Puberty in Boys and Girls

76 Puberty in Boys and Girls Dennis M. S tyne

Melvin M. Grumbach

Department of Pediatrics University of California, Davis Sacramento, California 95817

Department of Pediatrics University of California, San Francisco San Francisco, California 94143

T h e study of behavior related t o the hormonal changes of puberty in human beings is fraught with difficulties. The obvious ethical limitations of the study of children and adolescents is only the beginning. The endocrine changes of puberty begin in fetal life. The effects of hormones on central nervous system (CNS) development during gestation may only be manifest a decade later, during puberty. Social influences on human development are far more variable than those found in any experimental animal and in the human being, in contrast to all other models, social influences can overcome some patterns that might be otherwise determined by endocrine development. Further, the serum levels of hormones that figure prominently during the adolescent period are mostly released in boluses in an episodic and often diurnal fashion, so that single determinations of serum values at one time during the day rarely tell the whole sto W. Pubertal development is a continuous process but may, for convenience, be broken down into five stages of physical development; physiological changes relate better to these stages than to chronological age. Although, rarely used in psychological studies for ethical reasons, the stage of skeletal development (bone age) is an even better reflection of physiological status. Many studies correlate serum hormone with behavior according to chronological age rather than to the stage of puberty, so children and adolescents at different physiological states are often mixed together in the analysis.

Nonetheless, certain patterns can be deduced about the influence of hormones on behavior during puberty, but some of the more generally accepted relationships (e.g., aggression and testosterone) are surprisingly difficult to support with clinical data. Our aim is to describe normal pubertal development and the CNS control of puberty, followed by a review of studies of behavior related to pubertal development and the influence of environment on pubertal development that may, in turn, affect behavior.

I. N O R M A L STAGES OF PUBERTAL D E V E L O P M E N T IN GIRLS A N D BOYS Secondary sexual development is divided into five stages for the purposes of clinical studies and patient evaluation. Most subjects at the same stage of puberty will have a similar endocrine milieu. The stages in wide use were developed by Marshal and Tanner (1969, 1970) and are called Tanner stages or sexual maturation ratings (SMR). The descriptions of the stages are listed in Table 1. The stages of pubertal of development in males are also correlated with the volume of the testes, determined by comparison to solid ellipsoids (Prader orchidometer; Zachmann et al., 1974).

A. Utility of Bone Ages Bone age is a reflection of physiological status, which in many situations is a more appropriate measure than

Hormones,Brainand Behavior VOLUME FOUR

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Copyright 2002, Elsevier Science (USA). All rights reserved.

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IV. Development of Hormone-Dependent Neuronal Systems TABLE 1

Human Developmental Stages a

Female Development Breast stages B1 B2

Pubic hair stage

Description

B3 B4 B5

Prepubertal; no pubic hair Sparse growth of long, straight, or slightly curly minimally pigmented hair, mainly on the labia; this stage is very subtle and sometimes missed on cursory examination Considerably darker and coarser hair spreading over the mons pubis Thick adult-type hair that does not yet spread to the medial surface of the thighs Hair is adult in type and is distributed in the classic inverse triangle

PH1 PH2

Prepubertal: elevation of the papilla only Breast buds are noted or palpable with enlargement of the areola; this is quite subtle and often missed on examination Further enlargement of the breast and areola with no separation of their contours Projection of areola and papilla to form a secondary mound over the rest of the breast Mature breast with projection of papilla only

Description

PH3 PH4 PH5

Male Development Genital stages G1 G2

G3 G4 G5

Description Preadolescent The testes are more than 2.5 cm in the longest diameter excluding the epidydimus; and the scrotum is thinning and reddening Growth of the penis occurs in width and length and further growth of the testes is noted Penis is further enlarged and testes are larger with a darker scrotal skin color Genitalia are adult in size and shape

Pubic hair stages PH1 PH2

PH3 PH4 PH5

Description Preadolescent; no pubic hair Sparse growth of slightly pigmented, slightly curved pubic hair mainly at the base of the penis; this stage is very subtle and may be missed on cursory examination Thicker, curlier hair spread laterally Adult-type hair that does not yet spread to the medial thighs Adult-type hair spread to the medial thighs

aModified from Marshall and Tanner (1969, 1970).

chronological age. Skeletal maturation is determined by comparing radiographs of the hand, knee, or elbow with standards of maturation in a normal population (Greulich and Pyle, 1959; Tanner etal., 1975). Bone age in delayed puberty correlates better with the onset of secondary sexual development than does chronological age. Bone age is more closely related to menarche in girls than is chronological age. In addition, bone age, height, and chronological age can be used for the prediction of final adult height from the Bayley-Pinneau tables (Bayley and Pinneau, 1952) or by the use of the Roche-Wainer-Thissen (RWT) (Roche et al., 1975), Tanner-Whitehouse (Tanner et al., 1975), or Walker (1974) techniques.

Skeletal maturation is more advanced in girls than in boys of the same chronological age. For example, the bone ages of 11-yea>old girls and 13-year-old in boys (bone ages of early puberty in each sex) are equivalent stages of skeletal maturation. A difference between bone age and chronological age must exceed 2 standard deviations (SD) (according to tables available in the respective bone age atlases) to be of biological significance. African American children have slightly more advanced bone ages than do white children of the same chronological age (Roche, 1975). As commonly estimated, there is a degree of subjectivity in the interpretation of bone age and this is more a qualitative measure than a true quantitative measure.

76. Puberty in Boys and Girls

The assessment of skeletal maturation adds to the determination of the physiological stage over Tanner staging and certainly over chronological age. No studies of hormones and behavior have used this method of standardizing their patient populations; indeed, there are may be ethical considerations to performing one or multiple radiographs for a psychosocial study. B. Age of O n s e t of P u b e r t y The only data on the age of attainment of various stages of puberty in the United States began with subjects 12 years of age, which was uninformative about the lower limits of the age of onset of puberty (MacMahon, 1973; Harlan et al., 1979, 1980). This is in contrast to the plentiful information about the age of puberty in many other countries. A longitudinal study of white boys and girls in the United States started at 9.5 years of age and adds to the determination of the mean age of attainment of the stages of puberty (Roche et al., 1995); nonetheless, it starts too late to include those normal children entering puberty at an age earlier than 9.5 years. A large cross-sectional study of 17,070 girls who were evaluated by 225 trained pediatric observers started at 3 years of age, but ended at 12 years of age and so excludes a proportion of normal children who enter puberty at a later age (Herman-Giddens et al., 1997). This is the largest study of girls available in the United States, although some criticize it for not being planned as a prospective study of normal children at set intervals rather than a study of children who happen to go to a doctor's office for various reasons and are only then included in the study. A comprehensive large longitudinal study that starts early enough and ends late enough to include the youngest and the oldest normal pubertal subjects is needed but not available in the United States. Because there is no ideal study in the US and no careful study of boys early in childhood, we have to combine the available data to develop guidelines for normal puberty. The mean age for a U.S. boy to reach G2 or P2 is 11.2 years, with a SD of 0.7 years---t-2.5 SD range from 8.9 to 13.3 years, and for simplicity we can say the mean age of onset of puberty in boys is 11 years with the limits of 2.5 SD at 9 to 13.5 years of age (these are similar to the limits invoked in the past that went up to 14 years and 14 years is still widely used as the up-

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per limit of normal male pubertal development; Roche et al., 1995). In the evaluation of girls using the longitudinal data of this same study, a mean age for the onset of puberty is 11.2 years. This correlates with the U.S. Health Examination Survey of 1977, from which it was decided that normal female puberty (in a cohort in which ethnic groups were not analyzed separately) occurred between 8 and 13 years of age (Harlan et al., 1980). However, in the large cross-sectional study previously, mentioned, 3.0% of white girls moved to B2 development by 6 years and 5.0% by 7 years, whereas 6.4% of African Americans achieved B2 development by 6 years and 15.4% by 7 years (Herman-Giddens et al., 1997); these percentages seem too high to attribute an abnormality to all of these girls, although it is possible that some of them had identifiable conditions to cause their early development. Thus, there must be a modification to the longitudinal study of the age of onset of puberty skewed to include these younger ages. Using the large number of white and African American girls in the cross-sectional study (Herman-Giddens et al., 1997), the mean age of onset is 10.6 years for whites, with the range between 6.7 and 13 years, and 8.9 years for African Americans, with the range between 6 y and 13 years. African American girls have an earlier onset of pubertal development of approximately 1 year than white girls, even though their average age of menarche in the cross-sectional study had only a 7-month difference (12.2 years for African Americans and 12.9 for whites). Of interest is the evidence that in normal girls maturing at different ages, the length of puberty between time of onset and the age of menarche depends on the timing of puberty onset--the earlier the age of onset, the longer the duration of puberty before menarche (Marti-Henneberg and Vizmanos, 1997). There is no difference between African American and white boys in age of attainment of the stages of pubertal development according to the older U.S. data (Harlan et al., 1980). Thus a new standard for the onset of pubertal development (4-2.5 SD) in girls may be set at 7-13 years for whites and 6-13 years for African Americans (Grumbach and Styne, 1998), earlier than previously considered (Kaplowitz and Oberfield, 1999). These lower limits of normal pubertal development refer only to girls without evidence of neurological or other disorders or excessively rapid maturation Nevertheless, the

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data are inadequate to establish that the age of the onset of puberty in girls has advanced since the 1960s. We reemphasize that the age of menarche has not changed since the 1960s according to the best data available.

1. Influence of the Environment on the Age of Puberty There is a well-established change in the pattern of pubertal development due to nutritional deprivation. For example, the onset of secondary sexual development in girls of the Kikuyu people in Kenya is 13.0 years with menarche at 15.9 years (Monaghan et al., 1998), in contrast to the age of the onset of puberty in African American girls of 8.9 years with menarche at 12.2 years (Herman-Giddens et al., 1997); the Kikuyu start later and have a shorter time of transition to menarche than the African American girls. Kikuyu boys enter puberty before or at the same age as Kikuyu girls (Monaghan et al., 1998). Further, boys of the Hadza people of Tanzania enter puberty 2 years earlier than girls (Jalal et al., 1994). This is in striking contrast to the United States and wherever else puberty has been studied in the Western world, where girls enter puberty, on the average, before boys by at least 6 months and often more. We may investigate the causes of these contrasts by looking to the past. Historical records indicate that puberty occurs at an earlier age today than in the distant past; this change is thought to be due to changes in the health and nutrition of the population (Tanner, 1962, 1981a,b; Marshall and Tanner, 1986; Wyshak and Frisch, 1982). For example, the average age of menarche in industrialized European countries has decreased 2-3 months per decade since the 1850s, and in the United States the decrease has been approximately 23 months per decade since 1900. (Marshall and Tanner, 1986; Tanner, 1962, 1981a). This trend ceased in developed countries such as the United States and Holland in girls born since approximately 1940, presumably due to improved socioeconomic status and health and the benefits of urbanization (Gerver et al., 1994). Popular wisdom suggests that girls in the United States enter puberty earlier than their mothers did. Further, data on the number of girls who enter puberty earlier than the older guideline of 8 years of age (from the U.S. study of 17,070 girls previously discussed) shock the popular press into stating that all sorts of influences push girls into puberty earlier now than in the

last generation (Styne, 2000). However, there is no firm data to show that the age of puberty has changed in the United States since the 1950smthe mean age of menarche in U.S. girls has not advanced. Indeed, the growth charts just released by the centers for disease control (CDC) show no difference in height at a given age in 2001 compared to the 1970s (new charts and data can be found at http://www.cdc.govlgrowthchartsl). On the other hand, a recent analysis of the same pediatric office study data used for the updated statistics on the age of puberty for U.S. girls noted above (Herman-Giddens et al., 1997) yielded a relationship between BMI corrected for age and an earlier onset of puberty and of entering various stages of puberty for Caucasian girls (but less so in African American girls) (Kaplowitz, et al., 2001). Thus the girls with the highest BMI developed earlier. A study of the age of onset of puberty in 2114 American boys aged 8 through 19 years (HermanGiddens et al., 2001) suggests a decrease has occurred over the past decades, but a number of aspects of this study have been questioned (Reiter and Lee, 2001) due to methodological issues. The observations of genital stage are controversial, as the age of genital development was based upon the visual change in scrotal skin and enlargement of the testes (an unsatisfactory method of assessing the size of the testes compared to direct examination). The authors determined that the onset of pubic hair occurs earlier in African American boys than in Caucasian boys, with a tendency to later onset in Mexican American boys. Between the ages of 8 and 9 no Caucasian boys had pubic hair, whereas 5.3% of African American boys were at least at Tanner stage 2 by the beginning of age 8, the earliest age studied, and 35% of Caucasian boys, 37.8% of African American boys, and 27.3% of Mexican American boys purportedly had genital development at this age, earlier than expected from previous publications and studies. The height and weight of boys at the time they reached the stages of puberty were also greater than reported in the past. If the trend to increased BMI in U.S. children continues, we may anticipate a noncontrovertible decrease in the age of attainment of puberty in the future. In South America and Africa, rural children fare better and have earlier puberty and taller stature than urban children, who may be more nutritionally deprived, the opposite of the expected pattern based on urban vs rural populations in the European world

