Pharmacology and Sport; Sport Pharmacology in the Soviet Union

[SHINE]

Pharmacology and Sport; Sport Pharmacology in the Soviet Union

Morris Silber
Department of Food Science and Human Nutrition
Washington State University,
Pullman, WA
USA
(Formerly, Institute of Physical Culture, Lenningrad, USSR)




Pharmacology (Pharmacon, Greek - medicinal, Logos, Greek - study) is a branch of natural sciences which studies the action of chemical compounds on living organisms. Pharmacology mainly studies the effects of chemical substances employed for treatment and prevention of various diseases and pathological conditions. One of the most important tasks of pharmacology consists of search for new effective medicines and chemical compounds to prevent illness.
The range of pharmacological studies is very wide. Studies include the effects of chemical compounds on biological systems (total body to subcellular structures), subcellular metabolism, and regulation of biological systems by receptors and enzymes.
Pharmacology is closely related to theoretical and practical medicine and has significantly influenced the development of several biomedical disciplines, particularly physiology and biochemistry. For example, the mechanism of the synaptic transmission produced by acetylcholine and norepinephrine have been discovered through the use of vegeto-tropic substances. Development and production of agents that block certain enzymes or accelerate their synthesis had stimulated advances in enzymology. Several of the complex functions of the central nervous system have been discovered through the use of psychotropic substances. In experimental medicine, pharmacological substances are important because they control various biochemical and physiological processes.
Pharmacology has been particularly important for practical medicine. A wide spectrum of highly effective medicines, has revolutionized the treatment of most diseases. Pharmacological preparations are used to inhibit or stimulate the central and peripheral nervous systems, increase or decrease blood pressure, stimulate cardiac output and pulmonary activity, regulate blood cell production, and modify blood coagulation and metabolic processes. Antimicrobial and an***arasite medicines, now commonly used to treat and prevent infectious diseases. Pharmacologic agents are widely used and are essential in practical medicine.
Progress in pharmacology has greatly affected the development of clinical medicine. The discovery of narcotics, anesthetics, curaremimetc agents and ganglioblockers has stimulated progress in surgery. Psychotropic substances have led to progress in psychiatry. Isolation and synthesis of hormones has considerably improved the diagnosis and treatment of patients with endocrine disorders. Effective treatment of infectious diseases became possible only after the introduction of antibiotics and sulfanilamides. Organ transplantation surgery has become possible only after obtaining immunodepressive medicines. Table 1 outlines the primary role of pharmacology in the development of medicine.
Because of the important role of pharmacotherapy to practical medicine, medical doctors of any specialty must have strong knowledge in pharmacology. Modern medicines have very high biological activity. Any tiny imprecision in their prescription might cause considerable negative effect on the patient's condition.
The most important task of pharmacology research consists of searching for new medicines. The process involves chemical synthesis and isolation (extraction) of natural compounds from plants, animal tissues and minerals. For example, studies might involve extraction of natural metabolites in yeasts and microorganisms. These sources contain almost every chemical compound found in man and have vast pharmacological potential. The search, screening and testing of new medicines is based on close cooperation of a multi-disciplinary team of experts, including pharmacologists, chemists, systematic botanist or zoologist, biochemist, molecular biologist and physicians. The intermediate position of pharmacology within theoretical and practical medicine explains the variety of scientific problems considered by pharmacology.

