The development of hormone supplementation therapy during menopausal transition and late menopause has gone through decades of history, and its development and people’s understanding of its benefits and dangers have gone through a tortuous process. The experts in the field of menopause in China have formed this new edition of hormone supplementation therapy guidelines based on the 2006 guidelines in China, hoping to provide some guidance to the general practitioners in terms of the latest progress, practicality and operability in the field of HRT.
Guidelines for the Clinical Application of Hormone Supplementation Therapy in the Transitional and Postmenopausal Periods
Menopause is a transitional period in which a woman’s ovarian function gradually declines from its vigorous state to complete disappearance, including the period before and after menopause. During menopause, women can experience a series of physical and psychological changes. Most women are able to go through menopause smoothly, but there are a few women who are plagued by a range of symptoms that affect their physical and mental health due to the large physical and psychological changes that occur during menopause. The World Health Organization (WHO) states that perimenopause includes the menopausal transition and menopause. Menopause is a period of time from a few months before the complete cessation of menstruation to a number of years after menopause, generally starting from the age of 45 to about 55. When women enter menopause, ovarian function begins to decline, firstly, luteal function is in progressive decline, follicles only develop to a certain extent, that is, they atrophy on their own, no longer ovulate; no corpus luteum formation, manifesting as fertility function decline, but in the early stage of ovarian function decline, follicle stimulating hormone (FSH) secretion increases, luteinizing hormone is still at normal levels. In the early stage of ovarian decline, however, follicle stimulating hormone (FSH) secretion increases and luteinizing hormone remains at normal levels. As women age, ovarian function becomes unstable and declines, and the balance becomes unbalanced, often manifesting abnormal menstruation, menstrual cycle disorders, prolonged periods and bleeding before menopause, while symptoms such as premenstrual tension syndrome, cyclic breast pain, edema and headache disappear.
General treatment of menopause
(A) Prevention and treatment principles
The transition from a period of normal fertility and sexual activity to perimenopause to old age is a natural and irresistible law. The basic physiological changes of this process are the decline of ovarian function and even complete loss of estrogen; the activity of hypothalamic-pituitary-ovarian axis gradually stabilizes from having normal fluctuations, mainly manifesting as a decline in fertility and sexual activity, sparse menstruation and even cessation, progressive atrophy of sexual organs and gradual aging. To prevent and treat this disease, a comprehensive medical examination should be conducted to diagnose the disease and subhealth conditions, and comprehensive measures should be taken to maintain the physiological functions of women without significant changes due to menopause. Maintaining the physiological function of the body requires consideration of multiple factors.
(ii) Healthy lifestyle and physical exercise
Hormone therapy is only one component of the management of the menopausal transition and postmenopause. A healthy lifestyle is important at all times; active lifestyle improvement, increased social and mental activity; participation in any physical activity is better than being sedentary; maintaining a normal weight is important; the basic components of a healthy diet include: eating at least 250 g of fruits and vegetables daily, whole grain fiber, fish twice a week, and a low-fat diet. The basic components of a healthy diet include: at least 250g of fruits and vegetables daily, whole grain fiber, 2 fish foods per week, and a low fat diet. Salt intake should be limited (less than 6g/day) and women should drink no more than 20g of alcohol per day; smoking cessation is promoted.
Hormone therapy
(i) Hormone individualized treatment-IMS
Hormone therapy is part of an overall treatment strategy that includes a rational lifestyle and must be individualized. For women under 60 years of age who are perimenopausal and do not have cardiovascular system disease, starting HT will not cause early harm to patients and will reduce the incidence of cardiovascular system disease and mortality in patients. continued use of HT in women over 60 years of age should be part of a comprehensive risk-benefit analysis. HRT must follow treatment norms and strictly control the indications and contraindications for treatment, avoiding abuse but not It is necessary to avoid misuse and non-use, so that women of appropriate age can obtain the maximum benefit with low risk.