76. Puberty in Boys and Girls

(Delemarre-Van de Waal, 1993). Thus socioeconomic conditions, nutritional status, and states of health influence the age of the onset of puberty and the progression of pubertal development (Buffon, 1981; Daw, 1970; Kill, 1939). The interaction of nutrition, energy expenditure, and puberty is of particular importance in areas of the world where nutrition is suboptimal. All of these influences can affect an analysis of behavior and pubertal development. Many confuse the term menarche (the age of onset of menstruation) with the age of the onset of puberty in girls, but menarche is removed from the onset of puberty by several years in most cases. The age of menarche is partly determined by environment, as previously described, and partly determined by genetics. But there is evidence that even the environment in which women are living might influence menarche. A convergence of the onset of menses in women or girls living together has been noted (McClintock, 1971). Several publications followed that studied the spontaneous onset of menses in women living together and even the onset of menses when axillary odor scent was given to women; some studies noted synchrony and others did not. The methodology of the studies have been criticized and the positive findings deemed fallacious (Wilson, 1992). Nevertheless, one group of investigators studied menstrual synchrony in a variety of conditions in college women and older subjects and found that closeness of sleeping conditions was not a prerequisite to synchronizing menstrual cycles, but that being close friends was of significance (Casper, 1998; Persky,

~987). In a group of white girls, there was a trend for the mother's age at menarche to predict an adolescent's age at menarche; this was found in other studies and suggested a genetic influence. However, breast development, weight, family relations (including the absence of a father), and depressive affect were predictive of age at menarche in this group, with family relations more strongly predicting the age at menarche than the influence of breast development or weight; the question arose whether psychological stress decreased the age of menarche or, on the contrary, whether the stress occurred due to the earlier menarche (Graber et al., 1995; Hayward et al., 1997; Moffitt et al., 1992). Another study of the age of menarche, however, confirmed the influence of the mothers' age of menarche on the

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age of menarche in daughters, but found no influence of stress caused by family problems on early menarche (Campbell and Udry, 1995). It is reasonable to suggest that environmental influences should be considered in the study of the age of menarche, but only some of these influences appear to of greater significance than genetic patterns.

II. C O N T R O L OF THE PUBERTAL G R O W T H SPURT The pubertal growth spurt is a striking change during secondary sexual development because the individual grows faster than at any time in his or her life, with the exception of fetal and early infant growth. The hormonal control of the pubertal growth spurt involves several factors. Growth hormone (GH) clearly plays a role in increasing growth at puberty through the stimulation of insulin-like growth factor I (IGF-I) production. The secretion of GH increases with pubertal development in boys and girls (Miller et al., 1982; Ross et al., 1989; Costin and Kaufman, 1987; Costin et al., 1989; Gamier et al., 1988; Link et al., 1986; Martha et al., 1989; Mauras et al., 1987; Wennink et al., 1991). GH-deficient (Tanner and Whitehouse, 1975; OgilWStuart and Shalet, 1992) or GH-resistant (Rosenfeld et al., 1994) children have delayed puberty in most, but not all, studies, whereas GH therapy normalizes puberty (Rosenfeld et al., 1994; Darendeliler et al., 1990; Stanhope et al., 1992). This phenomenon can be reproduced in the rhesus monkeymGH (Wilson et al., 1989) or IGF-1 (Wilson, 1998) treatment advances pubertal development, whereas GH suppression with octreotide delays the onset of ovulation (Wilson and Tanner, 1994). Increased GH pulse amplitude and the amount of GH secreted per pulse in the basal state are mainly responsible for the augmented GH levels in puberty; frequency and metabolic clearance rate play no role (Martha et al., 1989, 1992). The increase in GH secretion occurs earlier in girls coincident with the onset of breast development, B2, and is maximal at B3-B4; in boys the increase occurs later and peaks at G-4 of genital development. The concentration of plasma IGFI increases during puberty to reach a peak earlier in girls than in boys (Bala et al., 1981; Harris et al., 1985) and then decreases to adult levels with diminishing GH

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secretion (Marin et al., 1994; Bouix et al., 1994). Increased GH secretion also occurs in sexual precocity, but GH secretion decreases with the fall in estrogen levels after the treatment of children with true precocious puberty with potent luteinizing-hormonereleasing hormone (LHRH) agonists (Ross et al., 1989; Mansfield et al., 1988; Harris et al., 1985). Estrogen affects growth hormone secretion by the indirect effect of inducing increased GH secretion and, thus, the consequent increase in IGF-I production, and a direct effect on cartilage and bone by stimulating local production of IGF-I, among other local factors (reviewed Attie et al., 1990; Rogol, 1994). Estrogen has both growth-promoting and maturational actions on chondrocytes and osteoblasts. The maturational action that eventually leads to epiphyseal fusion and the cessation of longitudinal growth in both boys and girls is mediated mainly by estrogen either directly secreted (in girls) or arising from the conversion of testosterone and androstenedione to estrogen in peripheral tissues, including bone by aromatase in boys (Come et al., 1994; Smith et al., 1994; Morishima et al., 1995; Grumbach and Auchus, 1999; Grumbach, 2000). Patients with isolated GH deficiency (Rimoin et al., 1968) or GH resistance (Phillips, 1989) have an attenuated pubertal growth spurt, indicating the importance of GH and IGF-I in this time of rapid growth. Individuals with severe primary or secondary hypogonadism have a minimal growth spurt or no pubertal growth spurt, demonstrating the primary role of gonadal steroids in pubertal growth. Hypopituitary patients deficient in both GH and gonadotropins do not have an adolescent growth spurt when GH alone is replaced; gonadal steroids must also be given, substantiating the interaction of GH and gonadal steroids in the pubertal growth spurt (Tanner et al., 1976; AynsleyGreen et al., 1976). A pubertal growth spurt occurs in individuals with the complete form of androgen resistance (androgen insensitivity syndrome), which leads to a final height close to that of normal adults (Zachman et al., 1997), a finding that supports the critical role of estrogen in the adolescent growth spurt. The detection of estrogen resistance due to a null mutation in the gene encoding the estrogen receptor and of derangements in the CYP19 gene leading to severe cytochrome P450 aromatase deficiency have highlighted the cardinal role of estradiol,

but not testosterone, in both boys and girls in the pubertal growth spurt, complete epiphyseal maturation, and normal skeletal proportions and mineralization (Smith et al., 1994; Morishima et al., 1995; Grumbach and Auchus, 1999; Grumbach, 2000). Both types of patients had a very significant delay in epiphyseal fusion and osteopenia. Further, a supersensitive assay for plasma estradiol detected estradiol in prepubertal boys and noted a positive relationship between serum estrogen concentrations and the increased pubertal growth rate (Klein et al., 1994). The concentration of serum estrogen was positively correlated with the concentration of serum testosterone, but not with that of serum GH, again implicating estrogen in the pubertal growth spurt and skeletal maturation of boys as well as girls. Thyroid hormone also plays an important permissive role in pubertal growth; patients with primary hypothyroidism may not have a growth spurt, even when the disorder is accompanied by sexual precocity (Van Wyk and Grumbach, 1960). Thus, some of the same hormones that affect behavior and mood affect growth at puberty. Treatment with GH, a substance that would not ordinarily be implicated in changing pubertal behavior directly, changes the physical appearance of the individual enough to cause changes in mood and behavior through indirect means. Alternatively, extreme short stature, found in some of the syndromes discussed later, takes its own toll on mood and resulting behavior (reviewed in Stabler and Underwood, 1986). A study of the influence of growth and pubertal development is essential in the consideration of changes in behavior in puberty.

III. CENTRAL NERVOUS SYSTEM A N D PUBERTY (This section is modified from Grumbach and Styne, 1998.) The control of the onset of puberty is incompletely understood (Grumbach et al., 1974; Grumbach and Kaplan, 1974, 1990; Grumbach, 1980). Puberty is not an isolated de novo event but rather a critical stage, a developmental milestone that involves the reactivation of the hypothalamic LHRH pulse generator leading to augmented gonadotropin secretion. This system, operating actively during fetal life and infancy (Grumbach

76. Puberty in Boys and Girls and Gluckman, 1994; Grumbach and Kaplan, 1974, 1990; Kaplan et al., 1976; Grumbach, 1980; Kaplan and Grumbach, 1978), is suppressed to a low level of activity in childhood, as exemplified by the small amount of gonadotropin secretion during childhood. Three regulatory systems are involved in the control of human sexual maturation. First, in humans and nonhuman primates the neural component that controis gonadotropin secretion resides in the medial basal hypothalamus, including the arcuate region (Kinget al., 1985). The transducer LHRH neurosecretory neurons, which originate in the embryonic olfactory placode and migrate from the nasal septum via the forebrain to the hypothalamus (Schwanzel-Fukuda et al., 1996; Knobil, 1990), are few in number (~1500-2500 neurons) and dispersed rather than being segregated into a specific nucleus; however, the neurons are functionally interconnected (Silverman et al., 1994). These LHRH neurons translate neural signals into a periodic, oscillatory chemical signal, LHRH pulses, which are associated with episodic electrical activity in the hypothalamus of the same frequency (Mellon et al., 1990; Knobil, 1990; Martinez de la Escalera et al., 1992). The generation of LHRH pulse is an intrinsic property of the LHRH neurosecretory neuronal network, whereas other factors modulate the fundamental autorhythmicity of the LHRH neuron into the various pulses characteristic of various stages of development and the stages of the menstrual period (see Wetsel, 1995; Krsmanovic et al., 1996). The gene for LHRH contains four exons and three introns (Adelman et al., 1986) and is located on the short arm of chromosome 8. Mature LHRH is a decapeptide that is synthesized as part of a larger precursor protein. The LHRH neurosecretory neurons of the hypothalamic LHRH pulse generator exhibit spontaneous autorhythmicity (Mellon et al., 1990; Martinez de la Escalera et al., 1992; Wetsel et al., 1992) and function intrinsically as a neuronal oscillator for the entrainment of the repetitive release of LHRH. The mechanism for pulse generation, the coordinated synchronous discharge of LHRH from neighboring but dispersed ceils, is unknown, but may involve synaptic connections among LHRH neurons and the electronic coupling of cells through gap junctions (Mellon et al., 1990; Marshall and Goldsmith, 1980; Witkin and Silverman, 1985; Kramanovik et al., 1993) and by autocrine factors such as LHRH and nitric oxide (Morreto et al., 1993;

