HORMONES 2004, 3(4):244-251 A Paradox: The Roles of Inositolphosphoglycans in mediating insulinsensitivity and Hyperandrogenism in the Polycystic Ovary Syndrome Kai I. Cheang1, Paulina Essah2, John E. Nestler2,3 1Ph.D., Department of Pharmacy, 2M.D., Department of Internal Medicine, 3M.D., Department ofObstetrics and Gynecology, Medical College of Virginia Campus, Virginia CommonwealthUniversity, Richmond, Virginia
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Iaaf beta-2 agonists protocolIAAF BETA-2-AGONISTS PROTOCOL
In response to a generally recognised increase in the use of beta-2 agonists by athletes in the past, the
IAAF decided to implement a protocol for the authorisation of its use on the occasion of the IAAF
World Athletics Championships in Paris-Saint Denis in 2003. The aim was controlling and limiting the
misuse of beta-2-agonists. Lately, at the time the IOC Medical Commission established a Beta-2-
agonist for Athens 2004 Olympic Games the above mentioned IAAF protocol was amended and
expanded. IOC recently modified its protocol for Beijing 2008 Olympic Games. This lately modified
IOC protocol has taken seriously into account the guidelines and recommendations stated at the IOC
Consensus Statement on Asthma in Elite Athletes from January 2008, namely:
There was consensus that the diagnosis of asthma could not be made in elite athletes on the basis of respiratory symptoms alone and spirometric evidence of reversible airways obstruction or airway hyper responsiveness was needed to confirm the diagnosis. The use of national and international guidelines for treatment was recommended with a note that there are special issues for elite athletes. One of these issues relates to the tolerance that can develop with frequent use of inhaled beta 2 agonists and that those who use them daily may find them less effective against exercise-induced bronchoconstriction (EIB). The use of inhaled glucocorticosteroids was encouraged for treatment of asthma and EIB. The use of long acting beta 2 agonists as monotherapy was discouraged. The importance of athletes receiving education with respect to asthma, EIB and correct use of their medications was stressed. In addition to all the above, the new International Standard for Thereapeutic Use Exemption states at its Rule 7.13 that the use of beta-2-agonists by inhalation must have a medical file justifying the use. That file should meet a minimum of requirements that are in accordance with our IOC Consensus Statement. Taking all that into consideration the IAAF Medical and Anti-doping Commission issues the new IAAF Beta-2-Agonists Protocol as it follows: Applicants seeking the use inhaled beta-2 agonists will be required to submit A TUE Application Form Objective evidence of asthma and/or exercise-induced asthma (EIA) or EIB through the provision of test results (and supporting documentation, if available), as set out below All tests should have been performed from 1st October 2008 and within 3 months of the TUE Form Application Date. Note: all TUE Application Forms and supporting documentation must be submitted to the IAAF in either English or French. 1. Detailed Medical Records
Medical records should include (accordingly with the enclosed form): A precise diagnosis of the individual's condition requiring the use of inhaled beta-2 agonists. All relevant information concerning the individual concerned and his condition: o age of onset o symptoms suggesting airway obstruction following exercise, upper respiratory infection, at rest and at night and/or during the pollen season o identified triggering factors o past history of atopic disorders and/or childhood asthma o past physical examinations o results of skin prick tests or RAST to document the presence of allergic hypersensitivity Any specific information concerning the individual's coughing during or post-exercise, dyspnoea, shortness of breath, wheezing, chest tightness or excess sputum. Details of all consultations with physicians qualified in the treatment of asthma and details of any attendance in hospital emergency departments for treatment or admission to hospital for treatment of acute exacerbation of asthma. Details of the individual's currently prescribed medication and any other medication prescribed in the last 6 months. Details of medication in the 3 months prior to provocation tests (see below) must also be notified. 2. Provocation Test Results
The measures of forced expiratory volume (FEV1) at rest, as well as changes in FEV1 in response to
either an inhaled bronchodilator or to a bronchial provocation test, are the essential criteria that must be
send together with the application form for inhaled beta2 agonists (see below for further details on
Peak Expiratory Flow (PEF) measurements are unacceptable.
In the application form, information must be provided for at least one of the tests below.
Only tests performed after 1st October 2008, and within 3 months of the TUE Form Application Date,
will be taken into consideration by the IAAF TUE Sub-commission.
