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Home , Adrenarche, Precocious puberty, Premature thelarche, Thelarche

Archives ofDisease in Childhood 1996;75:269-271 269 Annotations Arch Dis Child: first published as 10.1136/adc.75.4.269 on 1 October 1996. Downloaded from

Evaluation and management of precocious

Puberty is the developmental process that gives rise to sec- reflect either an LHRH dependent or LHRH independent ondary sexual characteristics and the capacity to repro- mechanism; contrasexual (appropriate for the opposite duce. Puberty beginning before the age of 8 years in girls or sex) development, such as a feminised boy or a virilised 9 years in boys is considered precocious. The incidence of girl, implies an LHRH independent mechanism. is estimated to be between 1:5000 and variant is a condition in which the clinical 1:1 0ooo.' Puberty can occur prematurely as one tail ofthe findings are intermediate between normal distribution of pubertal timing (a variant of and precocious puberty, and may be due to a disorder of normal) or because of pathologically increased sex steroid ovarian follicular maturation4 since mean ovarian volume concentrations. In general, precocious puberty can be class- slightly exceeds the normal prepubertal size, yet gonado- ified as luteinising releasing hormone (LHRH) tropin secretion is indistinguishable from that in premature independent or LHRH dependent. thelarche. Cyclic growth may be seen, often with associated growth acceleration and advancement. Normal puberty Patients do not progress to precocious puberty, nor does In girls, puberty typically begins with the breast development spontaneously resolve, as it may in (thelarche) between 8 and 13 years of age, although premature thelarche. approximately 15% of girls develop before the- larche. In boys, puberty begins with testicular enlarge- LHRH dependent precocious puberty ment, between 9 and 14 years of age. The normal progres- Precocious activation of the hypothalamic-pituitary- sion of secondary sexual development has been classified gonadal axis is referred to as LHRH dependent or central into five stages, beginning with stage 1 (prepubertal) and precocious puberty. Idiopathic precocious puberty ac- concluding with stage 5 (adult).2 Puberty is also accompa- counts for the majority of cases in girls, but less than 10% nied by a growth spurt that approximately doubles the of cases in boys,5 and is a diagnosis of exclusion. The child's prepubertal growth rate. is a matura- underlying mechanism appears to be the same as that of tional process involving the of the adrenal normal puberty, except for the earlier age of onset. gland resulting in an increase in adrenal Central nervous system (CNS) tumours can also cause secretion which stimulates the development of pubic and LHRH dependent precocious puberty. Hypothalamic

axillary hair. This event is independent of hamartomas are the most common CNS lesion associated http://adc.bmj.com/ (activation of the ). with precocious puberty. They are congenital, non- The mechanism underlying the activation of hypotha- progressing, LHRH producing masses.6 Neurofibromato- lamic LHRH secretion at puberty is currently unknown. sis may lead to precocious puberty with or without an optic Luteinising hormone (LH) and follicle stimulating hor- glioma.' Other CNS lesions may cause precocious puberty mone (FSH) are secreted in a pulsatile manner, even in the (table 1). Moreover, precocious puberty may occur long prepubertal child. levels rise gradually after a CNS .