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Mahachoklertwattana et al., 1994). LHRH is synthesized in these neurons and released episodically from axon terminals at the median eminence into the primary plexus of the hypothalamic-hypophyseal portal circulation (Reichlin, 1992). The hormone is then transported by the portal vessels to the anterior pituitary gland, where it causes the release of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The amplitude and frequency of the pulsatile LHRH signal are modified by catecholaminergic and serotoninergic neurons, through their effect on hypothalamic norepinephrine, dopamine, and serotonin, and by opioid peptide, corticotropin-releasing hormone, yaminobutyric acid (GABA) and excitatory amino acid neuronal networks in rodents. Aspects of these mechanisms are present in human beings, but, unlike in nonprimates, some are nonfunctional during the prepubertal period (e.g., the juvenile pause) (Reichlin, 1992; Gorski, 1974, 1990; Gallo, 1980; Ojeda et al., 1980; Kordon et al., 1994). In primates, the inhibitory effects of opioid peptides and corticotropin-releasing hormone on the LHRH pulse generator are the most firmly established mechanism in adulthood, but not during prepuberty. During prepuberty, GABA (Terasawa and Fernandez, 2001) and possibly neuropeptide Y (NPY) (El Majdoubi et al., 2000) apparently are the major inhibitory neurotransmitters. Further, in the rodent glia and glial growth factors influence LHRH release (Ojeda and Ma, 1998), but the role of glial growth factors (TGFol, TGFfi, etc.) in the onset of primate puberty is not known. On the other hand, human LHRH neurons possess IGF-I receptors (Zhen et al., 1997). The hypothalamic-pituitary gonadotropin unit is influenced by gonadal steroids, inhibin, activin, and follistatin (Burger et al., 1988; De Jong, 1988; Ying, 1988), and by complex neural influences that integrate various intrinsic stimuli and environmental factors and cues. Second, the pituitary gonadotropes response to the LHRH rhythmic signal by releasing LH and FSH in a pulsatile manner. Third, the gonads are modulated primarily by the amplitude of the gonadotropin pulse and translate this episodic gonadotropin signal into the secretion of gonadal steroids. After fetal life and early infancy periods, when there is much hypothalamic-pituitary-gonadal activity, the system is suppressed to a low level of activity during prepuberty by the CNS (the juvenile pause) and is

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derepressed or reactivated during puberty (Grumbach and Kaplan, 1990; Kaplan et al., 1976; Grumbach, 1980; Grumbach et al., 1974; Donovan and van der Werff, 1965; Critchlow and Bar-Sela, 1967; Reiter and Grumbach, 1982). The destruction of the inhibitory area by disease, trauma, or surgery may allow the premature onset of puberty (central precocious puberty). Thus puberty is the reactivation or disinhibition of LHRH neurosecretory neurons in the medial basal hypothalamus.

IV. PATTERN OF G O N A D O T R O P I N SECRETION There are two pulsatile secretory patterns of gonadotropinsntonic and cyclic. Tonic, or basal, secretion is regulated by a negative, or inhibitory, feedback mechanism in which changes in the concentration of circulating gonadal steroids and inhibin result in reciprocal changes in the secretion of pituitary gonadotropins. Tonic secretion is the pattern of secretion in the male and one of the control mechanisms in the female. Cyclic secretion involves a positive, or stimulatory, feedback mechanism in which an increase in circulating estrogens to a critical level and of sufficient duration initiates the synchronous release of LH and FSH (the preovulatory LH surge) that is characteristic of the normal adult woman before menopause. The secretion of FSH and LH is always pulsatile or episodic regardless of the developmental stage. Improvements in assay technology allow the demonstration of diurnal rhythms of pulsatile LH, FSH, and testosterone in children as young as 4-5 years in contrast to the limitations of earlier assays (Mitamura et al., 1999, 2000; Veldhuis et al., 2001). Serum LH and FSH concentrations show a night-day variation in a pulsatile fashion, and serum testosterone concentration is elevated in early morning in prepubertal boys. Mean 24-hour concentrations of serum LH, FSH, and testosterone also increase with developing puberty. A positive cross-correlation between serum LH and testosterone is seen in time series, indicating that LH was stimulating the release of testosterone. The mean lag time from the LH to the testosterone time series decreased with the change from prepuberty to puberty and with developing puberty. Thus, the endocrine apparatus of puberty is fully functional in nor-

mal prepubertal children and there is a diurnal variation in testosterone (as there is for estradiol) and an episodic secretion of LH and FSH. All of these endocrine variations make the analysis of a relationship between behavior and endocrine factors based on single samples problematic if not impossible. Few blood samples are taken during psychological studies of pubertal subjects. Although the inherent oscillatory characteristic of gonadotropin secretion is a consequence of the pulsatile release of LHRH, the continuous infusion of LHRH desensitizes LHRH receptors on the gonadotrope leading to the inhibition of gonadotropin secretion (Belchetz et al., 1978; Huckle and Conn, 1988; Hazum and Conn, 1988; Nett et al., 1981). Studies in rhesus monkeys using pulsatile administration of LHRH or constant infusion of LHRH provided evidence that the LHRH signal to the pituitary gonadotropes of the adult is frequency-coded (Knobil, 1980; Belchetz et al., 1978). The therapeutic pulsatile administration of natural LHRH has made possible the induction of ovarian or testicular maturation, including fertility, as well as the initiation of puberty in patients with hypothalamic hypogonadism. Further, the suppression of gonadotropin secretion is accomplished in boys and girls with true precocious puberty by using long-acting potent LHRH analog that act as a constant infusion of LHRH. V. O N T O G E N Y

A. Human Fetus Studies in the fetus demonstrated that normally LHRH neurons migrate from the primitive nasal area (the olfactory placode) to the hypothalamus. In a 19-week gestational male human fetus with Kallmann syndrome (gonadotropin deficiency and anosmia) due to a mutation in the KAL gene, causing absence of the adhesion molecule anosmin, there were no LHRH neurosecretory neurons detected in the usual location in the brain where these neurons are found in a normal fetus of this gestational age (Schwanzel-gukuda et al., 1989). However, dense clusters of LHRH cells and fibers were present in the primative nose, including the nasal septurn and cribriform plate, and in the dural layers of the meninges under the forebrain. The olfactory bulbs were absent. In subsequent studies, LHRH immunoreactivity was observed in the epithelium of the medial aspect of

76. Puberty in Boys and Girls

the olfactory placode by 42 days of gestation, but not at 28-32 days (Schwanzel-Fukuda et al., 1996).

B. Human Neonate The hypothalamic regulatory mechanisms for pituitary gonadotropins and other pituitary hormones are not fully developed at birth (Grumbach and Kaplan, 1990; Grumbach and Gluckman, 1994). A surge in LH release is found in boys, but not in girls, just after birth, followed by an increase in serum testosterone concentration that persists for 12 hours or more (Corbier et al., 1990). After the fall in circulating levels of steroids of placental origin (especially estrogens) during the first few days after birth, the concentration of serum FSH and LH increases and exhibit a pulsatile pattern in both sexes during the first few months. The FSH pulse amplitude is much greater in the female infant and is associated with a larger FSH response to LHRH throughout childhood; LH pulses are of greater magnitude in the male. This striking sex difference also is present in agonadal male and female infants (Grumbach and Kaplan, 1990; Lustig et al., 1987) and in the infant rhesus monkey (Plant, 1994). The high gonadotropin concentrations are associated with a transient differentiation of fetal-type Leydig cells and increased serum testosterone levels in male infants and with increased estradiol levels intermittently elevated during the first year of life and part of the second year in females (Winter et al., 1975; Forest, 1990). By approximately 6 months of age in the male and 2-3 years of age in the female, the concentration of plasma gonadotropins decreases to the low levels that are present until the onset of puberty due to the restraint of the hypothalamic LHRH pulse generator and the suppression of pulsatile LHRH secretion (and thus LH release; Grumbach, 1975, 1978; Grumbach and Kaplan, 1990). We are aware of no detailed early-period psychological studies of infants and children who experience serum gonadal steroid and gonadotropin concentrations that rival those during puberty.

VI. N E U R A L C O N T R O L

A. Timing and Onset of Puberty Body weight may be determined basically by genetic factors, but choices in eating behavior and

669

activity can modify weight, which exerts important effects on pubertal development. There is a strong relationship between nutritional factors and body composition in the onset of puberty as well as the age of menarche (Lander and Schork, 1994; Frisch, 1980, 1984; Frisch and McArthur, 1974). This relationship of nutrition and puberty is supported by the earlier age of menarche in moderately obese girls (Hartz et al., 1979; Zacharias et al., 1976), delayed menarche in states of malnutrition and chronic disease, in twins, and after early rigorous athletic or ballet training; and the relationship of weight and diminished body fat to changes in gonadotropin secretion and amenorrhea in girls with anorexia nervosa (Boyar et al., 1974), voluntary weight loss, and strenuous physical conditioning (Warren, 1980; Frisch et al., 1980, 1981; de Souza and Metzger, 1991; McArthur et al., 1980). Long-term studies of girls who had had malnutrition in infancy suggest that no permanent delay in puberty persists after early treatment (Cameron et al., 1988). A relationship has been characterized between the earlier onset of puberty in girls adopted in early childhood from an environment of deprivation (e.g., India) into an environment of plenty (several European countries), suggesting that early malnutrition influences later pubertal development (Proos et al., 1991, 1993; Virdis et al., 1998). Alternatively early exposure to endocrine disruptors has been suggested as a cause of early puberty in these girls. A toxicologic screen found a greatly elevated mean concentration of the organochlorine pesticide DDT derivative P,P'-DOE, which raised the possibility of the role of endocrine disrupters (Krstevska-Konstantinova et al., 2001). The link between nutrition and puberty has been elusive. Leptin, the adipocyte hormone, reflects body fat and hence adipose energy stores rising in those with increased adipose tissue and decreased in those excessively thin due to anorexia nervosa and athletic amenorrhea (see Spiegelman and Flier, 1996; Caro et al., 1996; Licinio et al., 1997; Considine et al., 1996). Leptin appears to function as a lipostat through its action on its receptors of the hypothalamus (Ahima et al., 1996; Schwartz et al., 1996; Campfield et al., 1995), which causes a decrease in appetite by acting as a satiety factor and an increase in energy expenditure by increasing sympathetic activity (Leibel, 1997). The administration of leptin to mice homozygous for a mutation in the ob gene (the Lep~ ~ mouse),

