Update on nandrolone and norsteroids: how endogenous or xenobiotic are these substances?This xenobiotic anabolic steroids updated second edition discusses the continuing controversy over their use in competitive sports. An introduction of the use and abuse of anabolic Anabolic Steroids and the Athlete, 2d ed. The first edition of this work, published inconcentrated on the athlete's use of and the physician's knowledge of, anabolic steroids. An xenobiotic anabolic steroids of the use and abuse of anabolic steroids is followed by chapters on such topics as anabolic steroid compounds, the anabolic-to-androgen ratio, basic xenobiotic anabolic steroids of muscle building, current anabolic steroid preparations, anabolic steroid regimes used by athletes, the enhancement of athletic performance, adverse physical effects and mental health risks, stwroids classification of anabolic steroids as controlled substances, growth winstrol gep opiniones and other anabolic hormones, the limits of urine drug testing, medical applications of anabolic steroids, muscle building and ergogenic supplements, and addictions.
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Over the last decade the number of laboratories accredited by the International Olympic Committee IOC has grown to The major urinary metabolites of AAS have been characterized and are identified by their chromatographic retention times and full or partial mass spectra. In five laboratories were accredited by the International Olympic Committee IOC 1 to perform national and international sport drug testing.
Now there are 25 accredited laboratories, and several more are training and preparing for the initial inspection and examination. The accreditation process is initiated by a recommendation from the National Olympic Committee and a commitment from the Committee or other relevant national authority to support the laboratory.
The laboratories are reaccredited annually on the basis of performance on one annual examination with blind samples and several proficiency tests. In addition, the laboratories are obliged to adhere to rules and regulations laid down in the IOC Medical Code 1. Of these, the most important is a provision that forbids testing samples from athletes outside of a regulated program that includes sanctions. For a program to help deter athletes from using drugs, an important factor is geographical access to a laboratory; thus, the ideal distribution of laboratories would be in proportion to population.
This is not yet the case, but it is improving. Seventeen of the laboratories are in Europe, three in North America, three in Asia, and one in Australia; South Africa is the most recent addition. There is still no laboratory in South America or the Middle East. A second, equally important factor is the number of tests performed on the national athletes. In some countries, Olympic-caliber athletes are tested many times a year by the national authority and may be tested other times by an International Federation.
In other countries, where there is little or no national testing, an elite athlete may be tested only at major national or international competitions. The total number of tests conducted by IOC-accredited laboratories and the percentage of those positive for anabolic steroids are shown in Fig. The total number of tests performed in , the latest year for which data are available, was 93 , compared with 33 in This corresponds to a time when sport organizations and the media were particularly focused on the influence of drugs on sport.
In the s, the annual growth has tapered off, averaging 3. Of greater importance than the number of tests is the proportion of tests performed on samples collected out-of-competition OOC , i.
It is encouraging that the percentage of OOC tests continues to increase at a rate equal to or greater than the total growth rate. Total number of urine samples tested in IOC-accredited laboratories by year bars ; the curve shows the percent of all samples that were reported positive for anabolic steroids. Laboratories that contribute data such as those reported in Fig. Ideally, the OOC competition category should be further subdivided by the actual amount of time elapsed between notice to test and collection of the sample—because some steroids have effective half-lives of detection of just a few hours.
Some of the OOC samples in Fig. In some countries, virtually all OOC tests are no-notice tests. The percentage of samples that test positive for AAS Fig. For example, an elite athlete who competes several times a year in track and field will probably give many samples, both in-competition and OOC, over the course of a year.
Further, the data do not take into consideration the ultimate disposition of the case. For example, not all cases illustrated in Fig. Despite the shortcomings in the available data, however, evidence is ample that a growing number of nations and sport federations are conducting credible testing. In about two-thirds of the steroid-positive cases shown in Fig. For these cases, detection is based on identifying the parent drug or metabolite s or both. Identification consists of obtaining the chromatographic retention time or relative retention time and the mass spectrum of the substance and showing that the relative retention time and spectrum match that of a reference compound.
The spectra of these three peaks matched those of known reference compounds data not shown. In this case the analysis identified not only a xenobiotic steroid but also two metabolites of the steroid. Thus the amount of analytical information obtained in this analysis is far beyond simple identification of a single substance; indeed, this analysis is helpful in responding to assertions that the sample might have been fortified, because the finding of metabolites is legal evidence that the individual who submitted the urine ingested the substance.
Total ion current chromatogram of a urine sample collected from a subject who ingested boldenone. The ability of the laboratories to detect xenobiotic AAS continues to improve, given a growing body of knowledge of the metabolism of the compounds, method improvements, and instrument advances.
The major metabolites of virtually all AAS are known and many have been synthesized 4. For some drugs, as many as 11 metabolites have been detected 5. The recent development of methods for analysis by high-resolution mass spectrometry HRMS is an important, but expensive, advance.
HRMS operates in the selected-ion monitoring SIM mode to screen for xenobiotics and in the full-scan mode for confirmations 6. This approach is particularly adept at screening for long-lasting metabolites of stanozolol and methandienone.
As in all sports drug testing, a confirmation assay is performed on samples that screen positive. One aspect of identification that continues to be debated is the absolute amount and nature of analytical information that must be obtained before a positive report is issued. Some advocate obtaining a full ion scan of at least one of the substances named in the positive report.