History

The history of pharmacology is as old as human kind (Table 1). Developments in pharmacology tended to occur during periods of rapid socioeconomic change. In primitive societies, plants served as medicines. Primitive people observed and mimicked the behavior of animals or discovered some curable properties of plants by accident. This period in pharmacology is commonly called the empirical period. Gradually, healing became the privilege of clergyman, who attributed the power of medicines to divine strength. This time is known as empirical-mystical period. During the feudal period, which coincided with a general decline in science and culture, progress in pharmacology and medicine ground to a halt. Medical art was in the domain of monks who preached scholasticism, a religious-idealistic philosophy of the Middle Ages. The effects of medicines were related to the position of the moon, constellations and planets. Astrology became an integral part of medicine, and alchemy grew very popular. This period of the history of medicine and pharmacology is usually referred to as religious-scholastic.
Pharmacology as a science began with the formation of large nation states and significant economic development of the 18th and 19th century. First, experimental methodology was introduced for the analysis and the determination of action of medicinal preparations. Extraction technique were developed, which, for example, allowed pharmacologists to obtain alkaloids from various plants. Pharmacology was particularly advanced with the development of synthetic preparations. These development gradually led to the formation of the chemical-pharmaceutical industry.
Pharmacology is usually subdivided into general and specialized. General pharmacology investigates the gross action of medicines. Special pharmacology deals with concrete pharmacological groups and individual preparations. The most attention in both subdivisions is given to pharmacokinetics and pharmacodynamics of the medicinal preparations. Pharmacokinetics is a part of pharmacology studying absorption, distribution in the body, metabolism and excretion of the medicine (fig. 1). Pharmacodynamics provides information about the effects of individual medicines and also their mechanism of action and localization. The effect of medicine results from its interaction with the organism. That is why pharmacological research is multidisciplinary. Pharmacology also involves the study of toxic and negative side effects of the medicines.
As discussed, pharmacology is involved in the treatment and prevention of various pathological conditions. During the last few decades, the pharmacology of health - pharmacosanation — has been developed into an independent subdivision of the applied pharmacology A pioneer in this area was Soviet pharmacologist, Israel Breckman (1980). Pharmacosanation is the study of the action of biologically active substances entering a healthy body in the form of food or medicines that prevent illness, increase resistance to various adverse factors, and enhance recovery from biological stressors. (Breckman, 1982).
Originally, the concept of pharmacosanation came from the science of health, or valeology (from the Latin word "valeo" meaning "I am well", "I am fit".) But very soon it became integrated into sports medicine. Known in the Soviet Union as sports pharmacology, its development was an important part of the sports achievement of athletes from the USSR and the East Bloc sports superpowers, East Germany, Hungary and Bulgaria.
The development of sports pharmacosanation occurred for many reasons. Besides the social and political motives, its appearance was a progressive step in the separation of preventative and treatment pharmacology. Competitive athletes are subject to many hardships — strenuous work, injuries, cold and heat, thirst and fatigue, and emotional stress. These stresses can lead to immunosuppression and illness. Sports pharmacology pharmacosanation has proven useful in helping athletes cope with the physical and emotional stresses of training and competition.
Sports pharmacology has developed its own methodology and philosophy. To some extent, people balance between health and illness throughout life.. In practical terms, very few people enjoy perfect health; most people live in an intermediate state between good and bad health. The capacity to resist illnesses is dependent upon a person's healthy reserve.
Medical science has emphasized curing disease as the primary method of achieving good health. However, modern research suggests that this has been a flawed approach. In spite of the incredible success of medical science in treating disease and the vast expenditure on medical care in Western Nations, the incidence of illness and medical costs are rising. During the past 20 years in the USA, the sharp increase in the proportion of the national income spent on health care has failed to produce a proportional fall in the death rate and in increase in the average life span (Sokolowska, 1978; Kaznacheyev, 1973). Neither social nor medical measures has had the anticipated effect of preserving the health of the general population.

Ergogenic Aids in Western Countries

Historically sport pharmacology was not acknowledged in the United States. Instead, the concept of ergogenic aids and sports supplements have been prompted. Ergogenic aids include any substances or methods believed to aid or improve athletic performance. Interest in ergogenic aids centers on the effects of drugs on athletic performance, particularly on the effects of anabolic steroids on increasing muscle size and strength. Most of the ergogenic aids have been borrowed from medicine and biological sciences, but few of them have been proven by experimental research to be effective and safe as sports performance enhancers. Also, there is no comprehensive methodology for their use. There is also little information about their toxicity (acute or chronic) or their effects on physical stimulation or recuperation. Moreover, the concept of ergogenic aids has become commercialized and served as an instrument for business rather than scientific support for athletes. Even multi-million dollar sports supplementation companies in the United States do not back up their products with satisfactory experimental studies.

Pharmacology and Sport in Soviet Union

Medicine tried to enhance public health mainly by treating disease. However, this method does not create optimal physiological function. Soviet scientists were among the first to clearly realize that optimal health and the treatment of illness are often distinct processes. Though the goals were closely interlinked, the strategy, tactics and "technology" of successfully reaching both targets presupposed two different scientific solutions and two separate systems to be implemented in practice. In the athlete, optimal health was associated with optimal performance.
The new methodology of health promotion (as opposed to treatment of disease) favored the principles of the structure-dose-effect, individualization, periodization and systemic patterns in selecting pharmacological means of promoting health and performance in athletes. Moreover, the methodology involved providing athletes with complexes of pharmacological agents, rather than administering them separately. The complexes were formulated with concern of the specific biological effect of the individual components on various systems of the athlete's organism (systemic approach). Consequently, complexes of medicines with versatile physiological effects have been developed, including adaptogens, nootropes, psychostimulants, anabolics, anticatabolics, immunomodulators, cardiovascular protectors, hepatoprotectants (liver guards), muscle protectants, recuperants. As the number of the consumed medicines sometimes exceeded 25, a special step-wise time scheduled mode of supplementation was elaborated when designing individual plans of pharmacosanation for athletes such factors as:
•. Individual athletic goals for the period;
• Individual training plans
• Results of biomedical laboratory exams.
It was common practice for Eastern Bloc athletes to be tested regularly using blood, urine and tissue analysis to determine health potentials and training condition. The goals of these tests were primarily to enhance the athletes' health and keep them in an anabolic state. By knowing the status of the organism, the coach could fine-tune the training program to maximize gains. This procedure greatly reduced the chance of illness, overtraining, or psychological distress.
The success of sports pharmacosanation is due to a large extent to the achievements of sports biochemistry. Modern methods of analytical biochemistry allow to carry out precise monitoring of biochemical changes within physiological range. Timely correction of the biochemical changes occurring in the athlete under strain training is the principle requirement of special pharmacosanation.

Principles of Pharmacosanation

The pharmacosanation plan should be designed by a physician familiar with sports medicine, biochemistry and endocrinology. Supplements, diet, and training should be prescribed on the basis of a complete biomedical examination of the athlete.

