Published online Aug 31, 2020.
https://doi.org/10.6118/jmm.20000
The 2020 Menopausal Hormone Therapy Guidelines
Based on the analysis conducted by the World Health Organization regarding the life expectancy in 35 Organisation for Economic Co-operation and Development (OECD) countries, South Korea's life expectancy is predicted to rank first in the world by 2030, with the life expectancy for women reaching 90.82 years. In other words, the importance of women's health and the quality of life (QoL) after menopause is increasing. The most effective treatment for vasomotor symptoms (VMS) and genitourinary syndrome of menopause (GSM) is menopausal hormone therapy (MHT), which is also effective in preventing osteoporosis. MHT is an effective therapy that offers more advantages than disadvantages for women aged less than 60 years or who have had menopause for less than 10 years. Therefore, the purpose of these guidelines is to provide help by sharing accurate knowledge and treatment methods regarding MHT based on recent research findings.
1. Examinations required prior to receiving MHT
Points to consider prior to initiating MHT include checking the indications and contraindications of MHT, which requires history recording, physical examinations, and other tests. Because the symptoms of menopause are varied, customized tests should be conducted for each risk factor based on the basic examination conducted according to the life cycle necessary for women [1, 2, 3].
The basic examination, which is a general examination conducted according to the life cycle, should identify lifestyles such as smoking and drinking habits; mental diseases such as depression; and with family history for diseases such as Alzheimer's disease, osteoporosis, diabetes, endometrial cancer, breast cancer, liver disease, thyroid disease, cardiovascular disease, and venous thromboembolism via history taking. In addition, the basic examination should include a physical examination for height, weight, and blood pressure as well as the pelvis, breast, and thyroid. Blood tests include tests for liver function, kidney function, anemia, and fasting blood sugar as well as lipid examination, followed by mammography, bone mineral density (BMD) test, and Pap smear screening [3]. Furthermore, it is reasonable to regard pelvic ultrasonography as part of the basic examination in Korea considering its cost-effectiveness. Elective examinations such as thyroid function test, breast ultrasonography, and endometrial biopsy are customized to fit individuals' risk factors. Depending on clinical manifestations and individual risk factors, the basic examinations and elective examinations are conducted at an interval of 1–2 years. MHT is used to prevent and treat symptoms and physical changes caused by estrogen deficiency, vasomotor symptoms, atrophy symptoms of the urogenital system, postmenopausal osteopenia, and osteoporosis. In the case of premature ovarian insufficiency (POI), MHT can be used at least until the mean age of menopause regardless of symptoms [1, 2]. In case of undiagnosed vaginal bleeding, estrogen-dependent malignant tumors (such as endometrial cancer), breast cancer, active thromboembolism, active liver diseases, and gall bladder diseases, MHT should not be used [1, 2]. Because the symptoms of menopause vary widely depending on an individual's physical, mental, social, cultural, and racial features, the physician is recommended to conduct an individualized menopause consultation and examination prior to MHT based on general principles of clinical examination as well as considering individual differences [3].
Key points: Examinations required prior to receiving MHT
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2. MHT for women in menopausal transition
Menopausal transition refers to the period from the moment of increased variation in menstrual cycle until the moment immediately prior to the last day of menstruation. It varies among individuals and is a period that often includes vasomotor symptoms such as hot flushes alongside frequent or excessive menstruation. Hot flushes vary among individuals but may appear from 1 year to 3 years prior to the last day of menstruation and are especially severe around the last day of menstruation. They may even last for several years. Approximately 75% of women aged between 45 years and 55 years suffer from symptoms of menopause, which may lead to low self-esteem, sleep disorder, and feelings of decreased energy. To evaluate the ovarian reserve during menopausal transition, measuring the serum level of anti-mullerian hormone (AMH), day 3 follicle-stimulating hormone (FSH), estradiol (E2), and ovarian antral follicle count (AFC) using pelvic ultrasonography is possible, but they are not used as indicators for predicting menopause. Additionally, because the function of the ovaries changes during this period, it is advised not to conduct a hormone test for menopause diagnosis [4].
Undergoing treatment for menopausal transition should be primarily decided according to the frequency and severity of the symptoms of menopause. Even in the case of menstruation, if a severe hot flush is experienced, a consultation is advised in order to discuss the necessary treatment to improve symptoms [4]. It is also possible to try alleviating the symptoms via improvement of lifestyles such as weight loss, stress reduction, hypnosis, and cognitive behavioral therapy. Medications such as omega-3, vitamin E, Cimicifuga racemosa, isoflavone, and soybean may be effective, but they are not more effective than placebo. In contrast, S-equol, a metabolite of soy isoflavone, seems to show slightly higher effectiveness than placebo [4].
Hormone therapies for treating the symptoms of menopause during menopausal transition are combination therapy of levonorgestrel releasing-intrauterine system (LNG-IUS) with oral or percutaneous estrogen, low-dose combined oral contraceptives (COCs), and estrogen–progestogen therapy (EPT) [4].
EPT is effective not only for treating women after menopause but also for controlling the symptoms of menopause in women in menopausal transition. However, the dose used in general MHT is very low compared with that used for treating women before menopause, and consequently, breakthrough bleedings could frequently occur. If contraception is simultaneously needed, the use of low-dose COCs is recommended. Low-dose COCs are effective for controlling irregular bleeding and alleviation of symptoms of hot flush [4].
In the case of using low-dose COCs, because the symptoms of menopause could worsen during the 7-day pill-free period, the use of continuous COCs or COCs such as Qlaira® with a shorter pill-free period is recommended. With regard to the safety of low-dose COCs, if there are no risk factors involved such as obesity, smoking, high blood pressure, and other cardiovascular diseases, it may be used carefully from 40 to 55 years of age. However, careful screening of each individual's risk factors is important [5, 6, 7].
The use of oral or percutaneous estrogen therapy (ET) together with LNG-IUS is not only effective for alleviating the symptoms of menopause but also for preventing endometrial hyperplasia. Even in the case of a normal menstrual cycle, if the symptoms of menopause are severe, the use of a combination therapy of low-dose percutaneous estrogen and LNG-IUS could effectively control a hot flush [8]. In addition, some reports have shown that it could help improve symptoms that appear during menopausal transition such as depression, reduced quality of sleep, and increased anxiety [9, 10].
However, as mentioned earlier, it remains unclear how ET initiated at this stage would affect cardiovascular diseases and breast cancer in the long term. Therefore, treatment during the menopausal transition period should be primarily based on the frequency and severity of the symptoms, and different treatment methods should be applied to improve symptoms according to the individual's risk factors [11].
Key points: MHT for women in menopausal transition
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3. Vasomotor symptoms and quality of life
3-1. Vasomotor symptoms
Hot flush, a common VMS, suddenly appears in the face and the upper body and spreads to the rest of the body. It usually lasts for approximately 2–4 minutes. Anxiety, shivering, palpitation, or perspiration may occur alongside, and night sweat is linked to sleep disorder.
The prevalence rate of VMS differs according to region and race. A lower prevalence rate of VMS is observed among Asians than among Westerners. The prevalence rate in Europe is 74%, North America 36%–50%, Central and South America 45%–69%, and Asia 22%–63% [12]. VMS are known to be highly related to the reduction of physical activity, low socioeconomic status, symptoms of anxiety and depression, hysterectomy, and smoking and the symptoms increase as body fat increases [13, 14].
Most severe VMS appear within 1–2 years from the last day of menstruation and usually continue for about 4–5 years. However, there are cases in which the symptoms last for more than 12 years, which is reported to be 10% of the total cases; therefore, the symptom duration greatly varies [13, 15].
Similar to standard-dose MHT, low-dose MHT is reported to be effective for treating VMS [16].
In a research with a multistage stratified random sampling design conducted in 2010 that targeted 40–60-year-old South Korean women in menopause or menopausal transition, 41.6% of women in menopausal transition, 53.1% of women in early-phase menopause, and 36.5% of women in late-phase menopause were shown to have experienced VMS [17]. In case of experiencing VMS, many women aged less than 45 years (50%) were shown to experience only hot flush as a monosymptom, whereas for women aged 45–60 years, the cases in which both hot flush and sweating were experienced increased up to 70% [17]. The results of a survey conducted by Korean Gallup Epidemiology Research in 2001 that targeted women aged 50–59 years in menopause showed that the main reason for receiving MHT was experiencing menopause symptoms, and 62.7% women reported that it was helpful [18].
In terms of the degree of improvement of VMS according to dose, a placebo showed 20%–40% reduction of symptoms, and the effect of extreme low-dose therapy, low-dose therapy, and standard-dose therapy in alleviating symptoms was 55%, 60%–70%, and 80%–90%, respectively, in MHT [19, 20, 21].