Flow volume curves are not mandatory any more. However, they may be requested at any time during
the evaluation period by the IAAF TUE Subcommission. Therefore, the medical files should record
them in order to allow the athlete to send them if requested.
Athletes must also present a positive test result from one of the following recognised provocation tests:
After administering a "permitted" beta2 agonist by inhalation, a bronchial reversibility test is
considered positive if the increase in FEV1 is 12% or more of the baseline FEV1 or the predicted FEV1
and exceeds 200 ml.
BRONCHIAL PROVOCATION TESTS:
Recommendation for withholding medications prior to tests
To provide the optimal test circumstances, some medications must be withheld for 8 to 96 hours before
the bronchial provocation tests:
No short-acting bronchodilators, sodium cromoglycate, nedocromil sodium, or ipratropium bromide for 8 hours. No long-acting bronchodilators or antihistamines for 48 hours. No leukotriene antagonists for four days. Steroids should not be inhaled on the day of the test. No caffeine should be taken on the morning of the test. Avoid vigorous exercise for at least four hours prior to the start of the test and avoid any exercise on the day of testing. Various bronchial provocation tests may be used:
a) eucapnic voluntary hyperpnea test
b) exercise challenge in the laboratory or an exercise test in the field
c) hyperosmolar aerosols i.e. 4.5gm% saline or dry powdered mannitol
d) methacholine test
a) Eucapnic voluntary hyperpnea test
The eucapnic voluntary hyperpnea test is considered positive when a fall in FEV1 of 10% or more from
baseline is recorded after a 6 minutes period of hyperpnea in dry air. To overcome the problem of any
post-test respiratory muscle fatigue, the FEV1 should first be recorded at least 3 minutes after
challenge. It is usual for the reduction to be sustained over the next five minutes to be consistent with
b) Exercise challenge in the laboratory or an exercise test in the field
The response to the exercise challenge is considered positive when there is a fall in FEV1 of 10% or
more compared to baseline during the first 30 minutes post exercise.
To maximise the opportunity for a positive test, the exercise test should be performed breathing dry air
for 8 minutes with the intensity of exercise close to maximal for the last 4 minutes. To overcome the
problem of any post-test respiratory muscle fatigue, the FEV1 should first be recorded at least 3
minutes after challenge. It is usual for the reduction to be sustained over the next 5 minutes to be
consistent with exercise-induced bronchoconstriction (EIB).
c) Hyperosmolar aerosols
A fall in FEV1 of 15% or more from baseline after inhaling 22.5 ml of 4.5 gm% saline (e.g. 4.5 g
NaCl/100 ml water) or a dose of 635 mg of dry powdered mannitol is a positive response and is
consistent with a diagnosis of currently active asthma or EIA/EIB. The response to 4.5% saline and the
response to mannitol is usually reported as the dose required to provoke a 15% fall in FEV1 (PD15) but
should also be reported as the maximum fall after the final dose of aerosol .
d) Methacholine test
A test is considered positive if there is a fall in FEV1 of 20% or more from baseline at a dose (PD20)
less than or equal to 400 microgram / 2 micromoles (cumulative dose) or 200 micrograms / 1
micromole (non cumulative dose) or a concentration (PC20) less than or equal to 4mg/ml (tidal
breathing technique American Thoracic Society guidelines 1999) when the subject is not taking
inhaled corticosteroids or has taken them for less than one month.
For applicants taking inhaled corticosteroids for at least one month, the PD20 should be less than
or equal to 1600 micrograms /8.0 micromoles (cumulative dose) or 800 micrograms / 4.0 micromoles
(non cumulative dose), or a PC20 less than or equal to 16.0mg/ml (tidal breathing ATS guidelines
1999) to be accepted as proof of airway hyperresponsiveness (AHR).
It should be noted that a negative response to methacholine does not exclude exercise-induced
asthma/bronchoconstriction in an athlete and in the event of a negative response, an alternative
bronchial provocation test is recommended. The method of delivery of methacholine may influence the
outcome. If the values for PC20 or PD20, during methacholine challenge are in excess of the thresholds
mentioned above, the athlete may undergo an EVH test or an exercise test or a hyperosmolar aerosol
IAAF TUE Sub-commission strongly encouraged to submit athletes preferably either an EVH test or a
For a better understanding of the disease's physiopathology and adequate subsequent treatments, the
assessment of eosinophils and/or neutrophils on the provoked sputum is highly recommended and will
be especially welcome.