(II) Indications
HRT is the first and most important treatment to relieve menopause-related symptoms (e.g. vasodilatory symptoms and their associated sleep disturbances): in particular: vasodilatory disturbances: hot flashes, night sweats, sleep disturbances; improvement of the following complaints: fatigue; mood disturbances such as agitation, irritability, anxiety, nervousness or depressed mood, etc. Grade A recommendation. 2. A level of recommendation. 3. HRT is one of the effective ways to prevent postmenopausal osteoporosis, including the presence of risk factors for osteoporosis (such as low bone mass) and postmenopausal osteoporosis. A level of recommendation.
(iii) Contraindications
1. known or suspected pregnancy; 2. unexplained vaginal bleeding; 3. known or suspected breast cancer; 4. known or suspected sex hormone-dependent malignancy; 5. active venous or arterial thromboembolic disease (within 6 months); 6. severe hepatic or renal dysfunction; 7. hematoporphyria, otosclerosis; 8. meningioma (progestogen is contraindicated).
(iv) Caution cases
1. uterine fibroids; 2. endometriosis; 3. history of endometrial hyperplasia; 4. uncontrolled diabetes mellitus and severe hypertension; 5. tendency to thrombosis; 6. gallbladder disease, epilepsy, migraine, asthma, hyperprolactinemia; 7. systemic lupus erythematosus; 8. benign breast disease; 9. family history of breast cancer.
Hormone supplementation therapy
Hormone supplementation is the main method currently used for menopause-related symptoms, and its effects on a wide range of symptoms are of interest. Hormone supplementation therapy means that estrogen is supplemented for menopausal women to maintain the blood hormone concentration needed by the body to treat uncomfortable symptoms and prevent disease. China’s “Guidelines for the Clinical Application of Hormone Therapy in the Transitional and Postmenopausal Periods (2006)” states that hormone supplementation includes estrogen alone, sequential estrogen-progestin therapy and continuous estrogen-progestin therapy. Our and foreign guidelines also consistently state that hormone supplementation therapy is the only effective way to address menopausal health problems. According to the research results, hormone supplementation therapy has been widely used to improve the quality of life of menopausal and postmenopausal women, and has achieved good results. There are two types of hormone supplementation drugs used in clinical practice: natural hormones and synthetic hormones, and natural hormones are widely used because they are the same as the body’s own hormones and are safer. In China, natural hormone supplements such as Clomid have also been used in clinical practice to help women go through menopause safely. Hormone supplementation is not only used to treat menopausal symptoms, but also can be widely used to prevent and treat osteoporosis and coronary heart disease in menopausal women. Therefore, hormone supplementation is essential for menopause treatment.
(I) Principle of drug use
When HRT is applied, it should be individualized and the lowest effective dose that can achieve the therapeutic goal should be used under the premise of considering the therapeutic purpose and risk. Individualized risk/benefit assessment should be performed at least once a year for the application of HRT, and the length of treatment should be decided based on the assessment and whether to continue HRT for a long time, as long as it can be given when the benefits outweigh the harms; lower doses than the current standard usage should be considered, such as 0.3 to 0.45 mg of combined estrogens or 0.5 ~ 1 mg of estradiol valerate per day orally, 1.25 mg of tibolone mg, transdermal daily release of 25 μg 17-estradiol, or equivalent preparations.
In women with a uterus, administration of estrogen increases the risk of endometrial carcinogenesis, and the carcinogenic risk of estrogen increases with increasing dose and duration of treatment; the primary indication for progestin use in postmenopausal hormone therapy is to counteract estrogen and thereby protect the endometrium; in women who have had a hysterectomy, progestin need not be added; in the case of continuous estrogen use, progestin should be added continuously or In the case of continuous estrogen use, progestin should be added continuously or periodically, and progestin should be given no shorter than 10-14 days per month; there is insufficient information on the safety of ultra-low dose estrogen treatment with progestin-containing IUDs or confirmed without progestin addition.