In terms of the degree of improvement of VMS for non-hormonal therapies, selective serotonin receptor inhibitor (SSRI)/selective norepinephrine receptor inhibitor (SNRI) showed 40%–65%, gabapentin (900 mg/day) showed 50%, and pregabalin (150 mg/day) showed 65% improvement of symptoms [22, 23].
Progestogen (medroxyprogesterone acetate [MPA] 10 mg/day, oral megestrol acetate 20 mg/day, and MP 300 mg/day) is known to alleviate VMS with a minimal risk, and it is highly effective in the case of severe VMS. The symptoms are less likely to recur when progestogen therapy is discontinued compared with the discontinuation of estrogen therapy [23, 24].
In the case of MHT discontinuation, a report showed that VMS recurred at 50% and at most 87%; nonetheless, the severity of VMS in the case of recurrence was not as bad as that before starting MHT [25]. There is no difference in the recurrence rate of symptoms whether MHT is suddenly or gradually discontinued by eventually reducing the dose [2].
3-2. Quality of life
Evaluation of the QoL may be divided into the following criteria: health-related QoL (HRQoL), menopausespecific QoL (MSQoL), and global QoL (GQoL).
MHT reportedly not only enhances MSQoL by improving menopause symptoms but also increases GQoL. In particular, MHT improves HRQoL and MSQoL of women experiencing severe menopause symptoms.
The Korean epidemiology research on the QoL and menopause symptoms of women in menopause also showed a similar correlation between the two, but women receiving MHT were shown to have a high QoL in aspects such as VMS, psychosociological changes, and physical changes [26]. In an evaluation of QoL using the SF-36 questionnaire, the group receiving MHT was shown to have a higher QoL score than the group not receiving MHT [27]. In another study, there was an increase in the score of Women's Health Questionnaire (WHQ) and an improvement of physical symptoms, depression symptoms, and sleep disorder in the treatment group receiving MHT [28].
Based on the analysis of WHQ scores, low-dose MHT (E2 1 mg/norethindrone acetate [NETA] 0.5 mg) and tibolone have been reported to improve QoL. Tibolone mostly improved sexual function while showing effectiveness in improving VMS. MHT enhances the quality of sleep and reduces VMS and thus helps improve sleep disorder. In a study using a low-dose oral or percutaneous MHT (0.5 mg 17β-estradiol and 0.1–0.25 mg NETA) for 24 weeks, sleep disorder was improved by 40%–50% [24]. When oral progestogen is used, there may be reduced waking up and increased sedation [2]. In addition, when a premenopausal woman reaches menopause while using SSRI to treat depression, compared with SSRI therapy alone, SSRI in combination with estrogen is more effective in improving depression and shows a faster rate of treatment [29].
In contrast to the prevalent views, MHT is not associated with an increase in weight, and in fact, it helps treat the accumulation of abdominal fat during menopausal transition. In animal experiments, lack of estrogen led to accumulation of central abdominal fat, which was improved via injection of estrogen [22]. In many randomized controlled studies, MHT has been shown to reduce abdominal obesity [22]. In a research by the Women's Health Initiative (WHI) on EPT, maintaining MHT for 3 years was shown to help maintain underweight status and prevent transformation into android fat distribution [22]. ET improves the accumulation of abdominal fat because it improves insulin sensitivity and reduces the occurrence of type 2 diabetes, thereby reducing overall body fat [22].
Key points: Vasomotor symptoms and quality of life
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4. Urogenital atrophy and sexual dysfunction
4-1. Urogenital atrophy
Urogenital atrophy has been newly renamed as GSM. The term includes all the symptoms and signs caused by changes in the bladder, urethra, vagina, and genitalia due to the decreased estrogen level during menopause and vaginal atrophy. The main symptoms are vaginal dryness, burning sensation, and discomfort; sexual symptoms such as pain due to decreased lubrication; and urinary symptoms such as painful urination, recurrent urinary tract infections (UTIs), and urinary urgency [30].
GSM chronically progresses and requires long-term treatment because the symptoms recur if treatment is stopped. The principle of this treatment is to alleviate the symptoms by normalizing the physiological environment of the urogenital organs. For the treatment of moderate or severe vaginal atrophy, both systemic and topical estrogens are effective. They help recover normal vaginal flora, increase the quantity of vaginal discharge by improving the division of the vaginal epithelium, induce proliferation of capillaries, and improve the maturation index of the vaginal epithelium [31, 32, 33]. In particular, low-dose vaginal estrogen is effective and safe, although the quantity of absorption in the whole body is minimal. All types of topical estrogen medicine (cream, vaginal tablet, and vaginal ring) are effective in reducing the symptoms and signs of vaginal atrophy. However, because there is a potential risk of increasing the estrogen level in the blood even by the slightest degree, in women with breast cancer, especially those using an aromatase inhibitor to reduce the estrogen level, a breast cancer specialist must be consulted regarding the vaginal application of low-dose estrogen [34]. Because there is no clinical data to guarantee the safety of the endometrium for a long-term application of more than 1 year, the duration of using low-dose vaginal estrogen should be limited to less than 1 year, and afterward, it must be used along with the evaluation of the endometrium.
Ospemifene and dehydroepiandrosterone (DHEA) vaginal agents are non-estrogen medications that improve the symptoms of vaginal atrophy and dyspareunia. Ospemifene, which is a selective estrogen receptor modulator (SERM), is more effective than a lubricant in reducing dyspareunia by treating moderate or severe vaginal atrophy in menopausal women. Hence, it can be considered for women who are not suited to receive vaginal estrogen treatment [35].
Vaginal DHEA has received FDA approval as a medicine for the treatment of GSM because it reduces vaginal dryness and dyspareunia as well as vaginal acidity by recovering the thickness and safety of epithelial cells and increasing the quantity of vaginal discharge [36].
The North American Menopause Society (NAMS) recommends the use of a moisturizing cream or lubricant as the primary treatment for vaginal atrophy. If a lubricant and moisturizer are frequently used, they improve the symptoms of vaginal dryness, reduce discomfort, and maintain vaginal discharge during sex but do not transform the contracted internal environment of the vagina. The use of a vaginal moisturizer, lubricant, and regular sexual intercourse help in the treatment of vaginal atrophy. Some studies show that a vaginal moisturizer has a similar effect to topical estrogen; thus, it could be recommended to women who avoid using MHT [34].
Recently, carbon dioxide laser therapy has been shown to improve sexual function and alleviate symptoms such as dyspareunia, itchiness, burning sensation, and dryness by improving the quantity of glycogen inside the vaginal epithelial cells and encouraging remodeling of vaginal connective tissues for women suffering from vaginal atrophy. It is predicted to become a suitable treatment for patients who simultaneously suffer from symptoms of GSM, which leads to a huge concern about MHT [37]. However, because there have been reports of chronic pain, burning sensation, and dyspareunia after receiving laser therapy and the U.S. FDA warned against the safety and effectiveness of laser therapy in July 2018, attention should be paid toward future research findings [38, 39].
Pelvic floor muscle training, vaginal ring insertion, and topical estrogen treatment improve the function of vaginal epithelial cells and accelerate the ingrowing of connective tissue. Vaginal estrogen reduces urinary urgency, urinary frequency, overactive bladder, and urinary incontinence by reducing the contraction of bladder muscles via increasing the blood flow around the bladder neck and urethra. In contrast, systemic ET increases the occurrence of urgency urinary incontinence and stress urinary incontinence [40, 41, 42, 43]. In the case of women with existing symptoms of urinary incontinence, the therapy worsens the symptoms, which may lead to a reduced QoL [40, 41, 42, 43]. To treat the symptoms of an overactive bladder, changes in lifestyles and bladder training are very important and are recommended as the primary treatment methods. The systemic ET shows a similar effect to a placebo with regard to the treatment of the symptoms of nocturia and urinary frequency, but it is more effective than a placebo for the treatment of symptoms. Combined administration of vaginal estrogen and antimuscarinic drug is more suitable, and topical estrogen is considered to play an important role in treating an overactive bladder. Hence, the combination therapy of an antimuscarinic drug and topical estrogen is the primary drug therapy for menopausal women with symptoms of an overactive bladder [44, 45, 46]. Topical ET was shown to be effective in preventing recurrent UTIs by recovering microbiological changes that occurred within the vagina after beginning menopause and by reducing vaginal acidity, but systemic ET was not effective for preventing recurrent UTIs [47].
Key points: Urogenital atrophy
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4-2. Sexual dysfunction
Increased age and decreased estrogen level lead to harmful effects on sexual function and reduce sexual desire and sexual response as well as cause vaginal dryness and dyspareunia. They also cause sexual dysfunction even more in the case of surgical menopause, and it is highly possible that hypoactive sexual desire disorder (HSDD) develops as a result of various endocrine changes [48, 49, 50, 51, 52].
