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

A Cochrane Review suggested that treating subclinical hypothyroidism doesn’t seem to result in meaningful differences in symptoms or quality of life, nor does it decrease cardiovascular morbidity. Direct measurements of T3 and T4 do not seem to be useful in these cases since everything seems to indicate that external supplementation aims to cover the needs of thyroid hormones to maintain homeostasis. Therefore, it could be assumed that the metabolic pathways observed in a euthyroid individual after the administration of TH are not the same as those observed in athletes. The detection of the administration of TH, at least triiodothyronine (T3) and levothyroxine (T4) in urine could work when dealing with euthyroid individuals, either by applying cut-off values of ratios (for T3) or the presence of T1 (for T4).

• Cheating is as old as sport itself, yet the present endemic of doping using pharmaceutical drugs to boost sports performance is largely a Cold War legacy.
• It is a formidable challenge to validate an indirect biomarker as proof of an ADRV capable of withstanding vigorous medico-legal challenge when a proven ADRV would prevent an athlete from pursuing their profession.
• The thresholds are calculated by a variety of algorithms incorporating routine hematological parameters, notably hematocrit and reticulocyte counts.
• A strength of this test is that it is aimed at the exogenous doping agent itself, although it cannot definitively distinguish it from its endogenous counterpart.
• Two of 500 serum samples (184 females, 316 males) were unusable due to severe hemolysis so the analysis included 498 samples from 27 sporting discipline groups with the most frequent comprising football codes 127, aquatic sports (swimming) 76, cycling 75, weightlifting 66, and athletics 38.

MeSH terms

A strength of this test is that it is aimed at the exogenous doping agent itself, although it cannot definitively distinguish it from its endogenous counterpart. The major limitations of this differential isotope ratio test are its narrow window of detection (24-36 hr post administration) and its inability to detect indirect GH doping. While pituitary-derived human GH might not be detected, human pituitary GH, once obtained from national scale pituitary collection and purification programs, has not been available since 1985 when its risks of Creutzfeldt-Jakob disease were identified (225,226) with recombinant human GH replacing pituitary-extracted GH worldwide. This differential isoform test was first introduced for the 2004 Olympics (227) and led in 2010 to the first successful detection of out of competition GH doping (228). The best detection test for autologous hemoglobin doping at present is the hematological module of the ABP introduced in 2009 (148).

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

• TH abuse, including nonprescription use of T3, without critical reference to scientific data or medical supervision, is promoted unrestricted by some bodybuilding regimens operated by those marketing illicit supplies of drugs.
• Hence inhibiting prolyl hydroxylase activity via blocking its required cofactors (ascorbate, ketoglutarate, iron) using cobalt, nickel, iron chelation, ketoglutarate analogs or mechanism-based chemical inhibitors can result in increased hemoglobin via stimulation of EPO secretion (171).
• These substances have unknown safety so that human testing is not feasible making athlete safety an important consideration.
• ConclusionThe Wall Street Journal‘s profile of Dr. Brown and his unorthodox management of elite athletes raises interesting questions about the basis of disease, the conditions for drug treatment, and the implications on the ethics of sports.
• Nevertheless, the 2 separate random samples of the Australian athletes provide consistent estimates of the T4 usage rates, both lower than the age-specific T4 prescription rates in the general Australian population.

Based on the structural similarity of TH and sex steroids, it is notable that sex steroid LCMS measurement displays highly stable and reproducible measurement after frozen (−80 °C) storage for 10 years 55. In 1 immunoassay study, serum TSH and FT4 were stable with small increases FT3 concentrations over up to 25 years of frozen (−25 °C) storage 56, 57. Another study of long-term storage at −80 °C demonstrated inconsistent serum TSH, FT4, and FT3 measurements using different assays. Repeated freeze–thaw cycles did not significantly change serum TSH 58, 59 or serum T4, T3, rT3, and FT4 measurements by immunoassays 58. For serum TSH immunoassays, most studies suggest stability of measured concentrations over prolonged storage or freeze–thaw cycles with only a single study reporting a reduction in serum TSH during frozen storage 60.

REFERENCES

This section collects any data citations, data availability statements, or supplementary materials included in this article. Roderick Clifton-Bligh, Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; Kolling Institute, St Leonards, NSW 2065, Australia; Northern Clinical School, University of Sydney, Sydney, NSW 2065, Australia.