Rational Nutrition
As a branch of Health Science the first and principal medicine for sport pharmacosanation is rational nutrition (alimentary pharmacosanation). This philosophy was espoused more than five thousand years ago by the great ancient physician and philosopher Hippocrates who taught that "food should be your medicine, and medicine should be your food." His philosophy became the basis for what modern sports medicine practitioners are attempting to put into routine practical use:
Rational nutrition implies a food intake in balance with energy expenditure taking into consideration the main food substances proteins, fats, carbohydrates, vitamins, minerals, and other biologically active substances which insure an adequate range of the degree of diversity and complexity of internal milieu. Rational nutrition is a primary factor in achieving genetic potential, increasing productivity, and maximizing performance.

Supplements for Specific Purposes
The second group of medicines for sport pharmacosanation includes substances that can be used by healthy individuals for specific purposes. These include substances that improve the body's overall nonspecific resistance, which enables it to respond more steadily to stress (Selye, 1976). Examples include adaptogens (eleutherococcus, ginseng), natural tranquilizers (Rauwolfia serpentina), and also biostimulants (extracts from the horns of European reindeers).
Natural pharmacologic techniques in conjunction with rational nutrition effectively improve recovery from heavy training, the ability to withstand hard work, and muscle growth. But again, practiced by the Soviet pharmacologists, it was not simply a matter of selecting one pill over another. Rather, the process involved a complex nutritional and pharmacological program individually formulated with regard to its systemic physiological effects, combined with proper training exercises and planning. It is no easy task, and demands constant attention to details by sophisticated athletes and coaches, sport physicians, and a team of scientific supervisors.
The requirements of all sport supplements is to supply the body with substances which will improve metabolic function, reduce the energy expense of exercises, and increase the restorative potential, without causing any negative side effects or damage. Over the past twenty years, a great amount of investigative work on this topic has been conducted within the USSR. The results of these laboratory experiments, as well as practical research on top athletes has resulted in further elaboration of the system of sport pharmacology through medicinal and nutritional means. This system is a complex of pharmacosanation means — rational diets, nutritional supplements, and biologically important pharmacological substances grouped into complexes by their systemic physiological effect introduced at specific times of the training cycle that leads to significant improvements either in performance or recovery ability, or both of them.
In my opinion, the Soviet system of sport pharmacology is the finest and most complete in the world. Until recently much of the research had been kept a secret from coaches outside the East Bloc. Further we will present the Soviet system of sport pharmacology (compared to the American use of ergogenic aids). It is highly effective and functions as an excellent compliment to the most demanding training and competitive programs.

[SHINE]

Sports Nutrition and Pharmacology in Western Countries
On the contrary, one of the major deficiencies of using pharmacological means and nutrition in the West is that there is no complete system. Dozens of colorful and glitzy advertisements in any major bodybuilding or other sport-related magazine are touting the benefits of the latest "miracle" supplement. But, there is no method for their use (time recommendation and periodization within the overall training cycle and single work-outs, or regarding food consumption and the restorative periods) no sound scientific research to back up their claims, and no system to complex them with other pharmacological substances or nutritional supplements and training means. This is very confusing to even the most educated coaches and athletes.
Little effort has been directed at educating athletes, and developing an effective system of sport pharmacology. Athletes and coaches are still asking the same questions they did ten years ago. There is no systematic plan for using effective sport pharmacology in coordination with contemporary training methods. Also, information is lacking about the systemic approach for combining various pharmacological substances into an effective formula that enhances health and performance. The following material concerning sport pharmacology will clear up much of the confusion surrounding the many substances used in Western sports nutrition and also address new substances previously available only in the USSR.

Nutrition, Pharmacology, and Training: A Systematic Approach

It is a great error to simply throw substances together. Some work against one another while others work together to strengthen the body. Particularly nutrition supplements are required at certain periods within the training cycle, and not others. No one substance should be used for any length of time (longer than 3 weeks without a break), as this causes adaptation to the supplement and a loss of effect. That is why all the pharmacological plans for Soviet athletes are based on the intermittent principle - three weeks on, one week off; this cycle for each component of the whole complex is repeated not less than three times during an evolutionary hard work training cycle (figure 2). The same principle is preserved in planning a precompetitive stimulatory and postcompetitive restorative programs. As it was shown by Soviet pharmacologists, there was about a 30-40% loss of the pharmacological effect of the supplementation complex, if the number of the pharmacological substances composing the complex exceeds six. So, the intermittent step-wise time-scheduled scheme has been designed to take into consideration dose-time relationships of the various supplements.
There is no single safe and natural medicine or supplement which will create super athletes overnight. Before using a sport supplement, there are a number of questions to be answered:
• What is the goal of supplementation program (i.e., structural, energetic, adaptogenic, protective, restorative, etc.)?
• In what doses are supplements effective and what is the athlete's individual sensitivity?
• In what part of the training cycle should supplements be used?
• How can supplements be combined for maximum effect?
• What is the current state of body homeostasis?

The last question is of particular practical importance. As it was reported from the Soviet Union (Silber et al., 1988) the anticipated effect of a pharmacosanation complex depends strongly on the state of the athlete's steroid hormone homeostasis (i.e., cortisol and testosterone).
The East European competitors have had a competitive advantage and have made great headway because they were taking sport supplements (including anabolic steroids). This was not done at random; rather, it was done under the careful supervision of scientists and pharmacologists. Several hormone tests have been developed to assess anabolic status, including tests for evaluation of steroid hormone homeostatis (both informative and prognostic) (Silber, 1991).This added precision to the athletes nutrition, training, and pharmacology programs.

