Estrogens (female sex hormones) are produced mainly by the ovaries, as well as by the adrenal cortex, placenta and testes. By their chemical nature, estrogens are derived from estranes – C-18-steroids. The process of converting C-19 steroids (androgens) to C-18 steroids (estrogens) is provided by the aromatase enzyme, which forms the phenolic group in ring A of the steroid structure. The main biologically active estrogen secreted by the ovaries is estradiol, which has a hydroxyl group in the 17th position. Estrogens may also be detected in the peripheral circulation.
weak biological activity: estrone secreted by the adrenal glands and ovaries, and estriol is a product of peripheral estrogen metabolism. The presence of keto-group in the 17th and 3rd position leads to a consistent decrease in estrogen activity.
Defining the physiological role of estrogens, it should be said that the processes of sexual differentiation in girls do not depend on the level of estrogens, however, by pubertal age, the formation of secondary sexual characteristics and the development of genitalia are completely mediated by estrogens. Estrogens induce the growth of the mammary glands, the growth of the uterus and vagina, contribute to the increase in pelvic bones and the feminine distribution of adipose tissue. Under the influence of estrogen proliferative processes in the endometrium increase, its vascularization increases. Estrogens have a metabolic and cholestatic effect. Like all steroids, estrogens contribute to the retention of sodium and water in the body. Estrogens increase the mineralization of the bone matrix and contribute to an increase in bone mass. In puberty, estrogen plays the main role in the processes of differentiation of the bone skeleton, as well as in the cyclicity of gonadotropic regulation of ovarian function in women.
The scientific approach of reproductive endocrinology was laid in the first decade of the last century, when the endocrine function of the ovaries was experimentally proved. Alien and Doisy (1923) laid the foundation for modern concepts in the field of ovarian steroids, which clearly showed that the ovary produces two different substances: one of them is responsible for the growth and preservation of the functions of the genitals, and the second for the development of secretory changes in the endometrium and preservation of pregnancy. Subsequently, almost simultaneously, in 1929, three major human estrogens were identified and identified in several laboratories: estrone, estriol and 17-B-estradiol, the most important and biologically active estrogen, which was synthesized from the urine of mares only in 1935. In 1934, Butenandt first identified a substance with progesterone activity, and Slotta accurately deciphered the structure of progesterone. For the progesterone synthesis technique, Butenandt and his group were awarded the Nobel Prize in 1935.
Further study of the synthesis of sex steroids and their metabolism, as well as the expression of receptors for these hormones in various organs and tissues of the female body and the characteristics of their interaction with these receptors, contributed to the disclosure of the development mechanisms of a number of dyshormonal diseases in women and the creation of drugs with sex steroid hormones , which provided the possibility of pathogenetic treatment of diseases associated with estrogen deficiency.
In women, estrogen deficiency, with the exception of cases of congenital hypogonadism, is observed during menopause, which is defined as the physiological, genetically programmed period of life, during which, against the background of general age-related changes, involutive processes in the reproductive system dominate, leading to a deficiency of sex hormones, cessation and then menstrual function.
The clinical symptom complex of climacteric syndrome includes vasomotor, endocrinological, metabolic, and neuropsychic disorders. The most adverse consequence is osteoporosis. Estrogen deficiency determines the development of symptoms that characterize the pathological condition of organs and tissues with specific estrogen receptors: increased vascular tone, increased vasospastic reactions, slowed blood flow, impaired blood circulation, decreased cardiac output, increased platelet aggregation, tendency to thromboembolism and ischemia. All the listed changes in the functions of the heart, blood vessels, hemostasis, as well as the metabolism of lipids and carbohydrates that occur in the menopausal period are commonly referred to as the general term “menopausal metabolic syndrome”. There are two groups of target organs exposed to estrogen: reproductive (genitals, mammary glands, hypothalamus, pituitary) and non-reproductive (brain, cardiovascular system, musculoskeletal system, urethra, bladder, skin, hair, large intestine, liver).
The estrogen-like effect in steroid-dependent organs and tissues is due to stimulating effects.The effect on estrogen receptors. Currently, two types of estrogen receptors (a, B) have been isolated.
Estrogens bind to a-and B-estrogen receptors, but the affinity for different types of receptors may be different. For example, estradiol binds equally to both types of receptors, estrone has a weak connection with the a-receptor, while ethinyl estradiol has twice as much activity against the a-receptors. Estrogens are commonly referred to as so-called pure estrogen receptor agonists, since they have a direct stimulating effect on this type of receptor. However, the strength of the receptor response caused may vary depending on the type of estrogen used.
Differences in the expression of estrogen receptor subtypes in various organs and systems, as well as the ability of different types of synthetic progestogens to stimulate these receptors provide an opportunity for a differentiated approach to the choice of hormonal drugs.
Pathogenetically justified treatment of symptoms associated with estrogen deficiency is the prescription of hormone replacement therapy (HRT), the purpose of which is the pharmacological replacement of the hormonal function of the ovaries.