IMPORTANT NOTE: The results of bronchial provocation tests using pharmacological agents
other than methacholine (e.g. carbachol, histamine or adenosine monophosphate) WILL NOT
WELL-CONTROLLED ASTHMA with negative response to all the tests In the case of an athlete
with known, but well-controlled, asthma recording a negative result to the bronchial provocation
test(s), but still seeking approval for the use of inhaled beta2 agonist(s), the following documentation
must be included in the medical file: consultations with their physician for treatment of asthma,
hospital emergency department attendance or admission for acute exacerbations of asthma or treatment
with oral corticosteroids. Additional information that may assist includes those quoted at point 1 above
(Detailed Medical Records).
FEV1 = Forced expired volume in one second.
PD15 FEV1 = Is the provocative dose of 4,5%saline or mannitol causing a 15% fall in FEV1
PC20 FEV1 = Is the provocative concentration of methacholine causing a 20% fall in FEV1
PD20 FEV1 = Is the provocative dose of methacholine causing a 20% fall in FEV1
References: 1. Brannan JD, Anderson SD, Perry CP, Freed-Martens R, Lassig AR, Charlton B. The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir Res 2005;6: 144 2. Cockcroft DW, Davis BE, Todd DC, Smycniuk AJ. Methacholine challenge: comparison of two methods. Chest 2005; 125:839-844 3. Cockcroft DW, Davis BE. The bronchoprotective effect of inhaling methacholine by using total lung capacity inspirations has a marked effect on the interpretation of the test result. J Allergy Clin Immunol 2006; 117:1244-8 4. Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacoline and exercise challenge testing-1999. Am J Respir Crt Care Med, 2000; 161:309-29. 5. Fitch KD, Sue-Chu M, Anderson SD, Boulet LP, Hancox RJ, McKenzie D, Backer V, Rundell KW, Alonso JM, Kippelen P, Cummiskey JM, Garnier A, Ljundqvist AL. Asthma and the elite athlete: Summary of the International Olympic Committee's Consensus Conference, Lausanne,Switzerland, January 22-24, 2008. J Allergy Clin Immunol 2008;122:254-60. 6. Gold WM. Pulmonary function testing. IN. Murray JF, Nadel JA, (eds.) Textbook of Respiratory Medicine. 2nd ed. WB Saunders Co, Philadelphia 1994: 798-893. 7. Hurwitz KM, Argyros GJ, Roach JM, Eliasson AH, Phillips YY. Interpretation of eucapnic voluntary hyperventilation in the diagnosis of asthma. Chest, 1995; 108: 1240-5 8. Medical Commission. International Olympic Committee. Beta2 adrenoceptor agonists and the Olympic Games in Beijing. 9. Medical Commission. International Olympic Committee. IOC Consensus Statement on Asthma in Elite 10. Sterk PJ, Fabbri LM, Quanjer PH, et al. Airway responsiveness: Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur Respir J, 1993 ; 6 (Suppl 16):53-83. 11. Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, Cummiskey J, Delgado L, Del Giacco SR, Drobnic F, Haahtela T, Larsson K, Palange P, Popov T, van Cauwenberge P. Exercise-Induced Asthma, Respiratory and Allergic Disorders in Elite Athletes: Epidemiology, Mechanisms and Diagnosis: Part I of the Report from the Joint Task Force of the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) in Cooperation with Ga2len. Allergy 63: 387-403, 2008. 12. Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, et al. Treatment of exercise- induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the report from the Joint Task Force of European Respiratory Society (ERS) and European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA(2)LEN. Allergy 2008;63(5):492-505. 13. Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: Challenges for diagnosis. J Allergy Clin Immunol 2002;110(3):374-380. 14. Holzer K, Anderson SD, Chan H-K, Douglass J. Mannitol as a challenge test to identify exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003;167(4):534-547. 15. Pedersen L, Winther S, Backer V, Anderson SD, Larsen KR. Airway responses to eucapnic hyperpnea, exercise and methacholine in elite swimmers. Med Sci Sports & Exerc 2008;40(9):1567-1572.
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