Abstract】Menopausal hormone treatment (MHT) has played a very positive and important role in relieving perimenopausal symptoms, treating genitourinary tract symptoms, preventing and treating osteoporosis, and enhancing and improving the quality of life of menopausal and postmenopausal women. However, the safety of MHT, especially the risk of MHT with malignant tumors (breast, endometrial and ovarian cancer) and cardiovascular diseases (coronary heart disease, venous thrombosis, stroke) has also been a focus of concern and debate. The causes of tumor and cardiovascular disease are multifactorial, with individuals having their own risk factors, and hormone therapy may have an influence in their development. An individualized MHT treatment program, including choosing the right timing of drug administration (“potential treatment window”), using natural estrogen and progestin, the lowest effective dose, and regular review, can not increase or even decrease the risk of developing tumors and cardiovascular diseases. Menopausal hormone treatment (MHT) has been introduced into the medical field since the 1960s and has played a very positive and important role in menopausal and postmenopausal women to relieve perimenopausal symptoms, treat genitourinary tract symptoms, prevent and treat osteoporosis, and improve the quality of life of menopausal and postmenopausal women. prevention and treatment of cardiovascular and cerebrovascular diseases has also attracted wide interest from the medical community and the general public. However, the 2002 WHI (Women’s Health Initiative) study showed that the commonly used treatment with estrogen (conjugated estrogen) plus progestin (methacholine, i.e., progesterone) increased the risk of breast cancer, increased the risk of venous thrombosis and stroke, and increased the risk of myocardial infarction [1 ]. After a decade of dispassionate analysis and clinical observational studies, how should we now view the risk of MHT and tumors (breast, endometrial, and ovarian cancer) and cardiovascular disease (coronary artery disease, venous thrombosis, and stroke)? This article will present this controversial issue in the context of the American Endocrine Society’s scientific statement “Postmenopausal Hormone Therapy” published in the Journal of Clinical Endocrinology and Metabolism [2] and recent literature. Breast cancer, endometrial and ovarian cancer is the most common cancer among women, and in 2002, the incidence of breast cancer in the United States and Western Europe ranged from 78.2 to 96.7 cases per 100,000 population, while the incidence in Asian women was not as high, at 18.1 cases per 100,000 population [3], but has been increasing in recent years. What are the causes of breast cancer? There is no clear answer internationally. However, there are some high-risk factors: for every 1,000 women aged 50-64 years, there are 11 more cases of invasive breast cancer in women whose mothers had breast cancer; 16 more cases in heavy smokers (>20 cigarettes/day) who have been smoking for more than 40 years; 9.8 more cases in passive smokers; 8 more cases in alcohol consumption (30-60 g/day, 2-5 times/day); and 8 more cases in obesity [body mass index ( In the WHI study, the number of new breast cancer cases was only 5.1 for 5.2 years with combined estrogen and progestin treatment, and even 4.5 cases for 6.8 years with single estrogen treatment. It is suggested that both genetic and environmental factors play an important role in the development of breast cancer. Among the genetic factors, women whose mothers had breast cancer before menopause were nine times more likely to have breast cancer themselves; women with sisters who had breast cancer were three times more likely to have it. It is important to emphasize that breast cancer is not directly inherited, but is a “cancer quality” inheritance, and relatives of breast cancer patients do not necessarily have breast cancer, but are more likely to have breast cancer than the general population. Early menarche and late menopause are two risk factors for breast cancer. The relative risk of breast cancer increases 2.2 times when the age of menarche is less than 12 years old compared to more than 17 years old. Age at menopause greater than 55 years old increased the risk of breast cancer by 1-fold compared to those younger than 45 years old, suggesting a significant association between the occurrence of breast cancer and sex hormone status. Among environmental factors, heavy smoking, passive smoking, alcohol consumption, and obesity are also high risk factors for breast cancer, of which estrogen is only one cause, with a lower risk than obesity and alcohol