throughout puberty, with increased peak amplitude at on September 30, 2021 by guest. Protected copyright. night from stages 1 to 4; however, by stage 5, day-night dif- LHRH independent precocious puberty ferences disappear.3 The gonadotropin response to Precocious sex steroid secretion that is independent of intravenous synthetic LHRH changes at puberty from an pituitary gonadotropin is referred to as LHRH independ- FSH predominant to an LH predominant response. ent, peripheral, or pseudoprecocious puberty. LH and FSH concentrations are low and response to exogenous Differential diagnosis LHRH is suppressed. Exposure to increased sex hor- The most common forms of sexual precocity are mones, however, can lead to CNS maturation and premature thelarche (isolated premature breast develop- subsequent secondary LHRH dependent precocious ment), and premature adrenarche (isolated sexual hair puberty. As a result, the presence of central precocious development). Premature thelarche most commonly oc- puberty does not exclude the possibility of an underlying curs before 2 years of age, may begin at birth, and may be LHRH independent cause. unilateral or bilateral. Breast development rarely Congenital adrenal hyperplasia is a common cause of progresses beyond stage 3 and may resolve spontaneously. LHRH independent precocious puberty. The classic forms Premature adrenarche is the early appearance ofpubic hair of 21-hydroxylase and 1 1-hydroxylase deficiency cause (below 8 years in a girl or 9 in a boy) due to the early virilisation, growth acceleration, and accelerated bone occurrence of the adrenarchal rise of adrenal androgen maturation. Unless secondary central activation has secretion. Neither condition progresses to full blown occurred, boys will not have testicular enlargement and puberty and neither is associated with major increases in girls will not have breast development. The non-classical, the rate of growth or bone maturation. or late onset form of congenital adrenal hyperplasia may If a child has more than isolated breast or pubic hair present in childhood or with early pubic hair development, or also has an increase in growth rate or bone and , or in early adulthood with menstrual irregularity, maturation (by more than two standard deviations), then , or infertility. Approximately 5-10% of children the many causes of precocious puberty must be consid- with premature adrenarche are estimated to have late onset ered. Isosexual (appropriate for sex) development may congenital adrenal hyperplasia.8 270 Merke, Cutler

Table 1 Lesions causing precocious puberty levels.'2 The puberty is reversible with thyroid hormone administration.

Disorder Phenotype Arch Dis Child: first published as 10.1136/adc.75.4.269 on 1 October 1996. Downloaded from Premature thelarche or thelarche variant Isolated breast Diagnostic evaluation development Evaluation ofthe child with premature puberty depends on Premature adrenarche Isolated pubic hair development the clinical features. At a minimum, an x ray of the left LHRH dependent precocious puberty Isosexual hand should be done to determine bone age. Further development investigation is warranted if the bone age is more than two Idiopathic CNS lesion standard deviations above chronologic age. Hypothalamic hamartoma The history should include the rate of pubertal progres- Other tumours Astrocytoma sion, and the presence or absence of acne, body odour, Ependymoma oiliness of the skin, and nocturnal emissions in Glioma (often associated with neurofibromatosis) boys, and or bleeding in girls. Parents Other CNS lesions Head trauma may also describe an increase in growth rate. A family his- (meningitis, encephalitis, abscess) tory of unexplained early death in a male sibling may sug- gest congenital adrenal hyperplasia. Precocious puberty in Ventricular cysts Granulomas male relatives suggests familial male limited precocious Secondary to LHRH independent precocious puberty puberty. LHRH independent precocious puberty Isosexual or An LHRH test determines whether there is activation of contrasexual development the hypothalamic-pituitary axis, and helps to differentiate Adrenal between LHRH dependent and LHRH independent 2 1-hydroxylase deficiency Contrasexual disorders. An intravenous bolus ofLHRH (100 jg) is given (girls) 1 1-hydroxylase deficiency Contrasexual and LH and FSH are measured at 30 and 60 