Measuring the level of sexual hormones is not helpful. The serum androgen test has been used to diagnose androgen deficiency in healthy women, but it is also not recommended because there is mostly inconsistent correlation between the androgen level and particular symptoms and signs. Especially in the case of sexual dysfunction, the role of vaginal atrophy must always be considered because the most common symptoms of vaginal atrophy are vaginal dryness and dyspareunia, which significantly affect other aspects of sexual response (sexual desire, arousal, orgasm, and satisfaction) [53]. Because female sex possesses a variety of fundamental characteristics, the effect of MHT on women's sexual dysfunction cannot be clearly proven, and ET or EPT leads to improvement of sexual function and is especially effective in reducing dyspareunia in women in early menopause or with symptoms of menopause [31, 54, 55, 56, 57]. Tibolone is highly valuable for the treatment of women's sexual dysfunction because it is known to show a significant effect on improving vaginal dryness, sexual desire, sexual arousal, and frequency of sexual intercourse when compared with using estrogen or progestogen [58].
Systemic MHT and low-dose vaginal ET are effective in treating urogenital atrophy and improve sexual function by increasing vaginal lubrication, blood flow, and sensory function. Although ET is effective for the treatment of menopausal symptoms, it does not increase sexual desire, arousal, and orgasm. In the case of women who are in need of systemic MHT expressing decreased sexual desire, percutaneous therapy is preferred to oral therapy because oral intake of estrogen reduces free testosterone by increasing sex hormone-binding globulin (SHBG). An injection of testosterone for women suffering from sexual dysfunction due to decreased sexual desire improves sexual satisfaction, desire, arousal, and orgasm; thus, it is effective for both natural menopausal or surgical menopausal women and is effective regardless of whether the woman is receiving MHT. Testosterone is also effective for the treatment of sexual desire disorder and sexual arousal disorder, which are related to antidepressants [59, 60, 61]. Because the side effects of virilization due to testosterone therapy occur in proportion to the quantity administered, they may be reduced using the lowest quantity and medications suited for individual women [62, 63]. Vaginal testosterone therapy, which is another treatment option for GSM, improves dyspareunia, sexual desire, lubrication, and satisfaction when administrated alone or simultaneously with vaginal estrogen three times a week compared with a placebo [64, 65, 66].
Combination therapy of conjugated equine estrogen (CEE)–bazedoxifene also improves certain sexual functions as well as genitourinary atrophy and dyspareunia in menopausal women [22, 30, 67].
Key points: Sexual dysfunction
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5. Coronary artery disease
Based on a meta-analysis of existing observational studies, hormone therapy reduces the risk of coronary artery disease by 28% and the mortality risk by 38% for current users [68]. In the Heart and Estrogen–Progestin Replacement study (HERS) regarding the effect of hormone therapy on secondary prevention of coronary artery disease, CEE/MPA combination therapy showed no prevention effect and the risk increased by 50% in the first year of treatment but decreased thereafter [69, 70]. Additionally, in a study by WHI about the effect on primary prevention of coronary artery disease, CEE/MPA combination therapy showed no primary prevention effect and the risk significantly increased by 80% in the first year of treatment but showed trends of decline thereafter [71]. Conversely, in another study by WHI, CEE alone showed no prevention effect, but no increase in the early-phase risk was observed [72].
Considering that hormonal therapy did not prevent coronary artery disease in large-scale randomized control studies, unlike in observational studies, it is important to note that the mean age of participants was older than 60 years old. It has been suggested that the results may not apply to women younger than 60 years who have recently experienced menopause.
Hence, their different characteristics compared with those of healthy, early menopausal women in observational studies are considered to be important aspects. Thus, women who are relatively older or for whom a long time has passed since menopause (average age, 63.2 years) in the WHI study may not have experienced any significant effect on cardiovascular protection from hormone therapy as women in early menopause who are in good cardiovascular health. In a subsequent WHI analysis, the risk of coronary artery disease actually showed differences according to the starting period of hormone therapy since menopause. For women who started the therapy within 10 years of reaching menopause, there was a trend toward reduced risk, whereas for women who started the therapy more than 20 years after reaching menopause, the risk significantly increased [73].
Based on the result of analyzing 23 other clinical tests, the risk of coronary artery disease reduced by 32% for early menopausal women who have been in menopause for less than 10 years or women who were younger than 60 years of age; however, for women aged 60 or more, such cardioprotective effect did not appear [74]. Based on the recent results of meta-analyzing 19 randomized controlled studies, starting hormone therapy within the first 10 years of menopause led to reduction of total mortality risk by 30% and cardiovascular mortality risk by 48% [75]. Additionally, women in their 50s who were previously enrolled in the ET arm of the WHI study showed significantly lower coronary artery calcification scores than those who received placebo [76].
In the Danish Osteoporosis Prevention Study, when hormone therapy was conducted for 10 years with 1,000 young menopausal women with the average age of 50 years, there was a 52% reduction of the indicator, which is a combination of mortality, heart failure, or myocardial infarction [77]. On the other hand, in the Kronos Early Estrogen Prevention Study (KEEPS), when hormone therapy was administered for approximately 4 years to young women with an average age of 52 years and all within 3 years of their final menstrual period, there was no significant difference in the rate of progression of carotid–intima-media thickness between the treatment and placebo groups. However, there was a nonsignificant trend for less accumulation of coronary calcium in the hormone therapy arms than in the placebo arms [76]. In the Early versus Late Intervention Trial with Estradiol study, the use of hormone therapy for about 5 years for younger postmenopausal women who were less than 6 years past menopause showed that the carotid–intima media thickness significantly decreased compared with the use of a placebo but showed no difference compared with the use of a placebo for women who were 10 or more years past menopause at the time of randomization [78]. In summary, such research findings strongly imply (“timing hypothesis” or “window of opportunity”) that the effect of hormone therapy on the cardiovascular system could differ depending on the timing of initiation.
On the other hand, considering there were differences in the effect of hormone therapy on coronary artery disease between CEE alone and CEE/MPA combination therapy, attention must be paid to the type of hormone used, particularly progestogen.
In contrast, the International Menopause Society (IMS) (2016) claimed that hormone therapy has shown to reduce the incidence of new-onset diabetes mellitus and has a beneficial effect on vascular function, lipid levels and glucose metabolism, which are risk factors for cardiovascular disorders [22]. There is strong evidence showing that the mortality rate and the incidence of coronary artery disease are reduced if started around the time of menopause or under the age of 60 or within 10 years of menopause. Progestin combination therapy also shows a similar tendency. Accordingly, hormone therapy does not increase the risk of coronary artery disease in young and healthy menopausal women, but it is not effective in case they already have the disease.
The mortality rate by ischemic heart diseases (myocardial infarction and angina) in South Korean women was 25.0 deaths per 100,000 individuals in 2017, but for women aged above 65 years, the mortality rate was very high, reaching 148.8 deaths per 100,000 individuals. A more significant factor is that the mortality rate by ischemic heart diseases in OECD countries was reduced by 52% in 2016 compared with that in 1990; it was increased in South Korea by 43%. Not only the mortality rate but also the economic burden of diseases are increasing as the number of patients who received treatments for ischemic heart diseases has almost doubled from 510,000 in 2004 to 860,000 in 2016, which led to the more than quadruple increase in health insurance fees from 2,900 billion won to 1 trillion 2,400 billion won; therefore, attention is required.
Key points: Coronary artery disease
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6. Cerebral stroke
A meta-analysis including the WHI study found no increased risk of stroke in women aged less than 60 years or who were fewer than 10 years from menopausal onset [73, 75, 79, 80].
In the WHI study, in case of EPT, the risk of stroke for women who initiated hormone therapy when aged younger than 60 years and/or who were within 10 years of menopause onset was rare (< 1/1,000) and statistically insignificant.
In case of ET, if the women initiated hormone therapy at the age of 50–59 years, the risk was reduced by 1/100,000 person-year, but for women fewer than 10 years from menopause onset, there was a trend of increase in the risk by 1/100,000 person-year. These results were inconsistent but were not statistically insignificant.
On the other hand, for women who initiate HT when aged above 60 years and/or who are more than 10 years from menopause onset, hormone therapy increases the risk of stroke. The risk differs depending on the age range; in case of EPT, the HR was 1.45 (95% CI, 1.00–2.11) for women in their 60s and 1.22 (95% CI, 0.84–1.79) for those in their 70s; hence, there was no statistical significance. In case of ET, HR was 1.55 (95% CI, 1.10–2.16) for women in their 60s and 1.29 (95% CI, 0.90–1.86) for those in their 70s.
