July 2008
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Precocious Puberty: Aspects of Diagnosis and Treatment
By Jakub Mieszczak, MD; AND Peter A. Lee, MD, PhD
Early pubertal development (see sidebar, Key Points: Onset of Puberty) is diagnosed when puberty begins younger than the lower limit of age of onset. Approximations for this age for girls in the United States from the NHANES (National Health and Nutrition Examination Survey) database are 8.0 years for white girls, 6.6 years for African American girls, and 6.8 years for Latina girls. Extrapolation of the available data for boys suggests the early limit of development approximating 9.0 years for white boys, 8.0 years for African American boys, and 9.5 years for Latino boys. Hence, it is not possible to determine an exact date when puberty is early. Practically, each presentation with the complaint of early puberty must be evaluated individually, with particular attention to rate of progression.
Data recently summarized1 for girls suggest a continuation of the secular trend toward an earlier age but fail to verify this, whereas data for boys are inadequate to interpret. It has also been suggested—but not verified—that among girls, there is a relationship between the onset of puberty and obesity. This is based upon early breast development, however, which may be difficult to ascertain, particularly in the somewhat heavy girl with fullness of the chest area. Palpation of firm tissue beneath the areolae is indicative of breast development and soft tissue beneath the areolae compared with surrounding subcutaneous tissue does not. It has not been shown that such early breast budding is in fact the onset of puberty as substantiated by either the demonstration of secretion of pubertal levels of gonadotropins and estradiol or normal progression of puberty. Even if there is earlier onset of breast development, such progresses very slowly, and puberty is not being completed earlier than during recent decades, further suggesting that the initial minimal breast development is a consequence of minimal increases in estrogen stimulation, which may be related to a greater proportion of adipose tissue rather than the pubertal increase in activity of the hypothalamic-pituitary-ovarian axis.
Precocious puberty is diagnosed when physical changes of puberty occur; the first evidence is usually breast development in girls and genital growth in boys. Hence, it is pertinent to verify in girls that chest fullness is in fact breast development, most clearly manifest by disks of firm tissue centered beneath the areolae and protrusion and increased diameter of nipples. Findings include not only the onset progression of physical changes of puberty but also acceleration of linear growth and skeletal maturity.
Precocious puberty can be classified as either central precocious puberty (CPP) or peripheral precocious puberty (PPP). CPP is physiologically normal puberty occurring early as a consequence of reactivation of the hypothalamic-pituitary-gonadal (HPG) axis. Pituitary gonadotropin secretion results from increased frequency and amplitude of the episodic release of gonadotropin-releasing hormone (GnRH) secretion. Activated gonads, which secrete hormones, cause the physical changes of puberty, stimulate a premature pubertal growth spurt and sperm maturation in boys, and follicular maturity in girls. CPP is much more common among girls, usually with no underlying abnormality. CPP in boys, as normal puberty, presents with increased testicular volume of >4 cc. An underlying abnormality, most commonly of the central nervous system, is more frequently present among boys compared with girls with CPP. CPP as a consequence of radiation or chemotherapy occurs among male and female oncology patients. It may be accompanied by anterior pituitary or endocrine end-organ deficiencies, particularly growth hormone deficiency.
Initial assessment of precocious puberty involves a careful review of growth to ascertain acceleration of growth rate, verification of general findings on physical examination with a record of Tanner staging of puberty, measurement of serum levels of gonadotropins, particularly luteinizing hormone (LH) and estradiol in girls and testosterone in boys, and, if growth acceleration or progression of pubertal changes are present, a roentogram of the hand and wrist for bone age determination.
PERIPHERAL PRECOCIOUS PUBERTY
Diagnosis. PPP is a consequence of stimulation from hormones present independent of activation of the HPG axis (see sidebar, Pertinent Findings in PPP). PPP, which is less common than CPP, is usually a consequence of sex steroids from a pathophysiologic or autonomous source, most commonly congenital adrenal hyperplasia among boys. These rare sources of sex steroids are adrenal, gonadal, or from differentiated neoplastic tissues. Activating mutations are associated with PPP in McCune-Albright syndrome (MAS) (Figure 1) and in familial male-limited gonadotropin independent precocious puberty (FMPP) (activating mutations of the LH receptor). Gonadotropin (hCG)-producing tumors are associated with precocious puberty among males but not females.
