Nuances of modern hormone replacement therapy
Looking back, it's a little creepy how the history of hormone replacement therapy (HRT) began. Too simple logic was the basis of this method - if the body stops producing hormones (according to its own laws), then we will simply introduce them from the outside, not caring much about whether the body itself is ready to continue to be subjected to hormonal stimuli. HRT has already been widely used in different countries of the world, while no one yet knew about the different types of estrogen and progesterone receptors, isoforms of various steroid-converting enzymes were not discovered, growth factors were only for the first time determined in laboratories, how. Actually, genotyping, and despite this, millions of women took drugs with high doses of hormones, and the reverse side of such carelessness did not appear behind external well-being.
Obviously, the emphasis in evaluating the effectiveness of HRT was shifted towards a noticeable leveling of the symptoms of menopause, improving the appearance and general well-being of a woman. Still, it would seem that the eternal dream of women to remain young and attractive as long as possible is close to being realized, the question of price in such cases is of little concern. And for doctors in general, the feeling of an imminent victory over the growth of cardiovascular diseases and osteoporosis clouded the eyes and did not allow to fully appreciate the risk of the downside of such experiments.
The need to create drugs that can stop the aging process is so high that in this continuous race of scientific thought, constantly accelerated by the interests of pharmacological giants. The problem of the safety of drugs presented on the market is shyly taken out of the scope of paramount interests. It must be clearly understood that the true, delayed effects of certain drugs for HRT are revealed at the stage of post-registration studies, that is, when the drug is already widely used.
The results of a large study conducted in America, which was designed for 8 years, forced to reconsider the attitude towards HRT. But by the fifth year, the study had to be stopped due to an increase in cases of breast cancer, heart attacks, strokes and thromboembolism. Despite the positive effect of HRT on menopausal symptoms and the preventive effect on colorectal cancer and bone fractures. In 2002, the main amendment was formulated - HRT should be prescribed primarily for therapeutic purposes and should not be prescribed for the purpose of disease prevention.
Hormone replacement therapy in cases where hormones have ceased to be produced ahead of time is obvious. The body is still tuned to certain concentrations of hormones and they are deprived of them. Here, hormonal deficiency is a disease that needs to be treated.
Are menopausal disorders a true disease that has a cause, or is it still a violation of the body's adaptation to naturally programmed stress. Millions of women live their lives according to the program that was originally laid down by the body, a program that provides for periods of maturation, pregnancy, lactation with the characteristic restructuring of the body. The period of extinction of the reproductive system is also biologically provided. It is unlikely that the body provides for the development in this case of a serious illness. It seems unlikely that the transition from one phase of life to another, not less in duration than the previous one, and in general, characterized only by the end of the reproductive age, should be so destructive for the organism as a whole.
Climacteric phenomena do not develop in all women, not all women begin to lose bone mass dramatically and become patients of cardiologists. How do they differ from those who, without substitution therapy, gradually turn into a disabled person. Maybe the reason is that they had menopause earlier than it was genetically laid down and the body is under stress of a discrepancy between its needs for hormonal effects and the existing level of hormones. Another likely cause may be a life history of such women, rich in diseases and unhealthy lifestyles, a small number of pregnancies and a short period of breastfeeding, smoking and alcohol abuse, unhealthy diet and physical inactivity. In other words, by the time of menopause, such an organism comes in such a worn out state that it cannot cope with hormonal changes. That is, if there is a severe climacteric syndrome, we are dealing with a "worn-out organism", the treatment of which from all the manifested diseases individually is a difficult and generally harmful task. Then the meaning of HRT becomes more or less clear, in such cases - substitution therapy is doping, a means of prolonging the previous period of life, to which the “worn out” organism has already adapted. Such a “time machine” slows down the “wear and tear” of the body, but at the same time it is doping with all its characteristics - to mobilize forces for a short time, despite the fact that all this time is “additional”. What is the essence of the last thought - without HRT, a “worn-out” organism would more quickly face all the diseases that are coming to it, and sooner or later a fatal complication would occur. With HRT, the body delays the onset of diseases, reduces the likelihood of their severe manifestation, providing the patient with additional comfort. existence, even in the face of a relatively small risk of complications from such "doping".
