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The neuroendocrine control of the onset of puberty in rodents has been extensively reviewed over the years (1-7). In this chapter, we will provide both a brief account of the basic mechanisms underlying the pubertal process in these animals and an update of some recent developments in the field. Because the rat is the animal most extensively studied, we will discuss mainly results obtained in this species, and when available, we will offer the reader a comparison of these results with those obtained in mice [ABSTRACT FROM AUTHOR]

In internationally adopted girls a high frequency of precocious puberty has been reported in series of patients, and a low age at menarche has been reported from retrospective cohort studies. Data estimating the risk of precocious pubertal development suggests a highly increased risk in internationally adopted girls, possibly related to country of origin and age at adoption. Genetic factors, intrauterine growth retardation, nutritional status prior to adoption, pre- and post adoption growth patterns as well as environmental exposures and psychological stress has been hypothensized to trigger early puberty. However, the mechanism behind precocious and early puberty in adopted girls is still unknown, and central as well peripherally mediated puberty has been suggest. In daily clinical practice, the challenge is therefore to establish guidelines that ensure appropriate recognition of those adopted children who need medical examinations for precocious puberty and to identify the subgroup of patients who will benefit from treatment with GnRH analogs. Prospective, longitudinal studies on growth and development in internationally and domestic adopted children are neaded to disentangle these questions and to understand the pathophysiology. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that the age of pubertal onset in children is occurring earlier than previously reported. The precise trigger for the onset of puberty is not known, but it is believed to be a complex interaction between genetics, hormones, and environmental influences. Endocrine disruptors are natural or synthetic environmental chemicals that may result in adverse health by disturbing normal endocrine function through agonistic or antagonistic actions. Endocrine disruptors may result in an altered hormonal status through interference with cell signaling pathways or altering the action of hormone receptors as coactivators or corepressors (1). Several agents have been classified as endocrine disruptors, including phytoestrogens, topical and natural estrogens, pesticides, industrial chemicals, and phthalates. The potential role of endocrine disruptors in reproductive development has been a controversial topic since the early 1990s (2). Although there is a paucity of definitive data to support a role for endocrine disruptors in disturbing the onset and timing of human puberty, several environmental factors may putatively play a role. In this chapter, we discuss the compounds that have been implicated in altering the age of normal puberty, the role of these potential endocrine disruptors in pubertal development, and the implications in genital and reproductive function. [ABSTRACT FROM AUTHOR]

Ovarian and adrenal tumors are rare causes of precocious puberty. The pubertal progression is typically more rapid than is observed in central precocious puberty. Juvenile granulosa cell tumors are the most common ovarian tumors associated with premature sexual development, whereas Leydig cell tumors are the most common hormone-producing tumors of the testis. A variety of other sex cord tumors and less commonly germ cell tumors can be associated with premature pubertal development. These tumors can secrete androgens, estrogens, and a multitude of other hormones. Adrenocortical tumors (ACTs) are characteristically functional in children. Virilizing signs are the most common feature, although a mixed hormonal syndrome is often present. The association of ACT with several genetic syndromes has increased our understanding of the molecular mechanism of these tumors. Genetic abnormalities of chromosomes 11 and 17 are the most common finding. Complete surgical resection is potentially curative. Advances in therapy are still needed to improve outcome. [ABSTRACT FROM AUTHOR]

Familial male-limited precocious puberty (FMPP), also known as testotoxicosis, is a rare, dominantly inherited disorder that causes gonadotropin-independent sexual precocity in boys. Early signs of puberty, including virilization, growth acceleration, and skeletal advancement, develop in affected boys, usually by 3 years of age. Activating mutations of the human luteinizing hormone (LH) receptor result in increased testosterone production by the Leydig cells despite low LH levels. Diagnosis, molecular analysis, and therapy for FMPP are discussed. [ABSTRACT FROM AUTHOR]

McCune-Albright syndrome (MAS) is an extremely heterogenous condition in which a variety of systemic and endocrine abnormalities can occur. It is classically characterized by the triad of peripheral precocious puberty, café au lait skin pigmentation, and polyostotic fibrous dysplasia of bone. It is caused by activating mutations of GNAS, the gene encoding the alpha subunit of the stimulatory G-protein (G_s α), and result in constitutive, ligand-independent activity in affected cells. The GNAS activating mutations lead to a loss of intrinsic guanosine triphosphatase (GTPase) activity of Gs α , resulting in an inability to return the cell to its inactive basal state after stimulation by a hormone ligand. Thus, the presence of GNAS mutations in endocrine cells is associated with unregulated hormone production and the development of endocrine cells is associated with unregulated hormone production and the development of endocrine hyperfunction. Diagnosis is based on careful physical examination as well as biochemical and radiographic evaluation, while molecular diagnosis is currently best reserved for the research setting. Therapeutic approaches vary widely and must be individualized to target the presiding manifestations of the disorder. Because MAS is both rare and heterogeneous in nature, collaborative and multi-center research efforts are paramount to advance the understanding of the etiology, pathophysiology, diagnosis and treatment of this condition. [ABSTRACT FROM AUTHOR]

