Climax. Author of the article: obstetrician-gynecologist Starostina Antonina Viktorovna.

Klimonorm

Use during pregnancy and breastfeeding

HRT is not carried out during pregnancy and lactation.
Large-scale epidemiological studies of steroid hormones used for contraception or HRT have found no increased risk of birth defects in children born to women who took these hormones before pregnancy, or teratogenic effects of the hormones when accidentally taken during early pregnancy.

Small amounts of sex hormones can be excreted in breast milk.

Use for liver dysfunction

The use of the drug is contraindicated in case of current or history of liver tumors (benign or malignant), severe liver diseases.

Klimonorm should be prescribed with caution to patients with cholestatic jaundice or cholestatic itching during pregnancy.

For mild liver dysfunction, incl. in various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, medical supervision is necessary, as well as periodic liver function tests. If liver function tests worsen, HRT should be discontinued.

special instructions

Klimonorm is not used for contraception.

Before starting or resuming HRT, a woman is recommended to undergo a thorough general medical and gynecological examination (including examination of the mammary glands and cytological examination of cervical mucus) and exclude pregnancy. In addition, disorders of the blood coagulation system should be excluded. Control examinations should be carried out periodically.

If contraception is necessary, non-hormonal methods should be used (with the exception of calendar and temperature methods). If pregnancy is suspected, you should stop taking the tablets until pregnancy has been ruled out.

If any of the following conditions or risk factors are present or worsening, the individual risk-benefit ratio of treatment should be assessed before starting or continuing HRT.

Venous thromboembolism

A number of controlled randomized as well as epidemiological studies have revealed an increased relative risk of developing venous thromboembolism (VTE) during HRT, i.e. deep vein thrombosis or pulmonary embolism. Therefore, when prescribing HRT to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

Risk factors for developing VTE include individual and family history (the presence of VTE in first-degree relatives at a relatively young age may indicate a genetic predisposition) and severe obesity. The risk of VTE also increases with age. The possible role of varicose veins in the development of VTE remains controversial.

The risk of VTE may temporarily increase with prolonged immobilization, major elective and trauma surgery, or major trauma. Depending on the cause or duration of immobilization, the question of the advisability of temporarily stopping HRT should be decided.

Treatment should be stopped immediately if symptoms of thrombotic disorders appear or if their occurrence is suspected.

Arterial thromboembolism

Randomized controlled trials with long-term use of combined conjugated estrogens and medroxyprogesterone acetate did not provide evidence of a beneficial effect on the cardiovascular system. In large-scale clinical trials of this compound, a possible increased risk of coronary disease was identified in the first year of use. An increased risk of stroke was also found. To date, no long-term randomized controlled trials have been conducted with other HRT drugs to identify beneficial effects on cardiovascular morbidity and mortality. It is therefore unknown whether this increased risk applies to HRT products containing other types of estrogens and progestogens.

Endometrial cancer

With long-term estrogen monotherapy, the risk of developing endometrial hyperplasia or carcinoma increases. Studies have confirmed that the addition of gestagens reduces the risk of endometrial hyperplasia and cancer.

Mammary cancer

Clinical trial data and observational studies have found an increase in the relative risk of developing breast cancer in women receiving HRT for several years. This may be due to earlier diagnosis, the biological effects of HRT, or a combination of both. The relative risk increases with the duration of treatment (by 2.3% when used for a year), possibly increasing even more when estrogens are combined with progestogens. This increase is comparable to the increase in the risk of breast cancer in women with each year of delay in the onset of natural menopause (by 2.8% per year of delay), as well as with obesity and alcohol abuse. The increased risk gradually decreases to normal levels during the first 5 years after stopping HRT.

According to research, breast cancer detected in women receiving HRT is usually more differentiated than in women not receiving it.

HRT increases mammographic breast density, which in some cases may have a negative effect on X-ray detection of breast cancer.

Liver tumors

During the use of sex steroids, which include drugs for HRT, in rare cases benign, and even more rarely, malignant liver tumors were observed. In some cases, these tumors have resulted in life-threatening intraperitoneal bleeding. If there is pain in the upper abdomen, an enlarged liver, or signs of intraperitoneal bleeding, the differential diagnosis should take into account the possibility of a liver tumor.