In the results of a long-term follow-up observation up to 13 years after completing the WHI study, stroke risks did not differ significantly between women formerly assigned to hormones and women formerly assigned to placebo, and there was no statistical evidence that risks differed based on age or timing [81].
Based on the results of observational studies, lower-dose oral hormone therapy and lower-dose transdermal therapy has less effect on the risk of stroke [82]. The increased risk of stroke due to hormone therapy may be limited to ischemic stroke and has no effect on hemorrhagic stroke.
Based on Korean epidemiology and the data from the National Statistical Office (2017), cerebrovascular disease is the third highest cause of death in both genders and the mortality rate by cerebrovascular diseases in women is 46.1 deaths every 100,000 people. In the national statistics released by the Korean Stroke Society in 2018, ischemic cerebral stroke constituted 76.3% and hemorrhagic cerebral stroke constituted 23.4% of the total cerebrovascular diseases (change order) [83]. The stroke incidence in 2013 was similar to that in 2004, but the stroke mortality is declining.
Key points: Cerebral stroke
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7. Venous thromboembolism
Venous thromboembolism has an annual disease frequency of 5.4 diseases per 100,000 adult populations in Europe and the US regardless of gender. With an increase in age, some coagulation factors and activation increase, leading to an increase in the risk of thrombosis; however, this is rarely observed before the age of 60 years [84]. In case of women, it occurs in 1–2 women per 1,000 women annually. The risk factors of venous thromboembolism include age, obesity, personal history of thrombosis and genetic thrombophilia [85]. In general, a lower frequency of venous thromboembolism is observed in Asian women than in Western women [86].
In the U.S. Preventive Services Task Force (USPSTF) study, in which a meta-analysis was conducted with the WHI study, HERS study, and other references, the risk of venous thromboembolism due to hormone therapy approximately doubled and the risk was higher during the first year of oral estrogen use, with or without progestogen (Table 1) [87, 88, 89].
Table 1
Relative risk of venous thromboembolism (VTE) in hormone therapy users (RR or HR with 95% CI)
The absolute risk of VTE was significantly increased in women initiating hormone therapy more than 10 years from menopause onset [75]. In the WHI study, based on the analysis according to age, use of ET in women aged 50–59 years showed no significant increase in the risk. Because oral estrogen increases the activity of thrombin while reducing the activity of plasmin and has a higher thrombus tendency than that of transdermal estrogen, the use of transdermal estrogen could be better in case of women having a medical history or risk factors of venous thromboembolism [1, 22, 90]. Transdermal estrogen could be a better option for patients with diabetes, high blood pressure, and other risk factors of cardiovascular systems because it does not go through liver metabolism, thus leading to less stimulation of the synthesis of SHBG [87].
Regarding the risk of venous thromboembolism depending on the type of estrogen there is an opinion that CEE use was associated with a higher risk of incident VTE than estradiol use [75, 90]. The risk of VTE may be affected by the type of progestogen, MPA may be associated with greater risk of venous thromboembolism. However, micronized progesterone may be safe with thrombotic risk.
The risk of VTE was higher in users of oral estrogen plus progestogen than oral estrogen therapy alone [70, 85, 89]. According to the WHI study, hormone therapy for women with factor V Leiden mutation increases the relative risk of venous thromboembolism to 6.69 compared with that for women without any mutations who do not receive any hormone therapy. For women with a body mass index of more than 25, EPT significantly increases the risk of venous thromboembolism [91].
Based on the review of domestic references, the incidence of VTE is lower in Asian population than in Western populations. There was no factor V Leiden mutation reported in Korean subjects at high risk for thrombophilia. There was one case of venous thromboembolism after using MHT in South Korea, but even in this case, there was no factor V Leiden mutation [92].
Key points: Venous thromboembolism
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8. Breast cancer
There have been controversies regarding the association between MHT and breast cancer. Different results are being reported according to the forms and types of hormones such as ET, EPT, and CEE–bazedoxifene, dose, starting date of medication, period, and individual characteristics [93, 94, 95, 96, 97, 98]. According to a recent randomized controlled study on MHT and occurrence of breast cancer and the consultation instructions by British Menopause Society, ET did not increase breast cancer, whereas EPT showed a tendency of significant increase in breast cancer [93, 99].
Based on a 5.6-year observation in the WHI study, the EPT group showed an increase in the risk of infiltrative breast cancer by approximately 1.24 times (absolute risk: annual increase of nine cases per 100,000 people), and the increase of the risk was observed from the third year of MHT [100]. However, the increase of breast cancer was limited to women with a history of having received MHT prior to participating in the WHI study, and in case of women with such histories, the increase did not occur until the seventh year and the increase of breast cancer was not observed even during the 11-year follow-up observation period [101, 102]. In case of ET, based on the 7.2-year observation, there was a tendency of reduction of the risk of breast cancer (absolute risk: annual reduction of seven cases per 100,000 people), even though it was not statistically significant. In particular, in case of women without any history of receiving MHT or those who received it for more than 80% continuously, there was a statistically significant reduction (33%–35% reduction). In the 13.2-year cumulative follow-up observation after stopping ET, the occurrence of breast cancer was significantly reduced by 21% [81]. Moreover, in the extended study (on average, 5.9-year of use, 11.8-year of observation) conducted after the WHI study targeting women who wanted continuous single use of estrogen therapy, the risk of breast cancer significantly decreased [103, 104]. According to the Nurse Health Study, there was no significant increase in the risk of breast cancer in the ET group until the 15th year [105].
There is no reliable research finding about whether low-dose estrogen–progestogen combination therapy increases the risk of breast cancer. In case of long-term use of progestogen, there has been a report about the possibility of increasing the frequency of breast cancer occurrence. However, according to the E3N-EPIC cohort study conducted in France, there is a report about how natural progesterone use would not increase the risk of breast cancer. Therefore, the risk of breast cancer is expected to differ depending on the progestogen medicine [106].
In a small number of observational studies, MHT did not increase the risk of breast cancer in women with a family history of breast cancer or who received ovariotomy and have BRCA 1/2 [107, 108, 109, 110]. Thus, because MHT could increase recurrence in breast cancer patients, it is not advised [111]. However, in case of low-dose vaginal ET, it could be considered as an effective therapy after trying non-hormonal therapy when suffering from urinogenital atrophy due to minimal systemic absorption [112].
However, difference of Korean epidemiology from western epidemiology must be considered when indicating the association between breast cancer and MHT after reaching menopause. The risk of occurrence of breast cancer in American women begins from the age of 15 years and increases from the age of 40–49 years, and the highest rate of occurrence is observed at the age of 70–74 years, which gradually decreases afterward. In case of South Korea, the middle age at the point of diagnosis is 50 years and 40s is the age range in which the highest number of breast cancer cases occurred. The order of frequency of disease as per age is as follows: 40s, 50s, 60s, 30s, and 70s [113, 114, 115]. Compared with the past results, there is a general tendency of increase in the occurrence age, and from 2010, an increase in the number of patients in their 50s diagnosed with breast cancer was observed. Occurrence of breast cancer keeps increasing but is still relatively low as it is 1/2–1/3 of the occurrence in the west. In case of western women, the frequency of breast cancer increases as age increases, whereas in case of Korean women, the frequency increases until early 50s, then gradually decreases afterward [113, 114, 115]. The ratio of breast cancer before menopause is significantly higher than that in the west. There is a high occurrence rate in young patients in their 40s, and patients under 40s constitute about 13% of the cases, which is more than two times higher than that in the west [113]. The occurrence rate in American women is 126.4 cases per 100,000 people, whereas the mortality rate due to breast cancer is 20 cases per 100,000 people. The frequency in South Korea is 75.1 cases (2015), and the mortality rate is 9.6 cases (2016), which is a significantly low occurrence rate and mortality rate, therefore showing a very different aspect from an epidemiological perspective [113, 114, 115].
Key points: Breast cancer
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9. Ovarian cancer, endometrial cancer, colorectal cancer, and lung cancer
9-1. Ovarian cancer
Ovarian cancer, the 9th most common type of cancer in the west, occurs every 27 cases per 100,000 people among women aged above 50 years, and the average age at the point of diagnosis is approximately 64 years with more than 80% women aged above 50 years. Moreover, in South Korea, the number of ovarian cancer patients shows a trend of continuous increase (change of location) [116].
