Treatment of estrogen-dependent symptoms of postmenopausal HRT should be started only in cases of their adverse effect on the quality of life of women. To evaluate the ratio of benefits and risks of treatment with the drug, it is necessary to conduct a medical examination regularly, taking into account the individual characteristics of the patient, but at least once a year, using clinical and laboratory data. HRT should be continued only as long as the benefits exceed the risk.
Medical examination / control
Before starting / resuming HRT, you should collect an anamnesis and study the patient's medical history, conduct the necessary examination (incl.organs of the small pelvis and mammary glands), read the contraindications and special precautions for the use of the drug. Women should be advised to report any changes in the mammary glands to a doctor or nurse for the purpose of timely follow-up, incl. mammography.
Reasons for immediate withdrawal of treatment
Treatment should be discontinued if there are contraindications and the following conditions:
- jaundice or liver dysfunction;
- significant increase in blood pressure;
- a new attack of a migraine headache;
- pregnancy.
Endometrial hyperplasia
The risk of hyperplasia and endometrial carcinoma in women with an intact uterus increases with prolonged estrogen monotherapy (see "Side effects").
According to epidemiological studies, in about 5 out of 1,000 women aged 50-65 years who have not received HRT, endometrial cancer can be diagnosed. While monotherapy with estrogen, depending on its dose and duration of treatment, increases this risk by 2-12 times.
The addition of progestogen for at least 12 days per cycle significantly reduces this risk.Do not also use estradiol in a dose of more than 2 mg per day, even in combination with progestogen.
During the first months of treatment, bleeding / smearing bleeding from the vagina is possible. However, if bleeding / spotting spots are noted after the start of treatment or continue after the drug is discontinued, the doctor should be consulted immediately to rule out malignant changes in the endometrium.
Monotherapy with estrogen without progestogen can lead to precancerous or malignant foci of endometriosis.
Mammary cancer
Conducted epidemiological studies and one randomized, placebo-controlled study within the framework of the "Women's Right to Health" program (WHI), confirmed the increased risk of developing breast cancer, depending on the duration of HRT with estrogens, estrogen-progestagen drugs or tibolone (see "Side effects"), but it returns to its initial state for a few (maximum to 5) years after discontinuation of treatment . Based on the results of 51 epidemiological studies, incl. Epidemiological Study of a million women (MWS), the relative risk (RR) of breast cancer in HRT alone with estrogen was 1.3-1.35.
The relative risk of breast cancer increases with the addition of progestogen to estradiol, regardless of its type and mode of administration. According to the results MWS, compared with women who have never received HRT, the use of various types of combination (estrogen + progestogen) replacement therapy increases the risk of breast cancer (RR = 2), while in estrogen alone, OR = 1.3. According to WHI for women who received combined (estrogen + progestogen) HRT for 5.6 years, the relative risk of developing breast cancer compared with placebo was 1.24.
Absolute risk indicators calculated from data MWS and WHI, are presented below. Thus, according to MWS, when assessing data on the incidence of breast cancer in developed countries, it was found that:
- in approximately 32 out of 1,000 women who did not undergo HRT, breast cancer diagnosed between the ages of 50 and 64 is possible;
- for 1000 women undergoing or recently undergoing HRT, the number of additional cases of breast cancer will be:
- with estrogen replacement monotherapy: within 5 years - from 0 to 3 cases (an average of 1.5); for 10 years - from 3 to 7 cases (an average of 5);
- with combined (estrogen + progestogen) HRT: within 5 years - from 5 to 7 cases (an average of 6); for 10 years - from 18 to 20 cases (an average of 19).
In a study conducted within the framework of WHI, it was found that 8 diagnosed additional cases of breast cancer among 1000 women aged 50-79 years after 5.6 years of follow-up may be due to combination therapy (conjugated equine estrogens (EPL) + medroxyprogesterone acetate (MPA)). Based on the results obtained, it is established that:
- when taking placebo for 5 years, approximately in 16 out of 1000 women, there may be breast cancer;
- with combined (KLE + MPA) HRT for 5 years the number of additional cases of breast cancer can be from 0 to 9 (on average 4) - per 1000 women;
- the number of additional cases of breast cancer per 1000 women who start or continue combined (estrogen + progestogen) HRT, is the same and does not depend on age at the time of application (age between 45 and 65 years).
Data on the existence of differences in the risk of developing breast cancer, depending on the route of administration of the drug, are not available.
HRT, especially combined treatment (estrogen + progestogen), contributes to the increase in node density during mammography, which may have a negative effect on the timely diagnosis of breast cancer.
