Alan D. Rogol

Update of guidelines for the use of growth hormone in children: the Lawson Wilkins pediatric endocrinology society drug and therapeutics committee

The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee guidelines for the use of growth hormone were first published in 1983, near the end of the era of human pituitary-derived growth hormone (GH), and again in 1995, a decade after the introduction of recombinant human (rh)GH. The LawsonWilkins Pediatric Endocrine Society also endorsed an international consensus document led by the Growth Hormone Research Society published in 2000. This report serves to update those guidelines with an emphasis on new recommendations. The recommendations included here are limited primarily to the use of GH in infants, children and adolescents.

Position stand on androgen and human growth hormone use.

Hoffman, JR, Kraemer, WJ, Bhasin, S, Storer, T, Ratamess, NA, Haff, GG, Willoughby, DS, and Rogol, AD. Position stand on Androgen and human growth hormone use. J Strength Cond Res 23(5): S1-S59, 2009-Perceived yet often misunderstood demands of a sport, overt benefits of anabolic drugs, and the inability to be offered any effective alternatives has fueled anabolic drug abuse despite any consequences. Motivational interactions with many situational demands including the desire for improved body image, sport performance, physical function, and body size influence and fuel such negative decisions. Positive countermeasures to deter the abuse of anabolic drugs are complex and yet unclear. Furthermore, anabolic drugs work and the optimized training and nutritional programs needed to cut into the magnitude of improvement mediated by drug abuse require more work, dedication, and preparation on the part of both athletes and coaches alike. Few shortcuts are available to the athlete who desires to train naturally. Historically, the NSCA has placed an emphasis on education to help athletes, coaches, and strength and conditioning professionals become more knowledgeable, highly skilled, and technically trained in their approach to exercise program design and implementation. Optimizing nutritional strategies are a vital interface to help cope with exercise and sport demands (516-518). In addition, research-based supplements will also have to be acknowledged as a strategic set of tools (e.g., protein supplements before and after resistance exercise workout) that can be used in conjunction with optimized nutrition to allow more effective adaptation and recovery from exercise. Resistance exercise is the most effective anabolic form of exercise, and over the past 20 years, the research base for resistance exercise has just started to develop to a significant volume of work to help in the decision-making process in program design (187,248,305). The interface with nutritional strategies has been less studied, yet may yield even greater benefits to the individual athlete in their attempt to train naturally. Nevertheless, these are the 2 domains that require the most attention when trying to optimize the physical adaptations to exercise training without drug use. Recent surveys indicate that the prevalence of androgen use among adolescents has decreased over the past 10-15 years (154,159,246,253,370,441,493). The decrease in androgen use among these students may be attributed to several factors related to education and viable alternatives (i.e., sport supplements) to substitute for illegal drug use. Although success has been achieved in using peer pressure to educate high school athletes on behaviors designed to reduce the intent to use androgens (206), it has not had the far-reaching effect desired. It would appear that using the people who have the greatest influence on adolescents (coaches and teachers) be the primary focus of the educational program. It becomes imperative that coaches provide realistic training goals for their athletes and understand the difference between normal physiological adaptation to training or that is pharmaceutically enhanced. Only through a stringent coaching certification program will academic institutions be ensured that coaches that they hire will have the minimal knowledge to provide support to their athletes in helping them make the correct choices regarding sport supplements and performance-enhancing drugs. The NSCA rejects the use of androgens and hGH or any performance-enhancing drugs on the basis of ethics, the ideals of fair play in competition, and concerns for the athletes health. The NSCA has based this position stand on a critical analysis of the scientific literature evaluating the effects of androgens and human growth hormone on human physiology and performance. The use of anabolic drugs to enhance athletic performance has become a major concern for professional sport organizations, sport governing bodies, and the federal government. It is the belief of the NSCA that through education and research we can mitigate the abuse of androgens and hGH by athletes. Due to the diversity of testosterone-related drugs and molecules, the term androgens is believed to be a more appropriate term for anabolic steroids.Androgen administration in a concentration-dependent manner increases lean body mass, muscle mass, and maximal voluntary strength in men. However, the upper concentration for maximum effects remains unknown.Combined administration of androgens and resistance exercise training is associated with greater gains in lean body mass, muscle size, and maximal voluntary strength in men than either intervention alone.Testosterone therapy is approved only for the treatment of hypogonadism in adolescent and adult men. However, the anabolic applications of androgens and selective AR modulators are being explored for the functional limitations associated with aging and some types of chronic illness.The magnitude and frequency of adverse effects among androgen users have not been systematically studied. Potential adverse effects of androgen use in men include suppression of the hypothalamic-pituitary-gonadal axis, mood and behavior disorders, increased risk of cardiovascular disease, hepatic dysfunction with oral androgens, insulin resistance, glucose intolerance, acne, gynecomastia, and withdrawal after discontinuation. In addition, the polypharmacy of many androgen users (psychoactive and accessory drugs) may have serious adverse effects of their own.The adverse effects of androgen administration in women are similar to those noted in men. In addition, women using androgens may also experience virilizing side effects such as enlargement of the clitoris, deepening of the voice, hirsutism, and changes in body habitus. These changes may not be reversible on cessation of androgen use.In pre- and peripubertal children, androgen use may lead to virilization, premature epiphyseal closure, and resultant adult short stature.Since 1990, the use of androgens for a nonmedical purpose is illegal. Androgens are labeled as a schedule III drug. Possession of any schedule III substance including androgens is punishable by fine, prison time, or both. Prescribing androgens for bodybuilding or enhanced athletic performance is also punishable as noted above.Human growth hormone increases lean body mass within weeks of administration; however, the majority of the change is within the water compartment and not in body cell mass.Human growth hormone is unlikely to be administered as a single agent but often in combination with androgens.Combined administration of hGH and resistance exercise training is associated with minimal gains in lean body mass, muscle size, and maximal voluntary strength in men compared with resistance exercise alone.Human growth hormone is approved for the therapy of children and adolescents with growth hormone deficiency, Turner syndrome, small for gestational age with failure to catch-up to the normal growth curves, chronic kidney disease, Prader-Willi syndrome, idiopathic short stature, Noonan syndrome, and SHOX gene deletion. For adults, hGH is approved for the treatment of GH deficiency, AIDS/HIV with muscle wasting, and short bowel syndrome.The magnitude and frequency of adverse events associated with hGH use are clearly dose related. Potential adverse events include suppression of the hypothalamic-pituitary GH/IGF-1 axis, water retention, edema, increased intracranial pressure, joint and muscle aches, and those of needle injection (hepatitis and HIV/AIDS). These should be the same in women as well as in men.Continued effort should be made to educate athletes, coaches, parents, physicians, and athletic trainers along with the general public on androgen and hGH use and abuse. Educational programs should focus on potential medical risks of these illegal performance-enhancing drugs use, optimizing training programs and concurrent nutritional strategies to enhance physiological adaptation and performance. In addition, educating coaches on setting realistic training goals and expectations for their athletes will help reduce the pressures to use illegal PED and assist in potentially identifying potential users of illegal PED.The NSCA supports and promotes additional research funding to be directed toward effective educational programs, documentation of both acute and long-term adverse effects of androgen and hGH abuse, strategies for optimizing athletic performance through training and nutritional interventions, strategies to help athletes discontinue androgen and hGH use, and strategies for the detection of abuse of androgens and hGH.