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Steroid Homeostasis
The mechanism of the steroid hormone homeostatic inhibition is the most sensitive point of the entire process of adaptation to various stressors with sport activity among them. Soviet experts noticed that measurable changes of steroid hormone homeostatic self-regulation happened in athletes far earlier than any visible signs of developing stress, such as fatigue and decline in work capacity and fitness. To monitor these changes a two-hormone challenge test was proposed that:
• Predicted negative changes athletes' work capacity long before they could be actually measured.
• Provided athletes with purposeful corrections to their individual training and pharmacological plans.
The test involved administration of minimal therapeutic doses of methandrostenolone (metan-synthetic derivative of testosterone) and dexamethasone (DM- synthetic analog of natural human glucocorticoid cortisol) (i.e., 0.5 mg of dexamethasone and 5.0 mg of methandrostenolone). One tablet of each of them was taken during subsequent two days before bedtime at 10-11 p.m.. The nighttime urine was collected at 8-9 a.m. every morning during all three days of the test.
Cortisol and testosterone concentrations were measured and the percentile changes after taking dexamethasone and methandrostenolone was estimated. Figures 3 and 4 explain the idea of the two-hormone test. Peripheral steroid hormones (cortisol and testosterone) are important to develop the urgent (short-term) and delayed (long-term) adaptations to stress. There are specific dynamics in the blood concentration of the two steroid hormones during the process of adaptation. The controlling mechanism of the biosynthesis of glucocorticoids (cortisol) and androgens (testosterone) is feed-back homeostatic self-regulation. The blood and/or urine concentration of cortisol and testosterone determined at various times during the adaptation period gives reliable information about the character of the adaptive changes in the body. Normally, excess of glucocorticoids in circulation exerts an inhibitory suppression on the hypothalamic production of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secreted by the pituitary gland. That eventually results in reduced cortisol secretion. The same excess of blood androgens, inhibits the production of luteinizing Hormone (LH) with a subsequent reduction in testosterone secretion. This is the essence of the feed-back mechanism of steroid hormone homeostatic self-regulation.
Of course, simple measuring of cortisol to testosterone (and/or norepinephrine to epinephrine) ratio in blood and urine is also very informative for routine monitoring of the developing urgent or long-term adaptation. Unfortunately, these analysis' do not give dependable information about the state of the central mechanism of the neuroendocrine regulation during adaptation. This can be done, however, with high accuracy by the two-hormonal test, as described above.
Numerous examinations of healthy non-athletes by dexamethasone/methandrostenolone test showed that normally administration of these hormones caused a 30-40% reduction of blood cortisol and/or testosterone. It was shown in studies carried out on hundreds of Soviet national-level athletes, that approximately 35% of them did not respond normally to dexamethasone or methandrostenolone administration; they did not show a decrease of blood cortisol and/or testosterone. Moreover, some of them responded by increase of blood cortisol and/or testosterone.
In national-level athletes, approximately 65% responded to dexamethasone/methandrostenolone (D/M) administration by decreasing blood cortisol and/or testosterone concentration. This group of individuals was referred to as D/M sensitive, opposite to the first group classified as D/M resistant. Figure 4 reflects these observations.
D/M resistance is consistent with temporary or continuous dysfunction of the central mechanism of the endocrine homeostasis. It consists of loss of sensitivity of the steroid hormone receptors in the hypothalamus and pituitary gland to increased concentrations of cortisol or testosterone in circulation. As a result, for instance, high blood cortisol concentration which is observed usually after hard physical work will not inhibit the hypothalamic and pituitary activity (homeostatic inhibition, Fig 3). Continuously elevated concentration will reflect on the blood cortisol/testosterone ratio. Eventually, overstimulation of the stress-hormone production will rapidly exhaust the adrenocortical resource with a developing decrease of fitness and physical work capacity. At the same time if taken separately from the D/M test the cortisol to testosterone changes will become noticeable considerably later.
It was found in the same studies, classified in the USSR as Top Secret, that athletes with D/M resistance showed very low sensitivity to pharmacosanation. Often times doses 2 to 4 times as high as routinely used were required to obtain only a slight stimulating effect on D/M resistant athletes.
In further studies on athletes of different rank it was specified that D/M resistant athletes, independently of their rank, had always a higher level of basal metabolism, higher lactate and creatinine, higher ratios of cortisol to testosterone, lower ratios of norepinephrine to epinephrine (or according to Walter Cannon, 1938 lower "fight" and higher "flight" hormones) and also lower fitness and work capacity, compared to D/M sensitive athletes. Additionally, they have always been showing low blood concentration of insulin and creatine, decreased rate of blood clearance from energy metabolites (lactate and creatine) decreased rate of skeletal muscle relaxation, increased susceptibility to myocardial dystrophy, hypertension, injuries and infectious diseases. Figure 5 summarizes these observations.
The D/M test is both highly sensitive and informative. It shows changes in the central mechanism of homeostatic self-regulation long before (2 or 3 weeks) its manifestation in the athlete's performance and health. Moreover, during the recovery period on pharmacosanation supplementation, the dynamics of the two-hormone test is a reliable indicator of how recovery is proceeding. It gives the opportunity to implement timely the necessary pharmacological correction. Thus, this gives the athletes and coaches the advantage of keeping up with the training/recovery strategy.
Later, the researchers in the USSR had modified the final step of this double-hormonal test in order to accommodate it more to the "field conditions". For this purpose we proposed to evaluate the dynamics of lymphocytes to granulocytes ratio in peripheral blood at the end of the test instead of the more expensive and cumbersome cortisol and testosterone measurements. It was shown in our and other earlier studies (Silber 1991, Garkayi 1984). that a consistent reciprocal correlation exists between cortisol to testosterone vs. the lymphocytes to segmented leukocytes (granulocytes) in peripheral blood (Fig 6). This modification has many advantages, as the leukogram reading is technically easy and can be used even during a short (3 days) microcycle training program.
As a part of a complex pharmacosanation program the D/M test has proven to be of great help when anabolic steroid abuse is suspected and the athlete has to be taken under routine control. The routine use of the D/M test allows to prevent the anabolic steroid overdose and related to its negative side effects (Goldman, 1991). Repeated check-ups of athletes under various programs of anabolic steroid supplementation have given the Soviet specialists the advantage of controlling the situation in both ways, i.e., to minimize the hazardous effects of anabolic steroids and evade the doping control tests. Figure 7 exemplifies one of the several practical uses of the D/M test in the National Soviet Team during its preparation to the Olympic Games in Seoul in 1988.
The methandrostenolone test was also used to assess individual sensitivity to anabolic steroids. This test involved administering different doses of methandrostenolone and monitoring the response of testosterone and cortisol. Commonly, low doses of anabolic steroids (AS) caused a significant increase of blood cortisol in athletes in the methandrostenolone test. In contrast, the methandrostenolone test was always negative in athletes abusing AS. This means that an additional serving of even a minimal therapeutic dose of methandrostenolone causes a further decrease of blood cortisol in athletes overdosing AS, indicating at a profound reduction of the adrenocortical potentials. On the other hand, the negative result of the methandrostenolone test also means a loss of sensitivity and even specificity by the hypothalamic and/or pituitary steroid hormone receptors in athletes abusing AS. This notion is supported by the results of the second part of the double-hormone test. Administration on the second test day of a minimal therapeutic dose of dexamethasone to athletes taking AS in doses meeting their individual homeostatic limits, causes a drastic decrease in blood cortisol concentration, far exceeding the 40% cortisol decrease in the D/M sensitive athletes. Just the opposite, all athletes overdosing AS responded to dexamethasone administration by increasing blood cortisol, the same as D/M resistant individuals.
Thus, the double-hormone test makes it possible to demonstrate objectively the negative effect of AS overdose. Moreover, it had revealed the original cause of the impairment of the mechanism of the homeostatic self-regulation, such as loss of sensitivity and/or specificity of the steroid hormone receptors in the hypothalamus and pituitary glands Also this test demonstrated clearly that AS abuse can depress cortisol production. Anabolic steroid abuse is eventually characterized by decreased physical fitness and work capacity despite administration of higher and higher doses of anabolic steroids. Many of the negative side effects of the anabolic steroids have been avoided in Soviet athletes due to the implementation of the double-hormone test.
However, the major reason of the safe and efficient use of AS by the East Bloc athletes is that played only a small part in a large and scientifically elaborated pharmacosanation program. According to the report of the USSR State Sorts Committee (Goskomsport), the volumes of training loads in some of the speed/strength sports (weightlifting, throwing, etc.) had increased about three times in 1988, compared to 1968 (the years of the XXIV and XIX Summer Olympic Games). Needless to say, the advanced rehabilitation techniques have become critical in to avoiding injuries enabling increased training intensity. The pharmacosanation program included administration of complexes of pharmacological substances with anabolic, bioactive, and protective activities. These complexes were selected by their physiopharmacological action. Table 2 illustrates an example of the system and includes supplement compositions and the sequence of their use (see Fig 2 also). The effect of the pharmacosanation and physical training program on health, fitness and performance depends on the training plan and the athlete's individual metabolic response (the state of homeostatic regulation).