670

Iv. Development of Hormone-Dependent Neuronal Systems

which are leptin deficient, Cures their central infertility (Chehab et al., 1996; Mounzih et al., 1997; Wiegelmann et al., 1971); to normal female mice advances their puberty (Chehab et al., 1997; Ahima et al., 1997); and to food-restricted female rats repairs delayed puberty (Cheung et al., 1997). Although leptin stimulates LHRH release from in vitro hypothalamic median reminence-accurate nuclear explants from adult rats, LH secretion in intact rats, and LH and FSH from rat anterior pituitary glands (Yu et al., 1997)~leptin does not act directly on the hypothalamic LHRH pulse generator. Because animal studies in Lep~ ~ mice suggested that leptin may be a factor in the onset of rodent puberty, a question arises about the role of leptin in human puberty. Some human cross-sectional studies seemed to support the role of leptin in the onset of human puberty. A preliminary report claimed that in eight boys, leptin levels rose before the initial rise in testosterone (Mantzoros et al., 1997). But, this observation, which suggested that leptin and adipose tissue mass were the peripheral signals for the onset of puberty, was not confirmed in the male rhesus monkey (Plant and Durrant, 1997) or in normal children (Lee et al., 1997; Garcia-Major et al., 1997). Further, in a large cross-sectional study (Comuzzie et al., 1997) of prepubertal and pubertal children, the highest positive correlation of serum leptin between prepuberty and early puberty was with body mass index and age and less with early pubertal maturation (Clayton et al., 1997). The progressive rise in leptin during the prepubertal and early pubertal years was similar in both sexes. The mean peak concentration in boys occurred at G2 and was significantly lower by GS; in girls after the increase in B2, the leptin levels peaked at B5. In addition, a major quantitative locus on human chromosome 2 is linked to serum leptin levels and fat mass (Comu7zie et al., 1997); the structural gene that encodes leptin is located on chromosome 7 (Zhang et al., 1994), an additional indication that a variety of factors affect circulating leptin. Further, in considering puberty as an energydependent process, a group of 9- to 10-year-old boys followed for 18 months, during the months leading up to an increase in morning salivary testosterone concentrations, had a relatively constant basal metabolic rate (BMR)/lean body mass (LBM) ratio and an increase in the ratio of BMR/total daily energy expenditure. The suggestion is that a subtle energy-dependent process is

in play, possibly related to an increase in brain BMR as a secondary phenomenon at the initiation of puberty, or that a central rise in BMR is a signal for the onset of puberty (Brown et al., 1996). There are a few children with mutations of the ob gene for leptin who have been studied in depth. One girl, at 9 years of age, had an advanced bone age of 13 years, probably related to her pathological obesity, but nopulsatile gonadotropin profile that indicated the start of puberty had occurred along with the advancement of bone age. When she was treated with leptin, gonadotropin secretion increased in a pulsatile manner and, presumably, she will progress through secondary sexual development in futher studies (Farooqi and O'rahilly, 2000). A 4-year-old boy with mutation of the ob gene was treated with leptin chronically with no evidence of precocious puberty. Thus, the data seem more consistent with leptin serving a permissive function (Cheung et al., 1997) in the timing of human puberty, a metabolic signal to the CNS that energy stores, as reflected in the concentration of serum leptin, are adequate for pubertal development, than serving as a critical trigger for pubertal onset (Sahu and Plant, 2000). It may be that the role of leptin is a more critical factor in the onset of puberty in nonprimate animals (Plant and Durrant, 1997). Clinical and experimental data support the contention that the factors influencing the timing of puberty are expressed finally through CNS regulation of the onset of puberty (Grumbach et al., 1974; Grumbach and Kaplan, 1990; Donovan and van der Werff, 1965; King et al., 1985; Odell and Swerdloff, 1976; Davidson, 1974; Ramirez, 1973). In the human, the pineal gland and melatonin do not appear to have a major effect on this control system, as is found in rodents (Grumbach and Kaplan, 1990; Lenko et al., 1982; Cohen et al., 1982; Reppert and Weaver, 1995; Cavallo, 1993; Luboshitzky et al., 1995).

B. Mechanisms of Control In both humans and nonhuman primates, the increase in LH and FSH secretion in early infancy is followed by a long period in which the hypothalamic LHRH pulse generator is suppressed; as a consequence, the pituitary gonadotropin-gonadal axis is quiescent (Grumbach and Kaplan, 1990; Grumbach, 1980; Reiter and Grumbach, 1982). In humans, this

76. Puberty in Boys and Girls

prepubertal period, or juvenile pause, lasts approximately 1 decade. Two interacting mechanisms have been proposed to explain the prepubertal restraint of gonadotropin secretion (Grumbach and Kaplan, 1990; Come et al., 1980). The first is a gonadalsteroid-dependent mechanism, a highly sensitive hypothalamic-pituitary-gonadalnegative feedback system that is dominant in infancy and early childhood. The second is a steroid-independent mechanism that involves intrinsic CNS inhibition of the LHRH pulse generator in the medial basal hypothalamus (Grumbach and Kaplan, 1990; Reiter and Grumbach, 1982; Come et al., 1980) and that is predominant throughout childhood.

1. Negative Feedback Mechanism (Gonadal-S teroid-Dependent) There are several lines of evidence for an operative gonadal-steroid-dependent negative feedback mechanism in prepubertal children (Grumbach et al., 1974; Grumbach and Kaplan, 1990). 1. The hypothalamic-pituitary-gonadal complex is operative in childhood, but at a low level of activity. 2. The secretion of FSH and, to a lesser degree, LH is increased in the absence of functional gonads in the prepubertal child, as in patients with the syndrome of gonadal dysgenesis (Turner syndrome) or other congenital or postnatal gonadal deficiency. The elevated gonadotropin levels in infancy and early childhood in patients with gonadal dysgenesis suggest that even low levels of hormones secreted by the normal prepubertal gonad inhibit gonadotropin secretion, indicating that a sensitive, functional, tonic, negative feedback mechanism is active in infants and prepubertal children (Grumbach and Kaplan, 1990; Conte et al., 1975, 1980; Grumbach et al., 1974). 3. The administration of small amounts of gonadal steroids suppresses the low levels of LH and FSH, supporting the idea that the hypothalamicpituitary gonadotropin unit is highly sensitive to the feedback effect of gonadal steroids (Grumbach and Kaplan, 1990; Kelch et al., 1973; Grumbach et al., 1974). The negative feedback mechanism becomes operative in the fetus during middle to late gestation and es-

671

trogen levels increase with advancing age (Grumbach et al., 1974). With the decrease in circulating estrogen in the newborn infant, the plasma levels of FSH and LH increase from the low levels at birth in response to the diminished feedback suppression of the hypothalamicpituitary gonadotropin unit (Winter et al., 1975; Forest, 1990).

2. Intrinsic Central Nervous System Inhibitory Mechanism (Gonadal-Steroid-Independent) The diphasic pattern of basal and LHRH-induced FSH and LH secretion from infancy to adulthood is similar in normal individuals and in agonadal patients, but in the latter gonadotropin concentrations are higher, except during the middle childhood nadir (Come et al., 1975, 1980). The high concentration of plasma FSH and LH in agonadal children between infancy and 4 years of age and the increased gonadotropin reserve reflect the absence of gonadal steroid inhibition of the hypothalamic-pituitary unit by the low levels of plasma gonadal steroids. (Gmmbach and Kaplan, 1990). The striking fall in gonadotropin secretion between ages 4 and 11 even in the absence of gonads suggests the presence of a CNS inhibitory mechanism that, independent of gonadal steroid secretion, restrains the hypothalamic LHRH pulse generator during the juvenile pause until the onset of puberty (Grumbach and Kaplan, 1990; Kaplan and Grumbach, 1978). The gradual loss of this intrinsic CNS inhibitory mechanism leads to the disinhibition or reactivation of the LHRH pulse generator at puberty. 3. Interaction of the Negative Feedback

Mechanism and the Intrinsic Central Nervous System Inhibitory Mechanism The mechanisms discussed in the previous subsections interact to restrain puberty. During the first 2-3 years of life, the gonadal steroid negative feedback mechanism seems dominante, in view of the striking difference in gonadotropin secretion between the agonadal and the intact infant and young child. At approximately 3 years of age the intrinsic CNS inhibitory mechanism becomes dominant and remains so during the rest of the juvenile pause, reflected by the fall in FSH and LH levels between ages 3 and 10 despite the lack of functional gonads. The negative feedback mechanism is operative because agonadal patients in

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Iv. Development of Hormone-Dependent Neuronal Systems

this age group have higher mean plasma FSH levels than normal prepubertal children, but not as high as in infancy and puberty, and a greater FSH and LH response to the acute administration of LHRH (Conte et al., 1975, 1980). As puberty approaches, the CNS inhibitory mechanism gradually wanes, initially during nighttime sleep, and the hypothalamic LHRH pulse generator becomes less sensitive to gonadal steroid negative feedback (Grumbach and Kaplan, 1990). After the onset of puberty, gonadal steroid negative feedback attains the set point characteristic of the adult and is again the dominant mechanism in restraining gonadotropin secretion (along with inhibin). A similar pattern has been described in the infant monkey (Plant, 1980). Many neural, neurotransmitter and neuromodulator, hormonal, growth, and metabolic factors, as well as exteroceptive influences and cues (Bronson and Rissman, 1986), can influence the activity of the LHRH pulse generator, but the nature of the intrinsic inhibitory mechanism remains speculative. In the rhesus monkey, despite the damping of the LHRH pulse generator during the juvenile pause (Watanabe and Terasawa, 1989), the content of hypothalamic LHRH during this phase is similar to that in the infant and adult monkey (Fraser et al., 1989); the amount of LHRH messenger RNA also does not differ. The quiescence of the LHRH pulse generator during the human juvenile pause is not absolute because infrequent LH and FSH pulses are detectable by sensitive and specific immunoradiometric assays (Dunkel et al., 1990; Mitamura et al., 1999, 2000). The end of the juvenile pause is marked by an increase in both the LH pulse amplitude and frequency, most evident during the early hours of sleep (Hale et al., 1988; Wennink et al., 1988).

4. Potential Components of the Intrinsic Central Nervous System Inhibitory Mechanism Indirect evidence for an inhibitory neural network that arises or projects through the posterior hypothalamus and suppresses the L H R H pulse generator derives from studies of children with organic forms of central or true precocious puberty (reviewed in Grumbach and Kaplan, 1990) and studies in the female and male monkey (Terasawa et al., 1984; Schultz and Terasawa, 1988; Pohl et al., 1995). Children with true precocious puberty associated with posterior hypothalamic neoplasms (usually a pi-

locytic astrocytoma), radiation of the CNS, midline CNS developmental abnormalities such as septooptic dysplasia with deficiency of one or more pituitary hormones, or other CNS lesions provide indirect evidence for an inhibitory neural component located in or projecting through the posterior hypothalamus. As a consequence of these lesions, the neural pathway inhibiting the hypothalamic LHRH pulse generator is compromised, resulting in its disinhibition and activation (Grumbach and Kaplan, 1990). For example, a supracellular arachnoid cyst can cause true precocious puberty by compressing and distorting the hypothalamus (Grumbach and Kaplan, 1990). In some children with such cysts puberty is reversed, with regression of the hormonal and physical features of puberty, after decompression of the cyst. We suggest that the disinhibition of the CNS inhibitory mechanism was reversed by treatment of the cyst. The kHRH-secreting hypothalamic hamartoma, a heterotypic mass of nervous tissue that usually contains LHRH neurosecretory neurons (Hochman et al., 1981; Judge et al., 1977; Mahachoklertwattana et al., 1994) attached to the tuber cinereum or the floor of the third ventricle, can cause true precocious puberty. The LHRH neurons in the hamartoma with their axon fibers projecting to the median eminence secrete LHRH in pulsatile fashion. The hypothalamic hamartoma may be considered an ectopic LHRH pulse generator that functions independently of the CNS inhibitory mechanism that normally restrains the hypothalamic LHRH pulse generator (Grumbach and Kaplan, 1990). Moreover, the ontogeny of the fetal LHRH pulse generator suggests that its initial unrestrained (Krieger et al., 1982) function is followed by the differentiation of inhibitory mechanisms in late gestation (Grumbach and Kaplan, 1990). Similarly, the immortalized LHRH neurosecretory neuronal cell line exhibits spontaneous, synchronized autorhythmicity in the release of LHRH (Mellon et al., 1990; Martinez de la Escalera et al., 1992; Wetsel et al., 1992). Taken together, these observations suggest that a stimulatory input is not required for pulsatile LHRH secretion. In addition, precocious sexual maturation can be induced in the juvenile female rhesus monkey by posterior hypothalamic lesions (Terasawa et al., 1984); such lesions advance the age of the onset of a pubertal increase in LH secretion and the time of the first positive

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76. Puberty in Boys and Girls

The Yin and the Yang Neuroexcitatory amino acids

GABA

~POTHALAMy_ LHRH Neuron

Prepubertal Juvenile Pause (Intrinsic CNS inhibition) Stimulatory ~ GABA neurotransmitters ~' neurons Augmentation \'N,~._~.