Cholelithiasis

It is known that estrogens increase the lithogenicity of bile. Some women are predisposed to developing gallstones when treated with estrogen.

Other states

Treatment should be stopped immediately if migraine-like or frequent and unusually severe headaches appear for the first time, as well as if other symptoms appear that are possible precursors of a thrombotic stroke of the brain.

The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A slight increase in blood pressure has been described in women receiving HRT; a clinically significant increase is rare. However, in some cases, if persistent clinically significant arterial hypertension develops while taking HRT, discontinuation of HRT may be considered.

For mild liver dysfunction, incl. in various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, medical supervision is necessary, as well as periodic liver function tests. If liver function tests worsen, HRT should be discontinued.

If cholestatic jaundice or cholestatic pruritus recurs, which was observed for the first time during pregnancy or previous treatment with sex steroid hormones, HRT should be stopped immediately.

Special monitoring is required for women with moderately elevated TG levels. In such cases, the use of HRT may cause a further increase in the level of TG in the blood, which increases the risk of developing acute pancreatitis.

Although HRT may affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen of diabetic patients when undergoing HRT. However, patients with diabetes require monitoring when undergoing HRT.

Some patients under the influence of HRT may develop undesirable manifestations of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for endometrial examination.

If treatment for irregular menstrual cycles does not produce results, an examination should be performed to exclude an organic disease.

Under the influence of estrogens, it is possible to increase the size of uterine fibroids. In this case, treatment should be stopped.

It is recommended to discontinue treatment if endometriosis relapses during HRT.

If prolactinoma is suspected, this disease should be excluded before starting treatment.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. During HRT, women prone to chloasma should avoid prolonged exposure to the sun or UV radiation.

The following diseases and conditions may occur or be aggravated by HRT: epilepsy, benign breast tumor, bronchial asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, chorea minor. Although the connection of these diseases and conditions with HRT has not been proven, such patients should be under the supervision of a doctor when undergoing HRT.

Impact on laboratory results

Taking sex steroids can affect biochemical indicators of liver, thyroid, adrenal and kidney function, plasma levels of transport proteins such as corticosteroid binding globulin and lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and fibrinolysis.

Impact on the ability to drive vehicles and operate machinery

Does not affect.

PREMATURE MENOPAUSE

The term “menopause” is derived from the Greek “menos” (month) and “pausos” (end) and means the permanent cessation of menstruation or menstrual cycles, caused by a pronounced decrease and/or cessation (switching off) of ovarian function.

Depending on the time of onset, the following types of menopause are distinguished:

• timely (45-55 years, average 49-52 years);
• premature (36-40 years);
• early (41-45 years);
• late (over 55 years old).

Timely menopause is the most striking manifestation of the menopause or transitional period in a woman’s life. “Climacteric” (from Greek - step, ladder), the terms “menopause”, “menopause”, “menopause” are synonyms denoting the transition from the reproductive period to old age. This period is divided into premenopause, menopause, postmenopause and perimenopause. What is most characteristic of this physiological period? It is characterized by a gradual decrease and exclusion of ovarian function from a complex ensemble of endocrine glands. First, reproductive function decreases and turns off, then, against the background of progressive depletion of the follicular apparatus of the ovaries, menstrual cycles stop (menopause), and 3-5 years after menopause, the hormonal function of the ovaries also turns off.

Both premature and late menopause require close attention and correction of possible disorders. Due to the fact that it is always difficult to estimate which menstruation was the last, it is customary to estimate the date of menopause retrospectively, namely: one year after the last menstruation.

The age of menopause often depends on heredity, which is convincingly shown in identical twins, when the difference in the age of the first and last menstruation in twins ranges from 4-6 months. However, illnesses suffered by the individual and environmental factors play an important role.

Premature menopause is quite rare (1-2%), but there are many reasons for its occurrence. Often the true cause is quite difficult to establish.