Gonadotropin dependant precocious puberty is a heterogeneous disease with variable clinical presentations ranging from incomplete forms of precocious pubertal development to rapidly progressive forms. Although there is some controversy about the indications for treatment of central precocious puberty, in this chapter we review and clarify the indications as well as summarize the various methods available for monitoring therapy. Gonadotropin releasing hormone agonists (GnRHa) are currently considered the treatment of choice for central precocious puberty (CPP). Long-term outcome studies have shown that GnRHa have completely reversible suppressive effects on the hypothalamic-pituitary-gonadal axis, preserve final adult height, and have no long-term effects on bone mineral density and body composition in children with CPP. Newer therapies for use in CPP such as GnRH antagonists and third generation aromatase inhibitors are currently being studied and may be additional treatment options in the future. [ABSTRACT FROM AUTHOR]

Precocious puberty is puberty occurring earlier than 2.5 SD below the mean. In boys, this is before age 9. In girls, the age is controversial, but classically, has been considered age 8 for white girls and 7 for African American girls. Precocious Puberty can be centrally or peripherally mediated and is more common in girls than boys. In central precocious puberty (CPP) the concern is to identify whether the etiology is pathological or idiopathic. In girls, the cause of CPP is usually idiopathic but in boys a central lesion is more common. The most commonly identified cause of CPP is the hypothalamic hamartoma. A head MRI should be considered in any child with CPP to rule out occult intracranial lesions. [ABSTRACT FROM AUTHOR]

Early puberty, including premature adrenarche (PA) and precocious puberty (PP) can be a challenge for the practitioner as well as the parent and child. This chapter will focus on the Psychosocial problems that may be evident in children with PA or PP. To better Understand these issues, four specific areas will be addressed. First the chapter will focus on the existing empirical evidence of psychosocial problems in children with PA or PP and the limitations of these studies. Second, the chapter will address ways to better understand why certain psychosocial problems may occur in children with early puberty. The theoretical and empirical rationale for such problems will be discussed along with specific actions of hormones that may influence the brain and behavior. Third, implications for the practitioner caring for children with PA or PP will be addressed regarding psychosocial issues. Finally, directions for future research on psychosocial problems in children with PA or PP will be discussed. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a heterogenous disorder characterized by hyperandrogenism and chronic anovulation. The hyperandrogenism is secondary to excessive ovarian and/or adrenal androgen secretion. PCOS is a familial disorder with the phenotype reflecting both genetic factors and environmental influences. Signs and symptoms of PCOS often emerge during the peripubertal years. Indeed, for some girls, early development of pubic hair, known as premature pubarche (PP), is the earliest manifestation of PCOS. Understanding the path by which PP evolves to PCOS will help to identify risk factors and novel therapeutic options. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia, a family of autosomal recessive diseases of cortisol synthesis, is commonly associated with disordered puberty. Perturbations of pubertal onset and progress are determined by which hormones are overproduced and which are deficient. There may be precocious pubarche or puberty, sexual infantilism and failure to initiate or complete pubertal development, menstrual irregularity, hirsutism and infertility. In addition to glucocorticoid treatment to replace the deficient cortisol and mineralocorticoid if salt-wasting is present, treatment may include sex steroids, LHRH agonists, aromatase inhibitors and genital surgery. [ABSTRACT FROM AUTHOR]

There is increasing evidence that the in utero environment has a profound effect on later health. Fetal nutritional restriction, usually caused by uteroplacental insufficiency and that manifests with low birth weight for gestational age, is associated with neurocognitive problems, reduced growth potential, and an increased risk of the adult diseases comprising ‘‘the metabolic syndrome.'' There are also well-characterized metabolic abnormalities, the best described being reduced insulin sensitivity in childhood and pathological insulin resistance in later life. A growing body of evidence indicates that early life events can also modify aspects of puberty. Puberty occurs slightly earlier and at a different tempo, with an earlier but attenuated growth spurt resulting in reduced final height. There is also an increased incidence of premature and exaggerated adrenarche, ovarian hyperandrogenism, and polycystic ovary syndrome (PCOS). These conditions are discussed in more detail as are possible underlying etiologies especially insulin resistance and the amplifying effect of obesity. [ABSTRACT FROM AUTHOR]