Therapy. Treatment of PPP involves primary therapy for the underlying cause and use of agents to block production or action of sex steroids. Such therapy involves primary therapy if available for the underlying cause when present, but it is usually difficult and without complete effectiveness, involving the use of agents to block production or action of sex steroids. Examples of the former include surgical resection of tumors and glucocorticoid treatment of congenital adrenal hyperplasia and of the latter are noted later concerning MAS and FMPP. Because PPP is a consequence of sex steroid stimulation from sources other than early activation of the HPG axis, GnRH analogues (GnRHa) are ineffective in treatment. A consequence of continued exposure to elevated sex steroid levels of PPP is an eventual progression via activation of the HPG axis to CPP. When this occurs, GnRHa therapy should be considered as a treatment option.
Historically, treatments of precocious puberty in girls associated with MAS, such as progestational agents, were only moderately effective. Currently, third-generation aromatase inhibitors, compounds that attach to the cytochrome P450 portion of the aromatase enzyme and prevent conversion from androgens to estrogens reducing the serum levels of estrogens, are being studied.2,3 Tamoxifen, a selective estrogen-receptor modulator, diminishes estradiol production and stops pubertal progression,4 although it is associated with unexplained uterine volume increase.5 A pure estrogen receptor antagonist, fulvestrant (Faslodex, AstraZeneca), is being investigated for efficacy in halting vaginal bleeding and skeletal maturation in girls with MAS. Currently, however, there is no known completely effective treatment for PPP in girls with MAS.
MAS in boys is less common than in girls and is usually diagnosed at an older age. Treatment of PP in boys with MAS is similar to treatment of FMPP; the goal is to either inhibit the production or effect of adrenal and testicular androgens. Various therapeutic agents such as ketoconazole, spironolactone, and aromatase inhibitors (AIs) have been tried with marginal success.6-8 A pilot study of FMPP treatment with the nonsteroidal antiandrogen, bicalutamide and the third-generation AI, anastrozole (Arimidex, AstraZeneca), was associated with decreased growth velocity and skeletal maturation, but further studies are anticipated and needed.9
CENTRAL PRECOCIOUS PUBERTY
Diagnosis. Prior to deciding if treatment is warranted for CPP, it must be verified that the CPP is progressive rather than simply early onset of relatively minor physical changes, such a breast budding (nonprogressive) or normal puberty with early onset and normal growth potential.10
Progressive CPP (see sidebar, Diagnosis and Treatment of CPP) is diagnosed by documentation of progression of early pubertal development (Figure 2) and accelerated linear growth rate; pubertal gonadotropin secretion using either basal, GnRH, or GnRHa-stimulated levels; and an advanced skeletal age or accelerating rate of maturity. If random gonadotropin levels are not clearly pubertal, this must be verified using GnRH or GnRHa-stimulation testing.
Although not usually not necessary, ovarian and uterine size visualized by pelvic ultrasound may be useful in the differentiation of CPP from nonprogressive forms of early puberty. Indications for GnRHa treatment of CPP relate to the untimely physical and psychosocial consequences of early puberty. All children with progressive CPP should be considered for GnRHa therapy. The most frequent reasons for parents requesting therapy is to delay pubertal changes to allow the child to grow and develop similar to peers and to preclude or reclaim adult height potential. Before therapy, in addition to verifying that puberty is progressive and gonadotropin secretion is pubertal, height, growth rate, skeletal age, and predicted adult height in relation to target (genetically expected) height should be considered.
Treatment. The only effective therapy for CPP is a GnRHa. GnRHa occupies and downregulates the GnRH receptors on the pituitary LH and FSH-secreting cells within the pituitary, blocking GnRH leading to cessation of pubertal development. Therapy with GnRHa has been demonstrated to halt progression of physical pubertal changes (Figure 3) and stop or preclude menarche. If begun early, tall stature during childhood and foreshortened adult height is precluded. Among those with advanced bone age at onset of therapy, treatment is followed by slowing of bone age maturity with progressive reclamation of diminished growth potential.11 Both the patient and parents should be informed of the goals of therapy to stop or cause regression of pubertal development, including menstruation in girls, to attempt to gain genetically expected height potential, and to avoid psychosocial stresses related to earlier maturity than their peers. The decision regarding GnRHa treatment should be made with the parents considering their child's psychosocial as well as physical maturity. Most frequently, for parents of children that have markedly early or rapidly progressive puberty, parents chose GnRHa therapy. GnRHa therapy, by obstructing the GnRH-stimulated gonadotropin release, is the only highly effective treatment. GnRHa therapy is available as a depot injection used at 1 or 3 monthly intervals, as a subcutaneous implant,12 a daily subcutaneous injections, and a nasal spray.