Given the extent to which these athletes push their bodies, even a subtle amount of fatigue, if ameliorated, could potentially improve performance. From this perspective, it raises the question of whether thyroid replacement can be considered a form of doping – a recovery-enhancement or fatigue-deferring boost not available to athletes who didn’t go see Dr. Brown. 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. Athletes completing DCF samples had a mean age of 26.0 ± 5.3 years (median 25 years, interquartile range years).

A major challenge is the non-glycosylated primary structure of recombinant and endogenous 22 kDa GH, that lack the distinctive side-chain carbohydrate differences of exogenous glycoproteins EPO or hCG which provide a convenient basis for sensitive molecular detection coreg synthroid tests. Nevertheless, minor infidelities in commercial manufacturing of GH may incorporate distinctive non-natural chemical features proving an exogenous origin ( ) although these findings have not been developed into detection tests. Challenges to the detection of GH doping arise from the physiological pattern of endogenous GH secretion with its intermittent, pulsatile pattern subject to prominent influence of exercise, stress, and nutritional effects together with GH’s brief circulating half-life and low urine concentrations (220,221). Like other major doping classes, there are both direct and indirect forms of GH doping, involving either direct administration of GH or IGF-I or their analogs and indirect GH doping involving drugs that aim to increase endogenous GH and IGF-I secretion (Table 5).

The distribution of TH measurements was evaluated by the Shapiro–Wilks test for normality and optimal normalizing transformations were determined by Box–Cox analysis. As a result, for analysis serum TSH, T4, T3, and rT3 were log10 transformed whereas FT4 and FT3 were not transformed. The empirical 95% confidence limits for each TH were determined from the data by nonparametric estimation of the 2.5% and 97.5% percentiles of the distribution. In common with many endocrine axes, the thyroid axis works on a negative feedback loop mechanism to maintain homeostasis of circulating levels of the response hormone thyroxine (T4) in the normal range.

The urine T/E ratio thresholds were originally population-based, set initially at 6 and then subsequently lowered to 4. Furthermore, the possibility of false negatives and false positives of population-based thresholds are limitations which may require further analysis to confirm or refute T doping in individual cases. These considerations have led to establishment of the steroid module of the Athletes Biological Passport (ABP), a compendium of serial observation of any individual’s tests which creates adaptive individual-specific T/E ratio threshold (58). This substitution of an individual’s own person-specific, in place of the population-based, thresholds allows for more sensitive and accurate detection of individual deviations in urine T/E ratio as evidence of T doping. Overall, detection of direct androgen doping is now so effective that in WADA-compliant elite competitions it is restricted to the ill-informed, often using counterfeit or unlabeled products (120). Yet the potency of androgen doping in power sports continues to prompt development of novel androgen doping strategies.

This approach was simplified by a second generation algorithm using only routine hematological parameters (hemoglobin, reticulocytes) (154), and was subsequently combined with the concept of a sequential development of individual-specific reference ranges (155) into a third generation algorithms (156,157) which were refined for the ABP (148,149). The hematological module of the ABP currently employs an algorithm involving 8 parameters derived from routine hematological profile (hemoglobin, hematocrit, erythrocyte count, reticulocyte count and percentage, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration) (158). This is capable of detecting any form of hemoglobin doping, whether direct or indirect, with good but imperfect sensitivity ( ) and using only routine hematological tests. The reported increasing use of very low EPO doses (“micro-dosing”) would markedly reduce the magnitude of any dose-dependent ergogenic benefits (145) while still carrying risks of detection, disqualification, and disgrace. Limitations of this study include the privacy restriction, which limited relevant analytical clinical variables and prevented linkage of the sera to the DCFs. Nevertheless, the 2 separate random samples of the Australian athletes provide consistent estimates of the T4 usage rates, both lower than the age-specific T4 prescription rates in the general Australian population.

Immunoassays

However, none of these hormonal peptides have been registered for human therapeutic use with only one (pralmorelin) registered for single-dose, diagnostic use (for GH deficiency) in Japan and unacetylated cyclin ghrelin marketed in Europe for Prader-Willi syndrome. Although they may stimulate GH release initially, many failed to achieve sustained GH release due to desensitization and none achieved meaningful clinical improvements in any target diseases. If their unproven ergogenic benefits are due to sustained GH release this renders them unlikely to be beneficial; nevertheless, the caveat on not accepting negative conclusions without direct testing are also relevant to this class of peptides.