[SHINE]

Steroid Homeostasis
The mechanism of the steroid hormone homeostatic inhibition is the most sensitive point of the entire process of adaptation to various stressors with sport activity among them. Soviet experts noticed that measurable changes of steroid hormone homeostatic self-regulation happened in athletes far earlier than any visible signs of developing stress, such as fatigue and decline in work capacity and fitness. To monitor these changes a two-hormone challenge test was proposed that:
• Predicted negative changes athletes' work capacity long before they could be actually measured.
• Provided athletes with purposeful corrections to their individual training and pharmacological plans.
The test involved administration of minimal therapeutic doses of methandrostenolone (metan-synthetic derivative of testosterone) and dexamethasone (DM- synthetic analog of natural human glucocorticoid cortisol) (i.e., 0.5 mg of dexamethasone and 5.0 mg of methandrostenolone). One tablet of each of them was taken during subsequent two days before bedtime at 10-11 p.m.. The nighttime urine was collected at 8-9 a.m. every morning during all three days of the test.
Cortisol and testosterone concentrations were measured and the percentile changes after taking dexamethasone and methandrostenolone was estimated. Figures 3 and 4 explain the idea of the two-hormone test. Peripheral steroid hormones (cortisol and testosterone) are important to develop the urgent (short-term) and delayed (long-term) adaptations to stress. There are specific dynamics in the blood concentration of the two steroid hormones during the process of adaptation. The controlling mechanism of the biosynthesis of glucocorticoids (cortisol) and androgens (testosterone) is feed-back homeostatic self-regulation. The blood and/or urine concentration of cortisol and testosterone determined at various times during the adaptation period gives reliable information about the character of the adaptive changes in the body. Normally, excess of glucocorticoids in circulation exerts an inhibitory suppression on the hypothalamic production of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secreted by the pituitary gland. That eventually results in reduced cortisol secretion. The same excess of blood androgens, inhibits the production of luteinizing Hormone (LH) with a subsequent reduction in testosterone secretion. This is the essence of the feed-back mechanism of steroid hormone homeostatic self-regulation.
Of course, simple measuring of cortisol to testosterone (and/or norepinephrine to epinephrine) ratio in blood and urine is also very informative for routine monitoring of the developing urgent or long-term adaptation. Unfortunately, these analysis' do not give dependable information about the state of the central mechanism of the neuroendocrine regulation during adaptation. This can be done, however, with high accuracy by the two-hormonal test, as described above.
Numerous examinations of healthy non-athletes by dexamethasone/methandrostenolone test showed that normally administration of these hormones caused a 30-40% reduction of blood cortisol and/or testosterone. It was shown in studies carried out on hundreds of Soviet national-level athletes, that approximately 35% of them did not respond normally to dexamethasone or methandrostenolone administration; they did not show a decrease of blood cortisol and/or testosterone. Moreover, some of them responded by increase of blood cortisol and/or testosterone.
In national-level athletes, approximately 65% responded to dexamethasone/methandrostenolone (D/M) administration by decreasing blood cortisol and/or testosterone concentration. This group of individuals was referred to as D/M sensitive, opposite to the first group classified as D/M resistant. Figure 4 reflects these observations.
D/M resistance is consistent with temporary or continuous dysfunction of the central mechanism of the endocrine homeostasis. It consists of loss of sensitivity of the steroid hormone receptors in the hypothalamus and pituitary gland to increased concentrations of cortisol or testosterone in circulation. As a result, for instance, high blood cortisol concentration which is observed usually after hard physical work will not inhibit the hypothalamic and pituitary activity (homeostatic inhibition, Fig 3). Continuously elevated concentration will reflect on the blood cortisol/testosterone ratio. Eventually, overstimulation of the stress-hormone production will rapidly exhaust the adrenocortical resource with a developing decrease of fitness and physical work capacity. At the same time if taken separately from the D/M test the cortisol to testosterone changes will become noticeable considerably later.
It was found in the same studies, classified in the USSR as Top Secret, that athletes with D/M resistance showed very low sensitivity to pharmacosanation. Often times doses 2 to 4 times as high as routinely used were required to obtain only a slight stimulating effect on D/M resistant athletes.
In further studies on athletes of different rank it was specified that D/M resistant athletes, independently of their rank, had always a higher level of basal metabolism, higher lactate and creatinine, higher ratios of cortisol to testosterone, lower ratios of norepinephrine to epinephrine (or according to Walter Cannon, 1938 lower "fight" and higher "flight" hormones) and also lower fitness and work capacity, compared to D/M sensitive athletes. Additionally, they have always been showing low blood concentration of insulin and creatine, decreased rate of blood clearance from energy metabolites (lactate and creatine) decreased rate of skeletal muscle relaxation, increased susceptibility to myocardial dystrophy, hypertension, injuries and infectious diseases. Figure 5 summarizes these observations.
