Testosterone supplementation in older men restrains insulin-like growth factor's dose-dependent feedback inhibition of pulsatile growth hormone secretion / Johannes D. Veldhuis, Daniel M. Keenan, Joy N. Bailey, Adenborduin Adeniji, John M. Miles, Remberto Paulo, Mihaela Cosma, Cacia Soares-Welch

• Journal of Clinical Endocrinology & Metabolism 94 (2009) 1 (1 January), p. 246-254
• PMID: 18984660
• PMCID: PMC2630862
• DOI: 10.1210/jc.2008-1516

Abstract

Background: Pulsatile GH secretion declines in older men. The causal mechanisms are unknown. Candidates include deficient feedforward (stimulation) by endogenous secretagogues and excessive feedback (inhibition) by GH or IGF-I due to age and/or relative hypoandrogenemia.

Hypothesis: Testosterone (T) supplementation in healthy older men will restrain negative feedback by systemic concentrations of IGF-I.

Subjects: Twenty-four healthy men (ages, 50 to 75 yr; body mass index, 24 to 30 kg/m(2)) participated in the study.

Methods: We performed a prospectively randomized, double-blind, placebo-controlled assessment of the impact of pharmacological T supplementation on GH responses to randomly ordered separate-day injections of recombinant human IGF-I doses of 0, 1.0, 1.5, and 2.0 mg/m(2).

Analysis: Deconvolution and approximate entropy analyses of pulsatile, basal, and entropic (pattern-sensitive) modes of GH secretion were conducted.

Results: Recombinant human IGF-I injections 1) elevated mean and peak serum IGF-I concentrations dose-dependently (both P < 0.001); 2) suppressed pulsatile GH secretion (P = 0.003), burst mass (P = 0.025), burst number (P = 0.005), interpulse variability (P = 0.032), and basal GH secretion (P = 0.009); and 3) increased secretory pattern regularity (P = 0.020). T administration did not alter experimentally controlled IGF-I concentrations, but it elevated mean GH concentrations (P = 0.015) and stimulated pulsatile GH secretion (frequency P = 0.037, mass per burst P = 0.038). Compared with placebo, T attenuated exogenous IGF-I's inhibition of GH secretory-burst mass (P < 0.038) without restoring pulse number, basal secretion, or pattern regularity.

Conclusion: The capability of systemic T to mute IGF-I feedback on pulsatile GH secretion suggests a novel mechanism for augmenting GH production.

Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial / Ralf Nass, Suzan S. Pezzoli, Mary Clancy Oliveri, James T. Patrie, Frank E. Harrell Jr, Jody L. Clasey, Steven B. Heymsfield, Mark A. Bach, Mary Lee Vance, Michael O. Thorner. - (Annals of Internal Medicine 149 (2008) 9 (4 November); p. 601-611)

• PMID: 18981485
• PMCID: PMC2757071
• DOI: 10.7326/0003-4819-149-9-200811040-00003

Abstract

Background: Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence. The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated.

Objective: To determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevents the decline of fat-free mass, and decreases abdominal visceral fat in healthy older adults.

Design: 2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.

Setting: General clinical research center study performed at a university hospital.

Participants: 65 healthy adults (men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy) ranging from 60 to 81 years of age.

Intervention: Oral administration of MK-677, 25 mg, or placebo once daily.

Measurements: Growth hormone and insulin-like growth factor I levels. Fat-free mass and abdominal visceral fat were the primary end points after 1 year of treatment. Other end points were body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function, and quality of life. All end points were assessed at baseline and every 6 months.

Results: Daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels to those of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677 group (change, -0.5 kg [95% CI, -1.1 to 0.2 kg] vs. 1.1 kg [CI, 0.7 to 1.5 kg], respectively; P < 0.001), as did body cell mass, as reflected by intracellular water (change, -1.0 kg [CI, -2.1 to 0.2 kg] vs. 0.8 kg [CI, -0.1 to 1.6 kg], respectively; P = 0.021). No significant differences were observed in abdominal visceral fat or total fat mass; however, the average increase in limb fat was greater in the MK-677 group than the placebo group (1.1 kg vs. 0.24 kg; P = 0.001). Body weight increased 0.8 kg (CI, -0.3 to 1.8 kg) in the placebo group and 2.7 kg (CI, 2.0 to 3.5 kg) in the MK-677 group (P = 0.003). Fasting blood glucose level increased an average of 0.3 mmol/L (5 mg/dL) in the MK-677 group (P = 0.015), and insulin sensitivity decreased. The most frequent side effects were an increase in appetite that subsided in a few months and transient, mild lower-extremity edema and muscle pain. Low-density lipoprotein cholesterol levels decreased in the MK-677 group relative to baseline values (change, -0.14 mmol/L [CI, -0.27 to -0.01 mmol/L]; -5.4 mg/dL [CI, -10.4 to -0.4 mg/dL]; P = 0.026); no differences between groups were observed in total or high-density lipoprotein cholesterol levels. Cortisol levels increased 47 nmol/L (CI, 28 to 71 nmol/L (1.7 microg/dL [CI, 1.0 to 2.6 microg/dL]) in MK-677 recipients (P = 0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677 recipients. Increased fat-free mass did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results.

