When Anti-Doping reveals pathology an Australian experience

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1 When Anti-Doping reveals pathology an Australian experience WADA TUE Symposium Dr Susan White ASDMAC Chair. Member WADA TUE-EG, Member FINA DCRB

hcg normal physiological production hcg is a glycoprotein produced normally in females by placental tissue used to confirm pregnancy produced in small

2 hcg normal physiological production hcg is a glycoprotein produced normally in females by placental tissue used to confirm pregnancy produced in small amounts by the pituitary hcg occurs in multiple forms including the intact α/β heterodimer, glycosylated, free β and α sub-units, and nicked fragments

3 Recombinant hcg Used in medical practice to manage infertility prohibited by IOC (and now WADA) since 1987 prohibited in males only briefly prohibited in females- significant issues around AAF actually being due to pregnancy Social/emotional Wanted/unwanted pregnancy

hcg as a doping agent hcg stimulates Leydig cells to produce endogenous Testosterone Anecdotally hcg is used to reverse adverse effects of a supressed

4 hcg as a doping agent hcg stimulates Leydig cells to produce endogenous Testosterone Anecdotally hcg is used to reverse adverse effects of a supressed pituitary-testicular axis due to androgenic anabolic steroid use Testicular atrophy Infertility (decreased spermatogenesis) *TUE requests gynecomastia

5 hcg as a doping agent Recombinant hcg serum and urinary hcg serum and urinary Testosterone serum and urinary LH Marked increase in T:LH ratio Minimal change in T:E ratio Handelsmann,D. Effects of recombinant human LH and hcg on serum and urine LH and androgens in men. Clinical Endocrinology (2009) 71,

6 Elevated hcg as a marker of pathology hcg can be produced by tumour cells in both men and women In men, most common are germ cell tumours (testicular seminomas) 5% germ cell tumours are extra-gondal (mediastinal) Rarely other tumours bladder, lung

7 hcg- where doping meets pathology WADA has considered the possibility that an elevated hcg detected during an anti-doping urine test may result from the presence of an hcg producing tumour WADA has developed Guidelines for reporting and management of hcg findings (Version 1.0, 2011)

Tumours detected through anti-doping testing Track and Field athlete UK 1989 Weight-lifter Australia 2005 hcg 66 (fell to < 0.5, 5/52 postop) LH < 0.2 (rose to 4.5) FSH <0.

8 Tumours detected through anti-doping testing Track and Field athlete UK 1989 Weight-lifter Australia 2005 hcg 66 (fell to < 0.5, 5/52 postop) LH < 0.2 (rose to 4.5) FSH <0.2 (rose to 15.1) Testosterone 33.5 (fell to 6.7) Normal testicular ultrasound Mediastinal seminoma on chest CT scan (Newcombe AE et al J Thorac Cardiovasc Surg 206;132:722-3)

Tumours detected through anti-doping testing Italian Soccer player 2013 Initially given an AAF and banned from sport Once diagnosis made- banned reversed English Soccer player 2013 Investigated after

9 Tumours detected through anti-doping testing Italian Soccer player 2013 Initially given an AAF and banned from sport Once diagnosis made- banned reversed English Soccer player 2013 Investigated after initial screen and diagnosed (Weiler,R. Tombides, Urwin,J. Clarke,J. Verroken, M. Football for life versus anti doping for the masses: ethical anti doping issues and solutions based on the extenuating experiences of an elite footballer competing while undergoing treatment for metastatic testicular cancer. Br JSportsMed published online Mar )

10 WADA hcg Lab Guidelines Urine Anti-doping tests Initial screen for total hcg content If initial screen is > 5 miu/ml (adjust to SG 1.020) proceed to a confirmatory test Confirmatory test for intact hcg only

11 WADA hcg guidelines Lab Guidelines If Confirmatory test < 5 = ATF (atypical finding)* >5 = AAF (adverse analytical finding) *Atypical Finding may result from: Tumour Immunoassay artefacts (mainly Immulite assay broad specificity for hcg and its fragments) Familial hcg? (Laurence Cole 2011), altered excretion?