~

Inhibition

LHRH pulse generator

LHRH

/

Neuroexcitatory Early Puberty amino acids (glutamate) Noradrenergicpathways NPY GABA Nitric oxide neurons Neurotrophicfactors Growth peptides 1 ~ Y US + POTHALAM

I

(Pituitary Gonadotropes ) I LH/FSH ~,

Augmentatiol

LHRH pulse

hibition

generator

LHnH~ _U_,L ( Pituitary Gonadotropes )

LH/FSH

FIGURE 1 The yin and the yang of the neuroendocrinology of the prepubertal juvenile pause and its intrinsic central inhibition of the LHRH pulse generator and the reversal of this inhibition and termination of the juvenile pause, which leads to the onset of puberty. The GABAergic neuronal network and its neurotransmitter GABA is the most ubiquitous inhibitory transmitter in the hypothalamus as well as the brain. During the prepubertal juvenile pause, this neurotransmitter system appears to play the major neural role in inhibiting the LHRH pulse generator. (Suppression of GABAinhibition during this period promptly results in reactivation of the suppressed LHRH pulse generator in the rhesus monkey.) With the approach of puberty GABA inhibition of the LHRH pulse generator wanes, and its reactivation gradually occurs. This reactivation is quite likely augmented by stimulatory neurotransmitters (e.g., excitatory amino acids), some of which are dependent on increased gonadal steroids for their activation, and by neurotrophic factors and growth peptides. As a consequence, the amplitude and, to a lesser extent, the frequency of LHRH pulses increase, which, in turn, leads to increased pulsatile secretion of FSH and LH and the activation of the ovary and testis. As shown experimentally in the monkey, the LHRH pulse generator can function in the absence of hypothalamic stimulatory factors. The nature of and factor or factors responsible for this transition from central inhibition and the postulated dominance of GABA to the release of inhibition and reactivation of the LHRH pulse generator are unknown. (From Grumbach and Styne, 1998).

feedback effects of estrogen (Schultz and Terasawa,

1988). There are many neural, neurotransmitter, and neuromodulator factors that may play a role in the restraint of the LHRH pulse generator during the juvenile pause. Noradrenergic, dopaminergic, serotoninergic, and opiotergic pathways; inhibitory neurotransmitters (e.g., GABA) and excitatory amino acids (e.g., glutamic and aspartic acids); and other brain peptides, includ-

ing pineal secretions (melatonin) and corticotropinreleasing hormone, affect the hypothalamic LHRH pulse generator (Germak and Knobil, 1990; Ojeda et al., 1990; Arslan et al., 1988; Bettendorf et al., 1988; Gambacciani et al., 1986; Kuljis and Advis, 1989; MacLusky et al., 1988; Plant et al., 1989; Thind and Goldsmith, 1988; Wilson et al., 1984). However, the precise mechanism of the CNS inhibition is uncertain. The studies of Plant (1994) in monkeys and of others in

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IV. Development of Hormone-Dependent Neuronal Systems

humans exclude melatonin as a critical restraining factor in primates (Grumbach and Kaplan, 1990; Cohen et al., 1982; Reppert and Weaver, 1995; Luboshitzky et al., 1995; Ozata et al., 1996). Many studies have assessed the role of endogenous opioid peptides as possible mediators of the juvenile pause. None provides support for an important role of this family of neuropeptides in the juvenile pause (Kelch et al., 1990; Fraioli et al., 1984; Petraglia et al., 1986; Mauras et al., 1986; Saunder et al., 1984). A critical advance in our understanding of the nature of the juvenile phase and the central inhibition of the LHRH pulse generator was provided by the studies of GABA, the most important inhibitory neurotransmitter in the primate brain including the hypothalamus, by Terasawa and her colleagues (Mitsushima et al., 1994, 1996). Using the technique of in vivo perfusion of the stalk median eminence of prepubertal, early pubertal, and mid-pubertal female monkeys, the studies showed: (1) the direct infusion of bicuculline, a GABAAreceptor blocker, evoked a rapid and large increase in LHRH release in the prepubertal but not the pubertal monkey; (2) GABA infusion suppressed LHRH release in pubertal monkeys, but not prepubertal monkeys and (3) endogenous GABA release was much higher in prepubertal monkeys than in pubertal monkeys. Further, the pulsatile infusion of bicuculline into the median eminence of the female rhesus advanced the age of puberty (Keen et al., 1999). The results suggest that there is a potent inhibition by GABA of the LHRH pulse generator in prepuberty and that exogenous administration of GABA in prepuberty is ineffective because of the high endogenous GABA levels (Mitsushima et al., 1994). Glutamic acid decarboxylase (GAD) is the enzyme that catalyzes the conversion of glutamate to GABA. Two classes of GAD, GAD-65 and GAD-67, are present in the mammalian brain. Both GAD mRNAs are detectable in the mediobasal hypothalamus, the site of the LHRH pulse generator. Moreover, antisense oligodeoxynucleotides for GAD-6? and GAD-65 mRNAs infused into the stalk median eminence of prepubertal monkeys induced a striking increase in LHRH release, whereas nonsense D-oligos did not (Mitsushima et al., 1996). When LHRH increased after the blockade of GAD and therefore a decrease in the production of GABA, glutamate increased; these data suggest that glutamate stimulates a secondary rise in LHRH release after the initial

rise caused by the decrease in GABA (Terasawa et al., 1999). A similar, but smaller increase in LHRH occurred in pubertal female rhesus monkeys infused with antisense oligodeoxynucleotides for GAD-67 (Kasuya et al., 1999). By inhibiting GABA synthesis these studies provide additional support for GABA arising from interneurons as the major inhibitory neurotransmitter-the intrinsic CNS inhibitormduring the juvenile pause of prepuberty. The effect of GABA probably has a direct action on the LHRH pulse generator neuron because GABA, through both GABAA and GABAB receptors, affects LHRH secretion in the perifused mouse GT1 LHRH-releasing neuronal cell line. Many studies of the effects of GABA were derived in the intact female monkey. NPY (a 36-amino-acid peptide) gene expression and protein are found in the hypothalamus of the agonadal male monkey in a pattern opposite of the expression of LHRH, suggesting that NPY acts as brake on the LHRH pulse generator during the juvenile pause of male nonhuman primates (reviewed in Plant, 2000). Because the inhibitory tone on the LHRH pulse generator is greater in the male than the female rhesus monkey, the rise in NPY mRNA is predicted to be greater in the male than in the female during the juvenile pause. Among the facilitory neurotransmitters that affect the release of LHRH are the ot-noradrenergic influences, NPY, galanin (a 29-amino-acid peptide isolated from porcine small intestine), leptin, and the excitatory amino acid transmitters (the major stimulatory neurotransmitters in the brain). Neither norepinephrine nor galanin appear to have a critical role in the control of the onset of puberty in primates (see Cheung et al., 1996), even though they may function as facilitators once the LHRH pulse generator is reactivated. There may be a role for NPY as an inhibitory neurotransmitter acting on the LHRH pulse generator during the juvenile pause, but its importance remains to be established. The potential role of leptin in the onset of puberty, controversial in humans, but a factor in rodents, has already been discussed. On the other hand, studies of the effect of excitatory amino acid neurotransmission have provided data bearing on pubertal mechanisms. Studies of excitatory amino acid neurotransmitters using the analog N-methyl-D-aspartate (NMDA), which binds to a subtype of glutamate and aspartate receptors

76. Puberty in Boys and Girls

that mediates excitatory amino acid synaptic transmission, indicate that NMDA receptors are widely distributed throughout the CNS, including the hypothalamus. NMDA stimulates LH release in neonatal (Urbanski and Ojeda, 1987) and adult rats (Price et al., 1978), fetal sheep (Bettendorf et al., 1988), and prepubertal and adult monkeys (Wilson and Knobil, 1982; Plant et al., 1989). NMDA evokes LHRH secretion from rat hypothalamic explants (Bourguignon et al., 1989) from a LHRH neuronal cell line (Mahachoklertwattana et al., 1994b), but does not have a direct effect on pituitary gonadotropes (Bettendorf et al., 1988). Studies by Plant and associates (1989) indicate that in prepubertal monkeys, chronic intermittent administration of NMDA induces true precocious puberty and complete activation of the hypothalamic LHRHpituitary-gonadal system. Earlier studies by this group showed that the effect of NMDA on LHRH and LH release could be blocked by a specific NMDA receptor antagonist, DL-2-amino-5-phosphonopentanoic acid. Further, NMDA receptors are present on GT1 LHRHsecreting neurons (Mahachoklertwattana et al., 1994b), consistent with a direct effect of NMDA. These observations provide additional evidence that the hypothalamic LHRH neurosecretory neuron is not a limiting factor in puberty. The pulse generator now joins the anterior pituitary gland, gonads, and gonadal steroid end organs as elements that are functionally intact prepubertally as well as in the fetus and that can be fully activated before puberty and in the fetus by the appropriate stimulus. Hence, the CNS restraint of puberty lies above the level of the autorhythmic LHRH neurosecretory neurons in the hypothalamus. There are direct or indirect effects of the GABA inhibitory and the excitatory amino acid (as represented by NMDA receptors) stimulatory neurotransmitters upon LHRH release. In the primate the GABA hypothalamic neural network seems to be the major component of the intrinsic CNS inhibitory mechanism during the juvenile pause.

5. Sleep-Associated Luteinizing Hormone Release and Onset of Puberty Episodic (or pulsatile) secretion is the fundamental mode of release of pituitary LH and FSH and is evoked by the pulsatile LHRH signal originating from the hypothalamic LHRH oscillator. Discrete episodic

675

bursts of LH release occur approximately once every 120 min (about 12 episodes over a 24-hr period) in adult men (Spratt et al., 1988; Judd, 1979; Rebar and Yen, 1979) and about once every hour during the midfollicular phase in women (Crowley et al., 1985). The low concentrations of plasma LH and FSH made it difficult to demonstrate pulsatile secretion in prepubertal children in the past for methodological and statistical reasons, but this problem has been overcome by the use of sensitive immunoassays, which demonstrate secretory pulses of LH in prepubertal children (Dunkel et al., 1990; Corley et al., 1981; Wennink et al., 1988; Kelch et al., 1990; Kelch and Marshall, 1990); the pulses are of lower amplitude and usually of lower frequency than those in pubertal children or adults. In adult men and in women during most phases of the menstrual cycle, little difference in the amplitude or frequency of these episodic pulses is apparent during a 24-hr period. The infant exhibits episodic gonadotropin secretion (Waldhauser et al., 1981); the amplitude of the pulses is large and correlates with the increased plasma gonadotropin levels during the first 6 months in boys and the first 1-2 years in girls (Winter et al., 1975; Forest, 1990). After this age, pulsatile secretion is more difficult to detect before the peripubertal period, but it is demonstrable at low amplitude and frequency mainly at night (Grumbach and Kaplan, 1990; Dunkel et al., 1990; Kelch et al., 1990; Kurtzke and Hyllested, 1986; Kelch and Marshall, 1990). In pubertal children Boyar and colleagues (1972, 1974a; Kapen et al., 1975) described the mainly sleep-associated pulsatile release of LH in early and mid-puberty; only in late puberty were prominent LH-secretory episodes detected during the day, ultimately leading to the adult pattern. Sleep-associated LH release in the peripubertal period correlates with the increased sensitivity of the pituitary gonadotropes to the administration of LHRH in the peripubertal period and puberty. In the monkey, a striking increase in the pulse amplitude and a lesser increase in pulse frequency occurs between prepuberty and puberty (Watanabe and Terasawa, 1989; Plant, 1994). In boys, these augmented LH release during sleep leads to increased testosterone secretion and a rise in the plasma concentration of testosterone at night (Boyar et al., 1974a). This pattern of sleep-associated LH secretion occurs in agonadal patients during the pubertal

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IV. Development of Hormone-Dependent Neuronal Systems

age period (Boyar et al., 1973b), suggesting that it is not dependent on gonadal function. Furthermore, sleep-related gonadotropin release is demonstrable in children with idiopathic true precocious puberty (Grumbach and Kaplan, 1990; Boyar et al., 1973c) and in glucocorticoid-treated children with congenital adrenal hyperplasia who have an advanced bone age and an early onset of true puberty. Kulin and coworkers (1976)noted significantly increased excretion of urinary LH in prepubertal children at night than during the day, although the absolute differences were small. Sleep-enhanced LH secretion can be viewed as a maturational phenomenon related to changes in the CNS and in the hypothalamic restraint of LHRH release. However, the neural factors involved in the initiation of this circadian rhythm are unclear. The episodic release of gonadotropins is suppressed by anti-LHRH antibodies and by the administration of gonadal steroids or of certain catecholaminergic agonists and antagonists and is augmented by the opioid antagonist naloxone. Naloxone does not alter the testosterone-mediated supression of LH nor alter the testosterone effects on LH pulsatility in early to mid-pubertal boys (Kletter et al., 1994). We have suggested that an increase in endogenous LHRH secretion at puberty has a priming effect on the gonadotrope (Roth et al., 1972; Grumbach et al., 1974) and leads to increased sensitivity of the pituitary to LHRH (either endogenous or exogenous). The augmented LH release at night in both sexes is evidence that the hypothalamic LHRH pulse generator initially is reactivated or disinhibited during sleep. Hence, the increased pulsatile secretion of gonadotropins that is entrained during sleep is the neuroendocrine hallmark of the onset of puberty.

