Principles of effect of anti-estrogens and antigestagen

Selective modulators of estrogenic receptors (SMER, or English SERM) (And). Estrogenic receptors concern to group of the receptors regulating a transcription. Female sex hormone Oestradiolum is an agonist of these receptors. Substances of this group can work as antagonists though in many tissues behave as agonists. Such behavior is explained by the fact that for accession to an estrogenic receptor the ligand has to accept specific conformstion. The complexes of a ligand and an estrogenic receptor which are bound to certain sites of a genome act as koaktivator or korepressor. The structure of koregulyator in different tissues is various so effects of various drugs of the SMER group of an organospetsifichna. From the medical point of view important that drugs of estrogenic and anti-estrogenic action from this group of drugs differ on specificity.

It makes sense to give the characteristic to this group of drugs and to pay attention to their activity in the period of a postmenopause. Constant reception of Oestradiolum increases risk of development of endometrial cancer. If gestagena are in addition prescribed, then the risk of a disease decreases. More cases of a breast cancer are taped that however can speak intensifying of medical control. Oestradiolum increases risk of a thromboembolism. It facilitates course of a climacterium, weakening inflows of fever and a diaphoresis, and at the long use reduces risk of development of an osteoporosis as loss is interfered by the estrogenzavisimykh of the making bone tissues. However it isn't recommended to apply estrogens to this purpose after all because of an adverse ratio of action and possible risk.

Clomifene — derivative a stilbene — is applied to treatment of sterility at women. Owing to opposing action on estrogenic receptors of a forward share of a pituitary body negative feedback from action of Oestradiolum is broken, and production of Gonadotropinum is enlarged. Body height of the FSG level leads to acceleration of maturing of a follicle. Clomifene is prescribed at a failure of function of a yellow body owing to disturbance of maturing of a follicle, and also at polycystosis of ovaries. Drug is accepted only in certain days of a cycle, it has no constant effect.

Tamoxifen — derivative stilbene — is applied in case of the spreading tumor of a mammary gland for the purpose of blocking of estrogenic incentives to proliferation. Medicine facilitates course of a climax thanks to anti-estrogenic action. Along with it it has agonistichesky effect which shall be considered as risk factor.

Raloksifen apply to prevention of osteoporosis during the post-climacteric period. About benefits and shortcomings of medicine see the table.

Antagonists gestagen receptors. In a week after fertilization the embryo (in the form of blastotsita) takes root into endometrium. The germ produces LG operating similarly and promoting preserving a yellow body, products of progesterone and interferes with emergence of periods. Mifepriston as the antagonist the gestagen receptors interferes with preserving a mucous uterus in early terms of pregnancy, i.e. acts as abortive means. The possibility of its application is widely discussed (in respect of comparison of side effects of medicine and surgical intervention), and also the ethical aspect of its appointment is discussed. In Germany it is withdrawn from sale.

Anti-estrogenic medicines and sport

The other substances capable one way or another to reduce the level of estrogen in blood belong to the third class of anti-estrogenic medicines. Clomifene and its analogs, and also medicines of different pharmacological groups cyclophenyl and proviron belong to them first of all tamoksifen like medicine.

Clomifene in the form of citrate (clomid, klostilbegit, ardomon, gravozan, serofen, serpafar, it is fertile, fertomid, etc.) is close to nonsteroid estrogen to a dietistilbestrol, however, doesn't show estrogenic activity. In chemical structure clomifene is similar to the main representative of anti-estrogenic medicines from class IMRE — tamoxifen and represents 1-[4 (2-dietilaminoetoks) - phenyl] - 1,2-diphenyl - 2-chlorethylene citrate.

Clomifene belongs to anti-estrogenic medicines as specifically contacts estrogen receptors in a hypothalamus and ovaries. In small doses, thanks to the mechanism of negative feedback, clomifene and its analogs strengthen secretion of gonadotrophins (Prolactinum, follikulostimuliruyushchy and lyuteiniziruyushchy hormones) and stimulate an ovulation. In case of small content in an organism of endogenous estrogen clomifene shows moderate estrogenic effect, however, in case of high concentration of own estrogen has anti-estrogenic effect. Reducing content of the circulating estrogen, induces passing strengthening of emission of gonadotrophins; in high doses can break it.

