Diagnosis and treatment of delayed puberty
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K. Podolsky Professor of Medicine
- Harvard Medical School
- Nelly Pitteloud, MD
Nelly Pitteloud, MD
- Professor in Medicine
- Lausanne University Switzerland
- Section Editors
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
- Amy B Middleman, MD, MPH, MS Ed
Amy B Middleman, MD, MPH, MS Ed
- Section Editor — Adolescent Medicine
- Professor of Pediatrics, Chief of Adolescent Medicine
- University of Oklahoma Health Sciences Center
- Mitchell Geffner, MD
Mitchell Geffner, MD
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Keck School of Medicine, University of Southern California
Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics bounded by an age at which 95 percent of children of that sex and culture have initiated sexual maturation. The clinical staging of puberty is performed by the criteria established by James Tanner. According to the National Center for Health Statistics, the upper 95th percentile in the United States for age for boys is 14 (ie, an increase in testicular size being the first sign) and for girls is 12 (breast development being the first sign) (table 1). (See "Normal puberty".)
Delayed puberty usually results from inadequate gonadal steroid secretion which, in turn, is most often caused by a defective gonadotropin secretion from the anterior pituitary, due to defective production of gonadotropin-releasing hormone (GnRH) from the hypothalamus, the key functional defect in patients with constitutional delay of puberty. It can, however, also be caused by a variety of hypothalamic, pituitary, and gonadal disorders. (See "Etiology, diagnosis, and treatment of primary amenorrhea".)
PRIMARY VERSUS SECONDARY HYPOGONADISM
Dating back to the time of Fuller Albright and his colleagues, it has been useful to classify the syndrome pathophysiologically according to the circulating levels of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (table 2):
●High serum concentrations of LH and FSH are associated with various causes of gonadal disease, called primary hypogonadism and/or defects in their receptors on the membrane of the gonadal cells. (See "Causes of primary hypogonadism in males" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)
●Low or normal serum LH and FSH concentrations are associated with various causes of diminished GnRH-induced gonadotropin secretion, called secondary hypogonadism. This defect can be because of hypothalamic dysfunction (either anatomic or functional), hypopituitarism, hypothyroidism, or hyperprolactinemia. (See "Causes of secondary hypogonadism in males".)
- Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002; 87:1613.
- Caronia LM, Martin C, Welt CK, et al. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011; 364:215.
- Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007; 357:863.
- Rosenfield RL. Clinical review 6: Diagnosis and management of delayed puberty. J Clin Endocrinol Metab 1990; 70:559.
- Kaplowitz PB. Delayed puberty. Pediatr Rev 2010; 31:189.
- Boepple PA. Precocious and delayed puberty. Curr Opin Endocrinol Diabetes 1995; 2:111.
- Pugliese MT, Lifshitz F, Grad G, et al. Fear of obesity. A cause of short stature and delayed puberty. N Engl J Med 1983; 309:513.
- Sedlmeyer IL, Hirschhorn JN, Palmert MR. Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns. J Clin Endocrinol Metab 2002; 87:5581.
- Waldstreicher J, Seminara SB, Jameson JL, et al. The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab 1996; 81:4388.
- Balasubramanian R, Dwyer A, Seminara SB, et al. Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons. Neuroendocrinology 2010; 92:81.
- Gianetti E, Tusset C, Noel SD, et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 2010; 95:2857.
- Mitchell AL, Dwyer A, Pitteloud N, Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends Endocrinol Metab 2011; 22:249.
- Balasubramanian R, Crowley WF Jr. Isolated GnRH deficiency: a disease model serving as a unique prism into the systems biology of the GnRH neuronal network. Mol Cell Endocrinol 2011; 346:4.
- Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976; 51:170.
- Marshall JC, Kelch RP. Low dose pulsatile gonadotropin-releasing hormone in anorexia nervosa: a model of human pubertal development. J Clin Endocrinol Metab 1979; 49:712.
