Thyroid Hormone Abuse in Elite Sports: The Regulatory Challenge

Sanctions involve suspension from any elite competitive sport and carafate synthroid extend to support personnel and teams. This is generally believed to be longer than the ergogenic benefits of doping, although recent evidence suggests that androgen effects on muscle may create durable or even permanent effects (23) which might argue for much longer or permanent banning of androgen doping violators. Recent media have highlighted the controversy surrounding treatment of elite athletes for hypothyroidism. The World Anti-Doping Agency denied a request by the United States Anti-Doping Agency to ban the use of thyroid medication.

Serum thyroxine (T4), triiodothyronine (T3), and reverse T3 were measured by liquid chromatography–mass spectrometry and serum thyrotropin, free T4, and free T3 by immunoassays in 498 frozen serum samples from antidoping tests together with a separate set of 509 DCFs. Thyroid hormone (TH) abuse for performance enhancement in sport remains controversial and it is not prohibited in sports under the World Anti-Doping Code. Another approach to increase oxygen delivery to muscle has been to exploit the ability of 2,3 diphophoglycerate (2,3 DPG), whose binding to hemoglobin reduces its affinity for oxygen with the left-shift of its oxygen dissociation curve as an oxygen unloading mechanism in tissues. 2,3 DPG analogs, developed as radiation sensitizers for hypoxic radio-resistant tumors, enhance tissue oxygen delivery in vivo (174,175) but would feature only short-term, acute effects readily detectable by mass spectrometry (176,177).

Experience suggests that such innovator products can enter the doping black market before marketing approval (150,171).
Hence the yeast androgen bioassay was decisive in the first conviction for use of a designer androgen by proving that tetrahydrogestrinone (THG) was a potent androgen (84) and has also been used to screen synthetic progestins to show that, unlike the original androgen-derived progestins, the modern generation of progestins are not androgenic (85).
Yet, the prevalence of TH abuse among athletes undergoing antidoping tests for competition in WADA-compliant sports has not been studied systematically.

In individuals with hypothyroidism where the tendency is towards the maintenance of homeostasis (as in the case of athletes), it was not possible to clearly detect the consumption. HIF is a key generic biological mechanism for tissue sensing of hypoxia and triggering local (neovascularization, angiogenesis) and systemic (EPO) defensive reactions. The promoter of the EPO gene contains enhancer and inhibitor regions with the hypoxia-responsive element which binds HIF and a GATA binding site which enhance and inhibit, respectively, EPO gene transcription. HIF is a heterodimer formed by constitutively expressed subunits with the β subunit in excess and availability of α subunit limiting formation of bioactive HIF. The 3 HIFα subunit isoforms are subject to hydroxylation of specific proline residues by prolyl hydroxylase enzymes which inactivate HIFα by ubiquitination, a tag which targets it to proteasomal degradation. HIFα subunit inactivation is strongly dependent on tissue oxygenation being active during normoxia but reduced during hypoxia when persistence of HIFα stabilizes the HIF heterodimer.

Thyroid Hormone Abuse in Elite Sports: The Regulatory Challenge

The major gaps remaining in anti-doping science are (a) the lack of a definitive test for autologous blood transfusion, (b) need for more sensitive detection tests for peptide doping with wider windows of detection and (c) more economical, affordable and robust sample handling and storage procedures including dried blood spot sampling. These challenges must be met by adapting novel technologies such as quantitative proteomics, genomics, and metabolomics as well as implementing more out of competition and blood testing. Such progress depends on innovative applied research which is supported by WADA, Partnership for Clean Competition and certain national anti-doping organizations together with regular peer-review research granting agencies. Finally, the development of effective forensic intelligence investigations, a slow, complex and costly process but which can have salutary effects (e.g. for road cycling in the Lance Armstrong case), is proving a valuable complementary approach as an adjunct to effective laboratory testing.

Serum thyroxine (T4), triiodothyronine (T3), and reverse T3 were measured by liquid chromatography–mass spectrometry and serum thyrotropin, free T4, and free T3 by immunoassays in 498 frozen serum samples from antidoping tests together with a separate set of 509 DCFs.
Consequently there will be variations in practice between physicians in what they consider a “high” TSH and what’s considered “normal”.
Repeated freeze–thaw cycles did not significantly change serum TSH 58, 59 or serum T4, T3, rT3, and FT4 measurements by immunoassays 58.
DCFs from 509 antidoping tests were analyzed for declared substances comprising 197 females and 312 males representing 16 sports disciplines, including football 175, athletics 80, cycling 68, basketball 50, aquatics 46, cricket 25, and rowing 25.