Until now, there is no reliable data that could confirm the association between MHT and the occurrence of ovarian cancer. According to the 5.6-year observation in the WHI study, which is the only randomized controlled study that could analyze the association between ovarian cancer and MHT, the risk of ovarian cancer did not significantly increase in both ET group and EP group (HR, 1.24; 95% CI, 0.83–1.87, HR 1.41; 95% CI, 0.75–2.66) [117]. However, several observational studies have reported an increased risk: Nurses' Health Study reported an increased relative risk of ovarian cancer by 1.41 times (95% CI, 1.07–1.86) when using estrogen for more than 5 years; NIH-AARP Diet and Health Study reported an increased relative risk of ovarian cancer by 2.15 times (95% CI, 1.30–3.57) when using ET for more than 10 years and by 1.68 times (95% CI, 1.13–2.49) when using EPT for more than 10 years. However, even if MHT increases the risk of ovarian cancer, the increase is about 0.8 cases per 10,000 people annually, which is considered very rare.
Based on the meta-analysis, in ovarian cancer patients, MHT does not increase the mortality rate or recurrence rate of ovarian cancer, but there is almost no data available yet on low-grade serous cancer as well as granulosa cell tumor or cancer, which involve positive estrogen receptors such as Sertoli–Leydig tumor [118].
Key points: Ovarian cancer
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9-2. Endometrial cancer
In women with the uterus, administration of estrogen alone increases the risk of endometrial cancer in proportion to its dose and duration. Therefore, in the presence of the uterus, estrogen and progestogen should be administered in combination. In the WHI study, the continuous EPT combination therapy showed a similar result to the comparative group regarding endometrial cancer [117].
According to recent studies, among patients with endometrial cancer, if the patients that belong to endometrioid subtypes I and II had excision of the uterus and bilateral appendages and the estrogen receptors and progesterone receptors tested negative, the recurrence rate and mortality rate of endometrial cancer did not increase, even when MHT was applied [119]. However, even in case of early endometrial cancer, the therapy is recommended 5 years after complete recovery. For stages III and IV endometrial cancer, clear cell carcinoma, or serous papillary carcinoma patients, MHT is not recommended [120, 121].
The incidence of endometrial cancer in Korea has rapidly increased, increasing more than 10 times from 132 cases in 1991 to 1,619 cases in 2009 and reaching 2,404 cases in women in 2015. According to age groups, women in their 50s showed the highest incidence at 38.4%, followed by those in their 40s at 25.2% and those in their 60s at 17.9%.
Key points: Endometrial cancer
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9-3. Colorectal cancer
Observational studies including Nurses' Health Study showed that administration of hormone therapy during menopause significantly reduces the risk of colorectal cancer [121]. In the WHI study, which is a large-scale randomized controlled study, estrogen–progestogen combination therapy has been reported to reduce the risk of colorectal cancer by 38% when compared with a placebo (HR 0.62; 95% CI, 0.43–0.89) [122]. However, when the administration stops, the prevention effect of colorectal cancer disappears. Individual estrogen therapy does not have any effect on invasive colorectal cancer or on the mortality rate due to invasive colorectal cancer [123, 124].
In Korean women, colorectal cancer is the third highest type of cancer in females (10.7%) and occurred among 10,846 women in 2015. It occurred most commonly among women aged above 65 years. The mortality rate of colorectal cancer is the second highest after that of lung cancer.
Key points: Colorectal cancer
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9-4. Lung cancer
In the WHI study, both individual estrogen therapy and estrogen–progestogen combination therapy did not increase the occurrence of lung cancer. However, in case of estrogen–progestogen combination therapy, the mortality rate due to lung cancer increased, which was limited to past or current smokers aged above 60 years. The absolute risk was also very low as the increased mortality was 4 cases per 10,000 people and individual estrogen therapy did not have any effect on the mortality rate of lung cancer [125].
The IMS claimed that based on the analysis of many observational research findings, MHT has a protective effect against occurrence of lung cancer in patients aged less than 60 years. In South Korea, lung cancer is the fifth highest type of female cancer (7.2%), which affected 7,298 women in 2015 and has the highest mortality rate among female cancers.
Key point: Lung cancer
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10. Cognitive function and Alzheimer's
The WHI memory study (WHIMS), an ancillary study to WHI study, reported a significant increase in the risk (2.05) of probable dementia in the EPT group with women aged above 60 years every year, and the risk increased to 1.49 in the ET group, but no statistical significance was observed [126, 127]. The WHI study of cognitive aging, another ancillary study about cognitive function, observed a slight improvement in nonverbal episodic memory in the EPT group but a reduction in verbal episodic memory, although no particular effect was observed in the ET group [128]. Another ancillary study, the WHIMS-Magnetic Resonance Imaging study showed a reduction in the volume of some brain areas, especially of the frontal lobe and hippocampus in MHT patients compared with the control group [129].
In contrast, according to the findings from the MIRAGE study, which compared 426 Alzheimer's patients with patients without Alzheimer's, the risk of Alzheimer's in the group that received MHT was 30% lower than that in the control group for all age groups [130]. Similarly in case of the Cache county study, which targeted 1,889 women, the risk of Alzheimer's in the MHT group was significantly lower by 0.41 times (95% CI, 0.17–0.86) when compared with the control group [131]. Such observational research findings showed different results from the WHIMS study; this could be owing to the effect of difference of age and the starting point of MHT (Table 2) [132]. WHIMS's research target was women aged above 65 years who had relatively increased risk of Alzheimer's. Thus, the patients diagnosed with Alzheimer's during the study could have already well manifested Alzheimer's symptoms, which were not clinically revealed at the starting point of the study.
Table 2
Considerations for discrepant findings between most observational studies on MHT and the WHIMS randomized trials of MHT
In contrast to WHIMS, in the recently released KEEPS study, MHT did not have any effect on memory or cognitive function. This could also be because of the fact that the study targeted young women who had just reached menopause [133]. The “critical window hypothesis” refers to a concept that addresses that the effect of MHT on cognitive function could differ depending on the time of executing the MHT [134, 135]. Although the highest improvement effect on cognitive function could be expected if MHT is started immediately at the point of decline in ovarian function due to natural menopause or ovariotomy, if MHT is started in old women in menopause, it could actually cause a harmful effect on cognitive function.
In the Study of Women's Health Across the Nation study, a better recall score was shown in case of starting MHT before the last menstruation, whereas in case of starting MHT after the last menstruation, a decline in cognitive function was observed [136]. Another observational study reported that although starting MHT at midlife helped prevent cognitive disorder, starting MHT during late life caused a negative effect on cognitive function [134]. In the MIRAGE research findings, although the risk of Alzheimer's was reduced by 65% for the age range of 50–63 years when using MHT, for the age range of 64–71 and 72–89 years such effects did not appear and the effect of MHT on Alzheimer's seemed better with younger age [130]. Based on research findings about women with the average age of 74 years, Zandi et al. [131] also suggested the possibility of a period during which MHT influences cognitive function and reported that in case of MHT administered for more than 10 years but currently stopped, the risk of Alzheimer's occurrence was reduced by 83%, and in case of MHT administered in the past, the risk of Alzheimer's occurrence was reduced by 41% [6]. However, clinical evidence lacks such “critical window hypothesis” yet [90]. For example, in the WHIMS of Younger Women study, which targeted young menopausal women with the age range of 50–59 years and analyzed the effect of MHT on cognitive function, MHT using CEE did not result in improvement of general cognitive function regardless of combining with progestin [137].
Recently, the “healthy cell bias hypothesis” is often introduced instead of the existing “critical window hypothesis” about the difference in the effect of cognitive function regarding the execution time of MHT [138, 139]. This means that in terms of the effect of MHT, the woman's health is a more important determinant than physiological age. Even an old woman could benefit from the use of MHT if her cognitive function is “healthy.” However, both hypotheses share a limitation that they were not supported by large-scale random blind studies [90].
In case of surgical menopause, as the concentration of estrogen rapidly decreases, the effect on cognitive function could possibly differ from that in case of natural menopause [140, 141]. The faster the surgical menopause is done, the higher is the risk of Alzheimer's or cognitive disorder [142]. Guidelines from both the North American Menopause Society and IMS recommend that estrogen therapy immediately after surgical menopause could help improve cognitive function [22, 90].
In several small-scale studies that were conducted in 1980s–1990s on whether injection of female hormone could help improve cognitive function in women with Alzheimer's, improvement of cognitive function was reported when the female hormone was administered to the Alzheimer's patient [143, 144, 145]. However, the positive effect in the observational study could be because of the fact that the subjects were relatively young women and recall bias might have occurred. In the reported random double-blind study in 2000, no change in cognitive function was observed when administering individual female MHT for 1 year targeting 120 women with Alzheimer's who had undergone hysterectomy due to medical history [146].