The beginning of HRT use is considered to be the 40s of the 20th century, when drugs containing conjugated estrogens (a mixture of 10 different components) isolated from the urine of mares were created in the USA. Although HRT was first introduced into medical practice about 100 years ago, the first publication in a medical journal appeared in 1896 about using the extract of cow ovaries to treat women after ovariectomy.
Only in the 1970s, combined HRT, combining estrogen and progestogen (progesterone), appeared. To date, a lot of drugs have been created with various features of the chemical structure and biological activity of their components, release forms, routes of administration, regimens and administration regimens, requiring special training from a doctor with the ability to evaluate the effectiveness and tolerability of HRT at each stage of treatment. In recent years, the development of drugs with a selective effect on hormone-dependent organs, ensuring high efficacy and safety, the so-called tissue-selective regulators of estrogenic activity (STEAR), continues.
To date, drugs available in Russia for the treatment of estrogen deficiency, according to the International Classification of Drugs, can be divided into the following groups:
1 Traditional hormone replacement therapy:
● pure estrogens (conjugated estrogens, 17-B-estradiol, estradiol valerate);
● combined estrogen-progestin therapy (cyclic mode and continuous mode); ● combined estrogen and androgenic
2 Selective estrogen receptor modulators – SERM:
● tamoxifen; ● raloxifene.
3 Tissue-selective regulators of estrogenic activity – STАAR (tibolone).
“Natural” estrogens are estrogen preparations that are chemically identical to estradiol synthesized in the body of women. Thanks to modern technology, estradiol was created synthetically, but its chemical structure is identical to natural and possesses high quality. The estradiol preparations currently used in clinical practice contain:
- Synthetic “natural” 17-B-estradiol.
2 Estradiol valerate, which is biotransformed in the liver to estradiol. Therefore, estradiol valerate is considered as a precursor of natural estrogens, which are formed in the body from synthetic. It enters the bloodstream after converting it in the liver to natural estrogen – estradiol.
- Estrone (E1) and estrone sulfate (E1-S) – folliculin.
- Conjugated estrogens. They are so-called natural estrogens. They do not contain human estrogen, they are obtained from the urine of the mares. Therefore, it is more correct to use the term “conjugated equine-estrogen.” There are also conjugated estrogens (CES) derived from plant steroids.
- There are 2 main routes of administration of estrogen drugs – enteral and parenteral (Fig. 1) [SmetnikV. P., 2000].
- Oral estrogens are simple and easy to use, they have a positive clinical effect in typical menopausal syndrome, urogenital disorders, are successfully used to prevent and treat postmenopausal osteoporosis, reduce the frequency of cardiovascular diseases and improve the quality of life. Oral estrogen preparations have a positive effect on some indicators of the blood lipid spectrum: a decrease in total cholesterol, a decrease in low-density lipoprotein (LDL), an increase in high-density lipoprotein (HDL), and a decrease in LDL oxidation. A positive effect on metabolism in the vascular endothelium (synthesis of nitric oxide, prostacyclin, etc.) was noted, which contributes to a decrease in vascular resistance.
However, when using oral estrogen preparations, the following should be considered:
● incomplete absorption of oral estrogens in the gastrointestinal tract is possible, especially with its diseases;
● require high doses of drugs to achieve a therapeutic effect;
● daily pills are accompanied by peaks in the concentration of estradiol in the blood;
● active metabolism when passing through the liver;
● increased estrogen concentration in the liver can stimulate the synthesis of various biologically active substances: coagulation factors, angiotensin, globulin that binds sex steroids
(GSPS), a thyroxin-binding globulin;
● an increase in the synthesis of triglycerides, especially under the influence of conjugated equine-estrogens, which
may also be associated with hyperinsulinemia, with an increase in the concentration of procoagulation factors,
which are directly involved in the formation of atherogenic plaques;
● patients sometimes do not respond to oral HRT, which may be associated with a changed
sensitivity to minor fluctuations in estradiol levels or with active binding
proteins, or a violation of its absorption in the gastrointestinal tract;
● low biological effect or inadequate action can be detected when determining
serum levels of estradiol and FSH 12 h after oral administration. If estradiol binding is increased, its level can be normal, in the absence of a decrease in FSH (> 40-50 IU / l), the content of which is usually rapidly reduced while taking estrogen preparations. The factors outlined may affect the pharmacokinetics of hormonal drugs, causing fluctuations in their blood levels. In diseases of the liver and gastrointestinal tract, the absorption and metabolism of hormonal drugs is impaired.
Nevertheless, it should be noted that tablets are a more traditional form of medicine for patients, are easy to use, cheaper than other forms, and, moreover, they have long experience in using them (Table 5). Other forms of estrogenic drugs are created to improve their tolerability, to obtain a stable level in their blood serum and, accordingly, to increase efficiency.
