Hormonic antagonists and modulators (class s 4)

Substances with anti-estrogenic activity quite often use in professional sport for the purpose of braking of transformation of testosterone to female sex hormones (estrogen), and also for increase in muscle bulk.

Very often use of anti-estrogen is combined with reception of anabolic steroids. It is caused by metabolism of endogenous and exogenous anabolic steroid hormones in an organism. Emergence in an organism owing to receipt from the outside of exogenous steroids and (or) accumulation because of the reduced functional ability of a liver of excessively high concentration of endogenous anabolic steroid hormones, first of all, of testosterone, leads to the fact that excess of testosterone doesn't manage to be metabolized completely when passing a physiological way. In this case a part of anabolic steroid hormones passes through a roundabout way of metabolism — aromatization at which testosterone turns into estrogen by means of aromatasia enzyme. For braking of transformation of testosterone which strengthens synthesis of proteins and promotes thereby a hypertrophy of skeletal muscles, and also for decrease in contents in an organism of estrogen and shortenings of duration of their action unfair athletes in a pursuit of result can use substances with anti-estrogenic activity.

Classification

Anti-estrogens depending on mechanisms of the influence can be sectioned into three classes:

• selective (selective) modulators of receptors of estrogen (Tamoxifenum, Clomifene, Toremifen) - are used after a course
• aromatasis inhibitors (Anastrozol, Letrozole) - are applied on a course
• other anti-estrogenic substances.

There is also other classification of anti-estrogenic drugs (Baum, 2001). According to it, they can be divided also into three main classes:

• selective modifiers of estrogenic receptors (SERM);
• "pure" or steroid anti-estrogens;
• actually aromatase inhibitors: nonsteroid — aminoglutethimide derivatives (glutetimid, rogletimid) and derivatives of imidazole or triazole (letrozole, anastrozol); steroid — formestan, ekzemestan.

From our point of view, such classification doesn't consider reversibility and irreversibility of effect of drugs on estrogenic receptors and insufficiently fully considers generation of drugs and the mechanism of their action on receptors irrespective of steroid or nonsteroid structure of medicine. Therefore further the description of classes and groups of anti-estrogenic substances will be based on the first classification which in literature is widespread much more widely and much more proved. You can also like Hepatamin.

All representatives of classes of anti-estrogenic substances are forbidden (The list of the forbidden substances and methods, 2008). Reception of these drugs is followed by a series of the expressed side effects, development of numerous pathological states and can even lead to a lethal outcome.

The selective (selective) modulators of receptors of estrogen

The main representatives of the selective (selective) modulators of receptors of ekstrogen — IMRE, or SERM (English Selective Estrogen-Receptor Modulators) — are tamoxifen (synonyms — tamifren, nolvadeKs, nolvadeks-forte, Beale, inta, yenocsifen, tsemid, valodeks, cyto-zonium seu zitazonium), raloksifen (Evista®, "Eli Lilly", Great Britain), toremifen (Fareston®, "Orion Pharma", Finland), and also later, tamoxifen analogs which so far are a little researched (idoxifen, keoxifen, droloxifen). All called medicines of class IMRE are nonsteroid substances on the structure. To. to steroid representatives of class IMRE the fulvestrant belongs (fazlodeks).

Tamoxifen

The first anti-estrogen from representatives of class IMRE, tamoxifen, was synthesized by Soiye's group in 1971, and its active use as blocker of receptors of estrogen began. In the last decade the high-selective "net" steroid blocker estrogen receptors a fulvestrant who passes the III stage of clinical testing now is created.

The medicine of class IMRE which is the most often used in pharmacology is tamoxifen, competitive inhibitor peripheral the estrogen receptors. Now the point of view, witnessing that tamoxifen doesn't possess estrogen like action, is confuted as it is proved that in a certain measure medicine shows also estrogenic activity — the ratio of its agonistic and antagonistic activity constitutes 45/55.

Tamoxifen is derivative a trifeniletilena; chemical structure 1-[p-(2-dimetilamino) - etoks] - phenyl-trance-1,2-di-phenyl-1-butene, in the form of citrate. Release form: tablets on 10, 20, and 40 mg. Tamoxifen is well acquired in a stomach; the first peak of its concentration in plasma of blood is registered in 1 — 6 h after introduction, and the second — later 24 — 44 h. Medicine in blood long enough — as much as possible to 170 h circulates.

Removal of tamoxifen has long and two-phase character. The initial stage of semi-removal of medicine constitutes 24 — 53 h, and final, depending on a dose, from 3 to 18 days. Removal of medicine happens generally through a GIT, and with a stake and bile about 85 — 90% of metabolizirovanny medicine are allocated; its insignificant part is removed from an organism by kidneys.