One more distinctive feature of clomifene is that under certain conditions he acts not as a blocker, and as the activator the estrogen receptors. Everything depends on whether joined along with drug, a receptor a certain cofactor. The type of a cofactor, i.e. in one tissues (a hypothalamus, thoracal glands) clomifene is a blocker the estrogen receptor, and in others (bone tissue) — the activator of the same receptors. The last effect of clomifene on an organism is positive as helps to avoid development of an osteoporosis.

Such antiesrogen drugs as clomifene in the corresponding doses are used for stimulation of an ovulation at anovulatory dysfunction of ovaries, sterility, uterine bleedings of a dysfunctional genesis, some forms of an amenorrhea, etc. Thanks to gonadotrophic influence, this drug is used at an androgenic nedstatochnost, an oligospermatism at men and at a delay of sexual and physical development in teenagers.

Release form: tablets on 50 mg. At intake it is well soaked up. It is metabolized in a liver, excreted with bile, is exposed to an enterohepatic recycling. The elimination half-life makes 5 — 7 days.

Administration of drug at women during six cycles even in therapeutic doses (on 50 mg within 5 days) can lead to vision disorders, menorrhagias and a syndrome of hyper stimulation of ovaries (at cancellation); is followed by inflows, a dyscomfort in a stomach and an intestine, nausea, vomiting, a depression, cramps, and also visual disturbances. Besides, clomifene is enough that is expressed in emergence of sleeplessness, headache, giddiness. Contraindications for administration of drug are the expressed dysfunctions of systems of natural detoxicating (a liver, kidneys), uterine bleedings of an obscure etiology, including, in the anamnesis, an oothecoma, a tumor of a pituitary body or a pituitary failure, pregnancy.

Considering that in a hypothalamus genotypically it isn't enough full-fledged man of the receptors having affinity to estrogens, use of clomifene in strength sport is theoretically possible for stimulation of production of Gonadotropinums and intensifying of development of endogenic Testosteron-Depotum. Use of this drug for women, in connection with many-sided influence on a hormonal homeostasis, will lead to reproduction of estrogen and Progesteronum that will extremely negatively affect sportswear of the athlete. Therefore even in bodybuilding clomifene reception by women in therapeutic doses is limited two weeks with the subsequent break of the same duration. You can try Hepatamin.

Cyclophenyl (Fertodur, Neoclym, Rehibin, Sexo-vid) is not anabolic androgenic steroid which isn't registered in Ukraine. Drug is generally used for intensifying of natural development of Testosteron-Depotum at its failure. Popular literature for body builders often incorrectly describes it as nonsteroid drug. Cyclophenyl has the anti-estrogenic properties caused by partial blockade the estrogen receptors and at the same time enlarges own development of Testosteron-Depotum an organism. Cyclophenyl possesses also very poorly expressed estrogenic action.

Some athletes accept cyclophenyl together with steroids to support the low level of estrogen. Result of it, as well as reception of proviron, retardation of processes of a delay of liquid in tissues owing to reception of anabolic steroids and decrease of implications of a gynecomastia is. A musculation of the athlete takes at the same time more resilient form. Cyclophenyl can be acceptable during preparation for competitions. Body builders use it less often as they prefer available Tamoxifenum and proviron.

Cyclophenyl is noneffective at women as it has positive influence only on men's hormonal system. The effect of administration of drug in bodybuilding occurs not earlier than in a week.

Release form: tablets on 100 and 200 mg. At administration of drug in high doses cases of emergence of an acne, augmentation of a libido and feeling of inflows meet. The first two secondary symptoms are especially indicative. After the termination of administration of drug some athletes report about oppressed mood and decrease of physical force. On expression of anabolic effect of other anabolic steroids, widespread in bodybuilding, cyclophenyl in comparison with them is one of the most weak.

Proviron (mesterolon) is androgenic drug for oral administration which is rather slowly metabolized and isn't exposed to aromatization process. Proviron carries anti-estrogenic drugs because it has two-dimensional affinity with receptors of estrogens. It is necessary to notice that there is a drug under the similar name of proviron-depot (Proviron-depot) which is a combination of Testosteroni propionas and Testosteroni oenanthas and has no anti-estrogenic activity.