The D/M test is both highly sensitive and informative. It shows changes in the central mechanism of homeostatic self-regulation long before (2 or 3 weeks) its manifestation in the athlete's performance and health. Moreover, during the recovery period on pharmacosanation supplementation, the dynamics of the two-hormone test is a reliable indicator of how recovery is proceeding. It gives the opportunity to implement timely the necessary pharmacological correction. Thus, this gives the athletes and coaches the advantage of keeping up with the training/recovery strategy.
Later, the researchers in the USSR had modified the final step of this double-hormonal test in order to accommodate it more to the "field conditions". For this purpose we proposed to evaluate the dynamics of lymphocytes to granulocytes ratio in peripheral blood at the end of the test instead of the more expensive and cumbersome cortisol and testosterone measurements. It was shown in our and other earlier studies (Silber 1991, Garkayi 1984). that a consistent reciprocal correlation exists between cortisol to testosterone vs. the lymphocytes to segmented leukocytes (granulocytes) in peripheral blood (Fig 6). This modification has many advantages, as the leukogram reading is technically easy and can be used even during a short (3 days) microcycle training program.
As a part of a complex pharmacosanation program the D/M test has proven to be of great help when anabolic steroid abuse is suspected and the athlete has to be taken under routine control. The routine use of the D/M test allows to prevent the anabolic steroid overdose and related to its negative side effects (Goldman, 1991). Repeated check-ups of athletes under various programs of anabolic steroid supplementation have given the Soviet specialists the advantage of controlling the situation in both ways, i.e., to minimize the hazardous effects of anabolic steroids and evade the doping control tests. Figure 7 exemplifies one of the several practical uses of the D/M test in the National Soviet Team during its preparation to the Olympic Games in Seoul in 1988.
The methandrostenolone test was also used to assess individual sensitivity to anabolic steroids. This test involved administering different doses of methandrostenolone and monitoring the response of testosterone and cortisol. Commonly, low doses of anabolic steroids (AS) caused a significant increase of blood cortisol in athletes in the methandrostenolone test. In contrast, the methandrostenolone test was always negative in athletes abusing AS. This means that an additional serving of even a minimal therapeutic dose of methandrostenolone causes a further decrease of blood cortisol in athletes overdosing AS, indicating at a profound reduction of the adrenocortical potentials. On the other hand, the negative result of the methandrostenolone test also means a loss of sensitivity and even specificity by the hypothalamic and/or pituitary steroid hormone receptors in athletes abusing AS. This notion is supported by the results of the second part of the double-hormone test. Administration on the second test day of a minimal therapeutic dose of dexamethasone to athletes taking AS in doses meeting their individual homeostatic limits, causes a drastic decrease in blood cortisol concentration, far exceeding the 40% cortisol decrease in the D/M sensitive athletes. Just the opposite, all athletes overdosing AS responded to dexamethasone administration by increasing blood cortisol, the same as D/M resistant individuals.
Thus, the double-hormone test makes it possible to demonstrate objectively the negative effect of AS overdose. Moreover, it had revealed the original cause of the impairment of the mechanism of the homeostatic self-regulation, such as loss of sensitivity and/or specificity of the steroid hormone receptors in the hypothalamus and pituitary glands Also this test demonstrated clearly that AS abuse can depress cortisol production. Anabolic steroid abuse is eventually characterized by decreased physical fitness and work capacity despite administration of higher and higher doses of anabolic steroids. Many of the negative side effects of the anabolic steroids have been avoided in Soviet athletes due to the implementation of the double-hormone test.
However, the major reason of the safe and efficient use of AS by the East Bloc athletes is that played only a small part in a large and scientifically elaborated pharmacosanation program. According to the report of the USSR State Sorts Committee (Goskomsport), the volumes of training loads in some of the speed/strength sports (weightlifting, throwing, etc.) had increased about three times in 1988, compared to 1968 (the years of the XXIV and XIX Summer Olympic Games). Needless to say, the advanced rehabilitation techniques have become critical in to avoiding injuries enabling increased training intensity. The pharmacosanation program included administration of complexes of pharmacological substances with anabolic, bioactive, and protective activities. These complexes were selected by their physiopharmacological action. Table 2 illustrates an example of the system and includes supplement compositions and the sequence of their use (see Fig 2 also). The effect of the pharmacosanation and physical training program on health, fitness and performance depends on the training plan and the athlete's individual metabolic response (the state of homeostatic regulation).