Tamoxifen is emitted from an organism almost only in the form of metabolites. The main products of biotransformation are provided glyukuronidy and other conjugates, and also uncertain polar metabolites. Primary stage of biotransformation of medicine is the hydroxylation of an aromatic ring with education monohydroxyderivative. In an experiment this intermediate product was more active anti-estrogen, than tamoxifen. Perhaps, in clinical conditions this product of metabolization of tamoxifen promotes manifestation of anti-estrogenic action.

In more detail the pharmacokinetics and biotransformation of products of medicines of tamoksifenovy row were studied at women. After acceptance of the tableted medicine in a medical dose of 0,3 mg-kg "1 body weights its maximum content in blood is observed in an interval between 4 — 7 h. Elimination half-life when using in such dose constitutes 11 h; in 2 weeks content of tamoxifen in serum of blood corresponds to 0,013 mkg.

The initial dose of tamoxifen for medical practice constitutes 20 mg (on one tablet of 10 mg 2 times a day), then the dose is raised to 30 mg, and in 7 — 10 days brought to 40 mg a day. Long-term treatment — 2,5 — 3 months, and sometimes and more — up to 5 years. For many years treatment by tamoxifen was the gold standard of therapy at women in post menopause, patients with cancer of a mammary gland, with the estrogen-receptor-positive status. In recent years tamoxifen became wider to apply in treatment of women of childbearing age though by some authors justification of such appointment it is quite proved it is challenged (Endocrine..., 2002; Mammary gland..., 2006).

Side effects of Tamoxifenum

This the most widely known among representatives of class IMRE drug possesses also the widest range of by-effects. Though, it is necessary to notice that negative implications of this or that expression are observed after reception of one and all drugs of this class. The main biological effects of Tamoxifenum are taped in endocrine organs. Drug doesn't show neither androgenic, nor anti-androgenic, nor gestagen effect. At men at reception in high doses can reduce the mass of testicles, seed blisters and a prostate that results further in sterility and an impotency. After multiple dose of Tamoxifen the abnormal liver function is observed. At the same time the body weight gain finally lags behind that at the athletes who aren't accepting drugs of this sort. Tamoxifen can cause depression of level of a glucose and leucocytes in a blood, mainly at the expense of cells of a lymphocytic series, insignificant, but often dose decrease of activity of an alkaline phosphatase. Drug oppresses antitoxic function of a liver. When using high doses causes stagnation of bile (cholestasia) and formation of gallstones. Its multiple dose also leads to a hyperplasia of an adenoid tissue of a lien and lymphonoduses, perverting natural reaction of immune system of an organism. Negatively Tamoxifen influences and on osteal system, significantly enlarging risk of development of an osteoporosis and fractures.

Though Tamoxifen promotes decrease of content of cholesterol in a blood, its positive effect on the frequency of depression of cardiologic pathology isn't shown. On the contrary, are available! the observations testifying to augmentation of frequency of development of coronary heart disease, a myocardial infarction and thromboembolisms of a pulmonary artery. At female sportswomen reception of Tamoxifen in high doses can interfere with implantation of an ootid in a uterus wall. Use of this anti-estrogen on early durations of gestation often leads to its discontinuing by the termination of the body height of a uterus caused by Oestradiol and to emergence of teratisms in a fetus (teratogen effect). At prolonged use of Tamoxifen intensive body height of tumor cells is observed. At the same time is 4 (!) times more often than at the persons which weren't accepting this drug development of cancer of liver and endometrium is registered that is caused by significant and long increase in level of steroid hormones.

The medical effect of Tamoxifen and the synthesized late drug of the second generation of selective modulators the estrogenovykh of receptors — a raloksifen — is taped in the conditions of the raised Oestradiolum level against the background of suppression of secretion of Prolactinum. The main effect of these drugs is referred immediately on a tumoral cell target in which anti-estrogens block binding of estrogens on their specific receptors. Along with direct action on tumor cells, anti-estrogens of class IMRE lead to inhibition of tumoral body height by means of other mechanisms, affecting gipotalamo-pituitary system and ovaries.

Raloksifen

Raloksifen, as well as Tamoxifen, is usually applied to treatment of the extended and progressing breast cancer, and also the prevention of an innidiation. It is less often used at chemotherapy of a hysterocarcinoma and a mammary gland at men.

