 0.78, 95% CI 0.65–0.93), and this reduction persisted over two decades [95]. The breast cancer risk linked to CEE-MPA was found to be comparable to that associated with lifestyle factors such as obesity or low physical activity.
The Étude Épidémiologique auprès de femmes de la Mutuelle Générale de l’Éducation Nationale (E3N) cohort study reported that EPT regimens containing micronized progesterone or dydrogesterone were not associated with an increased breast cancer risk, in contrast to regimens containing synthetic progestogens, which showed a higher risk [96]. Similarly, a largescale Finnish study involving 221,551 women found no significant increase in risk with EPT containing dydrogesterone used for less than five years (RR 1.22, 95% CI 0.83–1.72), although further confirmation from RCTs is warranted [97].
Route of administration, whether oral or transdermal, did not appear to significantly alter breast cancer risk [98]. Vaginal estrogen use showed no association with increased risk, while clinical data for CEE-BZA combinations remain limited [99]. Importantly, studies involving BRCA1/2 mutation carriers or women with a family history of breast cancer who underwent prophylactic oophorectomy did not show additional risk from HT [100,101].
Due to concerns about potential recurrence, systemic MHT is generally contraindicated in women with a history of breast cancer [102]. Among those who developed breast cancer during the WHI study, mortality was significantly lower in the CEE-only group compared to controls (HR 0.60, 95% CI 0.37–0.97), whereas no difference was observed in the CEE-MPA group (HR 1.35, 95% CI 0.94–1.95) [95].
Globally, breast cancer accounted for 2.26 million new cases in 2020, representing the most commonly diagnosed cancer in women (24.5%) and contributing to 15.5% of cancer-related deaths [103]. In Korea, the incidence rate in 2019 was 115.6 per 100,000, with a median diagnosis age of 52.3 years. Unlike Western populations where incidence peaks later in life, breast cancer in Korean women tends to peak in the early 50s, with a higher proportion of premenopausal cases—10.5% occurring under the age of 40. Although Korea’s breast cancer mortality rate is comparatively low (6.4 per 100,000 in 2020), it exhibits distinct epidemiological features, including younger age at diagnosis and a higher prevalence of hormone receptor–positive disease compared to Western populations [103].
OVARIAN, ENDOMETRIAL, COLORECTAL, AND LUNG CANCER
Ovarian cancer
Key points
The WHI study showed no increased ovarian cancer risk with ET or EPT, while observational studies identified a slight increase, primarily for serous ovarian cancer among current or recent MHT users.
MHT may be considered for epithelial ovarian cancer patients with menopausal symptoms but is not recommended for estrogen-dependent ovarian cancers.
Short-term MHT is safe for BRCA mutation carriers undergoing early salpingo-oophorectomy.
Ovarian cancer ranks as the ninth most frequently diagnosed cancer and the fifth leading cause of cancer-related mortality among women in the United States. In South Korea, 3,221 new cases were reported in 2023, comprising 1.2% of all cancers and 2.4% of cancers affecting women, with an incidence rate of 12.5 per 100,000 individuals.
Data from the WHI study did not reveal a significant association between the use of ET or EPT and an increased risk of ovarian cancer. In contrast, some observational studies have indicated a slight elevation in risk, particularly for the serous histological subtype, among women who are current or recent users of MHT. This increased risk appears to diminish and return to baseline within five years after discontinuing MHT [104]. Based on these findings, it is estimated that there may be one additional ovarian cancer-related death per 1,700 to 3,300 MHT users.
In women with epithelial ovarian cancer, MHT does not appear to influence recurrence rates or overall survival, suggesting that it may be used to alleviate menopausal symptoms in this population. However, MHT is contraindicated in cases of estrogen-sensitive ovarian malignancies, such as granulosa cell tumors or lowgrade serous carcinomas [105]. For women carrying BRCA1 or BRCA2 mutations who undergo prophylactic bilateral salpingo-oophorectomy at a young age, short-term use of MHT is generally considered safe and may be offered to manage menopausal symptoms [105].
Endometrial cancer
Key points
In women with an intact uterus, EPT is required to protect the endometrium.
Low-dose intravaginal estrogen therapy does not increase the risk of endometrial cancer.
MHT may be considered for patients with stage 1 low-grade endometrial cancer who have undergone hysterectomy and bilateral salpingooophorectomy and are experiencing menopausal symptoms that do not respond to non-hormonal therapy.
MHT is not recommended for high-grade advanced endometrial cancers, endometrial stromal sarcomas, or leiomyosarcomas.
Between 1999 and 2019, the crude incidence rate of endometrial cancer in South Korea increased markedly, rising from 3.1 to 12.8 per 100,000 women—representing a fourfold escalation. As a result, endometrial cancer now ranks as the seventh most common malignancy among Korean women, placing it among the top ten cancers affecting this demographic.
In women with an intact uterus, ET has been shown to elevate the risk of endometrial cancer, with the degree of risk increasing in relation to both the dosage and the duration of therapy. To counteract this, the addition of a progestogen—either continuously or cyclically for 10 to 14 days each month—substantially reduces this risk. Accordingly, EPT is the recommended approach for postmenopausal women who retain their uterus.
A 13-year follow-up analysis from the WHI study revealed a reduced incidence of endometrial cancer in women receiving EPT compared to those in the placebo group. This finding may be partially attributed to the underlying risk posed by endogenous estrogen exposure in postmenopausal women [78].