minutes. A (girls) pubertal response is defined by an LH predominant Tumour Isosexual or response. Cut offs vary depending on the assay, and sex contrasexual Gonadal differences have been found.' Recent studies suggest that a McCune-Albright syndrome Isosexual baseline LH level may be a useful screening method when Familial male Isosexual using a highly sensitive immunochemiluminometric as- Tumour Isosexual or contrasexual say." If a child is diagnosed with LHRH dependent preco- Ectopic hCG secreting tumour Isosexual (boys) cious puberty, a computed tomographic scan or magnetic Gonadal (such as, choriocarcinoma) resonance imaging of the head is indicated. In addition, Extragonadal (such as, hepatoblastoma, tumour of the CNS or mediastinum) patients with idiopathic precocious puberty should be Exposure to exogenous sex steroids Isosexual or evaluated for underlying causes of LHRH independent contrasexual puberty, since these causes may induce secondary central Massive extraglandular aromatisation Contrasexual (boys) precocious puberty. Severe hypothyroidism Isosexual If the clinical features are consistent with premature the- larche (isolated breast development without accelerated CNS = central nervous system; hCG = chorionic gonadotropin; LHRH = luteinising hormone releasing hormone. growth or bone maturation), the patient may simply be fol- lowed clinically at intervals of three to six months. Further http://adc.bmj.com/ evaluation is necessary only if other signs of puberty Tumours ofthe , , or testes may cause develop, or if the bone age becomes advanced. A pelvic virilisation or feminisation depending on whether andro- ultrasound may also be useful in the evaluation of prema- gens or oestrogens are secreted. These rare ture thelarche. Multicystic morphology (>6 cysts of 4 mm require surgery or chemotherapy or both. Human in diameter or greater) is typically seen in girls with preco- chorionic gonadotropin (hCG) secreting tumours can cious puberty, while girls with premature thelarche cause precocious puberty in boys by stimulating Leydig typically have less than three cysts, and girls with thelarche on September 30, 2021 by guest. Protected copyright. cells to secrete . Unlike boys, girls with hCG variant have intermediate findings.4 secreting tumours generally do not develop precocious In the case of isolated sexual hair development and sus- puberty. Both LH and FSH stimulation are necessary for pected premature adrenarche, the diagnosis of non- ovarian activation. classical adrenal hyperplasia should be excluded by an Familial male limited precocious puberty, known also as ACTH test. Cosyntropin (0.25 mg) is given and testotoxicosis, is an autosomal dominant disorder that 1 7-hydroxyprogesterone is measured at 60 minutes. A level occurs only in boys, with signs of puberty beginning at of 17-hydroxyprogesterone greater than 48 nmol/l (1500 approximately 2 years of age. It is caused by constitutively ng/dl) indicates non-classical 21-hydroxylase deficiency. " activating mutations of the LH .9 Testosterone is Rapid virilisation suggests the possibility ofan endocrine markedly raised, and gonadotropin levels are low. secreting . In adrenal tumours, both testosterone The McCune-Albright syndrome causes precocious and dihydroepiandrosterone are usually markedly el- puberty, primarily in girls. The classic disorder comprises evated. A raised serum hCG suggests an hCG secreting the triad of polyostotic fibrous dysplasia, cafe-au-lait tumour. a-Fetoprotein and carcinoembryonic antigen pigmentation, and LHRH independent precocious pu- (CEA) are potentially useful markers of non- berty. The disorder results from an activating somatic germinomatous germ cell tumours. If the child has short mutation in Gs, the protein that transduces the signal of stature, delayed bone age, or signs ofhypothyroidism, thy- many 7-transmembrane domain receptors, including the roid function tests should be performed. If McCune- gonadotropin receptor.'" Another rare disorder, massive Albright syndrome is suspected because of cafe-au-lait extraglandular aromatisation, causes feminisation at the spots, fractures, or early menstrual bleeding, a skeletal sur- time of adrenarche." vey or bone scan is indicated. Severe hypothyroidism may rarely result in precocious puberty and, unlike other causes, is associated with skeletal Treatment and growth delay. The