Korean epidemiology reported that 4.2% of the elderly aged above 65 years has Alzheimer's. In the study that targeted South Korean Alzheimer's patients, MHT was administered for 1 year, and it was reported that the MMSE score did not decline, although it showed similar effects to the representative Alzheimer's medicine, tacrine, regarding cognitive function, and that the MHT improved the daily activity capacity. Thus, a positive effect of MHT was reported [147].
Key points: Cognitive function and Alzheimer's
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11. Depression
The prevalence rate of major depressive disorder in women of age 50 and over is 4.0%–5.4% in South Korea, which is about three times higher than that in men (1.3%–2.4%) [148]. Most women (more than 85%) in menopausal transition do not experience a new onset of depression, and the risk of depression is similar to that before or after menopause. However, hormonal changes and vasomotor symptoms can lead to new depressive symptoms and the risk of developing depression could increase during menopausal transition or early menopause [149, 150]. Although it has been shown that estrogen therapy has a positive effect on mood disorder in women who had surgical menopause, even without menopausal symptoms [151], it remains unclear whether MHT has a beneficial effect on mood disorder in women who are not diagnosed with depression [22, 152].
Until now, there have been very few randomized controlled studies on MHT in middle-aged women with depression. Although some studies reported that short-term estrogen therapy could alleviate symptoms of depression during menopausal transition in women with depression [153, 154], most studies failed to find a positive effect of MHT on depression in older menopausal women [155, 156, 157]. In women who experienced improvement in depressive symptoms with MHT, symptoms could get worse after stopping MHT [158].
Addition of progestogen could negatively affect mood in women with a past history of depression, premenstrual syndrome, or premenstrual dysphoric disorder [159]. The effect of progestogen on the central nervous system could differ depending on the ratio of estrogen and progestogen [160].
Key points: Depression
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12. Osteoporosis
12-1. Bone density
The standard dose of MHT increases bone density by inhibiting bone resorption and reducing bone remodeling process. The response of bone density to estrogen is dose-dependent. In the Postmenopausal Estrogen/Progestin Interventions trial, bone density increased at the lumbar spine and femur in women who received ET or EPT (0.625 mg CEE/MPA or micronized progesterone) for 3 years compared with the control group [161]. In the WHI study, bone density at the lumbar spine and femur increased by 4.5% and 3.7%, respectively, with the standard-dose EPT (0.625 mg CEE + 2.5 mg MPA) compared with the control group [162].
In a meta-analysis, 2 years of oral MHT increased bone density at the lumbar spine (6.8%) and femur (4.1%) compared with the control group [163]. Bone density significantly increased at both the lumbar spine and femur with low-dose ET or EPT (oral CEE 0.3 mg, 17beta-estradiol 0.25 mg, 17beta-estradiol 0.014 mg patch) in young (average age: 51–52 years) and old (average age: 67–74 years) postmenopausal women [164, 165].
12-2. Fracture
In the National Osteoporosis Risk Assessment (NORA) study, the risk of new fractures significantly decreased when evaluating 200,160 postmenopausal women using MHT with no history of osteoporosis. In current ET or EPT users, the risk of clinical fracture at the femur, spine, humerus, wrist, or rib was reduced, although this beneficial effect did not persist after stopping MHT for 5 years. In particular, the risk of fracture at the femur when women stopped MHT for 5 years was similar to that with no treatment [166].
In the WHI study, the risk of facture significantly decreased by 33% at the lumbar spine and 35% at the femur using EPT and by 38% at the lumbar spine and 39% at the femur using ET. This protective effect rapidly disappeared after stopping MHT, and the long-term follow-up study of WHI reported that the ET group showed a continued reduction effect of all fractures after stopping therapy, whereas the EPT group showed no reduction in all fractures [81].
Most (82%) menopausal women with fractures in the NORA study were reported to have osteopenia with a T score above −2.5, but even though the frequency of femur fracture was the highest in the study, only 6.4% of the patients had a T score below −2.5 [166]. Therefore, MHT is also necessary to prevent bone loss or fracture in women with osteopenia.
No difference was found between the continuous and cyclic use of progestogen, and no effect has been proven to reduce the risk of fractures using low- and ultralow-dose estrogen therapy.
NAMS reported that MHT prevents menopause-related bone loss and reduces osteoporotic fractures including those of the spine and femur in the low-risk group. MHT is an appropriate first-line treatment in menopausal women aged less than 60 years with an increased risk of fracture, but MHT is not recommended solely for the prevention of fracture in women aged above 60 years. MHT also prevents bone loss in women with premature ovarian failure [90].
The prevalence rate of osteoporosis in individuals aged above 50 years was 7.5% in men and 35.5% in women from the Korean National Health and Nutrition Examination Survey in 2008–2009. The incidence rate of femur fracture increased from 99.6 cases per 100,000 in men and 209.9 cases per 100,000 in women in 2008 to 110.5 cases per 100,000 in men and 243.1 cases per 100,000 in women in 2012 from the data from National Health Insurance Service [167]. In the multi-center retrospective observational study conducted by the Korean Society of Menopause in 2012, patients whose bone density was reduced after the first year of MHT showed increased bone density in the second year of MHT. In contrast, patients whose bone density was remarkably increased after the first year of MHT demonstrated relatively lower or decreased bone density in the second year of MHT. This finding was similar across EPT, ET, and tibolone users. It was concluded that even if bone density is temporarily reduced after MHT, it should not be the only reason for changing therapy [168].
Key points: Osteoporosis
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13. Sarcopenia
The prevalence rate of sarcopenia in community-dwelling older adults was 35.3% in women and 13.4% in men aged above 65 years from the Korean longitudinal study on health and aging. In another epidemiological study targeting the elderly in the Gangbuk district in Seoul, the prevalence rate of sarcopenia was 6.3% in men and 4.1% in women [169, 170, 171]. In addition, according to the cumulative data of more than 10 years from the Korean National Health and Nutrition Examination Study, 19.5% of women in their 50s, 16.6% of women in their 60s, 23.7% of women in their 70s, and 30.8% of women in their 80s were reported to have sarcopenia [172, 173, 174].
Several studies showed that MHT can preserve muscle strength and recover rapid loss of muscle strength. Muscle strength increased up to 24 months when using MHT, and the maximal voluntary force also increased in the MHT group in contrast to a decrease in the control group. Likewise, vertical jumping height and maximal walking speed were significantly higher with MHT in monozygotic twins. When combining MHT and exercise, the effect of improving the muscle tone, muscle mass, and muscle strength was enhanced. These results suggest that MHT can help increase muscle strength and prevent muscle contraction and movement limitation; furthermore, a meta-analysis showed that MHT helps improve muscle intensity. However, this beneficial effect was not found when MHT was used in older women aged above 60 years or when used for less than 6 months [175, 176].
In contrast to the consistent effect being reported regarding muscle strength, the effect of MHT on muscle mass remains controversial. In the WHI study, a preservation effect of body mass except fat was observed during the first 3 years of MHT, but this effect was reduced and disappeared during the 3 years afterward. This implies that the effect of MHT can depend on age [177].
In summary, MHT alone or combined with exercise could increase muscle mass, alleviate its reduction, and improve muscle function and regeneration of skeletal muscle. However, as most studies are small with different age, health condition, and exercise program, the interpretation of results could be affected. Therefore, additional studies are needed to draw a clear conclusion. On the other hand, although there is a lack of studies, plant hormones such as isoflavone are considered to have no effect on sarcopenia [178].
Key points: Sarcopenia
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14. Gallbladder disease and migraine
Gallstone (or gallbladder disease) occurs in 10%–15% cases in the US and increases by 1 million people annually. The occurrence of gallbladder disease has a close association with estrogen therapy. In South Korea, the frequency of gallstones is about 2%–4% and the number of patients with gallstones has increased by 49% from 129,226 people in 2014 to 192,551 in 2018, according to the data from the Health Insurance Review and Assessment Service. This is because of the westernization of eating habits. Gallstones are more common among women than among men. In South Korea, it is reported to occur 1.1 times more frequently in women than in men, and the frequency increases in both genders from 40 to 50 years of age [179].
Estrogen increases the risk of gallstone by accelerating the increase of secretion and saturation of cholesterol within the gallbladder, which leads to increased concentration of cholesterol and reduced activity of the gallbladder. Apart from MHT, factors such as use of combined oral contraceptive and pregnancy also increase the risk of cholesterol gallstones [180]. In the WHI study, the relative risk of cholecystitis and cholecystectomy was increased in case of both ET (79%) and EPT (61%) [181]. However, MHT was not associated with other bile duct surgeries. In a meta-analysis regarding the occurrence of cholecystitis, the relative risk increased to 1.8 in women who used MHT for less than 5 years, whereas it increased to 2.5 in women who used MHT for more than 5 years. The frequency of cholecystectomy was lower with non-oral MHT than with oral MHT [11, 90].