Low-dose intravaginal estrogen does not appear to increase the risk of endometrial cancer; therefore, the addition of progestogen is not advised for women using it to treat GSM. However, as most clinical trials with endometrial biopsy outcomes had only one year of follow-up, caution is warranted in women at increased risk of endometrial cancer [105].
According to a meta-analysis, the use of MHT did not negatively impact recurrence or survival in patients with stage 1 low-grade endometrial cancer who had undergone hysterectomy with bilateral salpingooophorectomy. Thus, MHT can be considered for the management of moderate to severe menopausal symptoms in this patient population. In contrast, for individuals with high-grade or advanced-stage tumors, as well as those with endometrial stromal sarcoma or leiomyosarcoma, MHT is generally discouraged due to insufficient evidence regarding its safety [104,105].
Colorectal cancer
Key points
Observational studies indicate that MHT use is associated with a reduced incidence and mortality of colorectal cancer.
The WHI study found a lower risk of colorectal cancer in the EPT group; however, cancers diagnosed in this group were more advanced.
According to the International Agency for Research on Cancer of the World Health Organization, South Korea reports the highest incidence of colorectal cancer worldwide, with 45 cases per 100,000 individuals. Observational studies have indicated that MHT may lower the risk of colorectal cancer by 20%–40%, although this benefit appears to diminish following cessation of therapy [106]. In the WHI study, women receiving EPT exhibited a reduced incidence of colorectal cancer compared to the placebo group (HR 0.62, 95% CI 0.43–0.89). However, cancers diagnosed in the EPT group tended to be more advanced, with a greater frequency of lymph node involvement [78,107].
Lung cancer
Key points
The relationship between MHT and lung cancer incidence or survival remains unclear.
Lung cancer has become the second most commonly diagnosed cancer in South Korea, rising from fourth place in 2010. Among individuals aged 65 years and older, its incidence reaches 1,480 cases per 100,000, making it the leading cancer in this demographic. This trend is largely attributed to the aging population.
Estrogen receptors and aromatase have been identified in lung cancer tissue, raising the possibility of a biological association between MHT and lung cancer. However, results from meta-analyses have been inconsistent [108]. Smoking status appears to be a significant modifying factor in this relationship. In the WHI study, increased lung cancer mortality was observed in past or current smokers aged 60 years or older who used EPT, although neither ET nor EPT was associated with a higher incidence of lung cancer [109]. The impact of MHT on lung cancer survival remains unclear.
COGNITIVE FUNCTION AND DEMENTIA
Key points
Initiating MHT, particularly EPT, in women aged 65 and older increases the risk of dementia.
Starting MHT in younger menopausal women or those undergoing early menopause due to bilateral oophorectomy may help prevent cognitive decline, though robust evidence from RCTs is lacking.
The effect of MHT on future cognitive function may depend on the baseline cognitive health at the time of therapy initiation.
MHT is not currently recommended solely for improving cognitive function or preventing cognitive decline.
The Women’s Health Initiative Memory Study (WHIMS), a sub-study of the WHI, found that initiating combined EPT at age 65 or older was associated with a 2.05-fold increased risk of probable dementia, translating to 23 additional cases per 10,000 personyears [110]. In contrast, ET did not significantly alter dementia risk in this population [111]. Further, in the WHI Study of Cognitive Aging, EPT was linked to slight improvements in nonverbal episodic memory but showed a decline in verbal episodic memory. ET users, however, demonstrated no significant cognitive differences [112]. Additionally, the WHIMS-Magnetic Resonance Imaging sub-study revealed reduced volumes in brain regions such as the frontal lobe and hippocampus in women receiving MHT, compared to placebo [113].
Contrasting these findings, observational studies such as the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology (MIRAGE) and Cache County studies reported a lower incidence of Alzheimer’s disease among HT users [114,115]. The Cache County study, for instance, showed a significant reduction in Alzheimer’s risk (HR 0.41, 95% CI 0.17–0.86) among MHT users. These discrepancies may stem from differences in study design, particularly in the age of participants and the timing of hormone initiation [116]. In observational researches, women usually started MHT at a younger age, closer to menopause, but WHIMS exclusively enrolled women aged 65 and above, who were at higher baseline risk for dementia and may have had subclinical Alzheimer’s at enrollment. These discrepancies support the “timing hypothesis”—MHT might help if started near menopause, but may be harmful if started too late.
The more recent KEEPS trial, which included younger postmenopausal women, found no significant effect of MHT on cognition or memory function [117]. This supports the “critical window hypothesis,” which posits that HT may be beneficial for cognitive health only when initiated near the onset of menopause [118,119]. For example, women who began therapy around the time of natural menopause or immediately following oophorectomy appeared to experience more favorable cognitive outcomes [120]. In the Study of Women’s Health Across the Nation study, initiating MHT prior to the final menstrual period was linked to improved verbal recall, whereas delayed initiation correlated with cognitive decline [121].
Additional observational data reinforce this temporal relationship. Starting MHT during midlife was associated with a lower risk of cognitive impairment, while initiating therapy later in life had neutral or negative effects [118]. In the MIRAGE study, HT reduced Alzheimer’s risk by 65% in women aged 50–63, but no protective effect was seen in those over 64 [114]. Similarly, Zandi et al. [115] found that women who had used MHT for over a decade experienced an 83% lower risk of Alzheimer’s, even after discontinuation. Despite these promising findings, clinical trial evidence supporting the critical window hypothesis remains limited. For instance, the WHIMS of Younger Women, which involved women aged 50–59, did not demonstrate any cognitive benefit from CEE, regardless of whether progestogen was added [122].