Release form: tablets on 25 mg. As the main active ingredient is included into structure of a proviron mesterolon, having androgenic and insignificant anabolic activity. Is a synthetic analog of Testosteron-Depotum. In clinical conditions it is applied at men sublingual or inside on 25 mg by 3 — 4 times a day within several months at a failure of function of gonads, disturbance of a potency, the sterility bound to an oligospermatism and a failure of cells of Leydiga and also at aplastic anemia. Course of treatment of 1 — 2 month.

It is contraindicative at a prostate cancer, liver tumors.

Contrary to unjustified judgments which often meet in popular literature for bodybuilders proviron isn't able to prevent aromatization of Aethers of Testosteron-Depotum in estrogens. In a dosage to 250 mg a day administration of drug is practically not followed by emergence of side effects. Advantage of this drug is almost total absence of suppression of activity of Gonadotropinums and process of a spermatogenesis.

The listed above drugs — Clamidum, cyclophenyl and proviron — conditionally belong to the class of blockers of estrogenic receptors; at the same time they don't reduce Oestradiolum level in a blood. Conditionally — as in addition have influence on various parties of a metabolism. Therefore in this chapter they entirely are reasonably carried to the third class of anti-estrogens.

Anti-estrogenic drugs of the third class also include the agonists of rileasing-factors of gonadotrophic hormones (busereline and its analogs) for the first time used in 1982 for an ovarialny supressiya as an ovariectomy alternative at patients with cancer of a mammary gland, and partially a megestrol the acetate having anti-luteinizing, and also anti-estrogenic effect. For secretion inhibition, but not synthesis of Prolactinum, can be used Parlodelum and Dostinex. Their independent use in clinical conditions as anti-estrogens much less effectively, than administration of drugs of class IMRE.

At introduction to an organism rileasing-factors of a natural parentage (from a hypothalamus of sheep, pigs), and recently — mainly their synthetic analogs, cause at first some rising of contents in Testosteron-Depotum blood in men (as defines their use by body builders) and estrogens at women. Subsequently, in 3 weeks of continuous introduction, there is a depression of content of sex hormones, up to their total disappearance, proceeding the entire period of use of drugs. This effect has reversible character: after cancellation of reception of rileasing-factors contents in a blood of Testosteron-Depotum and estrogens is gradually restored.

Under the influence of these anti-estrogenic drugs there is not only a release of Gonadotropinums, but also inhibition of their synthesis and weakening of linkng with androgenic and estrogenic receptors. Rising of contents in bloods of Testosteron-Depotum and linkng with estrogen receptors also defines use of rileasing-factors by body builders.

Anti-estrogenic drugs of this group find the main application at treatment of malignant neoplasms and pretumor diseases: at men of a prostate cancer, at women — a breast cancer and endometrium, and also a uterus fibromyoma on condition of sensitivity of these neoplasms to changes of the hormonal status. To drugs of group of Gonadotropinums-rileasing-factors, more precisely than the subthalamic factors releasing pituitary body hormones analogs of gonadorelin belong. These are agonists of rileasing-factors of luteinizing and follicle-stimulating hormones. All of them are close on structure and are the peptide substances containing 8 — 10 amino-acid remains.

Are issued in various dosage forms — for hypodermic, intramuscular, intranasal introduction. Some drugs are produced in the prolonged form (depot).

Buserelin is a synthetic analog of a gonadotrophin-rileasing-factor. Is issued; type of acetate (C60H86N16O13-C2H402). Competitively contacts receptors of cages of a forward share of a hypophysis and blocks their gonadotropny function, inhibiting L G secretion and FSG that leads to suppression of synthesis of sex hormones in ovaries and seed bubbles.

Release form: 0,3% - ι solution for injections, 0,2% - ι an aerosol, an implant in the form of two dosed cores on 6,6 mg for hypodermic introduction (Hoechst AG, Germany). Apply medicine intranazalno and hypodermically.

Buserelin has a wide range of side effects and can cause the dispeptichesc phenomena, impotence, a ginekomastia, allergic reactions (pour), mental disturbances (unmotivated alarm, sleeplessness, violation of memory and disorder of attention, a depression), dizziness, reactions, dryness of mucous membranes and skin, violation of functions of a liver, leucio-and thrombocytopenia, a hearing disorder. It is contraindicated in case of pregnancy and in the period of a lactation, and also in case of a spinal cord, hypersensitivity, violation of passability of mochetochnik.