In comparison with Tamoxifen ðàëîêñèôåí exerts less expressed impact on a demineralization of bones, to a lesser extent influences change of thickness of endometrium. Raloksifen is issued in the form of tablets, the coated, containing 60 mg of active agent; it it is recommended to apply in a dose 60 mg-days "1 to or during meal. As the agonist influences not genesial tissues and as the antagonist — on genesial. Enlarges concentration of the globulins binding hormones (including sexual, and also a thyroxine, corticosteroids), with simultaneous rising of their cooperative contents in a blood without augmentation of level of free fraction. About 60% of drug are quickly soaked up after intake. Before entering in a systemic blood stream ðàëîêñèôåí it is intensively metabolized with formation of glucuronides. Absolute bioavailability makes only 2%. Time before achievement of average maximum concentration in a blood plasma and biological availability depend on interconversions of a raloksifen in a systemic blood flow and transformations of drug and its glyukuronidnykh of metabolites in an intestine and a liver. Metabolization occurs generally in a liver therefore disturbance of its function is direct contraindication for drug use. Raloksifen is widely distributed in body tissues, and the volume of its distribution doesn't depend on a dose. The elimination half-life makes 27,7 h. The most part of drug and its metabolites is excreted within 5 days and it is found mainly in excrements, and also in urine (6%).

Side effects of raloksifen

Also as well as Tamoxifen raloksifen promotes depression of level of the general cholesterol and LPNP cholesterol, without influencing the content of cholesterol in LPVP. However by results of large-scale placebo - the controlled research RUTH of the EI Lilly company, it doesn't reduce risk of development of coronary heart disease and an acute coronary syndrome. Prolonged use of drug increases risk of emergence of tromboembolic episodes, especially within the first 4 months. Reception of a raloksifen can be followed by inflows, cramps of the lower extremities, and also emergence of peripheric edemas. Considering the above, and also that fact that drug is present at the List of the forbidden substances and methods (2008), its use in practice of sports preparation is hazardous to health of the athlete and will naturally lead to his disqualification.

Unfortunately, in sport, in particular bodybuilding, these anti-estrogens can be applied by athletes at the beginning phenomena of a feminization and to its prophylaxis. In a combination with proviron (not flavored androgen mesterolon) are used for giving to muscles of rigidity and relief at a stage of precompetitive preparation, and also for decrease of the activity the estrogen receptors at the end of a steroid cycle.

Toremifen

For the purpose of decrease of side effects of Tamoxifen and raloksifen in Finland new drug òîðåìèôåí (Fareston®, "Orion Pharma"), having, according to experimental and clinical data, a series of advantages was developed. First, as a result of stabilization of a structural formula of Tamoxifen due to accession of a chlorine atom larger fastness of molecular structure of drug to metabolic changes, including giperoksidation, in an organism is reached. Secondly, oncogenous and hepatotoxic effects of a toremifen become perceptible much less often. At the same time at prolonged use of toremifen cases of development of malignant tumors and their fast advance are recorded. The number of persons, accepting drug, has a loss of certain types of sensitivity.

On chemical structure toremifen represents nonsteroid derivative a trifeniletilen — (Z) - a 4-chlorine-1,2-diphenyl-1 - [4-[2 (di-metilamino) of an etoksa] - phenyl) - 1 butene, is issued in the form of citrate. As well as tamoxifen, toremifen contacts receptors of estrogen and renders anti-estrogenic (or estrogen like) effect depending on duration of treatment, nosological form, a sex of the patient, a target organ and other features. Toremifen competitively contacts receptors to estrogen and brakes estrogen - the mediated stimulation of synthesis of DNA and replication of cages. On experimental models it is shown that the effect of use of medicine in high doses is mediated mainly by anti-estrogenic action. However it is impossible to exclude, as other mechanisms (changes of an expression of genes, secretion of factors of induction of apoptosis, influence on kinetics of a cellular cycle) can also play a part in medical effects of medicine. Under the influence of a toremifen moderately expressed decrease in level of general cholesterol and LPNP cholesterol in blood serum is noted though this fact doesn't influence the frequency of development of complications from cardiovascular system.

Release form: tablets on 20 and 60 mg. Toremifen is quickly absorbed after intake. The maximum concentration in plasma of blood is on average reached in 3 h (from 2 to 5 h). Dynamics of concentration in plasma of blood is described by a curve. Elimination half-life in the first phase (distribution) constitutes 4 h (from 2 to 12) h. In the second phase (elimination) which duration on average equals 5 days (from 2 to 10 days) 99,5% of a toremifen contact proteins of plasma of blood, mainly albumine. The medicine pharmacokinetics in case of intake in doses of 11 — 680 mg-days "1 has linear nature. Equilibrium concentration of a toremifen in case of acceptance in a recommended dose (60 mg-days-1) averages 0,9 (0,6 — 1,3) mkg-days" 1.