To address the limitations of the critical window hypothesis, the “healthy cell bias hypothesis” has been proposed. This theory suggests that the effects of estrogen depend more on the baseline health of neural tissue than on age alone [123,124]. According to this model, women with intact cognitive function and healthy neurons may derive benefit from MHT, regardless of age. However, robust validation of either hypothesis through large-scale RCTs is still lacking [125].
Surgical menopause may exert different effects on cognition compared to natural menopause. Earlier age at oophorectomy has been associated with increased risk of cognitive decline and Alzheimer’s disease [126,127,128]. Notably, small trials have shown that prompt estrogen therapy following oophorectomy can improve verbal memory in the short term [129].
As for treating established dementia, early studies from the 1980s and 1990s reported modest cognitive improvements in women with Alzheimer’s disease who received estrogen therapy [130,131,132]. These findings, however, may have been influenced by methodological limitations such as selection bias and small sample sizes. In contrast, a 2000 double-blind RCT involving 120 hysterectomized women with Alzheimer’s disease showed no cognitive benefit from one year of ET [133]. Additional observational studies suggest no overall increased dementia risk with HT, although prolonged use of EPT (over five years) may be associated with a slight elevation in Alzheimer’s risk [134].
In Korea, an estimated 4.2% of women aged 65 and older have Alzheimer’s disease. A domestic study involving Korean women with Alzheimer’s reported that one year of MHT did not lead to Mini-Mental State Examination score decline and yielded comparable benefits to tacrine in terms of daily functional capacity [135].
DEPRESSION
Key points
ET may improve depressive symptoms in women during the menopausal transition while evidence is limited
Women who experience depressive symptom improvement with MHT may face a worsening of symptoms upon discontinuation.
There is insufficient evidence supporting the effectiveness of EPT in in improving depressive disorders in menopausal women.
MHT should not currently be recommended solely for the treatment of depression due to inadequate supporting evidence.
In South Korea, the prevalence of major depressive disorder (MDD) among women aged 50 and older ranges from 4.0% to 5.4%, approximately three times higher than that of men in the same age group (1.3%–2.4%) [136]. Although the frequency of depressive symptoms does not significantly differ between the pre- and postmenopausal periods, the likelihood of developing MDD appears to rise during the menopausal transition and early postmenopause [137,138]. Notably, women with a prior history of depression are particularly vulnerable to experiencing recurrence during this phase [139]. Therefore, in women with such a history, it is essential to proactively assess the risk of symptom relapse during menopause.
According to current guidelines, recurrent MDD during menopause should be managed primarily with antidepressants or evidence-based psychotherapies, such as CBT or interpersonal therapy. In cases where menopausal symptoms like VMS coexist with depression, MHT may be considered as an adjunct treatment [125,140].
Sherwin [141] demonstrated that estrogen therapy led to improved mood in women who had undergone surgical menopause, as well as in asymptomatic menopausal women. However, the broader application of HT in mood disorders among women without clinical depression remains inconclusive [125,142]. In a randomized study, Schmidt et al. [143] found that transdermal E2 administered over three weeks significantly alleviated depressive symptoms in menopausal women compared to placebo.
The mood-enhancing effects of estrogen are believed to stem more from improved sleep quality than from direct relief of VMS [144]. As such, managing insomnia is a critical aspect of addressing menopause-associated depression. Furthermore, estrogen may augment the therapeutic effects of antidepressants in perimenopausal women with depression [145]. Nevertheless, largescale RCTs assessing the efficacy of HT in treating depression in midlife women remain scarce [146,147,148,149].
Current evidence suggests that the antidepressant effects of ET are most pronounced during perimenopause, with little benefit observed in women further removed from the menopausal transition [148]. This supports the “window of opportunity” hypothesis, whereby ET may be most effective when initiated close to the onset of menopause. Women who respond to ET may also experience symptom recurrence upon cessation [150].
Overall, ET may be considered for perimenopausal women experiencing depression, especially when accompanied by bothersome menopausal symptoms. However, most existing research has centered on ET, and studies examining the efficacy of combined EPT across menopausal stages are limited [125]. One study did report that transdermal E2 combined with intermittent micronized progesterone helped prevent the onset of clinically significant depressive symptoms in euthymic perimenopausal and early postmenopausal women [11].
OSTEOPOROSIS
Key points
MHT effectively prevents menopause-related bone loss and reduces fracture risk, making it an appropriate option for osteoporosis prevention and treatment in early postmenopausal women aged less than 60 years or those with less than 10 years since menopause.
Bone protective effect is rapidly lost after stopping MHT.
Standard-dose MHT reduces fractures of the femur, spine, and other non-spinal sites, even in women without osteoporosis, although the benefits of low-dose therapies remain uncertain.
MHT is particularly essential for preventing bone loss in women with premature ovarian insufficiency or osteopenia.
Data from the 2008–2011 Korean National Health and Nutrition Examination Survey (KNHANES) show that the prevalence of osteoporosis is substantially higher in women (37.3%) than in men (7.5%) aged 50 years and older [151]. Nearly half of individuals in this age group present with osteopenia. In 2022, an estimated 1.18 million people in Korea were diagnosed with osteoporosis, and women accounted for 94.4% of these cases [152]. Between 2012 and 2022, the incidence of osteoporotic fractures in women rose by 32.8%. Fracture patterns vary with age: wrist fractures are most frequent up to the 60s, vertebral fractures become predominant in the 70s, and hip fracture rates rise sharply in the 80s. Hip fractures occur 2.3 times more often in women than in men, and the one-year mortality rate following a hip fracture was 15.7% in 2021.