Gozerelin (Zoladex "AstraZeneca") is synthetic decapeptide — an analog of a gonadotrophin-rileasing-factor (C59H84N lgOI4). On action it is close to a buserelin. Is issued in the form of special depot medicine — the core (capsule) containing 3,6 or 10,8 mg gozereli-on acetate. About 3,6 mg of a gozere-lin (depot form) once in 28 days are entered hypodermically. Duration of application can constitute up to 6 months.

Side effects: men have a violation of passability of mochetochnik, women have inflows, fluctuations of arterial pressure, violation of a menstrual cycle, allergic reactions and other skin manifestations. It is contraindicated in case of pregnancy and in the period of lactation.

Leyprorelin (lyukrin-depot, prostap) is 6-0-leytsinom-9-(N - ethyl - L - prolinamid) - 10-deglitsinamidy lyuteiniziruyushchy hormone a rileasing-factor (pork). Analog of a gonadotrophin-rileasing-factor. On action it is close to a buserelin. Bioavailability of medicine makes 75 — 98%, time of semi-removal of 3 h.

In case of intramuscular introduction is released from copolymer within 1 month, at the same time during the first 7 days content of sex hormones increases, and by 21 — 28 days decreases and remains at this level in case of the subsequent entering of medicine. Is issued in the form of the lyophilized microspheres in bottles on 3.75 and 7> 5 mg. The course of treatment shan't exceed 6 months.

Side effects: headache, dizziness, sleep disorder, dyspepsia, puffiness of the person and lower extremities, violations of sight and hearing, depression, decrease in a libido. Men, besides, can have a ginekomastia, reduction of testicles, and at women — vaginit, acne, girsutizm, decrease in density of a bone tissue.

Triptorelin is also a synthetic analog of a Gonadotropinum-rileasing-factor which from natural differs in smaller rate of a biotranformation and slower elimination from an organism.

Is issued in the form of an acetate (C64H82N18O13 hs2n402). At intramuscular and hypodermic introduction bioavailability makes respectively about 39 and 69%, time of semi-removal of 7,6 h. Release form: 0,01 and 0,55% - ι solutions for injections in disposable the syringe ampoules, powder for suspension for hypodermic introduction in vials on 0,1 mg, and also in the form of depot on 3,75 mg.

Prescribe " subcutaneously or intramusculary. It is subcutaneously applied at sterility treatment. With success also period at women with positive estrogen - the receptor status is used in pre-at cancer therapy of a mammary gland. Clinical trials showed that this drug has no direct cytotoxic effect on malignant cells.

Side effects at use of a triptorelin are similar to those when using a buserelin.

Medroksiprogesteron (depot pro-belief and pro-belief of production "Upjohn" (Belgium), farlutat, cyclotala, etc.), the representative of gestagen (Progestinums), belongs to the third class of anti-estrogenic drugs. On chemical structure it is close to Progesteronum derivatives, on the main action is Progestinum, however has also anti-estrogenic activity. In this regard it is generally used as antitumoral drug at gormono-sensitive (estrogen-receptor-positive) tumors of a mammary gland and a body of the womb. At a breast cancer correlation between efficiency of a medroksiprogesteron and concentration of receptors of estrogens and Progesteronum in a tumoral tissue is noted. In oncologic clinic it is generally used as drug of additional (palliative) therapy.

On structure it is a steroid, 17-oxy-6os-methyl-pregn-4-en-3,20-diona acetate. Release form: the tablets containing from 5 to 500 mg of active agent; granules from 2 to 1000 mg; 15 and 20% - I am suspension in vials and disposable the syringe tubes; the dosed aerosol. It is applied mainly intramusculary on 0,5 — 1,0 g a week it is long or on 500 mg a day within 28 days; inside and intranazalno in the form of an aerosol (only cyclotala, "Lemery", Mexico).

At use of a medroksiprogesteron of an acetate emergence of nausea and vomiting, edemas, arterial hypertension, tromboembolic episodes (thrombophlebites and thromboembolisms) is possible; abnormal liver functions, body weight augmentation, allergic reactions become perceptible. It is necessary to emphasize that all these reactions are characteristic of anti-estrogenic drugs, irrespective of their belonging to this or that class. With care it is necessary to prescribe at a diabetes mellitus and to persons with gemoreolo-gichesky disturbances (with prevalence of processes of trombogenez).