Toremifen is actively metabolized in an organism. Its main metabolite is dimetiltromephene with average elimination half-life of 11 days (4 — 20) ñóã. More than 99,9% of a metabolite contact proteins of plasma of blood in which three more less significant metabolites, prevailing from which are determined. Medicine is removed from an organism generally in the form of metabolites through a GIT, and 10% — with urine. Metabolism of a toremifen is performed with participation cytochrome of a R-450-zavisimogo fermental complex by N - demethylations.

Side effects of toremifen

Side effects from reception of toremifen in comparison with Tamoxifenum are less expressed and long and mediated mainly by the hormonal mechanism of effect of drug. In clinical trials the most frequent collateral effects are inflows (more than 20%), a sweating (14), nausea (8), go-a lovokruzheniye (4), peripheric edemas (3%), and also vomiting. Occasionally there can be an increased fatigue, headaches and dorsodynias, body weight augmentation, sleeplessness. Emergence of the specified symptoms, and also emergence of a paresis, a tremor in extremities, an anorexia, an asthenia is important for sports pharmacology.

At clinical use of toremifen in an oncology, and also at sportswomen the orientation of shifts of content of hormones similar to action of Tamoxifen in blood serum becomes perceptible, but their fluctuations are expressed to a lesser extent, except essential (by 4 times) depressions of level of follicle-stimulating hormone (FSG). At reception of toremifen Oestradiol level also increases, but it approximately at 70% of the sportswomen accepting drug is followed by simultaneous rising of maintenance of progesterone.

It is necessary to notice that lack of reliable changes of content of the studied hormones is explained by larger individual fluctuations though quite expressive dynamics concerning Prolactinum, Progesteron and FSG is distinctly traced (tab. 3.8).

As well as other drugs of class IMRE, toremifen causes abnormal liver functions what rising of activity of hepatic transaminases in blood serum testifies to. At the beginning of reception of toremifen development of hypercalcemia with disturbance in the subsequent density of a bone tissue and emergence of an osteoporosis is possible though these negative implications are observed less than at reception of Tamoxifenum. The osteoporosis caused by use of inhibitors of an aromatasia is possible to prevent and treat by peroral and intravenous use of bifosfonat (klodronat sodium, ksidifon, pleostat, bonefos, arediya, fosamaks, bondronat, rizedronatò) which prevent depression of density of a bone against the background of reception of selective blockers the estrogen receptors.

For assessment of mechanisms of action and efficiency of use of drugs of class IMRE it is necessary to consider not only their ability to be bound to receptors, but also significant effect on a hormonal homeostasis of the athlete that is very often ignored in nogone behind result. It is important that these drugs in clinical conditions are used mainly at women in the period of post menopause, and also at patients with cancer of a male mammary gland with obviously changed hormonal background. Therefore reception of anti-estrogenic drugs of class IMRE by female sportswomen of childbearing age, and also men, can do irreparable harm to organism.

Fulvestrant

The new antagonist of estrogens the fulvestrant (fazlodeks) who recently appeared in the pharmaceutical market and still finally not studied in clinical conditions, has steroid structure. Unlike Tamoxifen completely blocks trophic action of Oestradiol and has no estrogenic activity (therefore is called "pure" anti-estrogen). The first "pure" anti-estrogen was synthesized in 1987. Subsequently the fulvestrant ("AstraZeneca", Great Britain) who was introduced in clinical practice in June, 2002 was its most active derivative.

On a structure the fulvestrant is very close to ethenyloestradiolum is trietilen ((((((((((((((((ICI 182.780), eterizovan in positions of a 7-or 11 - and Oestradiolum.

The Fulvestrant is new type of antagonists the estrogen receptors. Being bound to receptors, it blocks them, causes degradation and the progesteron receptors reduces an expression. Its affinity to receptors of estrogens is 100 times higher, than at Tamoxifen. Indications to use of fulvestrant is the estrogen-receptor-positive breast cancer at women in a menopause progressing after anti-estrogenic therapy by Tamoxifen.

On pharmacological action the fulvestrant considerably differs from Tamoxifenum in lack of properties of an agonist and on expression of blocking the estrogen receptors. At the expense of steroid structure a fulvestrant with much bigger affinity, than Tamoxifenum, is competitively bound to estrogen receptors.