Effects of menopausal hormone therapy on bone density
MHT suppresses bone resorption and remodeling, resulting in a dose-dependent increase in BMD. According to the WHI study [153], standard-dose EPT led to significant gains in BMD at the lumbar spine (4.5%) and femoral neck (3.7%) compared to placebo. A meta-analysis [154] further supported these findings, reporting increases of 6.8% in lumbar spine BMD and 4.1% in femoral BMD over two years of therapy. Notably, even low-dose estrogen regimens were effective in improving BMD, including in older postmenopausal women [155,156]. In women with premature ovarian insufficiency, MHT has proven efficacy in preserving bone mass and preventing early-onset osteoporosis [125].
Effects of menopausal hormone therapy on fracture risk
The National Osteoporosis Risk Assessment study [157] found that 82% of postmenopausal women who sustained fractures had osteopenia, emphasizing the relevance of MHT in this group. Both the WHI and NORA studies demonstrated that current use of ET or EPT significantly lowers the risk of fractures, including those of the vertebrae and hip. However, this protective effect tends to wane within five years after discontinuing treatment. According to TMS guidelines, MHT is considered a suitable strategy for preventing bone loss in women younger than 60 years or within 10 years of menopause onset, although it is not recommended solely for fracture prevention in women older than 60 years [125].
SARCOPENIA
Key points
Sarcopenia is a major contributor to functional disability, physical impairment, reduced quality of life, and increased healthcare costs in postmenopausal women, necessitating prevention, early diagnosis, and long-term management.
Hormonal changes associated with aging, particularly the sharp decline in estrogen levels after menopause, play a significant role in sarcopenia progression.
MHT, especially when combined with exercise, may help preserve muscle mass, improve muscle strength, and enhance physical function. However, there is a lack of evidence regarding the use of MHT primarily for the purpose of preventing and treating sarcopenia; further research is needed to assess its long-term efficacy and safety.
Ethnicity influences skeletal muscle mass, and age-related changes in muscle composition may differ in Korean women compared to other populations. Research on HT tailored to the characteristics of Korean postmenopausal women remains limited, highlighting the need for further investigation.
Sarcopenia is a progressive, age-related condition characterized by the loss of muscle mass, strength, and physical function, often leading to increased risks of falls, fractures, disability, and institutionalization. Since its classification as a disease in the ICD-10-CM in 2016 and Korea’s KCD-8 in 2021, it has been recognized as both a geriatric syndrome and an age-associated disorder. While initial definitions focused solely on muscle mass, current diagnostic criteria encompass assessments of muscle mass, strength, and performance. Table 1 outlines criteria proposed by major international organizations [158,159,160,161], and the Korean Working Group on Sarcopenia has issued clinical guidelines highlighting the role of comprehensive geriatric assessments (Fig. 2) [162].
Table 1. Diagnostic criteria for sarcopenia presented by representative related societies.
| Decreased muscle mass | Decreased muscle strength | Decreased muscle performance | |
|---|---|---|---|
| EWGSOP-2 [156] | ASM/height2 (DEXA) | Grip strength | SPPB ≤ 8 |
| ≤ 7.0 kg/m2 (male) | < 27 kg (male) | Gait speed ≤ 0.8 m/s | |
| ≤ 5.5 kg/m2 (female) | < 16 kg (female) | ||
| ASM (DEXA) | |||
| < 20 kg (male) | |||
| < 15 kg (female) | |||
| IWGS [157] | ALM/height2 (DEXA) | Gait speed < 1.0 m/s | |
| ≤ 7.23 kg/m2 (male) | |||
| ≤ 5.67 kg/m2 (female) | |||
| AWGS-2 [158] | SM/height2 (DEXA) | Grip strength | Gait speed < 1.0 m/s |
| ≤ 7.0 kg/m2 (male) | < 26 kg (male) | 5-time chair stand | |
| ≤ 5.4 kg/m2 (female) | < 18 kg (female) | Test: ≥ 12 s | |
| SM/height2 (BIA) | SPPB ≤ 9 | ||
| ≤ 7.0 kg/m2 (male) | |||
| ≤ 5.7 kg/m2 (female) | |||
| FNIH Sarcopenia project [159] | ALM/BMI ratio (DEXA) | Grip strength | Gait speed ≤ 0.8 m/s |
| ≤ 0.789 (male) | < 26 kg (male) | ||
| ≤ 0.512 (female) | < 16 kg (female) |
EWGSOP: European Working Group on Sarcopenia in Older People, ASM: appendicular skeletal muscle mass, DEXA: dual-energy X-ray absorptiometry, SPPB: short physical performance battery, IWGS: International Working Group on Sarcopenia, ALM: appendicular lean mass, AWGS: Asian Working group on Sarcopenia, SM: skeletal muscle mass, BIA: bioimpedance analysis, FNIH: Foundation for the National Institutes of Health, BMI: body mass index.
