The modern stage of development of therapy with androgens began with the development in the 1930s in the Netherlands and Germany by divisions of the company Organon of the technology of industrial synthesis of testosterone. In the work “On the male hormone, in crystalline form, obtained from the testicles,” a professor of pharmacology Еrnst Laqueuer for the first time assigned the name “testosterone” to the hormone. At the same time, Professor Adolf Butenandt: 15 mg of crystals were obtained regarding the inactive product of the breakdown of testosterone, which he called androsterone. Later, he developed the structure of testosterone and its production from cholesterol, and the Yugoslav chemist Leopold Ruzi received a patent for a method for producing testosterone from cholesterol, for that they won the Nobel Prize in 1939. Within 2 years since the discovery of testosterone in clinical practice, several modifications have been received. These discoveries served as the basis for conducting large-scale experimental and clinical studies on the use of drugs of this hormone for the treatment of various androgen-deficient states.
Initial attempts to administer crystalline testosterone orally did not lead to the desired clinical effects, which was associated with its low bioavailability due to inactivation by microsomal enzymes during the initial passage through the liver. The first to find clinical use of testosterone drugs were its fatty esters, dissolved in oil and administered intramuscularly (testosterone propionate, etc.). It was found that daily injections of testosterone oil solutions were accompanied by frequent development of local complications. This circumstance entailed the development of prolonged drugs that included balanced combinations of testosterone esters with a short, medium and long half-life.
For use in medical practice currently used various derivatives of testosterone, obtained by synthetic means. Testosterone preparations differ in their chemical structure, methods of administration, and duration of action.
Among the chemically modified testosterone analogues, several groups of drugs are distinguished: – 17-hydroxylated and 17-alkylated testosterone derivatives (methyltestosterone);
drugs with a structural change of the steroid ring (Proviron);
Testosterone esters (Sustanon-250, Andriol, Nebido).
For some time, oral androgenic drugs such as fluoxymesterolone and methyltestosterone have been widely used. However, these drugs are 17-a-alkylated compounds with serious side effects – toxic and carcinogenic effects on the liver, as well as a negative effect on the blood lipid spectrum (a sharp increase in atherogenic levels and a decrease in the level of anti-atherogenic lipoproteins). In this regard, the use of 17-a-alkylated derivatives of testosterone in clinical practice has been discontinued. However, in some countries, including Russia, these preparations are still manufactured and used.
Testosterone preparations currently available in clinical practice differ in the following indicators:
duration of action (short-range, prolonged);
methods of administration;
Intramuscular injections of testosterone esters are classic, the most widely
applied method of substitution therapy in men with hypogonadism. The two most famous in the past testosterone ester – testosterone cypionate and testosterone enanthate – have similar pharmacokinetics. With the intramuscular administration of these drugs, a depot is created, from which the drug is released into the bloodstream. During the first 2-3 days after administration, testosterone levels rise to supraphysiological figures, and then slowly decrease over the next 2 weeks, dropping below normal values. In this regard, the determination of peak and minimum testosterone levels is of great importance. This is especially true for men over the age of 65, because the metabolic clearance of testosterone decreases with age, which must be considered when selecting the appropriate dose. Peak concentration should be measured 1-3 days after the injection of the drug; the minimum concentration level should be taken immediately before each subsequent injection.
The same effect is observed with the introduction of the most popular now drugs containing a mixture of esters of different durations of action (Sustanon, Omnadren). This causes patients a very unpleasant feeling, called the “rollercoaster effect” – the dependence of mood and well-being on sudden changes in testosterone levels. The positive side of these drugs at the time of their appearance was the duration of the therapeutic action. However, drastic changes in testosterone levels, often felt by the patient himself in the form of rises and decrease in libido, general well-being, emotional status, are undesirable negative qualities of these drugs. It should be added that, despite the fact that some patients can make injections on their own, most people need to visit their doctor every 2-3 weeks.
In this regard, great hopes are placed on the new drug Nebido of Schering, whose pharmacokinetics is significantly different from other testosterone esters.
Nebido is a testosterone undecanoate in the injection of prolonged action, which is used only 4 times a year and at the same time maintains the concentration of blood testosterone in the physiological limits throughout the period between injections without pathological rises and decreases. Such a long-term therapeutic effect is due to the unique combination of the molecular structure of the active ingredient, the oil base and the intramuscular administration of the drug, which together made it possible to achieve a half-life of about 90 days. After the hydrolysis of testosterone undecanoate, testosterone enters the systemic circulation, which has a therapeutic effect both by itself and through its main metabolites, 5-alpha-di-hydrotestosterone and estradiol, which determine the full range of androgenic activity. However, testosterone undecanoate does not have hepatotoxic and hepatogenic effects.
When applying Nebido it is recommended to use the following scheme. After the first injection of Nebido, the second injection is recommended for most patients after 6 weeks. to create the necessary “basic” level of testosterone. In the future, for stable maintenance of the normal concentration of testosterone, it is enough to make injections with an interval of 12 weeks.
An increase in testosterone concentration compared to baseline is observed the next day after the 1st injection. The physiological level is reached on the 3rd day. Monitoring the concentration of testosterone in the blood is recommended before the 4th injection. Testosterone levels should be in the lower third of the norm. In the future, the level of blood testosterone is enough to control once a year, slightly increasing or decreasing the intervals between injections, depending on the result.
In the world, the drug has been used since 2004, in Russia – since the beginning of 2006.
Intramuscular injections of prolonged testosterone esters have other positive points.