Venous thromboembolism
HRT is associated with a higher relative risk of venous thromboembolism (VTE) - deep vein thrombosis or pulmonary embolism. In the conducted studies, a 2-3 fold increase in the risk of VTE during HRT was established. It has been established that for 5-year period in non-treated patients, the number of cases of VTE is about 3 per 1000 women aged 50-59 years and 8 per 1000 at the age of 60-69 years. It is estimated that in healthy women who underwent a 5-year course of HRT, the number of additional cases of VTE for 5 years is 2-6 (on average 4) per 1000 women aged 50-59 years and 5-15 (an average of 9 ) per 1,000 women aged 60-69 years. The probability of occurrence of VTE is greater in the first year of HRT than in the following. As a rule, the risk factors forvenous thromboembolism include cases of VTE in the anamnesis (including in the immediate family) and the corresponding changes in the coagulogram, significant obesity (body mass index> 30 kg / m2), systemic lupus erythematosus. There is no consensus on the possible role of varicose veins in the development of VTE. HRT may increase the risk. It is necessary to analyze all cases of thromboembolism and / or spontaneous abortions in a personal or family anamnesis to exclude a predisposition to thrombophilia. Until the appropriate examination is carried out, HRT is contraindicated.
The appointment of HRT to women taking anticoagulants is only possible taking into account the benefit / risk ratio of HRT use. The risk of VTE may temporarily increase with prolonged immobilization, including due to trauma, surgical intervention, in the postoperative period. When planning operations, it is necessary to consider the desirability of terminating HRT 4-6 weeks prior to intervention in each specific case. Treatment should not be resumed until the coagulogram is normalized and mobility restored.If VTE develops after the start of treatment, HRT should be discontinued. The patient should suspend HRT and immediately inform their attending physician if symptoms such as soreness and / or swelling of the lower limb, sudden chest pain, shortness of breath occur.
Cardiac ischemia
The effectiveness of HRT in ischemic heart disease has not been proven. Two large, randomized, controlled clinical trials showed a significant likelihood of an increased risk of cardiovascular disease in the first year of combined HRT use (CLA + MPA). The results of clinical studies of other drugs for HRT are limited and contradictory.
Violation of cerebral circulation
In a large randomized clinical trial of WHI an increase in the risk of cerebrovascular accident in healthy women with combined HRT (KLE + MPA) has been established. So, in the absence of HRT, the number of cases of cerebral circulation impairment per 1000 women within 5 years was about 3 - at the age of 50-59 years and about 11 - at the age of 60-69 years. For 1000 women who used conjugated estrogens and MPA for 5 years,the number of additional cases of cerebral circulation disorder ranged from 0 to 3 (on average 1) - at the age of 50-59 years and 1-9 (on average 4) - at the age of 60-69 years. It is not known whether such an increase in risk extends to other HRT preparations.
Ovarian Cancer
The increased risk of ovarian cancer in women with a distant uterus is associated in some epidemiological studies with a prolonged (during 5-10 years) with estrogen monotherapy with HRT. It remains unclear whether the risk of ovarian cancer increases with long-term use of combined (estrogen and progestogen-containing) drugs for HRT, compared with estrogen alone.
Other states
Estrogens can lead to fluid retention in the body, which can worsen the condition of patients with impaired heart or kidney function. When taking Estrofem ® in the terminal stage of renal failure, the level of circulating active components increases.
Also, women with hypertriglyceridemia in the anamnesis are subject to a thorough examination and observation in the HRT process, since in the treatment with estrogens a significant increase in the triglyceride content in the plasma can result, leading to pancreatitis.
Estrogens increase the concentration of thyroxine-binding globulin, which leads to an increase in the total concentration of circulating thyroid hormones, determined by the content of protein-bound iodine, thyroxine (by column chromatography or radioimmunoassay) of triiodothyronine (in radioimmunoassay). The concentrations of free thyroxin and triiodothyronine remain unchanged.
Concentrations of other binding proteins of blood serum can be increased, incl. corticoid-binding globulin and globulin binding sex hormones, which leads to an increase in the concentration of circulating corticosteroids and sex hormones. Concentrations of free or biologically active hormones do not change.
The concentration of other proteins of angiotensinogen / renin plasma, alpha 1-antitrypsin, ceruloplasmin may increase.
There is insufficient evidence to improve cognitive function. Moreover, with behavior WHI-Investigation shows an increase in the risk of possible dementia in combined (CLA + MPA) HRT in women over 65 years of age.It is not known whether this applies to other HRT preparations and / or HRT in younger postmenopausal women.
Estrofem® contains lactose. Patients with rare hereditary diseases - intolerance to galactose, lactase deficiency or glucose-galactose malabsorption should not use this medication.