Fig. 2. Algorithm for sarcopenia assessment (proposed by Korean Working Group on Sarcopenia in 2023). SARC-F: strength, assistance with walking, rising from a chair, climbing stairs, and falls, M: male, F: female, SPPB: short physical performance battery, ASM: appendicular skeletal muscle mass, DEXA: dual-energy X-ray absorptiometry, BIA: bioimpedance analysis. Data from the article by Baek et al. (Ann Geriatr Med Res 2023; 27: 9–21) [162], used with permission of the original copyright holder.
Women experience more rapid sarcopenic progression, particularly around the menopausal transition, largely due to hormonal shifts. Declining estrogen levels have been linked to decreased muscle strength, mass, and metabolic efficiency. Studies show that menopause is associated with reductions in lean body mass, espeWomen experience more rapid sarcopenic progression, particularly around the menopausal transition, largely due to hormonal shifts. Declining estrogen levels have been linked to decreased muscle strength, mass, and metabolic efficiency. Studies show that menopause is associated with reductions in lean body mass, especially in the trunk, regardless of age or height, and that muscle strength—such as grip and pinch strength—drops sharply after age 55 [163,164].
MHT has demonstrated potential in preserving or improving muscle strength and slowing its decline. When combined with exercise, MHT appears to have additive benefits for muscle strength and, to some extent, mass. However, findings are inconsistent among older women and those with short-term therapy (< 6 months). Some studies and reviews suggest MHT supports muscle regeneration and function, but its effects on muscle mass remain inconclusive, varying by age and treatment duration [165,166]. Alternative hormonal therapies, including phytohormones, DHEA, and growth hormone, have shown limited benefits, while testosterone has been effective in increasing muscle mass but carries risks such as virilization and cardiovascular events [167,168,169,170]. Selective androgen receptor modulators are currently being explored as promising alternatives [171].
Given South Korea’s rapidly aging population, sarcopenia poses a growing public health concern. According to the Korean Longitudinal Study on Health and Aging, its prevalence among those aged 65 and older is 13.4% in women and 35.3% in men [172,173,174]. KNHANES data using Asian Working group on Sarcopenia criteria show that sarcopenia affects 19.5% of women in their 50s, 16.6% in their 60s, 23.7% in their 70s, and 30.8% in those over 80 [175]. Korean women typically reach peak muscle mass in their 30s or 40s, earlier than in Western populations [176,177,178]. However, no study has specifically examined the impact of MHT on sarcopenia among Korean postmenopausal women, pointing to a critical gap in the evidence [172].
Sarcopenia substantially affects mobility and independence and is closely associated with osteoporosis, raising fracture risk by 1.5 to 3 times. Mechanical loading from muscle activity and the secretion of myokines are essential for maintaining bone density, illustrating the close relationship between muscle and bone health [179,180]. Early detection and intervention are crucial. Although MHT may contribute to reducing sarcopenia-related complications, current evidence is insufficient to endorse it as a primary treatment strategy. Thus, clinical guidelines emphasize an integrative management plan that includes early screening, physical activity, and personalized interventions.
GALLBLADDER DISEASE AND MIGRAINE
Key points
The risk of gallbladder diseases increases with both EPT and ET.
Observational studies suggest that transdermal MHT has a lower risk of gallbladder disease compared to oral MHT.
MHT may exacerbate migraines in women, particularly in those with specific risk factors. If migraines remain poorly controlled during MHT, discontinuing HT and considering non-hormonal alternatives is recommended.
Gallbladder disease
Oral MHT has been associated with a higher risk of developing gallbladder-related conditions, including gallstones, cholecystitis, and the need for cholecystectomy [181,182]. This increased risk is primarily due to the first-pass hepatic metabolism of oral estrogen, which enhances cholesterol saturation in bile, reduces gallbladder motility, and promotes cholesterol crystal formation—factors that facilitate gallstone development [181,182]. Importantly, there is no evidence linking MHT to gallbladder cancer [183].
Findings from the WHI study indicate a significantly elevated incidence of gallbladder disease among women receiving EPT (CEE + MPA), with 47 cases per 10,000 person-years, and among ET (CEE) users, with 58 cases per 10,000 person-years. In the EPT group, the risk decreased after therapy discontinuation but remained higher than in the placebo group, whereas in the ET group, the post-treatment risk aligned with that of placebo. Additional studies have reported similar associations with both ongoing and previous MHT use [181,182,183].
Compared to oral formulations, transdermal estrogen therapy presents a lower risk of gallbladder disease, likely because it avoids hepatic metabolism. This protective effect has been consistently noted in observational research, though RCTs are still lacking [184,185]. For women treated for cholecystitis, transdermal MHT is generally favored regardless of whether management was surgical or conservative, and close follow-up is advised in cases of nonsurgical treatment [27,184,185,186].
Gallstone disease affects an estimated 10%–15% of the population in the United States and remains a major cause of hospitalization for gastrointestinal conditions [187]. In Korea, cholecystectomy was the seventh most frequently performed surgery reported to the Health Insurance Review and Assessment Service in 2015, reflecting a 27% increase from 2010 [188]. This rise is attributed to expanded screening programs, Westernized diets, increased fat and cholesterol consumption, and a growing prevalence of obesity—one of the leading risk factors. Women are about 20% more likely than men to develop gallbladder disease.
In conclusion, both ET and EPT are linked to an elevated risk of gallbladder disease, with oral formulations posing greater risk than transdermal routes. Among oral options, E2 may be associated with lower risk than CEE. Nonetheless, further randomized trials are needed to validate these findings.