Variable Degree of Growth Hormone (GH) and Insulin-Like Growth Factor (IGF) Sensitivity in Children with Idiopathic Short Stature Compared with GH-Deficient Patients: Evidence from an IGF-Based Dosing Study of Short Children

CONTEXTnWe recently showed that, in IGF-based GH therapy, the IGF-I target chosen affects GH dose requirements, and higher IGF-I targets are associated with more robust growth parameters.nnnOBJECTIVEnThe objective of the study was to compare the response of GH-deficient (GHD) vs. idiopathic short-stature (ISS) children to IGF-based GH therapy.nnnDESIGNnThis was a 2-yr, open-label, randomized trial.nnnSETTINGnThe setting was multicenter and outpatient.nnnPATIENTSnPrepubertal short children [height sd score (SDS) < -2] with low IGF-I levels (<or=-1 SDS), subclassified based on the peak stimulated serum GH concentration at baseline, into two subgroups: GHD (n = 63, GH < 7 ng/ml) and ISS (n = 102, GH >or= 7 ng/ml).nnnINTERVENTIONSnPatients were randomized 2:2:1 to three treatment groups: IGF-I target of 0 SDS (IGF0T), 2 SDS (IGF2T), or a conventional weight-based GH dosing of 40 microg/kg x d (Conv).nnnMAIN OUTCOME MEASURESnChange in (Delta) height SDS, IGF-I SDS, and GH dose was measured.nnnRESULTSnISS subjects required higher GH doses than GHD patients in the IGF2T (but not IGF0T) arm (medians 119 and 65 microg/kg x d, respectively), indicating that ISS represents a partial GH-insensitive state that manifests during treatment with higher doses of GH. GHD children grew more than those with ISS in both IGF-targeted dosage groups despite similar IGF-I levels (suggesting a degree of IGF insensitivity in ISS subjects): Delta height SDS of 2.04 +/- 0.17 for GHD and 1.33 +/- 0.09 for ISS groups in IGF2T, 1.41 +/- 0.13 for children with GHD, and 0.84 +/- 0.07 for those with ISS in IGF0T.nnnCONCLUSIONnIGF-based GH dosing is clinically feasible in both GHD and ISS patients, although GH dose requirements and auxological outcomes are distinct between these groups. This suggests a degree of both GH and IGF insensitivity in subjects with ISS that requires specific management strategies to optimize growth during GH therapy.