Adrenarche occurs only in higher primates, typically at 6-8 years of age in humans, when the innermost layer of the adrenal cortex, the zona reticularis (ZR), develops. This is an event of postnatal sexual maturation in which there is an increase in the secretion of adrenal androgens, mainly dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), not accompanied by an increase in cortisol secretion. Although adrenarche might be a multifactorial event, the main process regulating the production of adrenal androgens continues to represent one of the most intriguing mysteries in adrenal functional differentiation. Premature adrenarche, the early increase in adrenal androgen production, might be associated with ovarian hyperandrogenism and polycystic ovarian syndrome (PCOS) in females, as well as with insulin resistance in the two sexes, during puberty development and adult life, and even in childhood. However, many questions remain with incomplete answers, such as (i) the mechanisms of adrenarche and premature adrenarche, (ii) the physiological actions of adrenal androgens, acting as either direct ligands or pro-hormones, and (iii) the relationship between the activation of adrenal androgen secretion, growth restriction during fetal life, and chronic diseases in adulthood, transforming adrenal androgens in markers of diseases important for human health. Future research might contribute to provide responses for a better understanding of these questions. [ABSTRACT FROM AUTHOR]

Gynecomastia, defined as a palpable disk of breast tissue in males, is a relatively common condition. It is usually benign and self-resolving, especially in neonates and pubertal boys. An imbalance in the estrogen-to-androgen ratio is believed to be the culprit in the pathophysiology of gynecomastia. An increase in estrogen or a decrease in androgen is found in most pathologic entities associated with gynecomastia, such as hypogonadism, tumors, or enzymatic defects. A thorough history and physical examination is essential in distinguishing between benign and pathologic gynecomastia, as well as in directing further workup. Treatment of gynecomastia is usually for social and cosmetic reasons, and it is unnecessary in cases where it is mild or transient. However, in persistent or severe cases, treatment may be advisable. Androgens, antiestrogens, and P450 aromatase inhibitors have all been studied, with mixed results. Surgical treatment, while invasive and likely to leave scars in severe cases, is a definitive and more effective treatment option. [ABSTRACT FROM AUTHOR]

Premature thelache is the development of breast tissue prior to the normal age of pubertal onset. it can arise as a result of a number of different etiologies. This chapter provides an overview both of the physiology of normal breast development and of the causes of early thelarche, including benign self-limited premature thelarche, gonadotropin-independent precocious puberty, gonadotropin-dependent precocious puberty, exposure to exogenous estrogens, and non-hormonal mechanisms. A careful history and physical examination is essential is essential in order to determine the proper diagnostic approach. it is important for the clinican to differentiate benign premature thelarche from other causes that can have deleterious consequences, such as true precocious puberty. [ABSTRACT FROM AUTHOR]

It has been presumed by the media and the public that puberty is occurring earlier now than in past decades. This is the result of reports of earlier breast development in girls (Tanner stage 2, Br2) and earlier genital development (Tanner genital stage 2, G2) in boys. Nonetheless, owing to the lack of representative data, the intra- and inter-observer variability in Tanner staging, and the fact that initial sex hormone-driven physical changes do not always indicate the onset of puberty, bona fide evidence of an earlier pubertal onset is not available. The gold standard verifying pubertal onset involves documentation of hormonal responsiveness of the hypothalamic-pituitary-gonadal (HPG) axis. The evidence cited for an earlier onset of puberty involves the age of the first physical changes of puberty. In girls, the appearance of breast may simply be due to fatty tissue deposition, particularly in overweight children; alternatively, breast tissue may be a consequence of non-HPG-stimulated estrogen production. In males, genital staging is poorly defined and therefore subjective and prone to significance within and between observer disagreements. Inexperienced observers, unacquainted with the normal variation in prepubertal genital size and appearance, may erroneously assign G2 based on size alone. This is a possible explanation of recent studies showing a high percentage of 9-year-old boys in G2 in recent surveys in contrast to findings in the last 1970s. Data remain insufficient because of problems with sample size and selection, race, socioeconomic status (SES), assessment, and statistical methods to conclude that there is a significant continuation of the secular trend toward an earlier pubertal onset in boys or girls. [ABSTRACT FROM AUTHOR]