Limitation: Study power (duration and participant number) was insufficient to evaluate functional end points in healthy elderly persons.

Conclusion: Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.

CAS 2008/A/1565 World Anti-Doping Agency (WADA) v. International Military Sports Council (CISM) & Federico Turrini

Related case:

Swiss Federal Court 4A_10_2009 Federico Turrini vs WADA & CISM
July 8, 2009

• Aquatics (swimming)
• Doping (19-norandrosterone)
• Dies a quo of the time limit for the filing of the appeal
• Presence of a prohibited substance
• Conditions of reduction of the period of ineligibility based on exceptional circumstances
• Determination of the disciplinary sanction

1. It is very important that international sports law rules are equally applied for all parties, no matter if they are athletes or organizations, and that the application also must be foreseeable for those involved. If a party which have not taken part in the proceedings leading to the appealed decision shall have a fair opportunity to file an appeal it must be aware of that decision. In spite of the wording of the applicable rule, according to the applicable procedural rules, international sport law and CAS case law, the time limit for the filing of the appeal should not be counted from the date when the decision has been made, but when the party appealing the decision has been notified of such decision. In any event, it is for the respondent to prove that the decision was communicated more than 21 days prior to the appellant’s statement of appeal.

2. The presence of 19-norandrosterone which is an endogenous anabolic androgenic steroid at a concentration greater than 2 ng/ml in an athlete’s bodily specimen constitutes a doping violation incompatible with an endogenous production of the substance.

3. It is the professional duty of an athlete to consult the rules and to be well aware of all the duties an athlete has to fulfil. In this respect, an athlete must be active to ensure that no prohibited substance enters his/her body. As said in the Commentary to WADC, an athlete cannot rely on advice from his/her personal physician in these matters, especially when the doctor is no expert on sports medicine. The fact that an athlete is a professional is also relevant. If the athlete has not done anything to ensure this, s/he has not established that he bears no significant fault or negligence. There is therefore no ground to reduce the sanction on this basis.

4. It is well established that a two-year suspension for a first time doping offence is legally acceptable. Pursuant to the rules, the period of provisional suspension voluntarily accepted by an athlete shall be credited against the total period of ineligibility to be served. Furthermore, it is required by fairness that the starting date of the period of ineligibility should not constitute a disadvantage for the athlete when the process from the sample collection to the date when the sanction can be imposed has been far too long.

On 15 January 2008 the International Military Sports Council (CISM) decided to impose a suspended sanction of 2 years on the Italian swimmer Frederico Turrini after his sample tested positive for the prohibited substance 19-norandrosterone (Nandrolone).

Here the Athlete denied the intentional, accepted the test result and explained that the postitive test was caused by prescribed eye drops that contained the prohibited substance.

Hereafter in May 2008 the World Anti-Doping Agency (WADA) appealed the CISM decision with the Court of Arbitration for Sport (CAS). WADA requested the Panel to set aside the Appealed Decision and to impose a 2 year period of ineligibility on the Athlete.

Following assessment of the case the Panel concludes that the Athlete committed an anti-doping rule violation and that he failed to establish that he bears No Significant Fault or Negligence.

The Panel deems that the Athlete, in order to fulfil his or her duty according to Art. 2.1. of the WADC, has to be active to ensure that a medication that he or she uses does not contain any compound that is on the Prohibited List. In the present case, the Athlete has not done anything to ensure this.

Therefore the Court of Arbitration for Sport decides on 4 November 2008 that:

(1) The appeal filed by WADA on 30 May 2008 is admissible.

(2) The decision of CISM Discipline Commission dated 15 January 2008 in the matter of Federico Turrini. is set aside.

(3) Federico Turrini is sanctioned by a two (2) years ineligibility, which started on 6 February 2008. The period of voluntary suspension from 3 December 2007 to 5 February 2008 shall be credited against the total period of ineligibility to be served.

(4) All competitive results obtained by Federico Turrini from 19 October 2007 until the date of the present decision shall be disqualified with all of the resulting consequences including forfeiture of any medals, points and prizes.

(5) All other prayers for relief are dismissed.

(6) The award is pronounced without costs except for the Court Office fee of CHF 500,- (five hundred Swiss Francs) paid by Mr Federico Turrini and which is kept by the CAS.

