Pharmacologic and nutritional influences on growth (2013)

This issue of Current Opinion, focusing on the endocrinology of growth and development, covers an array of hot topics, from a perspective on the effectiveness and potential complications of growth hormone therapy, the effects of obesity, endocrine disruptors and nutrition on growth, and an update on genetic and environmental influences on the timing of puberty. A review on the endocrinologic approaches to children with gender dysphoria ties to these topics because treatment of these children may involve pharmacologic alteration of timing of puberty and interventions in sex-specific pubertal development. A focus on growth effects parallels physician and patient concern about short stature and obesity. This commentary will examine the rationale for the use of growth hormone to treat short stature, the effect of other commonly used medications upon growth, and finally, the effect of major nutritional shifts upon child health, weight and well-being. Despite parental and physician concern, treatment of short stature disorders, as discussed by Watson and Rogol (pp. 39–43), is complicated by the ambiguity of data assessing the need for such treatment. It is unclear whether moderate short stature affects quality of life. A recent study, for instance, found that adult height in the general French population did not correlate with clinically significant differences in physical functioning or other aspects of health-related quality of life and well-being if individuals with extreme short stature (boys less than 149.2 cm and girls less than 136.0 cm) were excluded from the analysis [1]. Watson and Rogol point out that despite more than 25 years of investigation and pharmaceutical promotion, growth-promoting effects of growth hormone in normal short children are relatively modest, although complications of treatment seem minimal. They particularly address several recent studies examining potential for increased mortality in growth hormone treated individuals and conclude that the data are not sufficient to reach consensus. Chronic drug treatment for common childhood conditions is increasing in prevalence, and some of the most common chronic pharmacologic interventions may affect growth. In 2002, 25.4/1000 children in the USA were prescribed a medication for attention deficit disorder and attention-deficit/hyperactivity disorder (ADD/ADHD) and 46.5/1000 children were prescribed an antiasthma drug [2]. Between 2002 and 2005, the prevalence rate for the use of medications to treat ADD/ADHD increased by 40.4% and use of antiasthmatic drugs increased by 46.5%. Drugs in these classes have been associated with growth attenuation. To very loosely paraphrase Samuel Johnson, many of the concerns about environmental and medication effects on growth and development have been a triumph of fear over data [3]. However, some have proved realistic, and others may prove important as more information is accrued. Adverse effects of ADHD medications on linear growth have been postulated. Some at-risk children with ADHD are small and thin from birth [4]. Large follow-up studies have pointed to a deleterious effect of ADHD medications upon both height and weight [5]. However, a more recent longitudinal naturalistic study [6] found no differences in adult height in children treated for ADHD and normal children. Although paediatricians and paediatric endocrinologists are bedeviled by the management of thin short boys who do not gain weight and seem to grow even more slowly while receiving drugs in the stimulant/amphetamine class, confusing studies to date do not confirm a long-term effect of such treatments. Large studies of adults with this disorder may shed more light on subtle derangements in growth that may be seen in association with ADD/ADHD or as a result of treatment. Inhaled synthetic glucocorticoids were introduced for the chronic prophylaxis of asthma with the hope that their actions would be local and would not affect growth. However, growth attenuation is common in children receiving higher doses of these agents. A recent definitive prospective study has now demonstrated that mean adult height is statistically lower in children chronically treated with inhaled glucocorticoids [7]. The effect is particularly noticeable in children treated before puberty and is dose-dependent. Whether the decrease in height, which averaged 1.2 cm in adulthood, is meaningful when compared with the improvement in quality of life achieved with inhaled glucocorticoid remains in doubt. Nonetheless, this study serves as a prospective model for the evaluation of growth effects of commonly used medications in childhood. Muhlhausler and Ailhaud (pp. 56–61) were asked to review the issue of maternal–foetal effects on growth and development and have brought to us a most interesting and stimulating review of the potential effect of major changes in fatty acid composition of our diet over the past 30 years upon the epidemic of childhood obesity. Their thesis is that the decrease in the ratio of omega-3 to omega-6 polyunsaturated fatty acids (PUFAs) may be contributory to the obesity epidemic in childhood. Although PUFAs are generally recognized to be healthy components of the Western diet, some PUFAs may be more healthy than others. Because of an increase in the human and animal consumption of soybean oil in both prepared products and in animal feed, there has been a marked decrease in the availability of omega-3 compared with omega-6 fatty acids in the US diet. One estimate examining fatty acid composition of foods today compared with foods at the beginning of the 20th century shows a 12% decrease in alphalinolenic acid (omega-3) and an almost 70% increase in linoleic acid (omega-6) in eggs today compared with the beginning of the 20th century [8]. These changes or greater in the omega-3/omega-6 ratio are found in all animal foodstuffs including dairy products. In addition, increased personal consumption of high omega-6 oils, such as soybean, corn and safflower oil, increases the omega-6 PUFAs available to most of us today. Although quite controversial, there are a number of studies suggesting that the imbalance between omega-3 and omega-6 PUFAs can increase the inflammatory process associated with cardiovascular disease, and perhaps increase the risk of certain malignancies [9]. On the contrary, the position of the American Heart Association is that although increase in omega-3 PUFA is beneficial, the data to support reduction in omega-6 are insufficient [10]. Nonetheless, omega-6 PUFA, linoleic acid, is converted readily to arachidonic acid, which is a known inflammatory mediator and is a precursor for a group of eicosanoids with vasocontrictive, proinflammatory and proaggregatory products, including prostaglandins, thromboxane A2 and leukotrienes [9]. As important, alphalinolenic acid (omega-3) is the precursor for eicosapentanoic acid (EPA), and docosahexanoic acid (DHA), important for neuronal development. As noted by the authors of this review, in recent years, infant formula has been enriched with DHA because of potential improved child developmental milestones in children fed an enriched formula. Muhlhausler and Ailhaud (pp. 56–61) review the animal literature on prenatal and postnatal feeding with various PUFA mixes and demonstrate that increases in linoleic acid seem to drive increased weight in the postnatal period. There are tantalizing hints that this might also be true in human infants. They suggest prospective studies to evaluate this risk, studies that may be difficult to do because of predetermined concerns about maternal–child health and development, but might be very useful in assessing whether specific PUFAs, which function not only as nutrient sources and essential fatty acids for neuronal development but also as precursors for compounds functioning as hormonal mediators of inflammation, can influence child health and development. It is still important as we improve drug therapies for common conditions and alter our food supply in the interest of efficiency, productivity and perceived ‘health’ to remain eternally vigilant to the potential to alter human development and long-term health. Acknowledgements None. Conflicts of interest Local Principal Investigator on growth hormone patient registry: Eli Lilly. Local Principal Investigator on growth hormone patient registry: Novonordisk.