- Wu FC, Butler GE, Kelnar CJ, et al. Ontogeny of pulsatile gonadotropin releasing hormone secretion from midchildhood, through puberty, to adulthood in the human male: a study using deconvolution analysis and an ultrasensitive immunofluorometric assay. J Clin Endocrinol Metab 1996; 81:1798.
- Kelch RP, Hopwood NJ, Marshall JC. Diagnosis of gonadotropin deficiency in adolescents: limited usefulness of a standard gonadotropin-releasing hormone test in obese boys. J Pediatr 1980; 97:820.
- Savage MO, Preece MA, Cameron N, et al. Gonadotrophin response to LH-RH in boys with delayed growth and adolescence. Arch Dis Child 1981; 56:552.
- Harman SM, Tsitouras PD, Costa PT, et al. Evaluation of pituitary gonadotropic function in men: value of luteinizing hormone-releasing hormone response versus basal luteinizing hormone level for discrimination of diagnosis. J Clin Endocrinol Metab 1982; 54:196.
- Wilson DA, Hofman PL, Miles HL, et al. Evaluation of the buserelin stimulation test in diagnosing gonadotropin deficiency in males with delayed puberty. J Pediatr 2006; 148:89.
- Ghai K, Cara JF, Rosenfield RL. Gonadotropin releasing hormone agonist (nafarelin) test to differentiate gonadotropin deficiency from constitutionally delayed puberty in teen-age boys--a clinical research center study. J Clin Endocrinol Metab 1995; 80:2980.
- Copeland KC, Paunier L, Sizonenko PC. The secretion of adrenal androgens and growth patterns of patients with hypogonadotropic hypogonadism and isiopathic delayed puberty. J Pediatr 1977; 91:985.
- Brook CG. Management of delayed puberty. Br Med J (Clin Res Ed) 1985; 290:657.
- Richman RA, Kirsch LR. Testosterone treatment in adolescent boys with constitutional delay in growth and development. N Engl J Med 1988; 319:1563.
- Soliman AT, Khadir MM, Asfour M. Testosterone treatment in adolescent boys with constitutional delay of growth and development. Metabolism 1995; 44:1013.
- Wilson DM, Kei J, Hintz RL, Rosenfeld RG. Effects of testosterone therapy for pubertal delay. Am J Dis Child 1988; 142:96.
- Butler GE, Sellar RE, Walker RF, et al. Oral testosterone undecanoate in the management of delayed puberty in boys: pharmacokinetics and effects on sexual maturation and growth. J Clin Endocrinol Metab 1992; 75:37.
- Adan L, Souberbielle JC, Brauner R. Management of the short stature due to pubertal delay in boys. J Clin Endocrinol Metab 1994; 78:478.
- Albanese A, Kewley GD, Long A, et al. Oral treatment for constitutional delay of growth and puberty in boys: a randomised trial of an anabolic steroid or testosterone undecanoate. Arch Dis Child 1994; 71:315.
- Büyükgebiz A. Treatment of constitutional delayed puberty with a combination of testosterone esters. Horm Res 1995; 44 Suppl 3:32.
- Bergadá I, Bergadá C. Long term treatment with low dose testosterone in constitutional delay of growth and puberty: effect on bone age maturation and pubertal progression. J Pediatr Endocrinol Metab 1995; 8:117.
- Albanese A, Stanhope R. Predictive factors in the determination of final height in boys with constitutional delay of growth and puberty. J Pediatr 1995; 126:545.
- Arrigo T, Cisternino M, Luca De F, et al. Final height outcome in both untreated and testosterone-treated boys with constitutional delay of growth and puberty. J Pediatr Endocrinol Metab 1996; 9:511.
- Raivio T, Dunkel L, Wickman S, Jänne OA. Serum androgen bioactivity in adolescence: a longitudinal study of boys with constitutional delay of puberty. J Clin Endocrinol Metab 2004; 89:1188.
- PRIMARY VERSUS SECONDARY HYPOGONADISM
- Physical examination
- Imaging studies
- Laboratory testing
- - General evaluation
- - Hormonal tests
- - Additional tests
- General principles
- Testosterone therapy
- Estrogen therapy
- Growth hormone therapy
- INFORMATION FOR PATIENTS