consumption. The American Endocrine Society’s scientific statement states that the risk of breast cancer caused by monoestrogen therapy for 5 years or “extra” is minimal, with a risk of 0-2.59/1,000 in women who start monoestrogen therapy within 5 years of menopause. suggesting that estrogen plays a pro-apoptotic role in these women, thereby reducing the risk of breast cancer in these women; after more than 5 years of treatment, estrogen increases the risk of breast cancer, especially in recently menopausal women. The increased risk disappears within 5 years after cessation of estrogen. In addition, linear modeling studies have shown that for each year of MHT exposure in slim women, the relative risk of breast cancer increases by 3%, while the risk is smaller in obese women. Estrogen levels in breast tissue represent the sum of locally synthesized estrogens and estrogens taken up from plasma through receptor-mediated mechanisms, and obesity may increase locally synthesized estrogens in the breast. These findings could explain the reduced risk of breast cancer in obese women who adopt MHT with predominantly localized aromatized synthetic estrogen; in contrast, slim women whose local estrogen levels in breast tissue are predominantly taken up from plasma have an increased risk of breast cancer. To date, an increased risk of estrogen-induced breast cancer cannot be ruled out. The main pathways by which estrogen may cause cancer are, first, that estrogen is to promote increased cell proliferation, i.e., that estrogen and estrogen metabolites achieve increased cell proliferation through different or complementary estrogen receptor signaling pathways. The prerequisite for estrogen to be carcinogenic is the presence of preexisting cancer cells, so estrogen actually acts as a “fuel for the fire” rather than as a “primary culprit,” and is therefore more important in older women because the likelihood of cancer cells increases with age. The potential for cancer cells increases with age. Autopsy studies have shown that there is a 7% rate of undiagnosed breast cancer (6% in situ and 1% invasive) in women aged 50 to 80 years, and estimates from the placebo group in the WHI trial suggest that only 30% of occult tumors progress to a clinically diagnosable size within 5 to 6 years. ) treatment increases the rate of confirmed breast cancer can be explained by the detection of occult undiagnosed breast cancer rather than the de novo development of new tumors [2]. The second is that estrogens are subject to the formation of potentially genotoxic and carcinogenic estrogen metabolites, leading to DNA alterations or damage and subsequently mutations. Originally, the body’s cells are equipped with a large number of multifactorial antioxidant defense mechanisms, and only in combination with additional damage can oxidative stress be caused and a harmful “vicious circle” of subsequent oxidation be formed. Existing basic studies have found that estrone (E1)/estradiol (E2) in vivo forms 4-hydroxy E1/E2 by the action of cytochrome 1B1 and E1/E2-3,4 quinone by the action of cytochrome 450 or peroxidase, which can act on DNA to form depurine products, for which purine-free sites are prone to cause base The wrong excision repair and consequently the formation of mutations and the appearance of breast cancer. Thus, all estrogens are capable of stimulating preexisting breast cancer cells, independent of the method of administration but in relation to the concentration; however, certain metabolites may be carcinogenic only in the presence of oxidative stress like smoking. Because cells are protected from oxidative stress by multiple mechanisms, carcinogenic effects are very rare. However, in patients with detoxification defects, mutagenic effects cannot be excluded, especially due to genetic polymorphisms of key enzymes. In addition, the growth rate of breast cancer varies from patient to patient, but in general, the volume of the mass increases approximately 1-fold in 100 days, and it takes about 10 years to grow from a malignant cell to a clinically recognizable mass (1 cm in size), by which time the mass has undergone 30 x 40 doubling, often causing severe (fatal) disease. In addition, the average size of an identifiable breast cancer is 2.5 cm (70-75% detected by the patients themselves), when 50% already have lymph node metastases [4]. Therefore, early detection and aggressive treatment is the key to prevent and treat breast cancer. It was found that long-term (5-10 years) application of MHT does increase the incidence of breast cancer, but it was also found that because patients were required to have regular checkups during the application of