Performance enhancement: Superhuman athletes / Helen Thompson
Enhancements such as doping are illegal in sport — but if all restrictions were lifted, science could push human performance to new extremes.
Preservation of GHRH and GH-releasing peptide-2 efficacy in young men with experimentally induced hypogonadism / Johannes D. Veldhuis, Daniel M. Keenan, Joy N. Bailey, John M. Miles, Cyril Y. Bowers
Abstract
Background: Somatostatin (SS), GHRH, GH-releasing peptide (GHRP), and the sex-steroid milieu regulate GH secretion.
Objective: To test whether GHRH and GHRP remain effective secretagogs in the face of short-term hypogonadism.
Design: Prospective, randomized double-blind.
Methods: Healthy young men (n=24) received a GnRH agonist twice 3 weeks apart followed by placebo (n=13, Pl) or testosterone (n=11, testosterone) addback.
Subjects: were then given consecutive i.v. infusions of l-arginine (to restrain SS outflow) and a maximally effective dose of GHRH or GHRP-2 (to test corresponding secretagog pathways).
Results: GH secretion stimulated by l-arginine/GHRH and by l-arginine/GHRP-2 was unaffected by combined testosterone/estradiol (E(2)) depletion. The low testosterone/E(2) milieu decreased basal (nonpulsatile) GH secretion (P=0.038), without altering fasting pulsatile GH secretion or IGF1 or IGF-binding protein (IGFBP)-3 concentrations. IGFBP-1 (P<0.0001) and abdominal visceral fat (AVF, P=0.017) correlated negatively with fasting basal GH secretion. By contrast, IGF1 (P=0.0012) and IGFBP-3 (P=0.015) correlated positively with fasting pulsatile GH secretion. AVF (P=0.0024) was a negative determinant, and IGF1 a positive determinant (P=0.018), of GHRH-driven GH pulses. Responses to GHRP-2 were unrelated to any of these factors.
Conclusion: l-arginine/GHRP-2 appears to be an especially robust stimulus of GH secretion, since efficacy is unmodified by profound short-term hypogonadism, a range of AVF estimates, and a spectrum of IGF1, IGFBP-1, and IGFBP-3 concentrations. Whether robustness also applies to chronic hypogonadism is not known.
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
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.
Secretagogues govern GH secretory-burst waveform and mass in healthy eugonadal and short-term hypogonadal men / Johannes D. Veldhuis, Daniel M. Keenan
Abstract
Background: GH pulses are putatively initiated by hypothalamic GH-releasing hormone (GHRH), amplified by GH-releasing peptide (GHRP), and inhibited by somatostatin (SS).
Objective: To ascertain how secretagogues control the waveform (time evolution of release rates) as well as the mass of secretory bursts.
Design: We quantified the shape of GH secretory bursts evoked by continuous combined i.v. infusion of maximally effective doses of GHRH and GHRP-2, and by bolus injection of each peptide after delivering L-arginine to restrain hypothalamic SS release in 12 healthy young men.
Methods: A mathematically verified and experimentally validated variable-waveform deconvolution model was applied to intensively sampled GH time series.
Results: The secretory-burst mode (time from burst onset to maximal secretion) was 19+/-0.69 min during saline infusion, and fell to a) 10.4+/-3.0 min during constant dual stimulation with GHRH/GHRP-2 (P<0.01), b) 14.6+/-1.8 min after l-arginine/GHRH (P<0.025), and c) 15.0+/-1.0 min after l-arginine/GHRH (P<0.01). Secretagogues augmented the mass of GH secreted in pulses by 44-, 42-, and 16-fold respectively, over saline (2.2+/-0.81 microg/l per h; P<0.001 for each). Pulse number and variability were unaffected. Applying the same methodology to ten other young men with acute leuprolide-induced hypogonadism yielded comparable waveform and mass estimates.
Conclusion: The present analyses in men demonstrate that peptidyl secretagogues modulate not only the magnitude but also the time course of the GH-release process in vivo independently of the short-term sex-steroid milieu.
Growth Hormone Secretagogues : Physiological Role and Clinical Utility / Felipe F. Casanueva, Carlos Dieguez
Abstract
Growth hormone secretagogues (GHSs) are artificial compounds developed to release GH in vitro. GHSs mimic an unknown endogenous factor that activates the GHS receptor in the pituitary and the hypothalamus. With the cloning of the human GHS receptor it has been demonstrated that GHS is a new physiological system that regulates GH secretion along with growth hormone-releasing factor (GHRH) and somatostatin. GHSs administered alone or in combination with GHRH are the most potent and reproducible GH releasers, and are useful tools for the diagnosis of GH deficiency when tested in a variety of pathological conditions, both in children and in adults. As therapeutic agents, they show clinical effectiveness in enhancing GH release after short-term treatment.
Growth hormone treatment in human ageing : benefits and risks / Roberta Giordano, Lorenza Bonelli, Elisa Marinazzo, Ezio Ghigo, Emanuela Arvat
Abstract
This paper will focus on the rationale of using Growth Hormone (GH) as an anti-ageing therapy in the healthy elderly with age-related decline in the activity of the GH/IGF-I axis, the so called "somatopause". Although the age-related decline in the activity of the GH/IGF-I axis is considered to contribute to age-related changes similar to those observed in Growth Hormone Deficient (GHD) adults, GH/IGF-I deficiency or resistance is also known to result in prolonged life expectancy, at least in animals. These data raise the question whether or not GH deficiency constitutes a beneficial adaptation to ageing and therefore requires no therapy. Moreover, although GH therapy has been shown to exert positive effects in GHD patients, its safety, efficacy and role in healthy elderly individuals is highly controversial. This review provides a comprehensive account of the implications of GH therapy in the ageing subject.
