Numerous hormones, such as growth hormone and testosterone, are subject to circadian rhythms. Relying on random measures of these hormones is therefore of limited diagnostic utility as their levels may peak and plateau at particular times throughout the day. Unless adjustments are made to take account of these circadian rhythms then random readings will not be sufficiently informative.

Ayling J. More guidance on growth hormone deficiency. J Clin Pathol. 2004; 57(2): 123–125.

Brambilla DJ, Matsumoto AM, Araujo AB, McKinlay JB. The Effect of Diurnal Variation on Clinical Measurement of Serum Testosterone and Other Sex Hormone Levels in Men. The Journal of Clinical Endocrinology and Metabolism. 2009; 94(3):907–913.

Hawkes C, Grimberg A. Measuring Growth Hormone and Insulin-like Growth Factor-I in Infants: What is Normal? Pediatr Endocrinol Rev. 2013; 11(2): 126–146. 

There is no consensus protocol on bone-age assessment of younger children and infants, particularly those under the age of two. Skeletal growth and maturation is most rapid in infants and toddlers, so accurate bone-age assessment in these children is challenging.

Of the bone-age measurement techniques available, there is a major inadequacy with one of the most used methods: the limited change in the appearance of the ossification centres of the hand/wrist change in the first months of life.  A recent survey found much lower rates of confidence in the accuracy of this technique when applied to the one-to-three-year-old group.  Although a recently reported and validated bone-age measurement technique based on fibular shaft length was found to outperform other methods, it still yielded significant errors when applied to infants (i.e. under one year). 

Breen, M.A., Tsai, A., Stamm, A. et al. Bone age assessment practices in infants and older children among Society for Pediatric Radiology members. Pediatr Radiol (2016) 46: 1269.

Tsai A, Stamoulis C, Bixby SD, et al. Infant bone age estimation based on fibular shaft length: model development and clinical validation. Pediatr Radiol (2016) 46:342–356.
 

Particularly given its low sensitivity, insulin-like growth factor binding protein 3 (IGFBP-3) does not significantly contribute to the diagnosis of childhood short stature resulting from growth-hormone deficiency (GHD), which can lead to the under identification of GHD. It should therefore not be used as a routine measure for the workup and diagnosis of children with short stature. However, IGFBP-3 testing may have a role, along with IGF-1 testing, as an auxiliary diagnostic index for provocative testing.

Boquete HR, Sobrado PG, Fideleff HL, et al. Evaluation of diagnostic accuracy of insulin-like growth factor (IGF)-I and IGF-binding protein-3 in growth hormone-deficient children and adults using ROCplot analysis. J Clin Endocrinol Meta 2003; 88:4702–8

Cianfarani S, Liguori A, Boemi S, Maghnie M, et al. Inaccuracy of insulin-like growth factor (IGF) binding protein (IGFBP)-3 assessment in the diagnosis of growth hormone (GH) deficiency from childhood to young adulthood: association to low GH dependency of IGF-II and presence of circulating IGFBP-3 18-kilodalton fragment. J Clin Endocrinol Metab. 2005;90(11):6028–34.

Shen Y, Zhang J, Zhao Y, et al. Diagnostic value of serum IGF-1 and IGFBP-3 in growth hormone deficiency: a systematic review with meta-analysis. Eur J Pediatr. 2015;174(4):419–27.
  

While there is some evidence that the use of GnRH agonists can achieve improvements in height in females with early puberty, it is also associated with the development of polycystic ovary syndrome (PCOS) in adolescence and risks compromising bone health. Its use outside of clinical trials is not recommended. Given that the treatment duration must also be lengthy for its benefits to be manifested, its use is not recommended to augment height in adolescents with short stature and normally timed puberty.

Chiavaroli V, Liberati M, D'Antonio F, et al. GnRH analog therapy in girls with early puberty is associated with the achievement of predicted final height but also with increased risk of polycystic ovary syndrome. Eur J Endocrinol. 2010;163(1):55–62.

Dunkel L, Treatment of idiopathic short stature: effects of gonadotropin-releasing hormone analogs, aromatase inhibitors and anabolic steroids, Horm Res Paediatr. 2011;76 Suppl 3:27–9.

Wit M, Visser-van Balen H, Kamp GA, Oostdijk W. Benefit of postponing normal puberty for improving final height. European Journal of Endocrinology 2004;151:S41–S45

Yanovski JA, Rose SR, Municchi G, et al. Treatment with a luteinizing hormone-releasing hormone agonist in adolescents with short stature. N Engl J Med. 2003; 348(10):908–17.         

Aromatase inhibitors are used as adjuvant therapy for breast cancer. There is growing acceptance of their use to increase the adult height of children with short stature and some evidence that aromatase inhibitors can at least improve short-term growth outcomes. One recent clinical trial of aromatase inhibitors used in paediatric patients found them to be safe and effective. Even so, there is still little evidence overall that this treatment improves final adult height or is sufficiently safe. A  2015 Cochrane review found a significant proportion of pre-pubertal boys undergoing this treatment suffered mild morphological abnormalities of their vertebrae. More evidence is needed to demonstrate safety and efficacy of aromatase inhibitors before they can be routinely prescribed to promote growth in children with short stature.

Diaz-Thomas A, Shulman D. Use of aromatase inhibitors in children and adolescents: what's new? Curr Opin Pediatr. 2010; 22(4):501–7.

Mauras N, Ross JL, Gagliardi P, et al. Randomized trial of aromatase inhibitors, growth hormone or combination in pubertal boys with idiopathic short stature. J Clin Endocrinol Metab. 2016; 6:jc20162891.

McGrath N, O'Grady MJ. Aromatase inhibitors for short stature in male children and adolescents. Cochrane Database of Systematic Reviews 2015; 10: CD010888..

Wit JM, Hero M, Nunezs SB. Aromatase inhibitors in paediatrics, Nature Reviews Endocrinology. 2012;8:135–147