(ii) Commonly used drugs and their doses
1.Sedatives: Suitable for patients with heavy insomnia, whose mental and physical status will be improved due to improved sleep. Usually taken at bedtime. The following drugs can be taken or alternated: Librium 10-20mg, Valium 2.5-10mg, Xuloxane 1-2mg, Luminal 30-60mg. If the daytime performance of restlessness, energy but can not rest quietly, can also be divided into daytime doses, the dose is reduced by half.
2. Colistin: 0.1-0.2mg, 2 times a day, can reduce hot flashes by 30%-40%.
3.Methyldopa: 250mg, 2 times a day, can reduce hot flashes by 20%, the mechanism of action is the same as colistin, with gastrointestinal side effects, such as nausea and vomiting.
4.Jialong Tablet: A tablet made of pure Chinese medicine, which is clinically used to treat menopausal symptoms with remarkable efficacy. Because it has no toxic side effects and is suitable for any women, especially when women are not yet menopausal or with menstrual disorders, Jialong Tablet does not interfere with bleeding but only controls the symptoms, does not affect the observation of bleeding, and does not need to consider the synchronization of medication and bleeding time, and is easy to use.
5.Soy isoflavones: Take 50mg of soy isoflavones daily, treatment can be expanded to 100mg, once a day in the morning and once in the evening, 50mg each time. soy isoflavones are more effective in controlling menopause, soy isoflavones do not have the side effects of estrogen.
(iii) Common methods
Progestin alone: used in cycles for menopausal transition and to adjust menstrual problems that occur during the decline of ovarian function; estrogen alone: for women who have had their uterus removed, and estrogen therapy alone for patients without a uterus, for example: combined estrogen 0.3mg to 0.625mg/day or estradiol valerate 0.5mg to 2mg/day, applied continuously. Combined estrogen and progestin: for women with an intact uterus; sequential combination: simulating the physiological cycle, progestin is added for 10 to 14 days per month on top of estrogen. It is also divided into cyclic and continuous, with the former stopping estrogen for 5-7 days per cycle and the latter not stopping estrogen; combined and combined: both estrogen and progestin are combined daily, also divided into cyclic (stopping estrogen for 5-7 days per cycle) and continuous (using both daily without stopping). Cyclic bleeding is often present in sequential and combined cyclic regimens, also known as early pre-term or in women willing to have regular menstrual-like bleeding; continuous combined regimens avoid cyclic bleeding and are indicated in postmenopausal women who are older or unwilling to have menstrual-like bleeding, but may have unpredictable unscheduled bleeding early in the course of implementation, usually occurring within 6 months of dosing; cyclic sequential, for example: cyclic Clomid or Fentanyl; or combined estrogen 0.3 mg to 0.625 mg/day or estradiol valerate 1 mg to 2 mg/day for 21 to 28 days, followed by progesterone 4 mg to 6 mg/day or dydrogesterone 10 mg/day or micronized progesterone pills 100 mg to 300 mg/day for 10 to 14 days, with 2 to 7 days of discontinuation before starting a new cycle; continuous Sequential, e.g., combined estrogen 0.3mg-0.625mg/day or estradiol valerate 1mg-1.5mg/day without interruption, with 2 weeks of progesterone 4mg-6mg/day or dydrogesterone 10mg/day or micronized progesterone pills 100mg-300mg/day; continuous combination, e.g., continuous application of Bemelo; or combined estrogen 0.3~0.45mg/day or estradiol 0.3~0.45mg/day or micronized progesterone pills 100mg-300mg/day. 0.45mg/day or estradiol valerate 0.5mg-1.5mg/day, plus progesterone enanthate 1mg-3mg/day or dydrogesterone 5mg/day or micronized progesterone pills 100mg/day. Tebolone: the general usage is 1.25mg~2.5mg/day, continuous application.