If the family concludes that early puberty is not a problem and need not be interrupted, therapy is not appropriate. This is a reasonable conclusion if there is not evidence of foreshortening of expected adult stature. In fact, there is evidence that if adult height in a girl is predicted to be >155 cm, there may be limited benefit from therapy.11 Such can be considered to be slowly progressing precocious puberty, a situation in which GnRHa therapy is usually considered not to be indicated.
PREMATURE THELARCHE
Premature breast development without other pubertal changes is called premature thelarche. Most commonly, this occurs during infancy and should be considered a variant of normal related to increased ovarian activity in the neonatal period. Breast development may represent a persistence of palpable breast tissue present at birth. This often regresses by 12 months of age but may persist to 24 months or beyond. Thelarche present older than 24 months is associated with increased FSH and inhibin B secretion indicative of enhanced follicular development13 and is related to somewhat greater estradiol secretion than is typical of childhood.14
When a girl presents with breast development but no other evidence of puberty, careful monitoring is indicated, as this might be the first evidence of CPP.15 When breast development is minimal without dramatic progression and growth rate is documented to be normal for a prepubertal child during recent months, assessment usually involves observation without laboratory testing. It is, however, useful to consider early pubertal changes to extend along a continuum from premature thelarche, non-PPP to CPP. Although it is the exception to have progression along this continuum, when development at presentation suggests the diagnosis of premature thelarche, it is appropriate to consider obtaining studies so that progression can be recognized in a timely fashion. Hence, serum LH, FSH, and estradiol levels and a skeletal age radiograph may be obtained.
PREMATURE ADRENARCHE
Pubertal-related increase in adrenal androgen production (adrenarche) can be documented by identifying pubertal levels of the weak adrenal androgen dehydroepiandrosterone sulfate (DHEA-S). This rise is commonly detectable as young as 6 years of age. Early development of sexual hair, referred to as premature pubarche, most commonly is a consequence of premature adrenarche. Premature adrenarche occurs independently of the onset of puberty.16 Other androgen-induced changes can include early onset of adult-type body odor, oily skin and acne, and axillary hair, which in fact may precede pubic hair development. Height and skeletal age may be advanced with premature adrenarche so growth before the onset of puberty may be accelerated, but growth during puberty is less so that adult height is not altered. Premature pubarche is more common among girls than boys, and it is important to realize that premature pubarche may be the first evidence of adrenal or ovarian androgen excess,17 including polycystic ovarian disease.18 The association of increased body mass index and early onset of sexual hair may later manifest in hyperinsulinism and the metabolic syndrome.
Whereas a single DHEA-S level within the early pubertal range is indicative of premature adrenarche, there may be instances in which androgen changes are untimely enough so that more laboratory evaluation is needed. Such may include DHEA, androstenedione and testosterone concentrations , and if findings suggest hyperinsulinism, concomitant glucose and insulin levels. Excessive virilization in both sexes, including clitoromegaly and hirsutism in girls, mandates further evaluation for hyperandrogenic states, including congenital adrenal hyperplasia, with consideration of measurement of 17-hydroxyprogesterone, androstenedione, testosterone, free testosterone, cortisol, and LH and FSH levels. Markedly severe virilization may be associated with rare adrenal- or ovarian androgen-secreting tumors. If virilization, skeletal age and growth rate are excessive, an underlying abnormality should be ruled out.
Jakub Mieszczak, MD, is in the Department of Pediatrics Indiana University School of Medicine, The Riley Hospital for Children, Indianapolis. Peter A. Lee, MD, PhD, is in the Department of Pediatrics, Penn State College of Medicine, The Milton S. Hershey Medical Center and Indiana University School of Medicine, Riley Hospital for Children, Indianapolis. Dr. Lee may be reached at plee@psu.edu; phone: 717-531-1022; or fax: 717-531-6139.
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