The similar mediated action on receptors of estrogen has a megestrol in the form of acetate ("Bristol-Myers Squibb", the USA), the synthetic Progestinum suppressing development of pituitary Gonadotropinums and having anti-luteinizing effect. It supressirut a producing androgens adrenals and ovaries, at the same time reducing by 80% also the level of estrogens in a blood. It is applied mainly to treatment of patients with cancer of a mammary gland in post menopause as the second line of a hormonetherapy, endometrial cancer; at an anorexia and cachexia at patients with AIDS.

Release form: tablets on 40 and 160 mg; suspension for intake in vials on 120, 240 and 480 ml with the content of active agent of 40 mg-ml "1. It is applied mainly in a daily dose of 160 mg (40 mg 4 times a day); at cachexia at patients with AIDS the daily dose can be doubled and more — to 800 mg.

It is necessary to notice that megestrol is one of the earliest drugs for which antiaromatasia action was shown. However in connection with chemical structure (Progestinums of steroid character), we consider proved to carry them to this, but not to the second class ("Aromatase blockers") of anti-estrogenic substances.

Very conditionally to anti-estrogen to ny drugs dopaminergetik Bromocriptinum (Parlodelum, "Sandoz", Switzerland) and caboreldine (Dostineks, "Upjohn", the USA), the secretions of Prolactinum Used mainly for suppression can be carried. Are prescribed in clinical conditions at a galactorrhea, benign tumors of mammary glands, acromegalia, a parkinsonism. Reception of these drugs often is followed by nausea, vomiting, a headache, giddiness, a sleepiness, and also emergence of a peripheric vasospasm. Kabergolin, besides, can provoke hypotensive reactions, an anorexia, a diarrhea, sleeplessness, edemas, emergence of inflows, feeling of a congestion of a nose.

Bromocriptinum is issued in tablets and capsules on 2.5 mg, cabergolin in tablets on 500 mkg.

And, at last, in connection with ability to block specific receptors of cells of gonads (gonads), including estrogen receptors, to anti-estrogenic substances it is partially possible to carry the chorionic gonalotropin person (CGP) rendering as well luteinizing action (synonyms: gonafor, gonakor, Pregnylum, profaz, Antelobinum, etc.). In clinical practice it is applied at men and women; for stimulation of activity of gonads in case of dysfunction of a hypothalamus and a pituitary body.

Drug is produced in the form of the lyophilized powder in vials and ampoules (on 500 — 5000 mg) complete with a dissolvent for injections. When using HGCh allergic reactions, a hypertrophy of testicles are possible: at a drug over dosage hyper stimulation of ovaries. Prolonged use of drug in connection with possible formation of antibodies and suppression of gonadotrophic activity of a pituitary body isn't recommended.

HGCh can be used by some athletes for suppression of activity of receptors of estrogen therefore it treats drugs from the List of the forbidden substances and methods (for men).

Thus, it is possible to draw the following conclusions. First, medicinal preparations, various on structure and the main mechanism of action, belong to anti-estrogenic drugs. Most of them is used in medical practice for treatment of malignant neoplasms, so far as concerns salvage or extension of life of the patient or, to a lesser extent, for correction of the hormonal status in case of serious functional violations. Secondly, use of anti-estrogenic substances of any class has a wide range enough serious by-effects of different degree of expression. Some of them can demand further surgical intervention (gynecomastia), and others directly threaten the athlete's life in connection with development of cardiovascular pathology or thromboembolism of a pulmonary artery. It is unlikely theoretical "advantage" of reception such enough toxiferous drugs is comparable to risk from their unreasonable use. Therefore it is necessary to represent accurately what can lead use of these drugs, especially at excess of the recommended therapeutic dose to. High toxicity of drugs with an anti-estrogenic orientation also served one of the reasons of their including in the List of the forbidden substances and methods. In case of emergency of reception of anti-estrogenic drugs in connection with treatment of various diseases at which they pathogenetically are reasonably applied strict control from the sports doctor and the expert of the corresponding profile is necessary for safety and conservation of health and the athlete's life.