The ovary is a complex structure within which the cortical and medulla layers are distinguished. In the ovarian cortex, eggs are laid in utero, surrounded by granulosa cells, forming follicles with eggs. By the time of the first menstruation in puberty, 300-400 thousand of these follicles are found in the ovaries. During the 25-30 years of the reproductive period, follicle maturation, ovulation and death (atresia) of follicles through apoptosis constantly occur in the ovaries. Only 0.1% of the number of follicles ovulate and can give birth to offspring, and 99.9% are atretic. By the age of 40, an average of about 10 thousand follicles remain. In addition, both female (estrogens and progesterone) and, to a lesser extent, male sex hormones are synthesized in the ovaries. These hormones are involved in the formation of a typical female physique and monthly prepare the reproductive organs for pregnancy.

Receptors for estrogen and progesterone have been identified not only in the reproductive organs. Hormonal receptors (representations), through which sex hormones exert their effects, are found in the heart and walls of blood vessels, in the central nervous system, bone, genitourinary and other organs and systems of the body. Since a young woman secretes sex hormones in a cyclical mode, then the organs and tissues experience their effects also in a cyclical mode.

With premature menopause, the cyclic release and influence of female sex hormones on various organs and tissues that have been exposed to this effect for decades ceases. In addition, the woman also loses the ability to conceive.

In recent years, the opinion has become increasingly widespread that it may be more appropriate to call this condition not “premature menopause”, but “premature ovarian failure”. Although, in essence, we are talking about the same process, from the point of view of deontology, it is more appropriate for both the doctor and the patient to call this condition “premature ovarian failure.”

The main causes of premature ovarian failure:

• genetic factors;
• autoimmune process;
• viral infection;
• iatrogenic (chemotherapy, radiotherapy, surgery on the uterus and ovaries);
• idiopathic (environmental toxins, fasting, smoking - more than 30 cigarettes per day).

According to our practice, premature ovarian failure is often observed in mothers and daughters. Despite the fact that there are many reasons, processes in the ovaries mainly occur according to two main scenarios:

• complete depletion of the follicular apparatus of the ovaries, the so-called ovarian depletion syndrome;
• syndrome of resistant (silent, refractory) ovaries, in which follicles are detected in the ovaries, but they do not respond to their own gonadotropic stimuli.

Clinical picture

Common to both options:

• secondary amenorrhea, infertility;
• well developed secondary sexual characteristics;
• FSH and LH levels are high;
• estradiol levels are low;
• symptoms of estrogen deficiency: hot flashes, sweating, insomnia, irritability, decreased memory, and ability to work;
• during the first 2-3 years, osteopenia develops, sometimes osteoporosis; an increase in atherogenic lipid fractions (cholesterol, triglycerides, LDL) and a decrease in HDL;
• occasionally genitourinary symptoms appear: dryness during sexual intercourse, itching, burning;
• improvement occurs when taking sex hormones.

The main differences between the two forms of premature ovarian failure are as follows.

When the follicular apparatus is depleted:

• with ultrasound - small size of the ovaries, absence of follicles in them;
• persistent cessation of menstruation, symptoms of estrogen deficiency progress;
  improvement occurs with hormone replacement therapy (HRT); with ovarian resistance:
• the ovaries are reduced in size, but the follicles are visible;
• There are rare episodes of menstruation.

When the ovaries are depleted, the symptoms of estrogen deficiency or the symptoms of typical menopausal syndrome are more pronounced.

With resistant ovarian syndrome, estrogen deficiency symptoms are less pronounced, since it is possible, although extremely rare, to activate ovarian function and, accordingly, improve the general condition.

Tactics for managing patients with premature ovarian failure

• Examination.
• Study of anamnesis.
• Determination of FSH, LH, TSH, prolactin, estradiol in the blood.
• Craniography, for headaches - computed tomography or nuclear magnetic resonance, color fields of vision.
• Ultrasound of the genitals with detailed characteristics of the ovaries and uterus.
• Determination of blood lipids.
• Mammography.
• For long-term amenorrhea (more than 2-3 years) - densitometry of the lumbar spine and femoral neck.

Since menopause is premature, and at this age the ovaries normally function, therefore, premature deficiency of sex hormones can contribute to the earlier appearance of typical menopausal disorders, the frequency of which is 60-70%.

Classification of menopausal disorders

Group I - early symptoms (typical menopausal syndrome)

Vasomotor: hot flashes, chills, increased sweating, headaches, hypotension or hypertension, rapid heartbeat.