Results of the researches conducted by M. Berhens and employees in 2006 showed that action of this steroid representative of class IRME is based on a deionization of receptors that interferes them with a sgerichesky regulation. In the researches in vitro and in vivo it is established that the fulvestrant reversibly enlarges the number of transformations of genetic nuclear material with parallel depression of number of defective molecules estrogen receptors in cells targets. It also multilaterally influences alarm ways of these receptors, blocking a dimerization, nuclear localization of an estrogen receptor and a receptor - a dependent transcription, and also reducing the number of a receptor in a cell.

According to immune histochemical researches, one intramuscular injection of drug renders dozozavisimy depression of quantity the estrogen and the progesteron receptors and Ki-67 gene receptor expression. So, in a dose of 250 mg the fulvestrant reduces the number of active receptors more than Tamoxifen.

During the III phase of clinical trials existence of positive properties of a fulvestrant in endocrine therapy of a breast cancer was shown. At patients against the background of adyyuvantny (postoperative) therapy or the first line of endocrine therapy efficiency of a fulvestrant along with good tolerance was comparable with that of anastrozol (see the second class of anti-estrogenic drugs).

Fulvestrant, "pure" anti-estrogen, passes the last phase of clinical tests as a blocker the estrogen receptors now. Due to the insufficient number of researches the fulvestrant isn't registered as "pure" anti-estrogen yet and described as the drug reducing activity the estrogen receptors.

Fulvestrant by short courses inside in a dose from 6 to 18 mg daily or in the form of intramuscular injections once a week in a dose from 50 to 250 mg is applied; on other sources — once a month at patients with cancer of a mammary gland in a post menopause. Release form: tablets on 6 mg; Solutio oleosa in vials on 250 mg / 5 ml.

Use of drug before operation the estrogen and progesteron receptors reduces a proliferation and (or) a reduction and disappearance of an expression. It reduces estrogenic activity in the majority of nonresectable cases of a breast cancer and is in this regard twice more active, than a megestrol an acetate — one of synthetic Progestinums which is also possessing anti-estrogenic action, generally due to depression of synthesis of estrogens (see the third class of anti-estrogenic drugs). The activity depression the estrogen receptors under the influence of a fulvestrant has dose character. The effect of influence on a pituitary and subthalamic arch at drug is absent. Thus, the fulvestrant as drug can be used in the second line of anti-estrogenic therapy of a breast cancer.

Side effects of fulvestrant

The side effects arising after reception of fulvestrant are same for all representatives of class IMRE. Rather often there are nausea, sometimes vomiting, a constipation, a diarrhea, dermal rashes, the increased sweating, headache, abdominal cavity. Occasionally there are a grippopodobny syndrome, sleeplessness, a depression, paresthesias, pharyngitis, dispnoe, tussis. At reception of low doses of drug side effects, such as a nagrubaniye of mammary glands or arise less than at reception in standard dosages. Against the background of low-dose therapy by a fulvestrant inflows of fever should be stopped in 60 — 70%, and against the background of standard dosages — already in 80 — 90% of cases. The same treats also conservation of density of a bone tissue. Process of its depression: the quantity of cases of an osteoporosis are higher at reception of high doses of drug, than at use of standard doses. Therefore use of a densitometry and definition of biochemical markers of a destruction of a bone tissue is recommended to the patients accepting a fulvestrant even in low doses without the corresponding therapy of maintenance. Frequency of emergence of this side effect can be reduced by use of adequate doses of drugs of a calcium and vitamin D.

The Fulvestrant in comparison with Tamoxifen and a megestrol an acetate influences changes of a lipide profile more favorably. At reception of standard doses of drug the maintenance of LPNP and LPONP respectively decreases by 12,3 and 14,2%, and the LPVP level, on the contrary, increases. At the same time the content of the general cholesterol and triatsilglitserol practically doesn't change.

For the unclear reasons, in the section S4 of the List of the forbidden substances and methods (2006) this; drug is carried to the third class of "other anti-estrogenic substances". However according to the action mechanism the fulvestrant as the steroid representative of IMRE has to be with good reason carried not to the third, and to the first class "substances with anti-estrogenic activity.

However in connection with incompleteness of the III phase of clinical tests and rather scrappy data on its pharmacodynamics and a pharmakokinetics, as a selective blocker the estrogen receptors, despite his expressed physiological activity wasn't widely adopted drug yet.

Therefore, according to the List of the forbidden substances and methods (2008), all medicines of an antiestrogen orientation (irrespective of a class) belong to banned drugs even if individually they aren't registered in the list of those yet. In clinical conditions it is accepted to transfer if necessary after administration of drugs of class IMRE patients to therapy by means of use of blockers of an aromatasia in recent years.