Now you can take a slightly different look at the problem of HRT and the significance of its complications. Patients with a “not worn out” body do not need doping, since the program of transition from one period of life to another has worked correctly in their body. Those whose body is “worn out” thanks to HRT have an extra time of comfortable existence, and then the small risk from taking HRT becomes insignificant compared to the absence of a sad scenario.
Hormone replacement therapy should only be part of a package of recommended interventions for a postmenopausal woman, including advice on diet, physical activity, alcohol intake, and smoking.
This approach is quite obvious: the extinction of the reproductive system is one of the most difficult periods in a woman's life, affecting all body systems. This is a test for which the body has its own resource of strength, its own compensatory capabilities and internal reserves. Quite important is the state in which the body has approached this milestone. Of course, frequent illnesses, injuries, exposure to external toxic and damaging factors can significantly weaken the compensatory capabilities of the body, which will manifest itself in the severe course of the menopause with exacerbation of chronic diseases. It is important to understand that a simple replacement of the missing concentrations of sex hormones cannot fully solve all the problems that have arisen as a result of the restructuring of the body that has begun. HRT in this situation acts as an anesthetic for a broken arm - acting symptomatically, it does not solve the problem as a whole. That is why, general recommendations for a proper, healthy lifestyle are more of a pathogenetic treatment, as they help the body itself mobilize natural reserves to complete the functioning of the reproductive system.
Physical activity during menopause is the basis of measures aimed at correcting menopausal disorders. Regular exercise reduces both overall mortality rates and mortality from cardiovascular disease. Physically active women during menopause usually have a good metabolic profile, muscle strength, intelligence and memory, and a significantly improved quality of life. Fewer cases of heart attacks, strokes, bone fractures and reduced incidence of breast cancer. However, we must remember that excessive physical activity can have a negative impact. 30 minutes of moderate intensity training 3 times a week are considered optimal. Two additional workouts a week with load-bearing exercises can have an additional positive effect.
In addition to physical activity, the normalization of the diet is of paramount importance. It is important that your daily diet includes fresh fruits and vegetables, fiber-rich foods, fish, and lean meats. Salt and alcohol should be reduced, and smoking should be stopped.
The next important point in the appointment of HRT is a strict individualization of treatment, which implies an assessment of the severity of symptoms, anamnestic data, data from other studies and an assessment of the benefit-risk ratio. It is necessary to clearly understand what is safer for the patient - her current condition or the risk of possible complications from HRT. In addition, it is important to remember that the risk of complications increases in older women.
It is clear and proven that women with premature menopause (before 45 years and especially before 40 years) due to iatrogenic causes or diseases have a significantly increased risk of cardiovascular disease and osteoporosis. In these cases, HRT is indicated for objective reasons, the benefit / risk ratio is significantly inclined towards the predominance of benefits. Replacement therapy in such patients should continue until the age of natural menopause, the need for its further use should be decided individually.
HRT should not be prescribed without evidence, it is not an elixir of eternal youth!!!
For HRT, drugs containing the minimum effective dose of hormones that can improve the quality of life should be selected. At the same time, there are currently no reliable data on the effect of minimally effective doses of hormones on leveling the risk of cardiovascular diseases.
In patients with a preserved uterus, HRT should be combined, that is, include progesterone or its analogues in its composition - this is necessary to prevent the development of endometrial hyperplastic processes and cancer. However, natural progesterone and some progestins can have a number of additional positive effects in addition to the protective effect on the endometrium. The combination of systemic estrogens with the Mirena intrauterine hormone releasing system is a completely logical approach to HRT. Local administration of estrogens for the correction of urogenital disorders does not require additional administration of progesterone.
Androgen replacement therapy should only be recommended for women with severe clinical manifestations of androgen deficiency.
Thus, we have presented the general characteristics of the modern approach to HRT. Below we will analyze in detail the positive and negative nuances of HRT.
Positive effects of HRT
The greatest effectiveness of HRT is manifested in relation to vasomotor symptoms (hot flashes) and urogenital disorders (problems with urination). Also, against the background of substitution therapy, pain in the joints and muscles, mood lability, sleep disturbances and libido are well leveled. In general, it is precisely due to the similar effects of HRT that one of the key indications for prescribing such therapy is to improve the quality of life and sexuality in women of this difficult period.