Emotional-vegetative: irritability, drowsiness, weakness, anxiety, depression, forgetfulness, inattention, decreased libido.

Group II - medium-term (after 2-3 years)

Urogenital: vaginal dryness, pain during sexual intercourse, itching and burning, urethral syndrome, cystalgia, urinary incontinence.

Skin and its appendages: dryness, brittle nails, wrinkles, hair loss.

Group III - late metabolic disorders (after 5-7 years)

Cardiovascular diseases (CHD, atherosclerosis), postmenopausal osteoporosis or osteopenia.

Individual selection of therapy

Taking into account the above, it seems important to develop an individual “program for restoring and maintaining health” for the long term, taking into account the family and personal risk of the main diseases of aging. Such a program should include regular examination, namely ultrasound, mammography, densitometry and/or determination of biochemical markers of bone remodeling, lipid profile, tumor markers, etc., as well as recommendations for lifestyle changes, such as increasing physical activity, a balanced diet, avoiding Smoking and other bad habits help reduce the risk of cardiovascular diseases and osteoporosis.

In recent years, there has been a constant search and improvement of therapeutic approaches to the rational use of HRT in each specific patient (individualization of therapy). HRT preparations differ from each other only in their progestogen component, since the estrogenic component is represented by 17β-estradiol or estradiol valerate, which correspond in structure to ovarian estradiol. In addition, recently much attention has been paid to the choice of route of drug administration (oral or transdermal).

The type of hormone therapy is also selected taking into account the following factors:

• a woman's desire to have a monthly "menstruation";
• when indicating surgical interventions - indications and scope of the operation and the presence of the uterus;
• the presence of fear of pregnancy, especially with resistant ovaries;
• decreased or absent libido;
• indications of heart attacks in young parents, recurrent miscarriage, liver disease, thrombophlebitis.

The goal of HRT is to pharmacologically replace the hormonal function of the ovaries in women with deficiency of sex hormones, using such minimally optimal doses of hormones that would actually improve the general condition of patients, ensure the prevention of late metabolic disorders and are not accompanied by the side effects of estrogens and progestogens.

Basic principles and indications for prescribing HRT

• The use of only “natural” estrogens and their analogues for HRT is indicated.
• Estrogen doses are low and should be consistent with those in the early proliferation phase of young women.
• The combination of estrogens with progestogens makes it possible to protect the endometrium from hyperplastic processes with an intact uterus.
• Women with a removed uterus are advised to use estrogen monotherapy in intermittent courses or continuously. If the indication for hysterectomy was endometriosis, then a combination of estrogens with progestogens or with androgens, or monotherapy with progestogens or androgens in a continuous mode, is used.

Women need to be provided with appropriate information to enable them to make an informed decision to undergo HRT. All women should be informed:

• about the possible impact of short-term estrogen deficiency, namely the occurrence of early typical symptoms of menopausal syndrome and the consequences of prolonged deficiency of sex hormones: osteoporosis, cardiovascular diseases, genitourinary disorders, etc.;
• about the positive effects of HRT, which can alleviate and eliminate early menopausal symptoms, and also actually serve to prevent osteoporosis and cardiovascular diseases;
• about contraindications and side effects of HRT.

To ensure optimal clinical effect with minimal adverse reactions, it is essential to determine the most appropriate optimal doses, types and routes of administration of hormonal drugs.

There are three main modes of HRT.

1. Estrogen monotherapy. In the absence of a uterus (hysterectomy), estrogen monotherapy is prescribed in intermittent courses or continuously.
2. Combination therapy (estrogens with progestogens) in a cyclic mode.
3. Combination therapy (estrogens with progestogens) in a monophasic continuous mode.

Regimes 2 and 3 are prescribed to women with an intact uterus.

Estrogen monotherapy: intermittent courses (estrofem, progynova, estrimax, divigel, estrogel, climar patch, ovestin) or continuous regimen for 3-4 weeks with weekly breaks.