(iv) Application of HRT during the menopausal transition
The transitional period of menopause refers to the period from the beginning of the manifestation of ovarian function decline to the last menstruation, during which women are prone to menstrual disorders. Hormone supplementation therapy during the menopausal transition period is mainly progesterone supplementation, which can be used periodically for 10-14 days per month. 200mg-300mg of micronized progesterone, 10mg-20mg of dydrogesterone or 4mg-6mg of medroxyprogesterone acetate can be used daily; if the menopausal symptoms still cannot be relieved, according to the severity of the patient’s estrogen deficiency symptoms and the response after estrogen supplementation, menopause If the symptoms of menopause still cannot be relieved, the patient’s response to estrogen supplementation should be taken into account.
(v) Application of non-hormonal agents
For women who do not want to use HRT or have contraindications to HRT, other non-hormonal agents can be used to treat menopausal symptoms. These agents include: black ascorbate-isopropyl alcohol extract (imported, trade name Livermin), ascorbate-ethanol extract (domestic, trade name Ximintine), selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), selective 5-hydroxytryptamine and norepinephrine; dual reuptake inhibitors (SNRIs), colistin (clonidine), gabapentin ( gabapentin), and other adjunctive and alternative medications. The available data suggest that these treatments can be effective in relieving menopausal symptoms, but their effects and side effects period planned bleeding, the protocol is different from HRT. Long-term information on the safety and efficacy of these treatments is lacking.
Application of topical estrogens The symptoms of vaginal dryness, pain, difficulty in intercourse, urinary frequency, urinary urgency and other symptoms of genitourinary tract atrophy are very common in postmenopausal women, and about 12-15% of women over 50 years of age have these symptoms. Topical vaginal application of estrogen can significantly improve the symptoms of genitourinary atrophy. Indications: Systemic administration can relieve the symptoms of genitourinary tract atrophy caused by decreased estrogen levels. Topical vaginal application is recommended when the medication is used only to improve genitourinary tract atrophy. Symptomatic vaginal atrophy and vaginal stenosis: caused by cancer treatment such as surgery, pelvic radiotherapy, chemotherapy, etc. For vaginal atrophy in women with non-hormone dependent cancer. Treatment is the same as for those without a history of cancer. Treatment recommendations for women with a history of hormone-dependent cancer depend on the choice of each patient after consultation with an oncologist. Dosage: Transvaginal once daily, after 2 weeks of continuous use for symptomatic relief, change to 2 to 3 times weekly dosing. Local application of higher doses of estrogen, or if symptoms of breakthrough vaginal bleeding occur during dosing, additional progestin withdrawal is required. There is insufficient information to recommend protection of the endometrium for those who have been using topical conventional doses of estrogen for more than 1 year, so long-term users should monitor the endometrium and decide whether to apply progestin withdrawal regularly based on testing.
Several issues of concern
(i) Cardiovascular disease
The vast majority of preclinical and observational studies support the benefit of hormone therapy in reducing the risk of cardiovascular disease; HRT is not recommended for the prevention of cardiovascular disease only; and there is evidence that starting HRT in recently menopausal women younger than 60 years of age without cardiovascular disease (known as the “time window”) does not cause early harm and The decision to continue HRT in women over 60 years of age is based on an overall risk-benefit analysis; women with a history of venous thromboembolism can be individually analyzed for the percutaneous route of HRT.
(ii) Breast cancer
(i) Estrogen/progestin therapy for 3 to 5 years does not significantly increase the lifetime risk of breast cancer; the available evidence-based data on the use of HRT suggest that the risk of breast cancer in those treated with HRT for more than 5 years is uncertain, and if it increases, the risk is small (less than 0.1% per year, at a rate similar to other risks (e.g., obesity and drinking more than 2 standard drinks per day). Breast cancer remains a contraindication to HRT.