MHT, breast cancer was detected early, at an earlier stage, with fewer metastases, good cell differentiation, high estrogen receptor positivity, and a good prognosis compared to women who did not use MHT. Therefore, there is no need to be overly fearful that MHT may increase the appearance of breast cancer. The American Endocrine Society’s scientific statement also states that combination estrogen plus progestin therapy, especially in combination with synthetic progestins, is associated with an increased risk of breast cancer, which may occur within 3 to 5 years of initiating treatment, and that this risk increases increasingly thereafter. This risk returns to be similar to that of non-users within 3 years after discontinuation, so the risk is only associated with current use or not and not with previous use. data from the WHI suggest that there is no increased risk of breast cancer 5.2 years after first receiving combined estrogen plus progestin therapy, and in fact it is likely that this is because most women are more than 5 years postmenopausal when they start MHT. It is not possible to independently estimate the absolute risk for an individual woman because the risk correlates with the time of initiation of treatment with the time of menopause, duration of treatment, body mass index BMI, and possibly with the type of progestin and family history of breast cancer as well. The effect of estrogen combined with progestin therapy in increasing the risk of breast cancer can be explained by the effect of estrogen plus progestin to enhance stem cell remodeling or to stimulate proliferation. Therefore, choosing the right progestin becomes a possible option to reduce the risk of breast cancer. The latest guidelines of the International Menopause Society (IMS) also state that the effects of different progestins on breast cancer vary, “compared with synthetic progestins, the combination of micronized progesterone or dydrogesterone with estrogen (oral or subcutaneous) for 4 years (or even up to 8 years) does not increase or even reduce the risk of breast cancer”. Special attention should be paid to the use of MHT in breast cancer survivors. The current findings suggest that whether standardized MHT use increases the risk of recurrence in breast cancer survivors is unclear, and the results of randomized clinical trials (RCTs) are controversial. Tibolone increased the risk of breast cancer recurrence, particularly in those female patients on aromatase inhibitors. Therefore, MHT should remain contraindicated in these patients. The decision to receive MHT in these women may be made only if the impaired quality of survival in these patients outweighs the survival/survival issues and after the pros and cons of MHT are fully understood. A brief summary of issues related to gynecologic oncology is also provided in the American Endocrine Society’s scientific statement Monoestrogen therapy without combined progestin leads to an increase in endometrial cancer (EC). Sequential combination therapy with estrogen plus progestin resists the effects of estrogen and does not lead to an increase in EC. Sequential estrogen plus progestin combination therapy also reduced the risk of EC compared to monoestrogen therapy, but was not as effective as sequential estrogen plus progestin combination therapy, yet had less adverse effects on the breast than sequential combination use. Long-term monoestrogen therapy resulted in a small increase in the risk of ovarian cancer of 0.7 per 1,000 population per 5 years. Combined estrogen and progestin therapy has no risk or only a very small risk. In coronary heart disease, basic science studies, animal models, and observational studies all support the hypothesis that MHT may prevent atherosclerosis and reduce cardiovascular diseases (CVD) events. On the one hand, estrogen has beneficial effects on lipids, including decreasing total cholesterol, LDL cholesterol, and apolipoprotein-B (Apo-B) concentrations and increasing HDL cholesterol concentrations, thereby reducing the area of arterial lipid plaque deposition. On the other hand, estrogen may effectively dilate blood vessels by increasing endothelial nitric oxide (NO) production, reducing the hemodynamic load on the heart and inhibiting the production of vasoconstrictive substances. Thus, estrogen may reduce the risk of coronary artery disease by improving endothelial vasodilation and vascular resistance in postmenopausal women and by helping to prevent the development of atherosclerosis. More recent studies in subgroups of the population suggest that because older women or those who have been menopausal for many years before starting to receive MHT lead to harmful