Although there is mounting evidence for a secular trend for earlier puberty in girls over the past 30-40 years, there is disagreement as to what factor(s) might explain this trend. This chapter summarizes the available information that supports a relationship between earlier puberty and the well-documented increase in obesity over the same time period. Although there are few studies that directly measured body fat as a predictor of earlier puberty in girls, there are many that examine the relationship between earlier puberty and increased body mass index (BMI) in girls, which correlates well with increased body fat in young girls. Using the data from the Pediatric Research in Office Settings (PROS) study of pubertal development in US girls between ages 3 and 12, a clear relationship was found in 6-year-old to 9-year-old girls between higher BMI and the presence of breast development and pubic hair. This relationship was stronger for White than for African-American girls. Data from other US studies [the National Health and Examination Survey (NHANES) III, the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS), and the Bogalusa Heart Study] support a role for increased BMI, as well as a few studies from other parts of the world. Whether increased obesity is a cause of or a consequence of earlier puberty in girls is still the subject of debate. There is so far no clear evidence linking obesity to earlier puberty in boys, and a few studies even suggest that obesity in boys may be associated with later puberty. Reasons why the effect of obesity may be different in girls than in boys will be discussed. In addition, the possible role of leptin and insulin resistance as factors linking obesity and earlier puberty in girls will be reviewed. [ABSTRACT FROM AUTHOR]

Determining trend directions in ages of pubertal charateristics with certainty in U. S. studies is not possible because studies using similar methods and measurement techniques do not exit, with the exception of the menarcheal data from the government surveys. Taking the methodological differences into account, the data for girls since the 1940s support a continued decline, through less steep than that during the later 1800s and early 1900s as based on menarcheal data. Modern girls appear to start development 5 months to a year earlier than those of 30 to 50 years ago with a longer tempo from onset to menses. The data from NHES and NHANES on menarche are exactly comparable and show a statistically significant drop of over a month per decade in the last 30 years to 12.34 years of age for white girls and 12.06 for black girls. Fewer studies exist for boys and the data are only cautiously suggestive of lessening trend. Testicular measurement has not been used in U. S. studies. Data since the 1940s show a very slight downward trend in onset of public hair growth for white boys. The most recent NHANES data on genitial growth would indicate a younger age as compared with several decades ago (onset of G2 now 10.1 and 9.5 years of age for white and black boys respectively from the 1988-1992 data set) however; the reliability of the assessments has been questioned. The American Academy of Pediatrics Pediatric Research in Office Settings study in the field since 2006 will provide much needed data.Supporting evidence for earlier puberty in both boys and girls includes limited growth and dental studies showing earlier achievement of final height and mature dentition as well as the obesity epidemic, a condition likely associated with an earlier onset of puberty, at least in girls. Changes in ages of onset of pubertal characteristics have profound public health and medical care implications. Just as rising ages may indicate lack of adequate nutrition or other harmful social or environmental conditions, lowering ages may reflect different kinds of harmful conditions such as overweight or certain environmental contaminants. Reliable trend data are needed for the care of our children and for appropriate public health interventions. [ABSTRACT FROM AUTHOR]

‘‘The timing of pubertal onset among humans is controlled by both environmental and genetic factors. Although the environmental factors are important, the high heritability of pubertal timing suggests that at least half of the variability of this trait is due to genetic variation within the population. Thus, identification of the genetic factors that control this trait will enhance our understanding of pubertal development. New research strategies in both humans and animal models are facilitating the identification of these genes. In this chapter, we will discuss data supporting the heritability of pubertal timing, investigative approaches, and progress that has been made in identifying the genetic factors that regulate pubertal timing.‘‘ [ABSTRACT FROM AUTHOR]

Puberty is a developmental milestone that involves the disinhibition or reaugmentation of the hypothalamic GnRH pulse generator and gonadotropin secretion. The hypothalamic GnRH pulse generator pituitary system in the human function during fetal life and early infancy is suppressed to a low level of activity during childhood (the juvenile pause) and is derepressed or reactivated during puberty. In this light, puberty does not represent the initiation or first occurrence of pulsatile secretion of GnRH or pituitary gonadotropins but the reactivation or disinhibition of GnRH neurosecretory neurons in the medial basal hypothalamus and the endogenous, apparently self sustaining, oscillatory secretion of GnRH after the period of quiescent activity during childhood. An increase in the pulsatile release of GnRH heralds the onset of puberty in the primate as well as other mammals The CNS, and not the hypothalamic GnRH pulse generator, pituitary gland, gonads, or gonadal steroid target tissues, restrains activation of the hypothalamic pituitary gonadal system during the prepubertal years according to a large body of evidence. This inhibitory effect of the CNS appears to be mediated through the hypothalamus on the neurosecretory neurons that synthesize and secrete GnRH in a pulsatile manner. [ABSTRACT FROM AUTHOR]

This chapter provides an overview of the mechanisms that govern the onset of puberty in the rhesus monkey, a representative higher primate. Particular attention is paid to the neurobiology that underlies the on-off-on pattern of pulsatile gonadotropin-releasing hormone (GnRH) release by the hypothalamus from birth until puberty, because the timing of the resurgence in the secretion of this brain peptide at the termination of juvenile development determines the age of gonadarche in both humans and monkeys [ABSTRACT FROM AUTHOR]