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Pharmacosanation And Periodization Of Training

The principle success of the pharmacosanation methodology compared to the nonsystemic use of ergogenic performance enhancers is that pharmacosanation affects the metabolic status of the athlete at the desired time. This strategy is consistent with the principles of periodization of training.
The general ideas and the scientific basis for periodization of training were adopted from the Selye's General Adaptation Syndrome concept. This model is usually used to explain adaptation to exercise training. Hans Selye described three stages involved in response to a stressor: alarm reaction, resistance development, and exhaustion (Selye, 1976 ).
The alarm stage is the prompt activation of non-specific defense mechanisms in response to challenges to which the organism is not adapted. The resistance stage is the adaptation of the organism to the continued challenge so that it does not seem as demanding. The exhaustion stage is the loss of adaptation during very prolonged exposure to challenge(s). Selye illustrated his General Adaptation Syndrome with a graph, which appears somewhat modified in Figure 9.
According to the findings of the Soviet biomedical researchers (Garkavi et al., 1979), the resistance development period includes two more important transitory stages: reactions of training and activation. Moreover, it was found that the main triad of the adaptation reactions (training, activation, stress) are repeated occasionally at different levels of the developed reactivity and depend completely on the strength of the stressor. Also, a quantitative method for measuring the reactivity and nonspecific resistance of the body was developed. Selye's original concepts, together with further research and empirical observations, have been employed to formulate the principle rules of periodization of training and pharmacosanation.
Periodization of training attempts to get the athlete to adapt systematically with a minimum risk of overtraining and injury. Small gains are planned over a long period of time. The system is designed to improve the athlete's fitness so that peak performance occurs at the desired time.
Selye observed that the alarm reaction is triggered through two systems, the nervous system and the endocrine system. Messages flowing through these systems eventually mobilize the body's defenses.
Further research showed that the other stages of the General Adaptation Syndrome are also triggered through the endocrine system with the leading role shifting from the catecholamines and glucocorticoids to androgens thyroid hormones and insulin (fig 10)
The neuro-endocrine basis for training adaptation has been exhaustively studied by Soviet Union sports endocrinologists. They have investigated many hormone-dependent events occurring during the course of training. It was found that glucocorticoids, due to their catabolic and antagonistic effects on anabolic reactions (i.e., protein and glycogen synthesis), are responsible mainly for the reactions of mobilization of the body's potentials. Anabolic adaptation is dependent entirely on other hormones, such as insulin and testosterone. We know now that insulin plays the key role in the process of utilization and membrane transport of the mobilized energy and structure substrates in the cell. Insulin and thyroid hormone activity are critical during late stages of adaptation (i.e., peak competitive period). However, the activities of these hormones are suppressed if the athlete falls into the alarm stage of the General Adaptation Syndrome because of increased activity of the glucocorticoid hormones (fig 11).
Soviet and East Germany national team members who were involved in heavy preparatory training (i.e., resistance developing stage of the adaptation) would compensate for the tendency to suppress insulin and thyroid activity by supplementing these hormones. Insulin was supplemented in a dose 1 IU per 70 kg body weight every third day, and thyroid hormone (Thyreocomb, GDR) 20-50 micrograms a day for a 20 day cycle.