Migraine
MHT may worsen migraine symptoms in certain women, particularly those with underlying risk factors such as menstrual migraines, migraines beginning at menarche, a history of premenstrual syndrome, or those who have undergone surgical menopause [189,190]. While migraine is not considered an absolute contraindication to HT, careful monitoring throughout treatment is recommended.
If migraine symptoms intensify during MHT, reducing the estrogen dose or transitioning to transdermal formulations may be beneficial, as these approaches help maintain more consistent serum estrogen levels [191]. When migraines remain refractory to these adjustments, it is advisable to discontinue MHT and explore non-hormonal therapeutic options instead [192].
THERAPEUTIC CONSIDERATIONS FOR MENOPAUSAL HORMONE THERAPY
Indications for progestogens
For women with an intact uterus, the addition of progestogens to estrogen therapy is essential to prevent endometrial hyperplasia and cancer. However, in women who have undergone hysterectomy, progestogens are generally unnecessary unless there is a prior diagnosis of endometriosis [193]. If unexpected vaginal bleeding occurs more than six months after starting EPT, further diagnostic evaluation is indicated.
The LNG-IUS offers localized endometrial protection while minimizing systemic progestogenic side effects [194]. In cases where localized vaginal estrogen or ultra-low-dose transdermal estrogen is used solely for bone protection, progestogen supplementation may not be required, though long-term safety data for these approaches are still limited [195,196].
Dosage
Commonly used regimens include CEE 0.3–0.625 mg/day, oral E2 1–2 mg/day, or transdermal E2 25–50 µg/day, with progestogen (e.g., MPA 2.5–10 mg/day or micronized progesterone 100–200 mg/day) added as indicated. Tibolone 1.25–2.5 mg/day is another therapeutic option. Detailed information is summarized in Table 2.
Table 2. Dosage of estrogens.
| Standard dose (mg/d) | Low dose (mg/d) | High dose (mg/d) | |
|---|---|---|---|
| Oral conjugated equine estrogen | 0.625 | 0.3, 0.45 | 0.9, 1.25 |
| Oral E2 valerate | 2.0 | 1.0 | - |
| Oral E2 acetate | 0.9 | 0.45 | 1.8 |
| Transdermal 17β-E2 patch | 0.0375, 0.05 | 0.025 | 0.06, 0.075, 0.1 |
E2: estradiol, -: not available.
Routes of administration
Non-oral HT, including transdermal and vaginal routes, avoids hepatic first-pass metabolism, thereby exerting minimal impact on triglyceride levels, C-reactive protein, and blood pressure. Transdermal estrogen is generally preferred for women with elevated risks of VTE, metabolic syndrome, hypertension, or for those who smoke. In contrast, vaginal estrogen is effective for treating localized genitourinary symptoms such as vaginal dryness or atrophy [42,197].
Timing of therapy initiation
MHT provides the greatest benefit when started during the perimenopausal period or within the first 10 years after menopause, preferably before the age of 60 [78,198].
In women with primary ovarian insufficiency (POI) (menopause before age 40) or early menopause (before age 45), MHT is recommended regardless of symptom presence to reduce long-term health risks [199,200,201].
Duration of therapy
At present, there is no universally recommended duration for MHT. However, if the lowest effective dose is used, the patient is fully informed of the potential risks and benefits, and regular clinical follow-up is maintained, there is no need to impose an arbitrary time limit on therapy.
In healthy women who begin MHT before age 60 or within 10 years after menopause—and who have low cardiovascular and breast cancer risk, persistent VMS, and no suitable alternative options—long-term therapy may be appropriate. Routine discontinuation of MHT at age 60 or 65 is not necessary [202,203].
For women over 65 who continue MHT, periodic attempts to taper or discontinue treatment are advised, along with reassessment of comorbid conditions [204,205].
In women with POI or early menopause, MHT should be continued at least until the average age of natural menopause to help prevent osteoporosis and CAD [200,201].
Methods of discontinuing treatment
Tapering and abrupt cessation of HT show no significant differences in symptom recurrence; therefore, the choice of discontinuation method can be guided by individual preference [205,206].
Bioidentical hormone therapy
Government-approved bioidentical hormones are considered safe, but compounded bioidentical HT lacks sufficient evidence regarding efficacy and safety and is not recommended [207,208].
Complementary therapies and lifestyle modifications
CBT and hypnosis may help alleviate VMS, but most complementary therapies lack strong scientific evidence. While weight loss may reduce symptoms, current evidence is insufficient to confirm the effectiveness of exercise and yoga in managing VMS.
TREATMENT GUIDELINES FOR TIBOLONE TREATMENT
Key points
Tibolone is effective in alleviating menopausal symptoms, including VMS.
Tibolone is associated with lower rates of breast tenderness, increased breast density on mammography, and vaginal bleeding compared to EPT.
Tibolone could be more effective for addressing sexual dysfunction compared to EPT.
Tibolone is more effective for alleviating symptoms such as mood disorders, sleep disturbances, concentration difficulties, and fatigue beyond VMS compared to EPT.
Tibolone increases BMD and reduces both vertebral and non-vertebral fractures.
Tibolone use in breast cancer patients is associated with an increased risk of breast cancer recurrence.
Tibolone treatment is not associated with an increased risk of stroke in women under 60 years of age; however, in women aged 60 years or older, the risk of stroke may be elevated.
Tibolone does not affect the risk of VTE or CAD.
Tibolone has muscle mass-enhancing effects.