6. Pituitary and Gonadal Sensitivity to Tropic Stimuli Puberty encompasses orderly maturational changes that involve, sequentially, the extramedial basal hypothalamus, hypothalamic LHRH pulse generator, pituitary, gonads, and gonadal steroid target organs (Grumbach et al., 1974; Grumbach and Kaplan, 1990). At each level, these structures may exhibit differences in responsiveness to neural or tropic stimuli depending on their sensitivity and on the particular hormonal mi-

lieu. If the increased secretion of gonadotropins at the beginning of puberty is a consequence of changes in both neural and hormonal restraints on the synthesis and pulsatile secretion of LHRH, the disinhibition and reaugmentation of the LHRH pulse generator should lead to the increased amplitude and frequency of pulses initially, followed by the priming of the gonadotropes, increased pulsatile gonadotropin secretion from the pituitary, and finally augmented output of steroids by the gonad. LHRH release is not directly measurable in the human. However, endogenous LHRH secretion can be estimated indirectly and qualitatively by determining the pulsatile pattern of LH and by the gonadotropin response to exogenous LHRH. The pituitary sensitivity to synthetic LHRH and the dynamic reserve or readily releasable pool of pituitary gonadotropins have been studied at different stages of sexual maturation (Grumbach et al., 1974; Roth et al., 197'2, 1973; Job et al., 1972) and in disorders of the hypothalamicpituitary-gonadal system. The results support the hypothesis that the prepubertal state is characterized by a functional LHRH deficiency (Grumbach et al., 1974; Grumbach and Kaplan, 1990; Grumbach, 1980; Reiter and Grumbach, 1982; Watanabe and Terasawa,

1989). The release of LH after the administration of LHRH is minimal in prepubertal children beyond infancy, increases during the peripubertal period and puberty (Grumbach et al., 1974; Grumbach and Kaplan, 1990), and is still greater in adults (depending on the phase of the menstrual cycle in women) (Yen et al., 1975; Keye et al., and Jaffe, 1975). The change with maturation in the pattern of FSH release is different from that of LH and results in a striking reversal of the FSH/LH ratio after the administration of LHRH to both males and females between prepuberty and puberty (Grumbach et al., 1974). FSH release after the administration of LHRH is comparable in prepubertal, pubertal, and adult males, indicating similar pituitary sensitivity to LHRH. Moreover, there is a sex difference in the FSH response--prepubertal and pubertal females release more FSH than males at all stages of sexual maturation (Grumbach et al., 1974; Roth et al., 1973). These observations suggest a striking change in pituitary sensitivity to LHRH in prepubertal and pubertal individuals, as well as a sex difference in the dynamic reserve of

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pituitary FSH (Grumbach et al., 1974). The sex difference in LH and FSH response to LHRH suggests that the pituitary gonadotropes of prepubertal females are more sensitive to LHRH than those of prepubertal males, even though there is no apparent difference in the concentration of circulating gonadal steroids at this stage of maturation. Prepubertal girls have a larger readily releasable pool of pituitary FSH than prepubertal or pubertal males. The sex difference in sensitivity to LHRH and releasable FSH and the low inhibin levels in prepubertal females may be factors in the higher frequency of idiopathic true precocious puberty in girls and in the occurrence of premature menarche (Reiter et al., 1975). The available data are consistent with the hypothesis that less LHRH is required for FSH release than for LH release. These findings also point out the difference between pituitary sensitivity and the actual secretory rate of FSH and LH. The responses to LHRH in peripubertal children who do not yet exhibit physical signs of sexual maturation provide evidence that the self-priming effect (Grumbach et al., 1974) of endogenous LHRH augments pituitary responsiveness to exogenous LHRH and is an important factor in the increased gonadotropin secretion at puberty. This change in responsiveness of the gonadotropes is apparently mediated by the increased pulsatile secretion of LHRH (Grumbach et al., 1974; Grumbach and Kaplan, 1990); the increased LH response to synthetic LHRH is one of the earliest hormonal markers of puberty onset. The degree of previous exposure of gonadotropes to endogenous LHRH appears to affect both the magnitude and the quality of LH responses to a single intravenous dose of LHRH. Studies of the effects of acute and chronic administration of synthetic LHRH in hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, constitutional delayed growth and adolescence, and idiopathic precocious puberty support this concept of self-priming (Grumbach et al., 1974; Roth et al., 1972; Job et al., 1972; Spratt and Crowley, 1988; Crowley et al., 1985; Yoshimoto et al., 1975; Jacobson et al., 1979; Crowley and McArthur, 1980; Valk et al., 1980). The prepubertal pituitary gland has a smaller pool of releasable LH and decreased responsiveness to the acute administration of synthetic LHRH. With the approach of puberty, the derepression of the hypothalamic LHRH pulse generator and the

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increased pulsatile secretion of LHRH augment pituitary sensitivity to LHRH and enlarge the reserve of LH. The reason for the discordance in FSH and LH release prepubertally is not clear, but the frequency of LHRH pulses may be a factor (Wildt et al., 1981; Gross et al., 1987; Knobil, 1980; Germak and Knobil, 1990; Pohl and Knobil, 1982). In the adult rhesus monkey with ablative hypothalamic lesions that eliminate endogenous LHRH secretion, the reduction in the frequency of exogenous LHRH pulses from one per hour to one every 3 hr increased the FSH/LH ratio (Wildt et al., 1981) Furthermore, inhibin and endogenous gonadal steroids may also affect this ratio through action on the hypothalamus, the pituitary gland, or both. These observations and the previously discussed role of the intermittence of the LHRH signal to the gonadotropes as an essential factor in the neural control of gonadotropin secretion have important implications for the induction of puberty. Pulsatile administration of LHRH to prepubertal monkeys promptly initiates puberty (and, in females, ovulatory menstrual cycles) and restores complete gonadal function in adult monkeys with hypothalamic lesions (Germak and Knobil, 1990; Plant, 1994; Pohl and Knobil, 1982; Knobil and Plant, 1978; Knobil et al., 1980; Wildt et al., 1980). Similar studies in humans yielded comparable results in prepubertal children and in adults with hypothalamic hypogonadotropic hypogonadism (Gross et al., 1987; Kelch et al., 1990; Kelch and Marshall, 1990; Yoshimoto et al., 1975; Jacobson et al., 1979; Crowley and McArthur, 1980; Valk et al., 1980; Boyar et al., 1973). These results provide further support for the reactivation of the hypothalamic LHRH pulse generator as the first hormonal change in the onset of puberty. Responsiveness of the gonads to gonadotropins also increases during puberty. For example, the augmented testosterone secretion in response to the administration of human chorionic gonadotropin (hCG) at puberty in boys (Winter et al., 1972) is probably a consequence of the priming effect of the increase in endogenous secretion of LH (in the presence of FSH) on the Leydig cell (Sizonenko et al., 1973).

7. Maturation of Positive Feedback Mechanism In normal women, the mid-cycle surge in LH and FSH secretion is attributed to the positive feedback effect of an increased concentration of plasma estradiol

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for a sufficient length of time during the latter part of the follicular phase (Knobil, 1980; Ross et al., 1970; Yen et al., 1975). Estradiol has both negative and positive feedback effects on the hypothalamic-pituitary system. Although the suppressive effect is probably operative from late fetal life on, the positive action of estradiol on gonadotropin release has not been demonstrated in normal prepubertal and early pubertal children (Grumbach et al., 1974; Grumbach and Kaplan, 1990; Reiter et al., 1974). Hence, the acquisition of positive feedback, a requisite for ovulation, is a late maturational event in puberty and, from the present evidence, probably does not occur before mid-puberty in normal girls (Grumbach et al., 1974; Grumbach and Kaplan, 1990; Reiter et al., 1974; Presl et al., 1976). Among the requirements for a positive feedback action of estradiol on gonadotropin release at puberty (Grumbach et al., 1974) are (1) ovarian follicles primed by FSH to secrete sufficient estradiol to reach and maintain a critical level in the circulation; (2) a pituitary gland that is sensitized to LHRH and contains a large enough pool of releasable LH to support a LH surge; and, (3) controversial in humans but not in lower animals, sufficient LHRH stores for the LHRH neurosecretory neurons to respond with an acute increase in LHRH release in addition to the usual adult pattern of pulsatile LHRH secretion. A major site of action of estradiol is at the level of the anterior pituitary. Knobil and Plant (1978) have shown in the rhesus monkey that positive as well as negative feedback can occur in adult ovariectomized females in which the medial basal hypothalamus is surgically disconnected from the remainder of the CNS. In monkeys with hypothalamic lesions, unvarying intermittent LHRH administration leads to sufficient estradiol release from the ovary to induce an ovulatory LH surge in the absence of an increase in the dose of the LHRH pulses (Knobil, 1980; Knobil et al., 1980). Estradiol has a positive feedback effect directly on the pituitary gland in normal women, and prolonged administration of estradiol is accompanied by an augmented LH response to LHRH administration in women (Keye and Jaffe, 1975). These observations suggest that in women estradiol exerts a major positive feedback action on the pituitary gland that is demonstrable in the absence of an increase in pulsatile LHRH secretion, but it does not

exclude a positive as well as negative action at the level of the hypothalamus. The failure to elicit a positive feedback action of estradiol in the prepubertal girl could be related to the functional immaturity of either the CNS or the pituitary, manifested by inadequate LHRH pulses or insufficient LH reserve, respectively, or by both components. The fact that gonadotropin cyclicity (Doring, 1963; Hansen et al., 1975) and estradiol-induced positive feedback can be demonstrated by mid-puberty and before menarche does not imply that the positive feedback loop is complete (Grumbach, 1975, 1978; Grumbach et al., 1974; Reiter et al., 1974; Presl et al., 1976). Indeed, the modulating effect of the pubertal ovary and its output of estradiol on the hypothalamic-pituitary gonadotropin unit may be insufficient to induce an ovulatory LH surge, even when there is an adequate pituitary store of readily releasable LH and FSH. The ovary, because of lack of sufficient gonadotropin stimulation, decreased responsivity, or other local factors, does not secrete estradiol at a high level or long enough to induce an ovulatory LH surge. We visualize the process leading to ovulation as a gradual one in which the ovary (the zeitgeber for ovulation; Knobil, 1980) and the hypothalamic-pituitary gonadotropin complex become progressively more integrated and synchronous until, finally, an ovary primed for ovulation secretes sufficient estradiol to induce an ovulatory LH surge (Grumbach, 1978). Studies of basal body temperature (Doring, 1963) and of plasma progesterone concentrations (Apter and Vihko, 1977; Winter and Faiman, 1973) suggest that as many as 55-90% of cycles are anovulatory during the first 2 years after menarche and that the proportion decreases to less than 20% of cycles by 5 years after menarche (Apter and Vihko, 1977). A cyclic surge of LH occurs during some anovulatory cycles in adolescence, but the mechanism of ovulation seems unstable and immature and does not appear to have attained the fine-tuning and synchronization requisite for the maintenance of regular ovulatory cycles.