There is a lack of data on the relationship between MHT and migraine, and evidence for banning the use of MHT merely due to migraines is very rare.
Key points: Gallbladder disease and migraine
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15. Cautions for HT
15-1. Indication of progestogen
For women with the uterus intact, estrogen must be administered together with progestogen to reduce the risk of endometrial hyperplasia and cancer. For women with no uterus, progestogen may not be administered, but if there is a history of endometriosis or a partial uterus left when performing hysterectomy and in case of an endometrioid type of ovarian cancer, administration of progestogen is required. In case of receiving vaginal estrogen therapy due to vaginal atrophy or receiving minimum dose transdermal estrogen therapy to prevent bone disappearance, progestogen may not be administered, but the long-term safety of progestogen administration for more than 1 year remains unclear [90, 159].
15-2. Route of administration
The route of administration can be oral and non-oral, and non-oral administration is known to have no first-pass effect on the liver and almost no effect on SHBG, blood pressure, neutral fat, and C-reactive protein level when compared with oral administration. In case of having only symptoms of vaginal atrophy and vaginal dryness, topical vaginal estrogen is recommended, whereas for women with a high risk of venous thromboembolism and high neutral fats as well as for obese women with metabolic syndrome, transdermal therapy should be selected first. For women with smoking habits and high blood pressure, transdermal therapy is also recommended [90, 159].
15-3. Timing of initiation
It is better to start MHT immediately once symptoms appear before or after menopause. If premature hypoestrogenism or early menopause (menopause under 45 years of age) is diagnosed, it is recommended to start MHT regardless of whether symptoms of menopause are present [182].
15-4. Duration of MHT
Based on the results of previous research, it is not yet possible to provide clear instructions regarding the duration of MHT. However, there is no need to impose a limit on the duration of MHT as long as an effective minimum dose is used, if women are well aware of the potential benefits and risks, and a regular clinical follow-up observation is accompanied. Particularly for healthy women aged less than 60 years or those who have started MHT within 10 years of reaching menopause, if there is no occurrence of new diseases, it is safe to continue MHT. There is no need to discontinue daily MHT at 60–65 years of age, and evaluating comorbidity, trying to temporarily discontinue or reduce hormone therapy, or eventually switching to safer transdermal therapy could be considered instead [90, 159].
When determining whether to continue MHT, the following factors should be considered: first, the positive effect of MHT for the treatment of continuous vasomotor symptoms, reduction of bone density, prevention of fracture, reduction of colorectal cancer, and prevention and treatment of symptoms of urinogenital diseases; second, consideration of the potential risk of breast cancer, which could increase as the duration of MHT increases, as well as thrombotic events (VTE, PE, and stroke). Additionally, although starting MHT when almost reaching menopause could help reduce the mortality related to coronary artery disease and other diseases, in women starting MHT who have already passed 10 years of menopause, especially more than 20 years after menopause or are above 60 years of age, it must be noted that the absolute degree of risk of thrombotic events (VTE, PE, and stroke) and coronary artery disease is higher than that in women who have started MHT at the beginning of menopause [90, 159].
Premature hypoestrogenism or early menopause does not have a high risk of breast cancer due to MHT, and in this case, diabetes and coronary artery disease could prematurely occur due to early menopause. Therefore, receiving MHT at least until the mean age of natural menopause (50–52 years) is advised [182].
15-5. Methods to stop MHT
There is no significant difference in the recurrence rate of vasomotor symptoms depending on whether MHT is gradually or abruptly discontinued. However, there is still no consensus on which is a better method to discontinue MHT [90, 159].
15-6. Bioidentical MHT
Bioidentical MHT may be administered in excessive or very low doses, with no guidelines established for administration and routine tests, including blood tests. Moreover, there is a lack of evidence regarding its safety and effects [90, 159].
15-7. Complementary therapy, non-pharmacological, lifestyle intervention
Reports claim that methods such as cognitive behavioral therapy, mindfulness training, hypnosis, and stellate ganglion blockade could help alleviate VMS, but there is a lack of evidence of the effects and safety of complementary therapy [90, 159].
15-8. Other medication
Using DHEA topically everyday may be effective in treating GSM [90]. Ospemifene, an optional estrogen receptor agent, has been approved for use in treating GSM and severe dyspareunia in women who have difficulties using estrogen [90, 159].
Key points: Cautions for HT
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16. Tibolone therapy
Tibolone, a 19-nortestosterone derivative as well as a combined steroid, shows a biological effect and action via three metabolites. After intake, tibolone is transformed into Δ4-tibolone in the liver and stomach, which has the characteristics of androgen, progestogen, and estrogen metabolite (3α-,3β-hydroxytibolone). It plays a similar role as estrogen via the estrogen receptor and shows effects of alleviating menopausal symptoms and preventing bone loss while not irritating breast and endometrial tissue by showing tissue selectivity due to the changes in enzyme activation. Tibolone is considered safe against breast cancer by selectively reducing estrogen levels in breast tissue. Tibolone does not have biological activation in itself, but as its metabolites show particular medicinal effects according to human tissue, it is categorized as a selective tissue estrogen activity regulator.
16-1. Effects on menopausal symptoms
Tibolone shows an estrogen action effect, which is effective for treating menopausal symptoms. Tibolone is effective in alleviating symptoms such as fatigue, headache, insomnia, and perspiration.
1) VMS
The optimal daily dose of tibolone for treating VMS is 2.5 mg, and it shows a significant effect within 4 weeks of administration and shows a maximum effect after 12 weeks of administration [183].
When taking more than 1.25 mg over a period of 12 weeks, 86% of participants experienced improvement of hot flush [183]. The results of the Tolerability Trial comparing Activelle with Livial study, which compared the effect on vaginal atrophy, VMS, and abnormal vaginal bleeding by randomly allocating 2.5 mg tibolone or low-dose MHT (E2/NETA, 1 mg/0.5 mg) to menopausal women with a mean age of 55 years, showed that VMS and vaginal atrophy were improved similarly in both groups when compared with the early phase of therapy [184]. In addition, the frequency of abnormal vaginal bleeding was significantly low in the group treated with tibolone during the first 3 months of therapy. In addition, the frequency of breast pain was significantly low in the group treated with tibolone when compared with the E2/NETA group.
2) QoL
In a randomized controlled trial (RCT) that compared a placebo, 17β estradiol (2 mg), and tibolone targeting women with surgical menopause, the group treated with tibolone presented a better effect in alleviating VMS as well as other symptoms such as mood disorder, insomnia, concentration disorder, fatigue or loss of energy, apathy, and migraine [185].
The International Tibolone Consensus Group in 2005 and Asia Pacific Tibolone Consensus Group in 2010 implied that tibolone is a treatment for menopausal women with mood changes as well as VMS because it shows a positive effect in treating mood disorder, sexual function, and sleep and causes less abnormal vaginal bleeding and less discomfort to the breast [185, 186].
Based on the analysis of WHQ scores, low-dose MHT (E2/NETA, 1 mg/0.5 mg) and tibolone were reported to improve QoL, and tibolone mostly improved sexual function and showed good results in treating VMS [187]. Tibolone increased muscle mass and reduced the waist–hip ratio in menopausal women [188, 189].
In an RCT that evaluated the effectiveness of medicine after administering tibolone (2.5 mg) or a placebo for 12 months to menopausal women with a mean age of 54 years, the muscle strength, which was evaluated by assessing the hand grip strength in the 12th month, in the group administered tibolone was improved compared with that in the control group [190].
3) GSM
Tibolone improves GSM, and women who received tibolone therapy experienced significant improvement of vaginal dryness, dyspareunia, and urinary symptoms [191].
4) Sexual function
Tibolone has the advantage of increasing libido by increasing the bioavailability of testosterone through the reduction of the direct androgen effect of Δ4-isomer and SHBG [192].
16-2. Osteoporosis
In the STEP RCT, which aimed to study the effect of tibolone on osteopenia and compared bone density after administering tibolone (1.25 mg) and raloxifene (60 mg) to menopausal women aged 60–79 years with osteopenia for 2 years, bone density in the tibolone group was significantly increased in both the lumbar spine and femur [193].
In the Long-Term Intervention on Fractures with Tibolone (LIFT) study, tibolone (1.25 mg) reduced vertebral fracture by 45% and the risk of non-vertebral fracture by 26% [194].
16-3. Cardiovascular disorders
When taking tibolone, high-density lipoprotein (HDL) cholesterol is reduced by 20%, total cholesterol by 10%, and triglycerides by 20%, and low-density lipoprotein (LDL) cholesterol is also reduced. Moreover, tibolone is effective considering the fact that it reduces anthogenesis and the acidity of LDL [195].