effects, a large proportion of CVD events in this subgroup were recorded in the WHI, and an overall analysis of the WHI found that MHT not only had no benefit but even increased the risk of CVD in this group, whereas in women who had been menopausal for less than 10 years or were less than 60 years of age If there is no other risk of CVD, the benefits of using MHT outweigh the disadvantages. Thus, the concept of “potential therapeutic window” is proposed, which means that if estrogen therapy is started during perimenopause and maintained for a long time, it will have some cardiovascular protective effects, and hormone replacement therapy (HRT) can improve insulin resistance, reduce the risk of diabetes, and have a positive effect on Other risk factors for cardiovascular disease, such as lipid composition and metabolic syndrome, can be positively affected. In women younger than 60 years of age, recently menopausal and without evidence of cardiovascular disease, HRT does not cause early damage and reduces the morbidity and mortality of coronary heart disease. The risk of venous thromboembolism (VTE) increases with underlying risk factors in relation to MHT. Underlying risk factors include advanced age, hypertension, diabetes, smoking, higher BMI, propensity to thrombosis, C-reactive protein (CRP), elevated homocysteine, family history of thrombosis, propensity to thrombosis, and surgery and braking. A scientific statement from the American Association of Endocrinology states that MHT increases the risk of VTE by nearly twofold when it comes to VTE. How to reduce and improve these underlying risk factors becomes a major part of future research. Data based on observational studies rather than RCTs suggest that transdermally absorbed estrogens may not increase the risk of VTE. Because transdermal estrogen administration avoids the first-pass effect in the liver, it reduces the risk of venous thrombosis and cardiovascular events that may be associated with oral estrogen administration by reducing stimulation of the liver. Transdermal estrogens require significantly lower doses than oral estrogens and have a better safety profile, reducing the risk of venous thrombosis and cardiovascular events, as well as the risk of breast cancer and gallbladder disease. In addition, the combined use of progestins modifies the effect of MHT on VTE. Progesterone derivatives such as natural progesterone, dydrogesterone, medroxyprogesterone, and chlormadinone do not increase the risk of VTE, whereas norethindrone derivatives increase the risk of VTE. The commonly used MHT in the past, methacholine progesterone (Angioprogesterone) has glucocorticoid activity with long-term use and may raise blood pressure; it also has adverse effects on lipid, glucose and insulin metabolism, all of which can increase the risk of VTE. Therefore, the use of natural estrogens with natural progestins is advocated for long-term use of MHT. Stroke can be viewed as a blood clot in the arteries, similar to VTE, and a scientific statement from the American Endocrine Society concludes that standard doses of oral MHT may increase the risk of stroke by 1/3 in the average healthy postmenopausal woman. in older women with pre-existing vascular disease, sex hormone use does not reduce the incidence of stroke. Low-dose estrogen therapy may not increase the risk of stroke. Therefore, it is now emphasized that long-term use of MHT should be at the lowest effective dose and reviewed regularly. Individualized MHT can significantly improve the quality of life of menopausal women. A survey of female medical staff at Peking Union Medical College Hospital in 2003 showed that 35.7% of our menopausal workers aged over 40 years underwent MHT, much higher than the 4.4% to 5.9% of the general population reported in China at that time; 32.28% of patients with MHT had been using it for ≥5 years [5,6]. It is suggested that long-term, low-dose, individualized MHT is effective and safe for improving women’s quality of life and work capacity. 80% of female medical staff at Peking Union Medical College Hospital >70 years old who used MHT were still working in the clinical front line, while only 9% of the control group who did not use MHT were working, which is an optimal experience of individualized MHT to maintain health after menopause. Therefore, we advocate that MHT should have clear indications for use, no contraindications, and individualized evaluation of the benefits and harms of MHT for each patient. Cardiovascular disease is not the primary purpose of MHT and is not currently an indication for MHT, with regular follow-up to reduce the risk of MHT, including the risk of breast cancer.