(iii) Osteoporosis
Prevention of bone loss in patients with premature menopause and secondary amenorrhea is an indication for HRT; HRT can be recommended as first-line therapy for postmenopausal women under 60 years of age who are at risk for osteoporosis-related fractures; HRT is not recommended to be initiated in women over 60 years of age for the sole purpose of fracture prevention; for those women who are already on HRT on an ongoing basis, the method and dose of its administration needs to be considered on an individual basis and For those women who have been using HRT continuously, it is necessary to consider its administration method and dose according to the individual and weigh it with other confirmed therapies; the lowest effective dose should be applied using HRT to prevent osteoporosis, and the transdermal administration method has fewer side effects than the oral one; after stopping HRT, bone loss will occur again, and women who are at risk of fracture should receive other medications with proven effective osteoprotective effects.
(iv) Urinary system
Genitourinary atrophy symptoms such as vaginal dryness, pain, painful intercourse, urinary frequency and urgency are very common in postmenopausal women; genitourinary atrophy symptoms respond well to estrogen, especially topical vaginal estrogen use. However, symptoms may reappear after discontinuation; pelvic floor muscle training and surgery are preferred for the treatment of simple stress incontinence, but perioperative topical vaginal estrogen facilitates surgical manipulation and recovery; for postmenopausal women with combined urge incontinence or overactive bladder (OAB), the first-line treatment is topical vaginal estrogen For postmenopausal women with combined urge incontinence or overactive bladder (OAB), the first-line treatment is vaginal topical estrogen plus antimuscarinic agents [first-line agent: the M-receptor antagonist tolterodine.
(v) Colon cancer
Evidence supports that HRT combinations may reduce the risk of colon cancer; however, HRT is not recommended for the sole purpose of colon cancer prevention.
Postoperative in patients with gynecologic malignancies
There is a lack of evidence from multicenter, randomized, large-sample, prospective, evidence-based studies on postoperative hormone supplementation for patients with gynecologic malignancies. The overall principle should be caution, adequate communication with patients, and informed choice. The available clinical research data can lead to the following conclusions about the application of HRT after ovarian cancer: for those with severe menopausal symptoms, it can be applied individually according to the patient’s condition, weighing the advantages and disadvantages in order to improve the patient’s quality of life. HRT after surgery for cervical squamous cell carcinoma has no risk of reducing progression-free survival and overall survival, while it may reduce the side effects of rectal, bladder and vaginal after radiotherapy, improve menopausal symptoms and improve the quality of life. However, there is a lack of research on HRT after surgery for cervical adenocarcinoma, which can be treated with reference to endometrial cancer. However, HRT should be used with caution in clinical practice and should be individualized according to the patient’s specific conditions, weighing the advantages and disadvantages, in order to relieve menopausal symptoms and improve the quality of life.
Women with premature ovarian failure, also known as “early menopause”, may have special needs and should be counseled additionally. Treatment; for women with post-surgical menopause, both estrogen and androgen therapy can be considered. Androgens may be associated with some menopausal symptoms (e.g., fatigue, decreased libido, etc.). There is a lack of clear objective assessment indicators and separate androgen medications, and tibolone is recommended in case of these problems.
Summary
In our Clinical Application Guidelines for HRT, it is recommended to start the application of hormone supplementation therapy as soon as ovarian-related symptoms appear, and to do annual monitoring and evaluation at the same time. For the purpose of prevention, it is advocated that it should be started as early as possible after menopause, such as for relieving menopause-related symptoms can be used for a short period of time usually 1 to 5 years; for osteoporosis prevention, long-term use is required and can generally be adhered to for more than 5 to 10 years; if there is no contraindication in the use of the drug and it is necessary, it can also be used for life. At present, 30% of women in developed countries use HRT and 25% of menopausal women in Taiwan use it, while less than 1% of women in China use it. 50% of women aged 40 to 50, who account for about 11% of the total population in China, have menopause-related symptoms or diseases of varying degrees, and they need to apply HRT. With social development and progress, modern women are more and more concerned about their health and quality of life. HRT can be used scientifically and rationally under the guidance of doctors to maximize the benefits and minimize the risks of HRT treatment, or even no risks at all.