Delayed Puberty

Abstract

Puberty is an indelible period of metamorphosis of the human life cycle, which culminates in sexual maturation and reproductive capability. The failure to develop in a normal and timely fashion can, therefore, cause profound anxiety in individuals and families. Furthermore, awareness that pubertal delay can indicate significant underlying pathology compels physicians to investigate any perceived deviation from a rigidly defined acceptable pattern of development. The ability to distinguish between various causes of delay and to differentiate significant underlying pathology from common benign delay can be daunting often requiring prudent investigation. Depending on the ultimate diagnosis, treatment options vary, but most patients can ultimately expect to achieve pubertal maturation and fertility.

Puberty is initiated when the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator begins secreting brief nocturnal pulses of GnRH from the hypothalamic arcuate nucleus that subsequently stimulate the pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Palmert and Dunkel, N Engl J Med 366:443–453, 2012). A recently discovered hormone, kisspeptin, acts on the hypothalamic GnRH neurons, stimulating GnRH secretion (Seminara and Crowley, J Neuroendocrinol 20:727–731, 2008). The gonadotropins (LH and FSH) promote gonadal maturation and gonads synthesize sex steroids, including testosterone and estrogen, and other proteins. LH acts on theca cells and interstitial cells to produce progestins and androgens which diffuse into adjacent granulosa cells. FSH acts on granulosa cells to stimulate aromatization of these androgens to estrogen. Estrogen and testosterone then promote pubertal changes throughout the body and provide negative feedback effect on the GnRH and gonadotropins (Fig. 17.1). The first physical signs of puberty are typically breast development in girls and testicular enlargement in boys (testicular volume >3 ml/≥2.5 cm in length). Some children, especially girls, have the appearance of pubic hair prior to the initiation of breast development, but in the absence of other puberty signs this usually represents adrenarche [adrenal source of androgens, independent of hypothalamic–pituitary–gonadal (HPG) axis maturation] and not true puberty. The trigger(s) for reactivation of the HPG axis is not completely understood; but, modifying factors include general health, nutrition, genetic determinants, and pubertal timing among primary relatives. Elevated body mass index is associated with delayed puberty in boys (Lee et al., Arch Pediatr Adolesc Med 164:139–144, 2010; Nathan et al., J Pediatr Endocrinol Metab 19:971–977, 2006). Many of the genes involved in the HPG axis maturation are still unknown. Kisspeptin-1 and its cognate receptor (GPR54, a G-protein-coupled receptor) are integral to the normal function of HPG axis and play a critical role in the physiologic regulation of puberty (Seminara and Crowley, J Neuroendocrinol 20:727–731, 2008; Messager et al., Proc Natl Acad Sci U S A 102:1761–1766, 2005). Kisspeptin is co-expressed with neurokinin B and dynorphin and hence these signaling pathways are also important in physiologic regulation of puberty (Silveira et al., J Clin Endocrinol Metab 95:2276–2280, 2010). There is evidence that leptin, a 16 kDa hormone product of the Ob gene, synthesized by adipocytes, plays a permissive role (Gueorguiev et al., Pituitary 4:79–86, 2001; Farooqi et al., N Engl J Med 341:879–884, 1999).

Although the lower limit of normal for the onset of puberty is contestible, the average age for this process is generally accepted to be 9–10 years for girls and 10–11 years for boys (Palmert and Dunkel, N Engl J Med 366:443–453, 2012; Parent et al., Endocr Rev 24:668–693, 2003). Delayed puberty can be defined as failure to demonstrate signs of pubertal maturation by an age that is ≥2 standard deviations above the population mean (Palmert and Dunkel, N Engl J Med 366:443–453, 2012). Lack of testicular enlargement by age 14 in males, lack of breast development by age 13 in females, absence of menarche by age 16 in girls, or absence of menarche within 5 years of pubertal onset (Delemarre et al., Eur J Endocrinol 159(Suppl 1):S9–15, 2008; Fenichel, Endocr Dev 22:138–159, 2012). Interestingly, males present far more often for evaluation of delayed puberty, but it has been suggested that this is in part due to a referral bias (Sedlmeyer and Palmert, J Clin Endocrinol Metab 87:1613–1620, 2002; Rosenfield, J Clin Endocrinol Metab 70:559–562, 1990).