Fate of the Soviet Sports Machine
Interestingly, that many of the leading sports scientists and coaches from the former Soviet Union, East Germany, Socialist Hungary and Bulgaria are working at present time in China, Israel, and South African Republic. These countries had recently surprised the world by their sport achievements.
The progressive ideas and methodology, the Russian sport pharmacologists have been developing during the last 40 years allowed them to contribute significantly to the athletic success of the former USSR and the East Bloc countries. Pharmacosanation is the only known system to support efficiently both the athletes' health and athletic success under conditions of ever-increasing environmental stress. In the United States, development, manufacture and marketing of innumerable ergogenic aids and sports supplements are in the control of businessmen rather than scientists. Until the situation will completely reverse there will always exist hazards for ever gullible athletes.

References

1. Anitshkov, S. The Selective Effect of the Neurotransmitters, Moscow: Meditzina,1974
2. Bobkov, Yu.G., V.M. Vinogradov Pharmacological Correction Of Fatigue. Moscow: Meditzina, 1984. p 208
3. Brechman, I.I. and I.F Nesterenko. Health; Food and Health in Brown Sugar and Health, London: Pergamon Press, 1983. p. 1-18.
4. Brechman, I.I. Man And Biologically Active Substances: The Effect Of Drugs, Diet And Pollution Of Health, London: Pergamon Press, 1980. p 132.
5. Dean W., and J. Morgenthaler. Smart Drugs and Nutrients, Santa Cruz, CA: B & J Publications, 1991 p 222
6. Fahey, T. and T. Fritz. Steroid Alternative Handbook, San Francisco: Sports Science Publication, 1991. p 175.
7. Garkavi, L., Kvankina E., and M. Ukolova. The Reactions Of Adaptation And The Resistance Of The Body. Moscow: Rostov State University Publications, 1979. p 126
8. Goldman, B., and R. Klatz. Death in the Locker Room. Chicago: Elite Sports Medicine Publications, 1992. p 380
9. Kaznacheyev, V.P. The Biosystem and Adaptation, USSR: Novosibirsk, 1973. p. 167
10. Lazarev, N.V. Drugs and body resistance to unfavorable environments; in abstracts of The Conference On Body Resistance To Unfavorable Environments, Leningrad (USSR), 1958 . p 50
11. Selye, H. Stress Without Distress, Toronto: McClelland and Stewart, 1974.
12. Selye, H. The Stress of Life. New York: McGraw Hill, 1976.
13. Silber M. The Results of Long Term Application of Hormonal Tests for Routine Monitoring of Homeostatic Regulation and Fitness in Top-Class Athletes. In the Transactions of the International Congress Humanity and Sports, Seoul, 1988. p 239
14. Silber M., Anabolic Androgenic Steroids in Soviet Sport, San Francisco: SRI Publications, 1991, p 140
15. Silber M., Yu. Bobrov, S. Soroko, and Yu. Sidorov (1988) The use of dexamethasone and nerobol for evaluation of homeostatic regulation in athletes, in the Transactions of Tartu State University (Estonia), p 141.
16. Sokolowska M. Medicine and society in the period of scientific and technical revolution. Problemy (Warsaw, Poland) 3:12-20, 1978

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(A-note)Commonly, low doses of anabolic steroids (AS) caused a significant increase of blood cortisol in athletes in the methandrostenolone test. In contrast, the methandrostenolone test was always negative in athletes abusing AS.

This means that an additional serving of even a minimal therapeutic dose of methandrostenolone causes a further decrease of blood cortisol in athletes overdosing AS, indicating at a profound reduction of the adrenocortical potentials. On the other hand, the negative result of the methandrostenolone test also means a loss of sensitivity and even specificity by the hypothalamic and/or pituitary steroid hormone receptors in athletes abusing AS.

HA!
all athletes overdosing AS responded to dexamethasone administration by increasing blood cortisol, the same as D/M resistant individuals.
Thus, the double-hormone test makes it possible to demonstrate objectively the negative effect of AS overdose. Moreover, it had revealed the original cause of the impairment of the mechanism of the homeostatic self-regulation, such as loss of sensitivity and/or specificity of the steroid hormone receptors in the hypothalamus and pituitary glands Also this test demonstrated clearly that AS abuse can depress cortisol production. Anabolic steroid abuse is eventually characterized by decreased physical fitness and work capacity despite administration of higher and higher doses of anabolic steroids.

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People worrying about high cortisol on cycles need to re-read this article.