pathophysiology is uncertain, but it Premature thelarche and premature adrenarche do not may be due to the intrinsic FSH activity of very high TSH require treatment. Initially, the child should be seen every Precocious puberty 271 three to six months to confirm the diagnosis through the simple virilising, also requires mineralocorticoid replace- lack of pubertal progression. The decision to treat ment, usually fludrocortisone 0.1-0.2 mg/day. precocious puberty is based on several factors including Surgery is rarely indicated in children with central Arch Dis Child: first published as 10.1136/adc.75.4.269 on 1 October 1996. Downloaded from the child's age, the emotional impact of experiencing early precocious puberty. Although precocious puberty may be puberty, and the predicted height. cured by the removal of pedunculated hamartomas,21 we The treatment of LHRH dependent precocious puberty prefer medical treatment for this disorder. hCG secreting is an LHRH agonist, which inhibits normal gonadotropin dysgerminomas can be cured by radiotherapy. If the pres- secretion. The long acting intramuscular depot prepara- ence of a-fetoprotein or CEA suggests a non- tion of leuprolide is probably the most commonly used germinomatous germ cell tumour, treatment should (0.3 mg/kg every three to four weeks). Leuprolide is also include chemotherapy. available as a short acting subcutaneous formulation, effective at daily doses of 30-100 jig/kg. , available Conclusion in a subcutaneous formulation, is effective at the daily dose Premature sexual development comprises a spectrum of of 10 jg/kg. Other LHRH analogue preparations include disorders including premature thelarche, premature adren- (4 ,ug/kg/d), a daily subcutaneous formulation, arche, and LHRH dependent and LHRH independent and , intranasal sprays, and , a forms ofprecocious puberty. Premature thelarche and pre- long acting depot formulation. mature adrenarche represent benign conditions that Similar results can be obtained with each of the available require no treatment. By contrast, LHRH dependent and LHRH analogues provided that adequate gonadotropin independent precocious puberty usually require treatment. suppression is achieved; however, gonadotropin suppres- The LHRH dependent causes of precocious puberty can sion has often been less complete with the intranasal be treated effectively with an LHRH agonist, but the deci- formulations. Suppression is most effectively monitored by sion to treat should be individualised. Treatment of the a peak LH following an LHRH test, usually performed LHRH independent forms of precocious puberty is deter- three months after start of treatment. Further biochemical mined by the underlying cause. evaluation may not be necessary if gonadotropin suppres- DEBORAH P MERKE sion is achieved, growth velocity and bone maturation GORDON B CUTLER JR return to prepubertal rates, and pubertal progression is Developmental Branch, arrested. Treatment of precocious puberty with LHRH National Institute ofChild Health and Human Development, National Institutes ofHealth, agonist has been shown to improve final adult height.'5 16 In Bethesda, MD 20892, USA general, the earlier the treatment is started, the better the adult achieved. 1 Cutler GB. Precocious puberty. In: Hurst JW, ed. for the practicing height Discontinuation oftreatment should physician, 2nd Ed. Woburn, MA: Butterworth, 1988:526-30. be individualised on the basis of height potential and the 2 Marshall WA, Tanner JM. Variations in pattern ofpubertal changes in girls. patient's and parents' wishes. Arch Dis Child 1969;44:291-303. 3 Oerter KE, Uriarte MM, Rose SR, Barnes KM, Cutler GB. Gonadotropin Before the introduction of LHRH agonist therapy, secretory dynamics during puberty in normal girls and boys. Jf Clin synthetic progestational agents were routinely used in the Endocrinol Metab 1990;71: 1251-8. 