Biosimilar epoetins and other "follow-on" biologics : update on the European experiences / Wolfgang Jelkmann
Abstract
After the patents of biopharmaceuticals have expired, based on specific regulatory approval pathways copied products ("biosimilars" or "follow-on biologics") have been launched in the EU. This article summarizes experiences with hematopoietic medicines, namely the epoetins (two biosimilars traded under five different brand names) and the filgrastims (two biosimilars, six brand names). Physicians and pharmacists should be familiar with the legal and pharmacological specialities of biosimilars: The production process can differ from that of the original, clinical indications can be extrapolated, glycoproteins contain varying isoforms, the formulation may differ from the original, and biopharmaceuticals are potentially immunogenic. Only on proof of quality, efficacy and safety, biosimilars are a viable option because of their lower costs.
Certification of steroid carbon isotope ratios in a freeze-dried human urine reference material / Ellaine Munton, Fong-Ha Liu, E. John Murby, D. Brynn Hibbert
Abstract
An accurate method for the measurement of carbon isotope ratios of steroids in human urine has been developed at the National Measurement Institute, Australia (NMIA) for the certification of a freeze-dried human urine reference material (CRM NMIA MX005). The method measures δ(13)C values by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) analysis following hydrolysis, solvent extraction and high performance liquid chromatography (HPLC) purification. Reference δ(13)C values for testosterone metabolites etiocholanolone, androsterone, and endogenous reference compounds (ERCs) 11β-hydroxyandrosterone and pregnanediol were determined, as well as information δ(13)C values for testosterone, epitestosterone, 11-oxoetiocholanolone, and a range of differences (Δ(13)C) between testosterone metabolites and ERCs. The measurement uncertainty was rigorously evaluated with expanded uncertainties for the reference δ(13)C values between 1.1 and 1.6 ‰ at the 95% coverage level.
Growth Hormone Releasing Hormone Treatment in Normal Aging / George R. Merriam, Suzanne Barsness, David Buchner, Monica Kletke, Lawrence H. Larsen, Karen E. Moe, Robert S. Schwartz, Michael V. Vitiello
Abstract
Because the aging pituitary remains responsive to stimulation by growth hormone (GH) secretagogues - GHRH, ghrelin, and their mimetics - these compounds could potentially be used instead of GH itself to increase GH secretion in aging. The factors contributing to the age-related decline in GH secretion are largely extrapituitary, and with repeated or continuous administration GHS's can significantly increase GH secretion and elevate levels of insulin-like growth factor-I (IGF-I) to the young adult normal range. Treatment with GHS's has both theoretical and practical potential advantages over GH - preserving feedback regulation by IGF-I to buffer against overtreatment, and yielding a more physiologic pulsatile pattern of GH secretion. Nonpeptide GHS's can also be administered orally. This review focuses primarily on results using GHRH; studies with ghrelin agonists are reviewed in detail in other articles from this symposium. We and others have shown that GHRH stimulates the brisk release of GH in healthy seniors, and that repeated administration of GHRH elevates IGF-I in a dose-dependent manner. In two 6-month treatment studies in healthy older women and men, subcutaneous injections of GHRH(1-29)NH2, self-administered once nightly, chronically increased nighttime GH secretion and produced sustained elevations of IGF-I levels. IGF-I increases were greatest in men, averaging 30%. Women not taking estrogen showed somewhat lesser increases (23%), and women taking oral estrogen replacement had no significant increase despite the greatest increments in GH secretion. Lean body mass increased; body fat was reduced by an average of 5-8%, with greatest effect on abdominal visceral fat; and again this effect was blunted in estrogenized women. Effects on physical function varied by group. In nonestrogenized women, physical function deteriorated in those receiving placebo; some measures were stabilized in women receiving GHRH. These changes were not significant in estrogenized subjects. GHRH appeared to improve cognitive function, especially in domains sensitive to changes in processing speed. The formulation of GHRH used in these studies is short-acting, with effects ending within a few hours. Perhaps for this reason, late-night GH secretion decreased after the initial GHRH-stimulated surge, and sleep quality was not improved. Side effects were those of fluid retention and were generally mild. The duration of these studies do not allow inferences to be drawn on prevention of the onset of clinical features of frailty. Thus, 6-month treatment with once-daily GHRH can elevate GH secretion and IGF-I, and improve body composition in a manner similar to the effects of GH. Effects on physical function are equivocal. Effects on cognition are encouraging but preliminary. The current GHRH formulation is too short-acting to provide optimal effects.
In April 2021 the United Kingdom Anti-Doping (UKAD) has reported an anti-doping rule violation against the rugby player Jamie Acton after reanalysis of his sample, provided in December 2014, revealed the presence of the prohibited substance GHRP-6. After notification a provisional suspension was ordered.
At first the Athlete stated that he was retired from rugby since April 2019, yet failed to provide an explanation for the positive test result. Hereafter in July 2021 the Athlete admitted the violation, waived his right for a hearing and accepted the sanction proposed by UKAD.
UKAD deems that the Athlete had committed one single first anti-doping rule violation pursuant to 2009 ADR without grounds for a reduced sanction.
Therefore UKAD decides on 27 Decemer 2021 to impose a 2 year period of ineligibility on the Athlete, starting on the date of the provisional suspension, i.e. on 30 April 2021.