(7) Each party shall bear its own costs.

Dufka F, Galloway G, Baggott M, Mendelson J. The effects of inhaled L-methamphetamine on athletic performance while riding a stationary bike: a randomised placebo-controlled trial. Br J Sports Med. 2009 Oct;43(11):832-5. Epub 2008 Nov 3.

The aging population - is there a role for endocrine interventions? / Ralf Nass, Gudmundur Johannsson, Jens S. Christiansen, John J. Kopchick, Michael O. Thorner. - (Growth Hormone & IGF Research 19 (2009) 2 (April); p. 89-100)

• PMID: 18977675
• DOI: 10.1016/j.ghir.2008.09.002

Abstract

The expected increase in the aging population will have a significant impact on society and the health system in the coming years and decades. Enhancing healthspan, "healthy aging", and thus extending the time that the elderly are able to function independently is a significant task and is imperative. Age-dependent changes such as weight loss, sarcopenia and anorexia, which contribute to the development of frailty in the elderly are discussed. The role of the age-dependent decrease in growth hormone secretion in this process and the potential benefits and risks of hormonal interventions to delay, prevent or reverse frailty in the elderly are reviewed.

Anabolic Steroids / Matthew Rhea, Pedro J. Marin Cabezuelo, Mark Peterson, Jeffrey L. Alexander, Ben Potenziano, Derek J. Bunker, Eric L. Sauers, Randy D. Danielsen. - (Clinician Reviews 18 (2008) 11 (November); p. 26-31)

Abstract

Illicit use of anabolic steroids, a significant issue in the United States, is by no means restricted to elite athletes or adolescent sport participants. While steroids can stimulate and enhance muscle tissue development, long-term or excessive use can increase the risk of heart attack, cancer, and/or psychologic impairments. This review examines the prevalence of steroid use, associated benefits and risks, and the importance of accelerating effective education and prevention efforts.

Supplements and Sports / David M. Jenkinson and Allison J. Harbert. – In: American Family Physician, 9 (2008), Vol. 78 (November), p. 1039-1046

Use of performance-enhancing supplements occurs at all levels of sports, from professional athletes to junior high school students. Although some supplements do enhance athletic performance, many have no proven benefits and have serious adverse effects. Anabolic steroids and ephedrine have life-threatening adverse effects and are prohibited by the International Olympic Committee and the National Collegiate Athletic Association for use in competition. Blood transfusions, androstenedione, and dehydroepiandrosterone are also prohibited in competition. Caffeine, creatine, and sodium bicarbonate have been shown to enhance performance in certain contexts and have few adverse effects. No performance benefit has been shown with amino acids, beta-hydroxy-beta-methylbutyrate, chromium, human growth hormone, and iron. Carbohydrate-electrolyte beverages have no serious adverse effects and can aid performance when used for fluid replacement. Given the widespread use of performance-enhancing supplements, physicians should be prepared to counsel athletes of all ages about their effectiveness, safety, and legality.

Results of the WADA monitoring program regarding substances which are not on the 2007 Prohibited List, but which WADA wishes to monitor in order to detect patterns of misuse in sport. These substances are:
- Caffeine
- Pseudoephedrine
- Synephrine
- Bupropion

Prevention through Education : A Review of Current International Social Science Literature : A focus on the prevention of bullying, tobacco, alcohol and social drug use in children, adolescents and young Adults / Susan Backhouse, Jim McKenna, Laurie Patterson. - Carnegie Research Institute; Leeds Metropolitan University. – Leeds : Leeds Metropolitan University. – 2009. – Review prepared for the World Anti-Doping Agency (WADA)

This review is the result of WADA’s identification of education and social science research as strategic priorities for developing evidencebased anti-doping education. To complete this commission we set out to identify evidence regarding the efficacy of prevention interventions across four social domains;
bullying, alcohol, tobacco and social drug use. The main purpose of this review is to highlight the factors which have been determined, to date, as the most successful preventive approaches in these respective domains. Broad conclusions are drawn from the literature with a view to recommending ‘recipes of success’ which could be further refined and applied in the design of future anti-doping prevention programmes.

The review process comprised two main stages. Stage one involved an examination and summation of tertiary and secondary level reviews (e.g., reviews of reviews metaanalyses, systematic reviews), published in the scientific literature or by government agencies between 2002 and November 2008. Stage two comprised the execution of a comprehensive search and review of primary studies based on the fact that the studies were (i) experimental or quasi-experimental, (ii) published from 2002 onward and (iii) not included (or excluded) in the reviews of stage one.

Report of the Independent Observers Beijing 2008 Paralympic Games / Anne Cappelen. - Independent Observer Team. - Montreal : World Anti-Doping Agency (WADA), 2008