Tibolone is a synthetic steroid derived from 19-nortestosterone that functions through three active metabolites. Once ingested, it is metabolized in the liver and intestines into two estrogenic compounds (3α- and 3β-hydroxytibolone) and Δ4-tibolone, which has both progestogenic and androgenic activity. Its estrogen-like effects are mediated via estrogen receptors, but tibolone displays tissue-selective actions by modulating local enzyme activity. This allows it to relieve menopausal symptoms and help maintain bone density without stimulating the breast or endometrial tissues. Notably, tibolone lowers estrogen concentrations specifically in breast tissue, which may underlie its favorable breast cancer risk profile. Although tibolone itself is inactive, its metabolites produce targeted effects across different tissues, classifying it as a Selective Tissue Estrogenic Activity Regulator.
Efficacy on menopausal symptoms
Tibolone exhibits estrogen-like effects in treating menopausal symptoms. It is effective in alleviating VMS, insomnia, fatigue, and other menopausal symptoms.
Vasomotor symptoms
A daily dose of 2.5 mg of tibolone is considered optimal for alleviating VMS, with noticeable improvement typically seen within four weeks and maximum benefit achieved by 12 weeks of use [209]. Clinical trials have shown that doses of 1.25 mg or higher administered over a 12-week period relieved hot flushes in approximately 86% of participants [209]. In the TOlerability Trial comparing Activelle with Livial study, postmenopausal women with an average age of 55 were randomly assigned to receive either tibolone 2.5 mg or a low-dose hormone regimen of E2/norethisterone acetate (1 mg/0.5 mg) [210]. Both treatments resulted in comparable improvements in VMS and symptoms of vaginal atrophy. However, during the initial three months, the tibolone group experienced significantly fewer episodes of vaginal bleeding. Furthermore, breast tenderness was notably less common in the tibolone group than in the E2/NETA group.
Quality of life
A RCT comparing tibolone, 17β-E2 (2 mg), and placebo in women who had undergone surgical menopause found that tibolone was more effective than E2 in improving not only VMS but also mood disturbances, sleep issues, problems with concentration, fatigue, and migraines [211]. Based on these benefits, both the International Tibolone Consensus Group (2005) and the Asia Pacific Tibolone Consensus Group (2010) endorsed tibolone as a therapeutic option for menopausal women, particularly those with mood-related symptoms. These groups emphasized tibolone’s benefits, including a lower incidence of vaginal bleeding, less breast discomfort, and favorable effects on mood, sleep quality, and sexual function [211,212].
Both tibolone and low-dose combined HT (E2/norethisterone acetate, 1 mg/0.5 mg) have been shown to improve health-related quality of life, as measured by the WHQ. Tibolone was especially beneficial for enhancing sexual function, while E2/NETA was more effective in relieving VMS [213]. In addition, tibolone has been associated with favorable changes in body composition, such as increases in muscle mass and reductions in waist-to-hip ratio [214,215]. In a randomized trial involving postmenopausal women with an average age of 54, those who received tibolone (2.5 mg daily) for 12 months demonstrated greater gains in grip strength—a marker of muscle function—compared to the placebo group [216].
Urogenital atrophy
Patients taking tibolone showed significantly greater improvement in vaginal atrophy compared to those taking raloxifene [217].
Sexual function
Tibolone enhances libido through its androgenic activity, primarily mediated by the Δ4-isomer metabolite, and by lowering SHBG levels, which increases the availability of circulating testosterone [218]. Women receiving tibolone have reported improvements in multiple aspects of sexual health, including diminished libido, vaginal dryness, dyspareunia, orgasmic function, and overall sexual satisfaction.
Bone mineral density
The Study of Tibolone’s Effects on Osteopenia RCT compared tibolone (1.25 mg/day) and raloxifene (60 mg/day) over two years in postmenopausal women aged 60–79 with osteopenia. Tibolone led to significantly greater improvements in BMD at both the lumbar spine and femur [219]. In the Long-term Intervention on Fractures with Tibolone (LIFT) study, tibolone at the same dose reduced vertebral fracture risk by 45% and non-vertebral fractures by 26% [220].
Cardiovascular disease
Tibolone has been shown to lower high-density lipoprotein (HDL) cholesterol by around 20%, along with reductions of approximately 10% in total cholesterol, 20% in triglycerides, and a decrease in low-density lipoprotein (LDL) cholesterol [221]. It also appears to reduce LDL oxidation, dense LDL particles, and atheroma development, which may indicate potential cardiovascular benefits.
However, in the LIFT study involving women aged 60 and above at risk for osteoporosis, tibolone use was linked to an increased risk of stroke, while no significant differences were observed for CAD or VTE [220]. The IMS similarly notes an elevated stroke risk in older women taking tibolone, without a corresponding increase in VTE risk.
In the Livial Intervention Following Breast Cancer: Efficacy, Recurrence, and Tolerability Endpoints (LIBERATE) trial involving women with a history of breast cancer, tibolone did not raise the incidence of stroke, coronary events, or VTE when compared to placebo [222]. To date, no large-scale prospective studies have evaluated cardiovascular events as a primary endpoint for tibolone.
Cancer
Breast cancer
Tibolone does not increase mammographic breast density and tends to cause less breast tenderness compared to conventional estrogen-progestogen combination therapies. In the study, daily administration of tibolone (1.25 mg) was associated with a reduced risk of invasive breast cancer [220]. However, the LIBERATE trial revealed that tibolone use in women with a prior history of breast cancer significantly increased the risk of cancer recurrence [222]. In this study, breast cancer recurred in 15.2% of patients in the tibolone group (237 of 1,556) versus 10.7% in the placebo group (165 of 1,542), representing a 1.4-fold increase. As a result, tibolone is contraindicated in women with a history of breast cancer.