8. Central Nervous System Anatomy and Function and Electroencephalogram R h y t h m There are significant changes in brain anatomy and function during late childhood and adolescence. Although the neonate has a synaptic density greater

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than that found in the adult, a reduction in cortical synaptic density (Huttenlocher, 1979), analogous to programmed cell death, is found between 2 and 16 years and is accompanied by a decrease in neuronal density. There is an increase in cortical metabolic rate in infancy to values above those of the adult, followed by a decline to adult levels starting in late childhood and ceasing in the end of the second decade. During this period, there is a reduction of brain plasticity reflected, for example, in the inability after puberty to learn to speak a foreign language without an accent (Feinberg and Carlson, 1968) and the inability of the adult to recover from a CNS injury that in the child might be followed by complete recovery (in the adult this might lead to aphasia). During this period, the ability to solve complex problems in a mature manner appears. It is postulated that the appearance of mania, depression, and schizophrenia, which are rare before puberty and more common afterward, is related to defects in these normal changes in brain architecture and function (Feinberg et al., 1990). There are well-described changes in electroencephalogram (EEG) patterns during puberty, indicating an increasing complexity of brain function during this period (Anokhin et al., 1996). Deep sleep is heralded by an increase in delta waves per minute and an increase in the amplitude of delta waves. The function of deep sleep (slow-wave or non-REM sleep) is thought to be restorative (Feinberg, 1974) to the functions during the awake stage, such as learning, and the most restorative portion is said to be during highamplitude delta-wave sleep. High-voltage delta waves, sigma spindles, and K-complexes develop during the first year and the sequence of non-REM sleep preceding REM sleep develops during the first few years after birth. During adolescence, the time spent in deep (stage 4) sleep declines by 50%. Further there is a decline in delta waves (0-3 Hz EEG waves) across childhood and adolescence (Feinberg et al., 1990).This change is due to an approximately 50-75 % decrease in the amplitude of the delta waves during sleep rather than a change in the period of delta waves. There is an increase in the prevalence of certain types of epilepsy, including primary reading epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with grand mal on awakening, during puberty (Wolf, 2000). In contrast, the most common id-

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iopathic epilepsy, benign epilepsy with centrotemporal (rolandic) spikes, goes into remission at puberty. As previously stated, GABA is an inhibitory neurotransmitter thought to withhold the onset of puberty by decreasing GnRH secretion. Although studies of nonhuman primate models demonstrate a decrease in GABA at the time of puberty, which may be the signal to allow puberty to procede, the use of GABAergic drugs in the clinical treatment of epilepsy in children reportedly does not cause a delay of puberty; this may simply be a result of inadequate data or it may be an indication that disruption of GABA by the oral route cannot interfere with the onset or progression of puberty (Wu, 2000). Nonetheless this shift in endogenous GABA at this stage may be a part of the explanation of the change in incidence of epilepsy at puberty. As shown later, there are limited data proving the effects of hormones on the risk-taking/novelty-seeking and other behaviors prominent in adolescence. However, there are prominent developmental transformations in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that cause a change in the balance between mesocortical and mesolimbic dopamine systems (Spear, 2000). Developmental changes in these stressor-sensitive regions probably contribute to the unique characteristics of adolescence and might be important in medicating the increase in addictive behavior during adolescence. Such changes might be mediated by hormones that themselves would not be accurately measured in the circulation if local action is of more importance, thus limiting researchers' ability to assess relationships between the serum concentrations of the hormones and the behavior under study.

VII. NORMAL PUBERTAL BEHAVIOR A N D PATHOLOGY IN PUBERTY Puberty is the biological process of attaining reproductive maturity, whereas adolescence is the psychosocial changes of the period. While the attainment of an adult role in society occurs within a few years of the achievement of reproductive maturity in non-Westernized societies (Hamburg, 1992), the more technologically advanced the society, the more protracted the length of time society allows for adolescent

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psychosocial development (Michael and Zumpke, 1990). The prolonged period of adolescent psychosocial development between childhood and adulthood became the norm only in the recent past. The most important psychological and psychosocial changes in adolescence are the emergence of abstract thinking, the growing ability of absorbing the perspectives or viewpoints of others, an increased ability of introspection, the development of personal and sexual identity, the establishment of a system of values, increasing autonomy from family and personal independence, greater importance of peer relationships of sometimes subcultural quality, and the emergence of skills and coping strategies to overcome problems and crises. (Remschmidt, 1994) To consider these changes and relate them to the endocrine milieu, adolescence may be divided into three periods by chronological age--early, middle, and late adolescence; However, these periods may be reached at different maturational ages because the rates of physiological maturation differ in individuals within these age groups (Slap et al., 1994; Weiner and del Gaudio, 1977; Susman et al., 1987b; Klerman, 1993; Petersen, 1993; Brooks-Gunn and Graber, 1994). Early adolescence, during ages 11-15 years, a period encompassing most of the biological changes of puberty previously outlined, includes a profound social change from the sheltered single-classroom environment of elementary school to the multiple-classroom and multiple-teacher experience of junior high school, with a wide exposure to new peers, often with different life experiences and behavior patterns, and maturing, but not mature, abstract-thought and decision-making processes developing out of the concrete reasoning of childhood. Middle adolescence, ages 15-17 years, occurring during the high school years, is a calmer period than that of early adolescence because the school experience does not represent a wrenching change from the past and many of the most prominent biological and physical changes of puberty are past. Partial independence becomes an issue in this period because there is acceptance of some increased autonomy, as reflected in society's acceptance of drivers' permits and licenses at these ages, but the individual still lives at home. The individual moves away from the family emotionally and

is less influenced by his or her peer group than are early adolescent individuals; friendships take on an increasingly important role. Late adolescence may be considered to start at the senior year of high school and is the time of accepting adult roles in work, the family, and the community. Those individuals who attend college have a more prolonged time to achieve these changes.

A. Behavior and Normal Puberty Although mood changes are more rapid and marked in the teenage years than in adults, truly tumultuous behavior in teenagers may be a sign of psychopathology that later develops into affective disorders; turmoil in adolescence is not a normal phase (Casper, 1998). In the early 1900s, Hall (1904), without using what would be considered contemporary research techniques, characterized the maturing child as experiencing Sturm und Drang (storm and stress), which is normally restrained by cultural influences. Many depictions of adolescent turmoil followed and continued into the twenty-first century in the popular media as well as in clinical treatises. Contrary to this view, most later empirical studies describe adolescent development as a continuous, adaptive phase of emotional growth more characterized by stability than by disorder and by harmonious relationships between generations than by conflict (Michael and Zumpke, 1990; Weiner and del Gaudio, 1977; Offer, 1969; Masterson, 1968; Udry et al., 1985). In a longitudinal study of 320 normal first-year high school students in the United States followed for 4 years and of 64 followed for 8 years, 25% experienced "continuous growth" characterized by smooth, well-adjusted functioning in spite of stressful situations; 34% experienced "surgent growth" demonstrating good adaptation in general and short periods of difficulty and distress after some stressful situations; and 21% were judged to be in "turmoil" (a tumultuous group) characterized by mood swings, anxiety, and depression. Thus 79% had successful adaptive development and the other 21% mainly came from homes characterized by conflict, familial mental illness, and socioeconomic distress (Offer, 1969). Consistent with these findings, a study of adolescent psychopathology demonstrated that many with adolescent turmoil "did not grow out

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of it" when studied 5 year later, in view of the eventual diagnosis of unipolar and bipolar depressive disorders (Masterson, 1968). Thus, it appears that approximately 80-90% of adolescents do well psychologically during puberty and are happy individuals, and 10-20% have significant difficulties (Offer and Schonert-Reichl, 1992). The normal fluctuation of mood over a period of hours or days due to the adolescent developmental process should be differentiated from long-standing mood and behavior changes of serious psychopathology. Thus turmoil may reflect actual psychopathology that will require diagnosis and treatment (Hamburg, 1992).

B. Sleep Patterns in Puberty Sleep patterns change in puberty; left to their own devices, adolescents stay up later and awaken hours later than a normal weekday schedule would dictate or than the schedule they followed at a younger age (Andrade et al., 1993). Indeed, daytime sleepiness is very prevalent in puberty. Older individuals awaken earlier and rate themselves as more morning-like than young adults. This change to eveningness from morningness appears to be related to biological as opposed to social factors, which were previously felt to be more important causative factors (Strickland, 1993; Carskadon et al., 1997). However, there are confounding social effects in the study of circadian rhythms in teenagers. Many factors affect sleep schedules, such as parental involvement, obligations of peers and work, and the frequent occurrence of insufficient sleep. Thus, the conclusions of studies in sleep laboratories are difficult to relate to real-world situations. An initial attempt to study this phenomenon demonstrated a significant relationship between the morning rise in melatonin (offset phase of melatonin secretion) and a tendency to a later midpoint phase of melatonin secretion (between the nocturnal rise and morning fall in melatonin values) with advancing Tanner pubertal stage (sexual maturation stage). These data support a biological process to explain the shift in sleep patterns (Carskadon et al., 1997).

C. Sexuality in Puberty Early and middle adolescence is the period of introduction to sexuality for many, but not for a majority of

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teenagers (Rodgers, 1997; Brindis et al., 1992; Hayes, 1987). There was an over 50% increase in sexual intercourse in urban white teenage girls between 1971 and 1981, with 17.3% of white and 23.2% of African American girls reporting sexual intercourse at 15 years and 39.5% of white and 46.7% of African American girls reporting sexual intercourse by 17 years of age (Hayes, 1987). The mean age of first intercourse was 17.5 years for white males, 15.5 years for African American males, 17 years for Hispanic males, 18.5 years for white females, 17.5 years for African American females, and 18.5 years for Hispanic females in the 1990s (Rodgers, 1997; Hayes, 1987). Fertility is reached before the adult phenotype and adult judgement is acquired. One million adolescents became pregnant in the United States each year, a rate of 110 per 100,000. However, there has been a decrease in pregnancies since the 1980s in adolescents; there was a 2-/% decrease in pregnancies in African American 15to 17-year-olds (from 99.5 to 72.9 per 1000) and a 6% decrease in whites (from 25.7 to 24.1 per 1000). A continuing decline in teenage pregnancies continues into the twenty-first century. There has, however, been an increase in abortions among teenagers (Brindis et al., 1992). Testosterone is commonly thought to be an obvious stimulator of sexuality and in laboratory animals this may be proven experimentally The results of the study of pubertal subjects, however, is more complex. Sexuality appears to be correlated with testosterone production in boys in some studies, but in others it appears modified by the social effects of pubertal maturation (Halpern et al., 1993b) The hormonal influences on female sexual behavior remain elusive; the striking increase in testosterone at puberty in boys stimulates their sexual interest more than the modest increase in testosterone in females. The social pressures are more mixed in their messages to girls, both encouraging sexuality and restricting it in a way more disparate than encountered by boys (Hutchinson, 1995). Nonetheless, the earlier onset of puberty compared to previous centuries (as described earlier) has had a profound effect on societal norms of sexual behavior. (Brindis et al., 1992; Money, 1994; Friedman, 1992). There may be significant differences in the results of the correlation of hormones and behavior depending on the plan of study. A cross-sectional study of