12 WADA hcg guidelines Lab Guidelines WADA Guidelines indicate for Atypical Findings. the ADO should alert the Athlete and advise that clinical investigations be performed to address the possibility of a pathophysiological condition as the cause of the elevated hcg

13 Anti-Doping Organisations advising athletes on pathophysiology There are currently no guidelines on how this advice should be managed. In Australia(until recently) the Science and Results Manager of the NADO(science graduate, not medical) rang the athletes and told them to see a doctor due to some abnormal results

ADOs advising athletes on pathophysiology in Australia Athletes often ignored the advice Didn t realise the potential severity Or Became very anxious Science manager

14 ADOs advising athletes on pathophysiology in Australia Athletes often ignored the advice Didn t realise the potential severity Or Became very anxious Science manager Unable to answer athlete questions regarding potential diagnoses unable to discuss/advise athlete s doctor (if they had one) difficulty in interpreting medical tests

15 Australian Process (2013 onwards) ASADA TUEC (ASDMAC) Contacted by Science and Results Manager when an ATF hcg is detected (i.e. initial >5, confirmatory <5) ASDMAC Chair allocates the case to a member (all physicians) ASDMAC Physician contacts athlete explains abnormal test and possible relevance Answers (lots of) questions Asks athlete to nominate a doctor to help coordinate the investigation

Australian Process for managing hcg -ASDMAC physician contacts athlete s Doctor Explains significance of elevated hcg Sends a summary of possible causes and suggested

16 Australian Process for managing hcg -ASDMAC physician contacts athlete s Doctor Explains significance of elevated hcg Sends a summary of possible causes and suggested investigations Requests Dr performs investigations (or refers to an endocrinologist) Requests a copy of investigations and a letter summarising outcome sent to ASDMAC member

17 Australian Process for managing hcg Medical file including letter and investigations are sent to, considered and retained by ASDMAC ASDMAC then advises NADO that either No tumour proceed to 2 further tests as directed in WADA lab guidelines or Tumour detected athlete being medically managed After 2 follow-up tests ASDMAC again reviews results? Tumour? doping

18 Elevated hcgs investigated by ASADA /4 13 Atypical findings (ATF) hcg (i.e > 5 on initial screen, < 5 on confirmatory) No Adverse Analytical Findings(AAF) during this time (ie >5,>5) 1 athlete has a TUE for infertility treatment (hcg always detected)

19 Elevated hcgs investigated by ASADA 11 investigated (2 moved overseas, difficulty with follow up) Range of screening hcgs: * (mean 6.67) (*all Immulite assays) One hcg= (16 yr old swimmer) All confirmatory hcg tests were <1

20 Elevated hcgs investigated by ASADA All those investigated had blood hcg, AFP, FSH,LH and a testicular ultrasound Most had mediastinal CT scan All investigations were normal All received medical clearance No tumours detected

21 Elevated hcg ATF coordinated by ASDMAC In summary - Positives Process has worked well most athletes were contacted, smooth process with discussion between doctors Athlete concerns/questions answered NADO able to close files that had been outstanding for a long time Sensitive medical information interpreted and retained by doctors

22 Elevated hcg ATF investigations coordinated by ASDMAC Concerns 1. Many low grade positives resulting in distress and possibly unnecessary investigations for athlete 2. What about >5,>5 ie AAF? Results currently managed as a positive anti-doping case. Are these at any less risk of being a tumour? Should the management for these cases involve some advice regarding medical investigation?

23 Considerations for the future hcg screening test possibly too sensitive- either change assay or change the reporting levels? WADA s New testing strategy: Focus on biologically active intact hcg only Different intact hcg assays for screening and confirmation (2 immunoassays or immunoassay + LC-MS/MS) Reporting levels (limits) being worked out from athletes reference data.

24 Considerations for the future Possible register of hcg events to assist in future management and guidelines? ADAMs acts as a register but not all NADOs/IFs use ADAMS: Sep 2011 Apr 2014: ~200 ATF, 24 AAF. ~3-4 testicular cancers detected. Increased use of ADAMs, better data

25 Considerations for the future Adverse Analytical Findings for hcg (ie >5,>5) Advice to the NADO to notify the athlete and advise clinical investigations If no pathology. then called an Anti-Doping Rule Violation.

26 Summary - some medical involvement in coordinating the investigation

WADA Technical Document TD2017CG/LH

WADA Technical Document TD2017CG/LH REPORTING & MANAGEMENT of URINARY HUMAN CHORIONIC GONADOTROPHIN (hcg) and LUTEINIZING HORMONE (LH) FINDINGS IN MALE ATHLETES The purpose of this Technical Document is to ensure a harmonized approach in