In the Livial Intervention following breast cancer: Efficacy, Recurrence, And Tolerability Endpoints (LIBERATE) study, which targeted patients with breast cancer, the tibolone group did not show an increase in the incidence of stroke, venous thromboembolism, and coronary artery disease compared with the placebo group [196].
In the LIFT study, which targeted women aged above 60 years with a risk of diabetes, the group administered tibolone experienced an increased incidence of cerebral stroke, but no significant difference was observed for venous thromboembolism and coronary artery disease [194]. The IMS also mentions that tibolone increases the risk of stroke in patients aged above 60 years but does not increase the incidence of venous thromboembolism [197]. However, there has been no large-scale prospective study with the purpose of examining the occurrence of cardiovascular disorder related to tibolone.
16-4. Cancer
1) Breast cancer
Tibolone does not increase the breast density in mammography and causes less breast pain than estrogen–progestogen combination therapy. In the LIFT study, tibolone (1.25 mg) reduced the risk of invasive breast cancer [194].
In the LIBERATE study, the risk of breast cancer recurrence was assessed in a clinical double-blind study of tibolone that compared the placebo group and patients who had undergone breast cancer surgery and had VMS [196].
Breast cancer was found to recur in 15.2% of patients in the tibolone treatment groups (237 of 1,556 patients) and in 10.7% of patients (165 out of 1,542 people) in the placebo group, and a 1.4-fold increase in the incidence of breast cancer was observed when taking tibolone. Therefore, tibolone should not be used in patients with breast cancer.
2) Endometrial cancer and colorectal cancer
Tibolone is associated with a lower incidence of irregular abnormal vaginal bleeding compared with estrogen–progestogen combination therapy [198]. Because it suppresses endometrial proliferation and estrogen activation, progestogen does not need to be added.
According to the results of the Tibolone Histology of the Endometrium and Breast Endpoints Study, tibolone does not cause endometrial proliferation or endometrial cancer [199]. In the LIFT study, tibolone (1.25 mg) reduced the risk of colorectal cancer by 69% [194].
In South Korea, no studies have assessed cardiovascular disease, breast cancer, and fractures, but some studies have assessed blood lipids and bone density. According to the results of a research on blood lipids, tibolone reduces neutral fats while reducing HDL cholesterol compared with MHT [200]. Tibolone generally showed a positive effect on bone density, and after comparing the effects of therapy for 1 year, an increased bone density of the lumbar, which is similar to that with MHT, was reported 42. Furthermore, tibolone users who had undergone surgical treatment for epithelial ovarian cancer and 33 tibolone non-users were retrospectively examined [201]. There was no evidence that tibolone negatively affects the overall survival rate as well as the survival-free rate of patients with epithelial ovarian cancer. Furthermore, in a study that compared 68 tibolone users who had received surgical treatment for endometrial cancer and the same number of nonusers, tibolone did not show any harmful effects in the prognosis of the patients with endometrial cancer [202].
Key points: Tibolone therapy
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17. Instructions for tissue-selective estrogen complex (TSEC) treatment
TSEC is a newly developed treatment that involves a combination of bazedoxifene, a SERM, and conjugated estrogen to improve drug tolerance of the existing progestogen to reduce the risk of breast cancer, breast pain, and vaginal bleeding in addition to treating menopausal symptoms [203, 204, 205, 206]. Combined estrogen/bazedoxifene (CE/BZA) is used to treat menopausal symptoms and osteoporosis through the unique pharmacological properties and mechanism of action of bazedoxifene, which acts as an agonist to estrogen receptors located in the bone and as an antagonist to those located in the uterus or breast. Moreover, while retaining the advantages of estrogen therapy, it secures stability against the endometrium. CE/BZA was approved by the Ministry of Food and Drug Safety in July 2014 for the treatment of VMS associated with menopause and the prevention of postmenopausal osteoporosis in women without an excised uterus.
17-1. Effects on menopausal symptoms
CE/BZA significantly improves QoL by improving sleep disorder, GSM, and hot flush while reducing irritation in the endometrium [207, 208, 209].
1) Vasomotor symptoms
The reduced incidence of hot flushes due to CE/BZA treatment starts to significantly appear (P = 0.008) from the third week of intake in a previous study. The daily average incidence of hot flush occurrence after 12 weeks of intake was reduced in the placebo group by 51%, whereas it was significantly reduced by 74% in the CE/BZA group (P < 0.01) [207].
2) GSM
Compared with placebo, CE/BZA significantly increased the number of vaginal epithelial cells and reduced the number of parabasal cells. According to clinical results, the effects of CE/BZA for improving sexual function and treating symptoms related to moderate-to-severe genital atrophy as well as for alleviating dyspareunia have been proven [208].
3) QoL depending on sleep disorder
Compared with placebo, CE/BZA has been shown to significantly improve QoL related to health and sleep. After 12 months, the CE/BZA group experienced significant improvement of sleep disorder and time taken to fall asleep. The vasomotor nerve function score as per The Menopause-Specific Quality of Life, which evaluates QoL related to menopause at 3–12 months, is also significantly improved [209].
17-2. Osteoporosis
CE/BZA increases bone density of the lumbar spine and femur and improves the markers of bone metabolism [204, 210]. A study was conducted for 1 year to compare the effect of CE/BZA on bone density with that of placebo and estrogen/MPA (CE/MPA) in a target group of 1,061 healthy menopausal women with ovaries who were aged 40–65 years. According to the results, CE/BZA significantly increased the bone density of the lumbar and femur and improved the bone metabolism markers [204].
17-3. Safety
CE/BZA has been shown to be safe for the endometrium [206, 211] while having a very low level of adverse reactions to MHT, such as breast pain, vaginal bleeding, and increased breast density, which are similar to those using a placebo [204, 205]. Lipid metabolisms showed a similar change as other MHT and did not lead to negative effect on hemostasis [212].
1) Increased breast density and breast tenderness
In recent studies, CE/BZA did not increase in incidence of breast cancer, breast pressure, or breast density compared with placebo. On comparing the placebo group with the BZA 20 mg/CE 0.45 mg group and CE 0.45 mg/MPA 1.5 mg group in a study targeting 940 healthy menopausal women with ovaries who were aged 40–65 years, after 12 months, the CE/MPA group was observed to have a noticeably increased dense breast tissue ratio compared with that in the placebo group, whereas the CE/BZA group was confirmed to show no significant difference in breast density changes compared with the placebo group. Breast tenderness was similar to that in the placebo group. In the CE/MPA group, breast tenderness was significantly severe [205].
2) Vaginal bleeding and endometrial proliferation
For menopausal women receiving MHT, vaginal bleeding is a common adverse reaction and is a reason for many patients to either never start or stop MHT [213]. Until 1 year from the time of beginning CE/BZA therapy, hemorrhage and petechial hemorrhage were not reported in 85.3%–99.2% of patients; this result was similar to that in the placebo group but was less than that in the CE/MPA control group (48.9%–83.2%; P < 0.001) [204]. On checking the occurrence of endometrial proliferation 12 months after oral administration of placebo, raloxifene 60 mg, CE 0.625 or 0.45 mg, and BZA 10, 20, or 40 mg once a day to 1,843 healthy menopausal women to evaluate the safety of CE/BZA for the endometrium, less than 1% of patients showed endometrial proliferation after the 1-year treatment, and the minimum dose of BZA that could reduce the irritation of the endometrium due to CE was 20 mg [206, 211].
3) Lipid and coagulation variables
Compared with placebo, CE/BZA reduced the levels of total cholesterol and LDL cholesterol while increasing the level of HDL cholesterol. In contrast to placebo, for hemostasis variables, CE/BZA reduced the activation of fibrinogen, PAI-1, and antithrombin and increased the activation of plasminogen. CE/BZA was demonstrated to not cause a negative effect on the balance of lipid metabolism and hemostasis [212].
17-4. Recommendations from abroad
1) NAMS [2]
NAMS recommends CE/BZA as an effective MHT for treatment of VMS and prevention of osteoporosis and fracture in menopausal women without an excised uterus and states that progestogen is not required as bazedoxifene protects the endometrium.
2) American Endocrine Society [214]
According to the clinical guidelines by the American Endocrine Society, CE/BZA could be used to prevent bone loss and alleviate VMS in menopausal women without an excised uterus as well as to treat side effects such as mood changes, breast tenderness, and progestogen-related vaginal bleeding. Moreover, CE/BZA was shown to improve QoL in menopausal patients by improving sleep disorders and reducing dyspareunia by increasing the maturity level of the vagina.
Key points: Instructions for tissue-selective estrogen complex (TSEC) treatment
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