A Korean population-based study using data from the national health insurance system reported no statistically significant increase in breast cancer incidence among tibolone users compared with those using other HTs [223].
Endometrial and colorectal cancer
Tibolone is associated with a lower incidence of irregular vaginal bleeding compared to conventional estrogen-progestogen combination therapies [224]. Because tibolone suppresses endometrial proliferation through its tissue-selective actions, additional progestogen administration is not required.
The Tibolone Histology of the Endometrium and Breast Endpoints Study trial confirmed that tibolone does not induce endometrial hyperplasia or increase the risk of endometrial cancer [225]. Moreover, the LIFT study showed that daily tibolone (1.25 mg) use was associated with a 69% reduction in colorectal cancer risk [220].
Although large-scale, prospective studies evaluating tibolone’s effects on cardiovascular disease, breast cancer, or fracture risk in Korean women are lacking, some domestic research has explored its impact on lipid profiles and bone health.
Tibolone has been found to lower triglyceride levels more effectively than conventional HT, though it also reduces HDL cholesterol [226]. With regard to BMD, tibolone has demonstrated comparable efficacy to estrogen-based HT in increasing lumbar spine BMD over one year of treatment.
Retrospective studies in women with gynecologic cancers have also provided reassuring data. Among 42 patients who received tibolone after surgery for epithelial ovarian cancer, no detrimental effects were observed on progression-free or overall survival compared to 33 non-users [227]. Likewise, tibolone use in 68 patients following surgical treatment for endometrial cancer did not adversely affect disease prognosis when compared with matched controls [228].
TREATMENT GUIDELINES FOR TISSUE SELECTIVE ESTROGEN COMPLEX
Key points
CE/BZA effectively treats menopausal symptoms, particularly hot flashes.
CE/BZA prevents osteoporosis by increasing lumbar spine and femoral BMD.
CE/BZA shows better tolerability than EPT, with reduced incidence of breast tenderness, vaginal bleeding, and mammographic dense breast.
CE/BZA does not increase breast density, breast pain or vaginal bleeding compared to placebo.
No RCTs of CE/BZA have been conducted with breast cancer, fracture, and cardiovascular disease as the primary endpoints to date.
CE/BZA is a promising option for alleviating VMS and preventing osteoporosis in postmenopausal women with an intact uterus.
The tissue-selective estrogen complex (TSEC) is a novel formulation that combines conjugated estrogens (CE) with the SERM BZA. BZA functions as an estrogen agonist in bone tissue and an antagonist in the uterus and breast, thereby providing endometrial protection without the need for additional progestogens. This combination has been shown to improve tolerability, particularly by reducing the incidence of vaginal bleeding and breast tenderness commonly associated with traditional estrogen-progestogen therapies [229,230,231,232].
Effects on menopausal symptoms
Vasomotor symptoms
The TSEC, a combination of CE/BZA, has been shown to be effective in alleviating VMS. In clinical trials, CE/BZA reduced the frequency of hot flashes by 74% after 12 weeks of treatment, compared to a 51% reduction observed in the placebo group [233].
Vulvovaginal atrophy and quality of life
CE/BZA has been shown to promote vaginal epithelial maturation by reducing the proportion of parabasal cells. In addition, it improves sleep quality by alleviating sleep disturbances and reducing sleep onset latency, thereby contributing to an overall enhancement in quality of life [234,235].
Effects on bone mineral density
CE/BZA increases BMD in both the lumbar spine and femur, while also improving bone turnover markers. In a one-year study, CE/BZA was associated with significantly greater increases in BMD compared to both placebo and CE/MPA [230,236].
Safety issues
Breast density, tenderness, and cancer risk
CE/BZA does not increase breast density or tenderness compared to placebo. In contrast to CE/MPA, which has been shown to significantly elevate breast density, CE/BZA exerts minimal impact on breast tissue [231]. Although observational studies suggest a potentially lower risk of breast cancer with CE/BZA compared to EPT, robust clinical evidence remains limited [237].
Vaginal bleeding and endometrial hyperplasia
CE/BZA is associated with significantly lower rates of vaginal bleeding compared to CE/MPA [230]. When administered with a minimum BZA dose of 20 mg, the incidence of endometrial hyperplasia remains below 1% [232].
Lipid and coagulation effects
CE/BZA improves lipid profiles by lowering LDL cholesterol and increasing HDL cholesterol. Additionally, it does not adversely affect coagulation balance and demonstrates favorable effects on hemostatic parameters [238].
Recommendations from abroad
The Menopause Society
The TMS recommends CE/BZA for the management of VMS and the prevention of osteoporosis in women with an intact uterus, citing its favorable endometrial safety profile and the advantage of a progestogen-free formulation [125].
Endocrine Society
The Endocrine Society highlights the efficacy of CE/BZA in treating VMS, preventing bone loss, and minimizing side effects associated with progestogen use [239].
American Association of Clinical Endocrinologists
The American Association of Clinical Endocrinology supports the use of CE/BZA for moderate-to-severe VMS and osteoporosis prevention but emphasizes that the long-term breast cancer risk associated with CE/BZA remains unclear [240].
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