Combination therapy (estrogens with progestogens) in a cyclic mode:

• two-phase drugs: intermittent cyclic regimen (Divina, Klimen, Klimonorm);
• two-phase drugs: continuous mode (femoston 2/10 or femoston 1/10);
• three-phase drugs in continuous mode (trisequence, triaclim).

With this regimen, a menstrual-like reaction is observed, which is extremely important psychologically for a young woman.

Monophasic combination therapy (estrogens with progestogens) in a continuous mode (cliogest, climodien, pausogest).

With a continuous regimen of hormone therapy, a menstrual-like reaction is excluded.

Livial (tibolone) has continuous estrogenic, progestogenic and weak androgenic activity.

If a hysterectomy is performed for genital endometriosis, preference is given to monophasic combination therapy (Climodien, Cliogest, Pausogest) or Livial in order to exclude stimulation of possible endometriotic heterotopies by estrogen monotherapy.

If the clinical picture is dominated by changes in the cardiovascular system and atherogenic fractions of lipids in the blood, preference should be given to two- or three-phase drugs in which the gestagenic component is represented by progesterone derivatives (Climen, Femoston).

If the clinical picture is dominated by weakness, asthenia, decreased libido, pain in bones and joints, and osteoporosis, then preference should be given to biphasic drugs with a gestagenic component - a derivative of 19-nortestosterone (klimonorm), as well as Divin (MPA with a weak androgenic effect) ( table).

For urogenital disorders in perimenopause, preference is given to local (vaginal) monotherapy with estriol without the addition of progestogens. When urogenital disorders are combined with systemic metabolic disorders (osteoporosis, atherosclerosis), a combination of local and systemic therapy is possible.

Cyclic two- and three-phase HRT, along with improving the general condition, contributes to the regulation of the menstrual “cycle”, as well as the prevention of hyperplastic processes in the endometrium due to the cyclic addition of progestogens. It is extremely important to inform the woman about the following:

• when taking two- or three-phase HRT, a monthly menstrual-like reaction is observed;
• HRT drugs do not have a contraceptive effect.

So, combined two- and three-phase drugs are most suitable for women with premature menopause, as they provide cyclic protection of the endometrium with progestogens, similar to what happens in the normal menstrual cycle.

For severe diseases of the liver, pancreas, migraines, blood pressure more than 170 mm Hg. Art., with a history of thrombophlebitis, parenteral administration of estrogens in the form of a weekly patch (Klimar) or gel (Divigel, Estragel) is indicated. In such cases, with an intact uterus, it is necessary to add progesterone and its analogues (duphaston, utrozhestan).

The following examination is recommended before prescribing HRT:

• gynecological examination with oncocytology;
• Ultrasound of the genital organs;
• mammography;
• according to indications - lipid profile, osteodensitometry.
  Contraindications for prescribing HRT:
• vaginal bleeding of unknown origin;
• acute severe liver disease;
• acute deep vein thrombosis;
• acute thromboembolic disease;
• cancer of the breast, uterus and ovaries (current; if in history, then exceptions are possible);
• endometriosis (estrogens monotherapy is contraindicated);
• congenital diseases associated with lipid metabolism - hypertriglyceridemia, the use of parenteral forms is indicated.

If there are contraindications to HRT, the issue of using alternative therapy is decided: phytoestrogens (climadinon) or homeopathic remedies (climatoplan).

It is appropriate to note that if a woman has a severe reaction to “menopause” and fears of pregnancy, it is quite possible to use low- and micro-dose combined oral contraceptives: Logest, Mercilon, Novinet, Marvelon, Regulon, Yarina - since the number of contraindications increases with age.

Hormone therapy should be continued until the age of natural menopause (50-55 years); in the future, the issue is resolved individually, taking into account the woman’s wishes, her state of health, and reaction to hormonal drugs.

Premature menopause (premature ovarian failure) is a condition characterized by premature shutdown of the ovaries and the development of an estrogen deficiency state. Women with this condition are indicated for hormone replacement therapy to improve their general condition, improve quality of life, and prevent premature aging and diseases of old age.

V. P. Smetnik, Doctor of Medical Sciences, Professor of the Scientific Center of Obstetrics, Gynecology and Perinatology of the Russian Academy of Medical Sciences, Moscow

Composition of biphasic drugs for HRT registered in Russia