Monitoring the preceding nominal mass allows demonstration that it is not substantially more intense than the ion of interest and thus excludes the possibility that the latter is an isotopic peak from some interference. The subsequent mass must have the expected response. Generally, drug-testing programs in the context of athletics ascribe to the full-scan approach for at least one of the substances reported.
This is in contrast to the widely accepted practice in drugs-of-abuse testing of reporting positive cases on the basis of SIM data 7 8. Another aspect of xenobiotic steroid testing that merits review is the question of the origin of the steroid and metabolites.
One report 9 describes the finding of small amounts of boldenone and two metabolites in the urine of a normal man who had not received boldenone. This case argues for caution in interpretation of positive tests for low quantities of boldenone, for additional studies of this issue, and for devising ways to discriminate between endogenous and exogenous sources of boldenone.
It is illegal in most countries to treat or feed cattle with anabolic steroids, and European countries in particular vigorously monitor meat for contamination with anabolic steroids; nevertheless, evidence of contamination exists The possibility that urine from untreated subjects may contain very low concentrations of nandrolone metabolites has been discussed 12 13 ; however, the mass spectrum of these substances has not been presented, and others find no evidence for nandrolone metabolites in human urine after ingestion of meat from animals that were treated with nandrolone decanoate 28 and 61 days before slaughter In an experiment designed to show human contamination, ingestion of meat from chickens deliberately treated with methenolone heptanoate led to finding methenolone and metabolites in urine Doping with endogenous steroids is the most serious issue facing sport today; when cleverly administered, these are very difficult to detect.
Quadrupole mass spectrometers cannot distinguish between pharmaceutical T and natural T because their spectra are identical. Various approaches to prove T administration have been considered within the practical constraint that only one untimed urine is available for the screening test. Instead, they advocated measuring the ratio of T to luteinizing hormone LH in urine, because chronic administration of T inhibits the production of LH and lowers the urine concentration of LH.
Doping with T was reported in the s 21 , but not until did an effective test became available: T and E differ chemically only in the configuration of the hydroxyl group on C Therefore, the definition of T doping has been changed: The highest three ratios were 30, 36, and If the athlete has never been tested before, one should try to obtain at least two additional samples at 3- to 6-week intervals, with as short a notice as possible.
At those values, the likelihood of natural increases is remote. This is in agreement with the data of Garle et al. For example, the volunteer in Fig. For the first 9 days a sample was collected each day, all were analyzed in one batch, and the CV was only 3. The rationale for caution is that precise numbers are readily attacked by litigation attorneys, and lay-adjudicators often do not understand measurement variability.
Expressing T and E concentrations in nanograms per milligram of creatinine is useful, but this approach has not been widely used, probably because of concerns that creatinine excretion rates are influenced by exercise and many other factors We also take into consideration the absolute value of the E and the amount of advance notice for the collections.
If, at this point, a clinical examination and serum tests have not been performed, we recommend serum tests that are routinely available to the clinician: If these evaluations are normal, the likelihood of a T-secreting tumor is extremely remote. If the serum T is increased or if the follicle-stimulating hormone or LH is low, or both, it is important to extend the evaluation and determine if there is an endogenous source of T or the use of exogenous T.
In difficult cases, a h urine may be collected; analyzed for the total amount of T, androsterone, and etiocholanolone; and the results compared with published norms For a few of the athletes we monitor, serum tests and clinical evaluation have been performed and the results have been normal.
If the first sample tested from an athlete exceeds When it does not, we recommend the clinical evaluation described above and, if possible, one or more of the ancillary tests described below.
In case the above approach still does not lead to a definitive determination of whether or not T has been used, additional tests may be performed—with the understanding that documented experience with these tests is limited and that more-invasive techniques are involved. The ketoconazole challenge test 26 27 40 involves collecting urines before and after administration of an oral dose of ketoconazole, which inhibits the synthesis of T. Experience to date with the ketoconazole test indicates that it differentiates between T users and nonusers.
At this time, the test is not widely used in the US because it requires drug administration and entails the risks related thereto, as well as commitment and expense on the part of the athlete or the sports organization. Another approach is based on measuring the concentration in serum of any substance that precedes T in the biosynthetic pathway to T and calculating a ratio of that substance to T; in the presence of exogenous T, the production of the precursors will be suppressed and the ratio should be high.
More experience with this test is desired. In the former case, the test measures the ratio of total T unconjugated T plus the T deconjugated from the glucuronide to total E. In the latter case, the unconjugated glucuronide and to some extent the sulfate fractions are taken into account. Additional studies of these and other proposals 30 of Dehennin are underway. To that end, Sanaullah and Bowers 43 have synthesized deuterium-labeled T and E glucuronides and sulfates and have developed a liquid chromatography—tandem mass spectrometry method for directly quantifying these moieties.
Another noninvasive test is the determination of the carbon isotope ratio CIR. Most carbon atoms are 12 C, and a very few are 13 C and 14 C. Further on-going studies are anticipated to improve on the measurement of CIR and on the premeasurement analytical techniques. In Falk et al. It will be important to advance these studies by adding placebo controls to factor out the effects of biorhythms and other sources of potential bias and to clarify dose—response relationships.
The reason for this is not known. Data on three cycles in one of these subjects have been presented Currently, the drug of choice for the management of hypogonadal syndromes is T enanthate, typically given by injection every 2 or 3 weeks in doses of — mg. Because parenteral injections are inconvenient, the pharmaceutical industry has been developing alternative formulations and routes of administration.