HRT is an effective means of preventing bone loss and significantly reduces the likelihood of bone fracture even in patients with a low risk of developing such complications. It is known that the degree of protective effect of HRT on bone tissue is correlated with the dose of estrogen, while drugs with low levels of estrogen also have a positive effect on bone density in most women. Therefore, the use of HRT is the first step in the prevention of bone fractures in menopausal women with a high risk of such complications. Especially up to the age of 60, and also actually the only way to preserve bone tissue in women with premature menopause.
With the discontinuation of HRT, the protective effect in relation to the preservation of bone mineral density decreases, but a prolonged effect of therapy is noted.
It is not recommended to prescribe HRT in standard doses to women over 60 years of age only for the purpose of preventing fractures, as well as to extend the course of already taken HRT after 60 years, if the purpose of such an extension is only the prevention of fractures. In the latter case, the issue of extending HRT should be decided individually, while the prolonged effect of therapy and the possibility of its replacement with other osteoprotective drugs should be taken into account.
Other drugs include bisphosphonates. Bisphosphonates inhibit bone resorption by osteoclasts and reduce bone turnover, thus reducing the risk of fractures. In this case, the effect of the treatment occurs extremely quickly, within a few weeks and persists throughout the treatment. In placebo-controlled trials of oral amnobisphosphonates for 4 years followed by continued therapy up to 10 years, bone quality has been shown to remain within normal limits. And the risk of fractures decreases as the duration of therapy increases. It is also noted that the positive effect on fracture prevention lasts more than 5 years after treatment is stopped.
Against the background of a decrease in estrogen levels, their protective effect against cardiovascular diseases, which in turn become the main cause of morbidity and mortality in postmenopausal women, decreases accordingly. The most important factors in the prevention of these diseases are known to be smoking cessation, diet, weight loss, control of blood pressure and blood lipid levels. The activities listed above are already capable of significantly affecting the risk of developing heart and vascular diseases. It is known that it is arterial hypertension and diabetes that are the most significant risk factors for cardiovascular diseases in women compared with men. Quite often, women can experience angina pectoris without damage to the coronary vessels, but in the event of a heart attack, the prognosis is usually worse than in men.
It has been proven that replacement therapy started on time, that is, from the period of perimenopause, and having a sufficient duration, can have a cardioprotective effect, significantly reduce the risk of developing diabetes and insulin resistance, which in turn. Reduces the risk of other factors in the development of cardiovascular diseases, such as dyslipidemia and metabolic syndrome.
In women younger than 60 years of age with recent menopause, even in the absence of cardiovascular risk factors, initiation of HRT reduces morbidity and mortality from cardiovascular disease. And it is not associated with a significant increase in the risk of complications of the therapy itself. The continuation of therapy after 60 years of age should be decided on the basis of benefit / risk for each individual patient.
There are studies that show a relative increase in cardiovascular disease during the first year of HRT use, but this is more true for women. Who are approaching the age of 60 and have an underlying cardiac pathology or multiple risk factors.
It is believed that any hormone therapy increases the risk of ischemic stroke, although data from a study of menopausal women suggests otherwise. In particular, there was no increase in the risk of strokes in women receiving HRT in the range from 50 to 59 years. It is also noted that the risk becomes even lower if drugs with a minimum hormone content are used for HRT, if therapy is started as early as possible, and if hormones are not administered orally.
In general, it is clear that HRT is able to reduce morbidity and mortality from cardiovascular diseases, it should not be used for this purpose in women over 60 years of age with an existing pathology.
Other Benefits of HRT
Substitution therapy has a positive effect on the condition of the connective tissue, skin, joints and intervertebral discs.