4 Stanhope R, Brook CCD. Thelarche variant: a new syndrome of precocious treatment of precocious puberty. acetate, a sexual maturation? Acta Endocrinol 1990;123:481-6. progestational compound, has been used extensively in the 5 Pescovitz OH, Comite F, Hench K, et al. The NIH experience with preco- cious puberty: diagnostic subgroups and response to short-term luteinizing treatment of precocious puberty but long term gonadotro- hormone releasing hormone analogue therapy. J Pediatr 1986;108:47-54. pin suppression is less effective than with LHRH agonist 6 Judge DM, Kuhn HE, Page R, Santen R, Trapukdi S. Hypothalamic hamar- http://adc.bmj.com/ toma. A source of releasing factor in precocious treatment. has also been used in the puberty. NEnglJMed 1977;290:7-10. early stages of LHRH agonist treatment to prevent the ini- 7 Laue L, Comite F, Hench K, Loriaux L, Cutler GB, Pescovitz OH. Preco- cious puberty associated with neurofibromatosis and optic gliomas. Am J tial stimulatory effect of LHRH agonist which may occur Dis Child 1985;139:1097-100. before its inhibitory effect.'7 This compound is not 8 Balducci R, Boscherini B, Mangiantini A, Morellini M, Toscano V. Isolated precocious : an approach.JClin EndocrinolMetab 1994;79:582-9. currently used in the United States, but is used in Europe, 9 Shenker A, Laue L, Kosugi S, Merendino JJ, Minegishi T, Cutler GB. A Japan, and elsewhere. constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993;365:652-4. Two treatments are available for familial male precocious 10 Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel on September 30, 2021 by guest. Protected copyright. puberty: (1) the combination oftestolactone and spironolac- AM. Activating mutations of the stimulating G protein in the McCune- 8 Albright syndrome. NEnglJ3Med 1991;325:1688-738. tone, and (2) ketoconazole.'9 Ketoconazole inhibits the bio- 11 Berkowitz GD, Guermani A, Brown TR, MacDonald PC, Migeon CJ. synthesis of testosterone. blocks the action of Familial with increased extraglandular aromatization of plasma carbon 19-steroid. J Clin Invest 1985;75:1763-9. androgen, and blocks the conversion ofandrogen 12 Anasti JN, Flack MR, Froehlich J, Nelson LM, Nisula BC. A potential novel to . The side effects of ketoconazole include mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endo- crinol Metab 1995;80:276-9. gastrointestinal distress and, rarely, hepatotoxicity. The main 13 Neely EK, Wilson DM, Lee PA, Stene M, Hintz RL. Spontaneous serum side effect of testolactone and spironolactone treatnent is gonadotropin concentrations in the evaluation of precocious puberty. J Pediatr 1995;127:47-52. transient gastrointestinal distress. 14 Azziz R, Dewailly D, Owerback D. Clinical review: nonclassic adrenal Testolactone is effective in treating girls with McCune- hyperplasia: current concepts. J Clin Endocrinol Metab 1994;78:810-5. 15 Oerter KE, Manasco P, Barnes KM, Jones J, Hill S, Cutler GB. Adult height Albright syndrome at a dose of 40 mg/kg/day divided in in precocious puberty after long-term treatment with deslorelin. J Clin three doses. Unfortunately, escape from the effects of Endocrinol Metab 1991;73: 1235-40. 16 Paul D, Conte FA, Grumback MM, Kaplan SL. Long term effect of treatment may occur after one to three years.20 After years gonadotropin-releasing hormone agonist therapy on final and near-final of exposure to oestrogen, many of these girls enter central height in 26 children with true precocious puberty treated at a median age of less than 5 years. GClin EndocrinolMetab 1995;80:546-51. precocious puberty and require treatment with an LHRH 17 Kauli R, Pertzelan A, Ben-Zeev Z, et al. Treatment of precocious puberty analogue. with LHRH analogue in combination with cyproterone acetate-further experience. Clin Endocrinol 1984;20:377-87. Children with non-classical congenital adrenal hyperpla- 18 Laue L, Kenigsberg D, Pescovitz OH, et al. Treatment of familial male pre- sia usually do not require treatment and, untreated, usually cocious puberty with spironolactone and testolactone. NEnglJ'Med 1989; attain 320:496-502. normal adult height. If treatment is indicated, an 19 Holland FJ, Fishman L, Bailey JD, Fazekas ATA. Ketoconazole in the man- adequate response can normally be achieved with a hydro- agement ofprecocious puberty not responsive to LHRH-analogue therapy. NEnglJfMed 1985;312:1023-8. cortisone dose not exceeding 10 mg/m'/day. The classic 20 Feuillan PP, Jones J, Cutler GB. Long term testolactone therapy for preco- form of congenital adrenal hyperplasia requires glucocorti- cious puberty in girls with the McCune-Albright syndrome. J Clin Endocri- nol Metab 1993;77:647-51. coid treatment, usually hydrocortisone 12-15 mg/m'/day. 21 Nishio S, Shigeto H, Fukui M. Hypothalamic hamartoma: the role of Classic 21-hydroxylase deficiency, whether salt wasting or surgery. Neurosurg Rev 1993;16: 157-60.