Important caveats on interpreting these few well designed studies are that the effects of higher GH and T doses, as used in doping, have not been studied so that more potent higher dose and/or interactive effects cannot be excluded in the absence of well controlled, high dose, placebo-controlled studies. Anti-doping science history suggests that caution is required before rejecting evidence for claimed ergogenic effects without investigations replicating the pharmacological doses used. The WSJ suggests that there may be some relationship between the rigorous training and the thyroid function itself, in which case the thyroid supplementation is simply restoring “normal” function. This seems to be what Brown believes, seeing dysfunction where other physicians see normal thyroid activity. Setting aside whether or not these athletes actually do have “low” thyroid, we can ask if thyroid treatment is actually offering a performance benefit when administered to patients with a TSH between what appears to be Brown’s cutoff of 2 and the standard cutoff of 4 or 5.

HEMOGLOBIN (BLOOD) DOPING

One had a high serum T4 (153 nmol/L) and FT4 (24.8 pmol/L) with normal serum T3 and FT3, and the remainder had normal serum T4, T3, FT4, and FT3. The method was applied to the total urine fraction (free + glucuronide conjugates + sulfate conjugates) but can be applied to the fractions separately. It was based on extraction at neutral pH to have a global idea of the excretion in urine of acidic (thyronacetic acids) and basic (thyronamines) metabolites. From the latest research on sports injuries, to experiences and insights of those working at the coalface of the Sport and Exercise world, we aim to provide cutting-edge content to the Sport and Exercise Medicine community around the world.

Using the criterion of suppressed serum TSH with increased serum T4, according to the empirical or expected reference ranges, the prevalence of biochemical hyperthyroidism was lower than the age-specific rate of T4 prescription among Australians of comparable age to the athletes. Crucially, however, reflecting the likely difficulties of solely laboratory-based surveillance for TH abuse, no clinical evaluation was possible due to the study’s privacy restrictions. Evaluating such biochemical thyrotoxicosis would require additional evidence to evaluate the possibility of TH doping. Notably a thyroid uptake scan would be required to distinguish endogenous thyrotoxicosis from natural causes such as Graves disease or toxic thyroid nodule(s) requiring medical management, from exogenous ingestion of T4 or T3 or of thyroiditis 37. A low thyroid uptake could be due to exogenous T4 or T3 ingestion but could also be due to thyroiditis, for which additional tests (thyroglobulin, inflammatory and immune biomarkers) would be required. This is analogous to the requirement for evaluating a positive human chorionic gonadotrophin (hCG) finding in a man’s urine antidoping test to distinguish between an early testis cancer and hCG doping 38, 39.

One of the disadvantages is the matrix effect, so it must be treated with particular care in the implementation process. Analysis of serum samples from athletes who reported levothyroxine consumption showed elevated levels of thyronine and tetraiodo-thyronacetic acid. At least preliminarily, these two compounds and the relationships that involve them (with T3 and T4) could be used as markers for the detection of levothyroxine consumption in serum. We plan to investigate the real analytical possibilities for determining the prevalence of use in sports using the available capabilities in the antidoping laboratories, ideally in already existing methods starting from urine or serum samples collected for other antidoping analyses. This would allow, if considered convenient, to include an additional section in the athletes biological passport (ABP) endocrinological module for these hormones. However, treatment with thyroxine, which is not warranted on clinical grounds, can potentially have adverse effects on health, for example, increased risk of cardiac arrhythmias.

Thyroid Therapy or Dysfunction in Athletes: Is it Time to Revisit the Clinical Practice Guidelines?

Other than its proper medical use in diabetics, the use of insulin and its analogs for doping is based solely on its easy availability coupled with anecdotal information from other drug users. There are no clinical studies showing any ergogenic effects of insulin or its analogs in non-diabetic individuals. The doping folklore appears to arise from the classification of insulin as being “anabolic”, in a loose generalization and mistaken analogy to androgens. In healthy non-diabetic individuals, insulin and its synthetic analogs stimulate weight gain via hypoglycemia and increasing appetite, but produce fat rather than muscle gain. The adverse effects include hypoglycemia, hypokalemia, injection-related infections and weight (fat) gain. Doping detection tests for insulin and its analogs continue to evolve and focus on highly sensitive and specific quantitative MS-based proteomics (244).

Immunoassays

Coupled with evidence from the ABP, manipulation of the EPO pathway may be detected in conjunction with corroborative measurement of inappropriately suppressed or elevated endogenous EPO for the prevailing hemoglobin level. Administration of natural androgens (T or DHT) or pro-androgens (androstenedione, DHEA), raises the problem of distinguishing between the exogenous and endogenous steroids. Exogenous T administration can be detected by the urine T/E ratio, the ratio in urine of T to its 17α-epimer epitestosterone (E), operating as a sensitive screening test. In males, both T and E are co-secreted by Leydig cells and excreted in urine consistently so that the urine T/E is usually stable for any individual over time, being typically around 1. Administration of exogenous T, which is not converted to E, increases the urine T/E ratio and, when it exceeds a specified threshold, is evidence for administration of exogenous T.