An analysis of the effect of HRT on the mental abilities of a woman in menopause, both natural and surgical, showed the absence of a significant effect on this indicator. Despite this, it is well known that the brain is a target for the action of sex hormones and, in particular, estrogens. Estrogens exert their effects directly through their effects on neurons and glia, and indirectly through their effects on brain blood supply and the immune system. Estrogens have the greatest effect on the areas of the brain responsible for memory, emotions and mood. In recent studies, it has been shown that a rapid drop in the level of estrogen in the blood leads to disturbances in the membrane of neurons. At the clinical level, this is manifested by memory impairment, a decrease in mental performance and emotional lability with a decrease in the level of sex hormones. Interestingly, many of the violations listed above are leveled against the background of HRT. Thus, studies that have shown the absence of a significant effect of HRT on mental abilities look somewhat strange. There are data showing that the risk of developing dementia increases with the use of HRT. In general, the question of the effect of HRT on the cognitive function of women is still unclear.
When started early, as early as perimenopause or early menopause, HRT may reduce the risk of developing Alzheimer's disease.
Serious side effects of hormone replacement therapy.
The greatest emphasis in the study of the side effects of HRT was made in relation to the increased risk of developing breast and endometrial cancer, venous thrombosis, strokes and heart attacks.
At the moment, despite numerous studies, the question of the relationship of HRT with the risk of developing breast cancer remains open. This is partly due to the different incidence of this type of cancer in different countries, which does not allow to fully summarize and evaluate the results of international studies.
At the same time, women should be informed that the risk of possible development of breast cancer associated with taking HRT is low (less than 0.1% per year).
Various competent studies of major world organizations claim a fairly wide range of results of their studies on the effect of HRT on the risk of developing breast cancer. According to some data, the use of combination drugs leads to an increased risk of developing breast cancer in the first year of therapy, but they are accused of methodological flaws. According to other materials, the use of pure estrogens does not increase the risk of breast cancer when using HRT for 7-15 years, while European studies suggest an increase in risk after 5 years from the start of replacement therapy.
It is believed that at the moment there is not enough data accumulated to assess the degree of influence of various forms of estrogens, progesterone, progestins and androgens, as well as their routes of administration, on the risk of developing breast cancer.
Thus, epidemiological studies still cannot come to an unambiguous opinion about the degree of increased risk of developing breast cancer on the background of HRT. At the same time, a number of new data have been obtained, allowing a better understanding of the pathogenetic mechanisms of the development of this disease and its relationship with substitution therapy.
In particular, it has been shown that circulating estrogens are less responsible for the development of breast cancer than estrogens synthesized locally in the breast tissue. Excess formation of catechol-estrogen quinones, through interaction with DNA, initiates a series of successive events leading to the development of cancer. The value of endogenous estrogens as the main damaging factor comes to the fore in women who have a genetic predisposition to this disease.
Despite the positive effects of combined replacement therapy, the addition of estrogens to progestogens leads to an increased risk of developing breast cancer, but this risk varies depending on the type of progestogen. Thus, combinations of oral or transdermal estrogens with micronized progesterone and dydrogesterone do not increase the risk of developing breast cancer at all. Or there is a minimal increase (when using HRT for 4 and possibly more than 8 years) compared with other synthetic progestogens, especially those with pronounced androgenic properties. The androgenic properties of progestogens can clearly increase the risk of developing breast cancer, since a number of studies have shown the presence of androgen receptors in some types of breast cancer and their role in carcinogenesis.
The risk of breast cancer declines rapidly after HRT is discontinued, so within 5 years the likelihood of developing breast cancer may not exceed that of women who have never taken replacement therapy.
As a result of recent research, data have emerged regarding the possibilities of preventing breast cancer. Were identified natural mechanisms that protect the tissue of the gland from the process of malignancy.
The lobules of the mammary gland reach their maximum development during pregnancy and lactation. They are represented by the so-called 4th type. After menopause, the lobules of both parous and nulliparous women regress to a level referred to as type 1. Undifferentiated type 1 lobules in nulliparous women retain high concentrations of epithelial cells (Stem Cells 1), which are the substrate for neoplastic transformation. An early full-fledged pregnancy ending in childbirth changes the genome of epithelial cells (Stem Cells 2), making them refractory to malignancy. Type 2 stem cells contain specific gene mechanisms that protect breast tissue from cancer. Currently, clinical studies are underway on the possibility of introducing genomic modifications characteristic of type 2 stem cells into breast tissue, which will allow creating the possibility of protecting the mammary gland from the process of malignancy.