Current Indications for Growth Hormone Therapy for Children and Adolescents

Growth hormone (GH) therapy has been appropriate for severely GH-deficient children and adolescents since the 1960s. Use for other conditions for which short stature was a component could not be seriously considered because of the small supply of human pituitary-derived hormone. That state changed remarkably in the mid-1980s because of Creutzfeldt-Jakob disease associated with human pituitary tissue-derived hGH and the development of a (nearly) unlimited supply of recombinant, 22 kDa (r)hGH. The latter permitted all GH-deficient children to have access to treatment and one could design trials using rhGH to increase adult height in infants, children and adolescents with causes of short stature other than GH deficiency, as well as trials in adult GH-deficient men and women. Approved indications (US Food and Drug Administration) include: GH deficiency, chronic kidney disease, Turner syndrome, small-for-gestational age with failure to catch up to the normal height percentiles, Prader-Willi syndrome, idiopathic short stature, SHOX gene haploinsufficiency and Noonan syndrome (current to October 2008). The most common efficacy outcome in children is an increase in height velocity, although rhGH may prevent hypoglycemia in some infants with congenital hypopituitarism and increase the lean/fat ratio in most children - especially those with severe GH deficiency or Prader-Willi syndrome. Doses for adults, which affect body composition and health-related quality of life, are much lower than those for children, per kilogram of lean body mass. The safety profile is quite favorable with a small, but significant, incidence of raised intracranial pressure, scoliosis, muscle and joint discomfort, including slipped capital femoral epiphysis. The approval of rhGH therapy for short, non-GH-deficient children has validated the notion of GH sensitivity, which gives the opportunity to some children with significant short stature, but with normal stimulated GH test results, to benefit from rhGH therapy and perhaps attain an adult height within the normal range and appropriate for their mid-parental target height (genetic potential).

Hormones as Performance-Enhancing Agents

Success in sports is often defined by winning, which drives some athletes to use performance-enhancing drugs to gain an advantage over opponents. The use of doping agents in sports has a long history, especially over the last years, secondary to scandals and controversy. Athletes and the general public are now more aware and educated about this issue. The World Anti-Doping Agency’s (WADA) mission is to lead a collaborative worldwide campaign for doping-free sport. A list of doping substances and methods banned in sports is published yearly by WADA (http://www.wada-ama.org. Accessed 17 July 2018) [1]. A substance or method might be included on the list if it fulfills at least two of the following criteria: enhances sports performance, represents a risk to the athlete’s health, or violates the spirit of sports.

Secondary exposure to testosterone from patients receiving replacement therapy with transdermal testosterone gels

Accepted: 19 December 2011; published online: 20 January 2012 Citation: Curr Med Res Opin 2012; 28:267–69 The potential for unintended transfer of testosterone to others from adult men receiving transdermal testosterone gel treatment for hypogonadism is a recognized safety concern, due to the undesirable pharmacologic ffects of testosterone in women and children. The following three papers present the results from five phase 1 studies that investigated the transfer of testosterone to adult women from male partners who applied a 1.62% testosterone gel (AndroGel 1.62%, Abbott). There are four gel products currently marketed in the United States for testosterone replacement therapy in hypogonadal males: AndroGel 1%, AndroGel 1.62% (Abbott, North Chicago, IL), Testim (Auxilium Pharmaceuticals, Malvern, PA), and Fortesta (Endo Pharmaceuticals, Chadds Ford, PA). In addition a 2% topical solution is available (Axiron, Lilly, Indianapolis, IN). These products are applied topically and deliver testosterone to increase serum concentrations to eugonadal levels in men with low testosterone levels. Testosterone gels are applied daily to the skin of the upper arms/shoulders and/or abdomen, or thighs of male patients, depending on their dosing instructions. Since only a low fraction of testosterone is absorbed transdermally from the gels, there exists a significant reservoir of steroid on the surface of the skin, and this residual testosterone could be transferred to others who come into direct skin contact with the patient’s site of gel application. Transfer of testosterone to women or children via skin contact with the application site following gel application has been reported. Even small quantities of testosterone transferred on a repeated basis to these individuals may result in the clinical signs and symptoms of hyperandrogenism, sexual precocity, or inappropriate virilization. The signs and symptoms of secondary testosterone exposure in children include the development of pubic hair, enlargement of the penis or clitoris, increased number of erections and libido, advanced bone age, and aggressive behavior. Usually these signs regress once the testosterone source is removed, although there are instances when the genitalia do not completely return to normal size, and bone age remains slightly greater than chronological age. The signs and symptoms of testosterone exposure in women are the development of acne, changes in body hair distribution or other signs of virilization, or menstrual irregularity. Testosterone product labeling states that testosterone is teratogenic and may cause fetal harm. Fetal exposure to androgens can cause virilization, so testosterone exposure should be particularly avoided during pregnancy. The United States Food and Drug Administration (FDA) addressed the issue of testosterone gel safety in May 2009. It reported the receipt of eight reports of secondary exposure to testosterone in children ranging in age from 9 months

Disorders of Growth and Development

This 4-yr-4-mo-old boy presented to the local pediatric endocrinologist for evaluation of accelerated growth velocity and development of pubic hair over the past year.