In a recent study, positive effect of substitution androgen therapy with intramuscular injectable testosterone enanthate preparations on hematopoiesis was established, which is a very important clinical observation relevant for older men. In this study, in 25% (8/32) of patients who received injectable androgens at 2 week intervals, the hematocrit was> 52% after 24 weeks. treatment compared with 8% (2/26) of patients treated with transdermal preparations. Supraphysiological level of testosterone, achieved by the use of injectable forms of testosterone enanthate, may be of value when it involves in the process of stimulating the production of either erythropoietin or directly erythrocyte progenitor cells.
Andriol (testosterone undecanoate) is more commonly used from oral medications. Andriol has been used in the world since 1975, but in our country it still remains relatively new drug. Oral administration of testosterone undecanoate due to its high lipid solubility, as well as the presence of a special solvent, oleic acid, is absorbed with chylomicrons through the lymphatic system of the small intestine, from which it enters the thoracic lymphatic duct and then through the system of the superior vena cava enters the systemic circulation. Thus, a sufficient amount of testosterone is not exposed to the primary hepatic metabolism, and therefore, inactivation in the liver, due to which therapeutic concentrations of testosterone are quickly achieved in the systemic circulation.
Oral administration of testosterone undecanoate, although less effective than intramuscular administration, is still able to maintain a full range of androgenic activity. The half-life of the drug from the plasma is 3-4 hours, and therefore even with 3-fold use during the day, testosterone levels can fall below physiological values, which can cause discomfort in patients. However, Andriol remains the drug of choice for replacement therapy for age-related androgen deficiency.
In some countries, mainly in Australia and England, the use of subcutaneous crystalline implants of testosterone, which provide a uniform release of the hormone for 6 months, has become widespread. The disadvantage in this case is the need for a small surgical intervention with the introduction of the drug – requires an incision of the skin with trocar to implant the drug. And although the effect of these drugs lasts up to 6 months, from time to time spontaneous extrusion of impurities may occur.
infection, as well as an infection at the site of invasive intervention.
Over the past 2 decades, much attention has been paid to the study of the advantages of transdermal application of testosterone preparations. Transdermal testosterone therapy involves the reflection of variations in testosterone levels that occur in normal men within the 24-hour circadian cycle. In European countries, patches (films) containing crystalline testosterone in the amount of 10 or 15 mg have recently found widespread use. Plasters are of two types – scrotal, used on the scrotum, and necrotal, used on other skin areas. The patch is secured by the patient on the skin of the back, thigh, or scrotum. The transdermal route of testosterone administration avoids its primary metabolism in the liver and inactivation, as is the case with oral androgenic drugs, and does not cause an increase in testosterone concentration above the supraphysiological level, as is the case with intramuscular administration of a mixture of testosterone esters (Sustanon, Omnadren) . In addition, therapy with the use of patches, if necessary, can be easily interrupted.
However, the use of scrotal patches has lost its attractiveness due to such inconveniences as the inability of the patch to firmly fix in one place and the need for frequent shaving of the skin of the scrotum. In addition, due to the high concentration of 5-alpha reductase in the skin of the scrotum, abnormally high levels of dihydrotestosterone are produced. Percutaneous non-wound patches provide a normal level of estradiol and, unlike
stemmed, provide normal levels of dihydrotestosterone. In addition to increasing the corresponding physiological level of testosterone, they reduce the level of GSPS, promote virilization and increase mineral bone density. Also patches with testosterone compared with injectable forms, minimize excess erythropoiesis and suppression of gonadotropins. The most common undesirable effects of skin patches are related to the need to use agents that enhance absorption; This often leads to the development of varying degrees of skin reactions, and sometimes significant chemical burns. The amount of these side effects can be reduced using triamcinolone.
In our country, patches are not registered.
Gel testosterone preparations (Androgel, Solvau Pharma) have all the advantages of patches, however, they are capable, although less often, of causing allergic reactions on the skin.
For more than 10 years, 5-alpha-dihydrotestosterone (ONT) -gel (andractim) has been used in France and Belgium. And although ONT is recognized as effective, it is not known whether the isolated use of an unscented androgen, like dihydrotestosterone, creates the same effect as testosterone, due to the fact that testosterone metabolites also include estradiol. According to many authors, the use of the drug for age androgen deficiency is not recommended, because dihydrotestosterone due to the impossibility of turning into estradiol does not have the full range of therapeutic properties of testosterone (for example, a positive effect on bone tissue and the cardiovascular system).
The pharmaceutical industry and the sublingual route of the introduction of androgens also did not pass by. A form of testosterone with cyclodextrin has been created, allowing it to be used under the tongue.
Not so long ago, data appeared on the creation of a trans-buccal form of testosterone (striant, Columbia Laboratories). The drug is recommended to be applied to a specific place on the gum 2 times a day. The buccal form of the testosterone drug has both advantages (does not pass the hepatic metabolism stage, does not require dose titration, and does not lead to an increase in dihydrotestosterone levels) and some undesirable effects, the most frequent of which are irritation of the mucous membrane of the gums, bitter taste in the mouth, headache and a change in taste.
Recently, the German company schering is actively exploring a new group of drugs with androgenic properties. These are the so-called selective androgen receptor modulators (SARM). Like them, modulators of estrogen receptors, such as tamoxifen, raloxifene, keoxifen, and droloxifene, are already and successfully used in practice. These drugs, acting on steroid receptors, show only a certain range of their activity, without rendering a number of undesirable actions, due to the different degree of their agonism to the receptors in different tissues. An example of such a compound is 7a-methyl-19-nortestosterone (ef-MENT). In addition, this compound is not metabolized to dihydrotestosterone, while able to aromatize. In studies, e-menT showed a more potent effect on gonadotrophs and less on prostate tissue. Research with this drug continues, it is being tested as a contraceptive for men and for the treatment of hypogonadism.