Thus, the problem of breast cancer and its relationship with HRT still remains unresolved. Some studies contradict others, the safe use of HRT varies from 5 to 15 years, there is no clear understanding of the effect of various progestins and forms of HRT administration on the risk of breast cancer. Methodological inaccuracies are visible in many studies, some studies are clearly guilty of bias on the part of pharmacological companies. Analyzing all currently available information, it can be concluded that there is a clear combination of a natural increase in the risk of breast cancer in this age group, and the degree of its increase with the use of HRT depends on the form. Routes of drug administration and duration of use. Equally important is the quality of the preliminary examination of the patient. In this situation, accuracy is of the utmost importance. evaluation of mammography images and their quality. After all, it can be assumed that in some cases, poor-quality analysis of mammograms leads to the appointment of HRT against the background of the existing initial stages of the neoplastic process.
Of course, breast cancer is not a problem that appeared with the beginning of the use of HRT, it is just that substitution therapy has sharpened the issue in relation to this disease to a greater extent. There is an opinion that the increase in the incidence of breast cancer in women taking HRT is due to more careful monitoring of these women and a greater frequency of mammograms, which increases the likelihood of detecting breast cancer. Compared to women who do not take HRT and are therefore less concerned about controlling their health.
Obviously, the introduction of pure estrogens into the body with a preserved uterus leads to unidirectional stimulation of the endometrium, which dramatically increases the risk of hyperplastic processes and cancer. Therefore, there is no doubt that in women with a preserved uterus, HRT should be combined or combined with the introduction of the Mirena intrauterine hormonal releasing system.
Venous thrombosis and thromboembolism are the most serious side effects of HRT. The risk of venous thrombosis while taking HRT increases with the age of the patient and is also associated with the degree of concomitant obesity and thrombophilia. In addition, there is an increase in the risk of thrombosis during the first year of therapy. Oral estrogens are known to inhibit fibrinolysis. With another route of estrogen administration, there is no first-pass effect through the liver, which manifests itself in a minimal effect on the blood coagulation system. Therefore, the non-oral route of estrogen administration is more preferable for patients predisposed to venous thrombosis.
The text below is more for specialists.
Therapeutic approaches to hormone replacement therapy
The main purpose of HRT is the pharmacological replacement of the hormonal function of the ovaries in women who are clinically deficient in sex hormones. It is important to achieve such minimally optimal levels of hormones in the blood, at which an improvement in the general condition would actually occur, and prevention of late metabolic disorders (atherosclerosis, osteoporosis and Alzheimer's disease) would be provided. And there would also be minimal side effects of estrogens, especially in the endometrium and mammary glands.
Basic principles and indications for the appointment of hormone replacement therapy
When prescribing HRT, a number of fundamental provisions should be taken into account.
- Choice of drug. For HRT, only "natural" estrogens and their analogues should be used.
- Doses of estrogen should be low and consistent with those in the early proliferation phase in young women.
- With an intact uterus, the combination of estrogens with progestogens helps protect the endometrium from the development of hyperplastic processes.
- Women with a hysterectomy are shown to use estrogen monotherapy in intermittent courses or in a continuous regimen.
- If the indication for hysterectomy was endometriosis or endometrial cancer, then a combination of estrogens with progestogens or androgens is used.
- Reception duration. To ensure the prevention of osteoporosis, atherosclerosis and the therapeutic effect of genitourinary disorders, the duration of HRT should be at least 5-7 years.
Indications for prescribing HRT in perimenopause:
- early (40-45 years) and premature menopause (up to 40 years of age);
- long periods of secondary amenorrhea and reproductive age;
- primary amenorrhea (except for the Rokitansky-Kyustner syndrome);
- vasomotor symptoms of climacteric syndrome in perimenopause;
- urogenital disorders;
- the presence of risk factors for osteoporosis and cardiovascular disease and Alzheimer's disease.
The main types of drugs for HRT
- preparations containing estrogens (monotherapy);
- a combination of estrogens with progestogens in various modes (cyclic or continuous);
- combination of estrogens with androgens;
- monotherapy with progestogens or androgens (rarely used).
New indications for HRT have now been identified
- Migraine (some forms)
- smoking, obesity
- Cardiovascular diseases
- Alzheimer's disease
- Prevention of cerebral stroke, myocardial infarction.