The parenteral route of administration pursues the main goal of delivering medicinal substances as quickly as possible and without loss to the internal environment of the body or directly to the pathological focus (Table 6). Estrogens with lipophilicity can penetrate the skin, be absorbed into the blood and have a systemic effect. Special therapeutic systems have been developed to ensure the percutaneous supply of drugs into the systemic circulation. Such systems are special dosage forms that are fixed by a sticky substance on the skin and provide slow and long-term absorption of the drug, thereby prolonging its action. Indications for parenteral administration of estrogens for HRT
● insensitivity to oral HRT;
● diseases of the liver, pancreas, gastrointestinal malabsorption;
● coagulation disorders, high risk of venous thrombosis;
● hypertriglyceridemia before and on the background of oral and,
especially, conjugated equine estrogens;
● increased risk of cholelithiasis;
● migraine headache;
Transdermal estrogen administration allows:
● avoid their passage through the liver and, accordingly, avoid metabolism in it;
● maintain a relatively stable level of estradiol in the blood without an early peak observed during oral administration;
● maintain an estradiol / estrone ratio> 1.
The degree of absorbability of the gel depends on the place of its application. It has been found that the thigh area is more permeable to gel with estradiol than other areas, such as the shoulder.
Estrogen injections can be given daily or prolonged (1 time) per month to get the effect, and then you can switch to oral or transdermal forms.
Subcutaneous implants are introduced 1 time in 6 months. Estrogens from implants are gradually absorbed into the bloodstream, ensuring their constant level in the blood for 6 months. They are most suitable for women after hysterectomy, which are well tolerated by estrogens. Negative is the impossibility of prekratit treatment quickly if necessary.
Estrogens can be used vaginally in the form of tablets, ointments, suppositories, and rings. In Russia, there is a long experience of using vaginal estriol Ovestin for urogenital disorders. Ovestin possesses colpotropic property. Since Ovestin has a weak proliferative effect on the endometrium, the addition of progestogens is not required.
Before the appointment of estrogen monotherapy is carried out generally accepted examination. Examination before the appointment of HRT:
● study of history (cancer, thromboembolism, liver disease, etc.);
gynecological examination with oncocytology;
● Ultrasound of the endometrium with an assessment of the thickness of the endometrium (thickness 5 mm); breast palpation and mammography;
● blood lipids;
● by indications: TSH test, hemostasiogram, ECG, osteodeno-sitometry;
The first control should be appointed after 3 months, in the subsequent – every 6 months.
Side effects of estrogen: nausea, pastoznost, weight gain, fluid retention, headache, migraine, excessive secretion of cervical mucus, cholestasis.
As for contraindications to hormone therapy, in this aspect a certain evolution of views is also noted. If 10 years ago, tumors of any localization and thromboembolism were contraindications for hormone replacement therapy, it has recently been considered that “contraindications today may become indications of tomorrow” [Kirkhayser M, 1998].
Contraindications for HRT in women today:
● uterine bleeding of unknown origin;
● acute severe liver disease;
● acute deep vein thrombosis;
● acute thromboembolic disease;
● breast and genital cancer (diagnosed, but not treated);
● endometriosis (estrogen monotherapy is contraindicated);
● meningioma (progestogens are contraindicated).
● endometriosis, uterine myoma;
● a history of breast, ovarian and cervical cancer;
● history of thromboembolism;
● gallstone disease.
“Neutral” circumstances (are not new indications, hormone therapy is not contraindicated, but requires attention):
● surgical intervention;
● bronchial asthma;
● multiple sclerosis;
● systemic lupus erythematosus.
Circumstances in which HRT is not contraindicated (according to the European Assembly of Experts in the United Kingdom, 1995);
● liver adenoma;
● varicose veins;
● Type 2 diabetes;
● sickle cell anemia;
● endometrial hyperplasia.
Prophylactic use of estrogenic HRT is indicated:
● if a woman wants to receive therapy, to improve the quality of life, prevent osteoporosis, cardiovascular diseases, Alzheimer’s disease, etc .;
● in the absence of symptoms of menopausal syndrome;
● in the absence of contraindications.
HRT, based only on estrogen-free progestogen preparations, increases the risk of endometrial hyperplasia and cancer and is applicable only to women who have undergone hysterectomy.
The undesirable effect of estrogen on the uterine mucosa is prevented by the addition of a progestogen component.
Progesterone is a hormone of the second phase of the menstrual cycle, the name of which itself explains its main purpose – pro gestatio, that is, for pregnancy. Progesterone deficiency often occurs with infertility and miscarriage, and therefore it is these pathological conditions that are primarily indicative of progestogen use.
It is also known that estrogens provide the processes of proliferation of the endometrium, and progesterone – its secretion in preparation for the implantation of a fertilized egg. Therefore, the relative or absolute deficiency of progesterone causes the development of hyperproliferative processes in the endometrium.
It is hyperplastic processes in the endometrium, as well as conditions with a high risk of their development, which are the second most frequent group of indications for the use of progestogens.
The study of the features of steroidogenesis in the ovaries and the metabolism of sex steroids in the body, as well as the discovery of the steroid-producing function of glia and the metabolism of neurosteroids in the brain led to the use of progestogens in the treatment of patients with diseases such as premenstrual syndrome, dysmenorrhea, etc.
Thus, today formulated the main indications for the use of progestogens in gynecological practice.