Current contraindications for HRT
- Vaginal bleeding of unknown origin
- Acute severe liver disease
- Acute deep vein thrombosis
- Acute thromboembolic disease
- Breast cancer and genital cancer (diagnosed but not treated)
- Endometriosis (monotherapy with estrogens is contraindicated)
- Meningioma (progestogens are contraindicated)
- Endometriosis, uterine fibroids
- History of breast, ovarian, and uterine cancer
- History of thromboembolism
“Neutral” circumstances (not new indications, hormone therapy is not contraindicated, but requires attention)
- Surgical interventions
- Bronchial asthma
- Multiple sclerosis
- Systemic lupus erythematosus
Circumstances in which HRT is not contraindicated (According to experts in Europe and the UK, 1995)
- liver adenoma
- Type II diabetes
- sickle cell anemia
- endometrial hyperplasia
Factors contributing to the increasing popularity of HRT among women
- increasing women's knowledge about the optimal duration of HRT;
- individualization of risk factors to realize the need and desire of a woman to take HRT;
- obtaining informed consent from women by physicians.
In the last two years, experience has been accumulating in Russia in the use of HRT in patients treated for breast and genital cancer. It should immediately be noted that such experience is acquired in highly qualified scientific institutions with the participation of a gynecologist, an oncologist and a patient with their full cooperation and obtaining the informed consent of the patient.
Examination before the appointment of HRT
Before the appointment of HRT, a thorough examination of the woman should be carried out: study the anamnesis, paying special attention to oncological diseases, thromboembolism, the reaction to combined hormonal contraceptives, liver disease, etc.
Mandatory examinations are:
- measurement of blood pressure;
- determination of the level of glucose, lipoproteins, FSH, E2 in blood serum, TSH, T3, T4;
- gynecological examination with oncocytology (PAP - smear from the cervix);
- Ultrasound of the endometrium with a mandatory assessment of its thickness;
- Breast palpation and mammography
According to the indications are carried out:
- consultation of a neuropathologist, cardiologist, therapist, urologist, endocrinologist.
With the thickness of the endometrium:
- up to 5 mm - HRT is not contraindicated;
- up to 8 mm - you can prescribe progestogens for 12-14 days (Dufaston 20 mg / day, MPA 30 mg / day, norkolut or premolyut-nor 5 mg / day) and repeat ultrasound on the 5th day of menstruation; In the absence of changes in the thickness of the endometrium, diagnostic curettage is performed.
- more than 8 mm - hysteroscopy and diagnostic curettage of the uterus are indicated.
after the appointment of HRT, it is recommended, especially in the first 3 months, to maintain an individual “menstrual” calendar with the registration of a menstrual-like reaction and possible bleeding from the uterus and adverse reactions.
A practical approach to prescribing HRT
A few important points to consider before prescribing HRT
- It is necessary to start therapy with a minimum dose of hormones.
- In modern conditions, it is preferable to use drugs containing 17 beta-estradiol as an estrogen component, and progesterone, dydrogesterone and dienogest as a progestogen. Other gestagens increase the risk of developing breast cancer to a greater extent.
- If an androgenic effect is needed, then it is better not to use 19-norsteroids, but to prefer Livial, and in perimenopause - symptomatic drugs (antidepressants, etc.)
- If there are only urogenital disorders - locally Ovestin, systemic - it is irrational.
- If the problem is only in osteoporosis - non-hormonal drugs (bisphosphonates, raloxifene, etc.)
- Concomitant pathology (thrombosis, cardiovascular diseases, depressive states) determines the preferred route of drug administration - parenteral (plasters, gels).
- The presence or absence of the uterus determines the composition of therapy (mono or combined)
It is believed that the duration of HRT should be on average 5-7 years, if we talk about the real prevention of osteoporosis, cardiovascular diseases and the treatment of urogenital disorders.
Given the data on a possible increase in the risk of breast cancer after 10 years, patients should be given maximum information about this situation. The main thing is the annual monitoring of the state of the genital organs (ultrasound, oncocytology) and mammary glands (mammography), according to indications - the determination of the lipid spectrum and blood glucose levels, the production of a hemostasiogram (assessment of the blood coagulation system).