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102 eighth- to tenth-grade boys demonstrated a direct relationship between serum-free testosterone and sexual thoughts and behavior including progression to coitus; this relationship was not due to the progression through puberty or age in this analysis (Udry et al., 1985). However, this study did not determine whether sexual activity increases over time due to a change in pubertal hormone values, and so another study was performed. In a longitudinal panel study of seventhto eighth-grade boys, the authors found that pubertal status and changes in pubertal development were significantly and positively related to changes in sexual ideation, noncoital behavior, and to the transition to sexual intercourse. Testosterone levels at study entry were significantly related to coital status at the beginning and also predicted the transition to nonvirgin status. However, changes in hormone levels during the 3 years of study participation did not predict changes in sexual ideation or noncoital sexual activity. Thus, in contrast to the previous study by the same investigators, the initiation of sexual activity was related to a change in pubertal development because of its social stimulus value and not solely because sexuality is determined by changing hormone levels (Halpernet al., 1993b). Last, an analysis of salivary testosterone determinations every month over 3 years and of sexual activity demonstrated a relationship between rising salivary testosterone and sexual activity (coital and noncoital) in the group. In addition, rising testsosterone was related to sexuality and falling salivary testosterone related to decreased sexual activity when pubertal status was controlled (Halpern et al., 1998) This last study, with the most closely collected values for teststosterone (using the noninvasive methods of saliva collection and more frequent sampiing), appear to replace testosterone on the roster of important factors in the onset and continuation of sexual activity in normal boys. Further analysis of these same panel data demonstrated an effect of religious activity on the onset of coitus. Those boys who attended religious services regularly had a lower likelihood of progression to coitus or even to more substantial sexual ideation than those that did not regularly attend religious services (Halpern et al., 1994). Boys with higher free testosterone levels at study entry who never or infrequently attended religious services were the most sexually active and had the most permissive attitudes. Boys with lower

free testosterone who attended services once a week or more were the least active and reported the least permissive attitudes. For some behaviors, differences between free testosterone and attendance groups increased over time, resulting in greater behavioral differences between the groups 3 years later. Thus, it may be concluded from this evidence that endogenous testosterone production is directly related to sexual behavior in boys, but that relationship may be modified by religious exposure. A study of normal puberty in girls in the eighth to tenth grades demonstrated that follicular phase levels of testosterone were associated with increased frequency of thinking about sex and masturbation (Udry et al., 1986). The anticipation of future sexual activity was predicted by serum concentrations of androstenedione (an androgen secreted from the ovarian follicles) and testosterone arising from peripheral conversion, and of dehydroxyepiandrosterone and its sulfate (DHEA and DHEAS) (androgens secreted from the adrenal gland), as well as by LH levels. Serum progesterone concentrations were inversely related to masturbation activity. Although this study demonstrated a relationship between hormones and female sexuality, peer influences exerted a strong effect on masturbation activity. It was postulated that societal influences exerted effects on the progression of sexuality and transition to first coitus. Religious activity appeared to decrease the likelihood of sexual intercourse in girls as well as in boys. Seventh- and eighth-grade girls were studied over 2 years to determine the relationship between pubertal hormone values and first intercourse in a longitudinal study. Although the expected relationship between testosterone and pubertal development was found, a relationship occurred between a rise in testosterone and transition to coitus and between a fall in testosterone and less likelihood of transition to coitus (similar to the results described in boys earlier). Further, when white girls who attended religious services regularly were considered, the relationship with testosterone became nonsignificant, although the relationship remained significant if girls who did not regularly attend religious services were considered. Thus it appeared that rising testosterone increased the likelihood of transition to first coitus, but that this tendency could be opposed by religious exposure as a reflection of social pressure in white girls (Halpern et al., 1997). The pubertal

76. Puberty in Boys and Girls developmental stage itself did not predict coitus, suggesting that physical maturity was not the motivating feature. The authors noted the fact that there was no relationship between thinking about sex or masturbation activity and serum testosterone values. This was difficult to explain in this model; it was suggested that the method of questioning for those activities was not specific enough. It may be concluded from these data that there is a direct relationship between endogenous testosterone production and sexual behavior in girls but, as in boys, this tendency may be modified by religious influences. A randomized, double-blind, placebo-controlled, crossover clinical trial of 39 boys and 16 girls with delayed puberty evaluated the effects of the administration of oral conjugated estrogen to girls and intramuscular testosterone enanthate to boys at three dose levels that were intended to simulate early, middle, and late pubertal levels (Finkelstein et al., 1998). There were three 3-month placebo and treatment periods and a questionnaire derived from the studies of Udry (noted previously) was used to detect the effect of sex steroids on self-reported sexual behaviors and responses. There was a significant effect of the administration of testosterone to boys, reflected in increased nocturnal emission and touching behaviors at the mid- and high doses. However, no other treatment effects on sexual behaviors or responses were seen in boys. Girls demonstrated a significant increase in "necking" related to the administration of estrogen only at the late pubertal dose. No other treatment effects on sexual behaviors or responses were seen in girls. It must be noted that sexual activity may be more difficult to demonstrate in delayed adolescence than in an unselected population. Thus, the administration of physiological (rather than higher) doses of sex steroids to boys or girls with delayed puberty had some mild effects on sexual behaviors and responses and was not related to progression to coitus. There was no significant effect on measures of mood in the boys or girls except for an increase in withdrawn behavior in girls taking estrogen. Likewise there was no effect of hormone treatment on cognitive abilities. However, there was an increase in social competence, reflected in higher scores on testing for romantic appeal and job competency for girls and for athletic ability and job competency for boys after two of the doses of sex steroids.

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These data included patients with Turner syndrome, gonadotropin deficiency, and constitutional delay in puberty, so the results cannot be directed to a single clinical disorder. Further, a 3-month period may be considered too short to allow the study of the evolution of sexuality. None the less, this model is a promising method of determining the effects of hormones on behavior in a prospective, interventional, and ethical manner and may be expected to yield further interesting results in the future. It may be concluded that exogenous testosterone or estrogen administered to reflect physiological levels has no prominent effects on sexuality in boys and girls. Prolactin has rarely been studied in relation to sexuality in puberty. Serum prolactin concentrations in adolescent males survivors of malignancies in childhood were inversely related to sexual interest and behavior; those individuals with elevated values did not date (Slimes et al., 1993). The authors concluded that even a slight elevation of serum prolactin above normal is associated with or may be reflected in the psychosexual development of adolescent males who have survived malignancies in childhood. However, the elevation of prolactin must reflect a dysfunction of the hypothalamus that in the normal state should suppress prolactin; thus other abnormalities in hypothalamic function must also be considered. A relationship between intelligence and sexuality emerged out of analysis data from the National Longitudinal Study of Adolescent Health (Add Health), which includes approximately 12,000 adolescents enrolled in the 7th to 12th grades (Halpern et al., 2000). The Biosocial Factors in Adolescent Development projects followed approximately 100 white males and 200 African American and white females from this larger data bank over 3- and 2-year periods, respectively. By using the Peabody Picture Vocabulary Test (PPVT) as an measure of intelligence and confidential self-reports of sexual activity, logistic regression models were used to determine relationships between the two measures and proportional hazard models used to examine the timing of the initiation of noncoital and coital activities as a function of intelligence. After controlling for age, physical maturity, and mother's education, a significant curvilinear relationship was found between intelligence and coital status; adolescents at the upper and lower ends of the intelligence distribution were less

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likely to have sex. Higher intelligence was also associated with the postponement of the initiation of the full range of partnered sexual activities.

ever, physical pubertal progression has no such clear effect.

E. Depression in Puberty D. Mood and Self-Image in Puberty Mood in adolescence is not closely related to stage of puberty; for example, one study found no significant mood or behavior changes as a function of pubertal stages in girls ages 10.6-13.3 years, controlling for age effects, except for a decrease in interest in sports with progression of pubertal stage (Warren and Brooks-Gunn, 1989). However, grouping the questionnaire results by four levels of serum estradiol revealed a significant curvilinear trend for depressive affect (increase, then decrease; P < 0.01), impulse control (decrease, then increase; P < 0.04), and psychopathology (increase, then decrease; P < 0.03) scales, indicating significant changes in these measures during times of rapid increases in hormone levels. These data suggest that hormonal changes may be more important than the physical changes as determinants of certain mood and behavior patterns at adolescence. Single-hormone determinations and physical changes of puberty in 10- to 14-year-old girls were correlated with psychological profiles. There was a closer relationship between social factors and negative life events with negative affect, but hormonal levels were minimally related to affect (Brooks-Gunn and Warren, 1989). Another study found that a negative affect was most prevalent during the sharpest rise in pubertal hormones (Hayward et al., 1992). There is no evidence that high doses of estrogen used in an attempt to treat tall stature in girls affects mood in any way other than the effects of the resulting shorter stature itself on social function (Duke, 1986). Change in mood during the menstrual cycle is frequently described, but rarely exhaustively studied. Anecdotal evidence noted during a study of urinary hormone changes during the menstrual period related that mothers felt that their daughter changed from being "irrational and difficult" to "more reasonable and responsible adults" with the change from anovulatory cycles to ovulatory cycles (Murphy et al., 1993). In summary, there may be a definable but small effect of endogenous hormone production on mood; how-

Prepubertal boys and girls have an equal frequency of depression, with girls having a more frequent occurance thereafter (Angold and Worthman, 1993). Depression is said to manifest in mid-puberty in girls, with a rather sharp demarcation at stage 3 (Angoldet al., 1998) when the female preponderance of depression emerges. Depression seems more related to serum sex steroid concentrations than to LH or FSH values or the physical changes of puberty (Angold et al., 1999). Another study suggested rather than reflecting hormonal differences, these statistics are due to the fact that girls who are oversocialized and overcontrolling are more influenced by the external environment and are more prone to negative self-image, whereas boys who are aggressive, undercontrolled, and self-aggrandizing are more prone to dysthymia (Sonis et al., 1985). A negative self-image is prevalent in young girls at the beginning of puberty. However, breast development leads to improvement on body image and adolescent adjustment questionnaires (Slap et al., 1994) and to a positive body image, positive peer relationships, and superior adjustment. Of several serum hormones measured, FSH concentrations were inversely related to the body image score and changes in testosterone were inversely related to adjustment score. Height achieved during puberty was directly linked to superior adjustment and career importance (Brooks-Gunn and Warren, 1988), whereas pubic hair appears to cause no changes. There is increasing investigation into the connection between the stress response~increased corticotropinreleasing factor (CRH) leading to increased adrenocorticotropin (ACTH), causing elevated cortisol secretion-in the development of various psychopathological diagnoses in childhood depression (Ryan, 1998). Indeed it is postulated that periods of biological transition, such as puberty, are times of increased psychological vulnerability that allow depression to manifest due to a misfunction of the stress response (Dorn and Chrousos, 1997). A difficulty in the interpretation of tests of the hypothalamic-pituitary-adrenal (HPA) axis in a role in stress is that the very test itself provides a

76. Puberty in Boys and Girls stress that can perturb the axis; thus what is studied is the variation in an individual's response to a stressful situation compared to a normal situation. The summary of the studies of response of the HPA axis in various pathological states is (1) basal cortisol hyposecretion (with salivary cortisol measurement) is associated with externalizing disorders; (2) basal cortisol hypersecretion and limited suppression with dexamethasone occurs in depression in adolescents, but probably less frequently than in adults; (3) hypersecretion of cortisol at the time of sleep may be a marker for depression or the risk of depression; and (4) a blunted ACTH response to CRH is found in abused children and mostly in those in ongoing negative social situations (Ryan, 1998). However, MDD (major depressive disorder) is associated with normal ACTH and cortisol response to ovine corticotropin-releasing factor (oCRH), as well as to normal urinary free cortisol in boys and girls (Dorn et al., 1996). Evening cortisol hypersecretion and morning DHEA hyposecretion were significantly, and independently, associated with major depression. There is an elevation of cortisol near the onset of sleep in adolescents with severe MDD who are suicidal or were studied in an inpatient environmentma reflection of the severity of the condition (Dahl et al., 1991). Indeed a ?-year followup demonstrated that an elevation of plasma cortisol at sleep onset predicted the recurrence of another episode of depression (Rao et al., 1996). The combination of a high evening cortisol level and low morning DHEA level identified subgroups of depressives with different types of adrenal hormone dysregulation (Goodyer et al., 1996) and was not affected by age or gender. Further, a study of adolescents at risk for psychopathology found that there was an additive predictive value of depressive symptoms, a recent loss or negative life event and one or more daily levels of cortisol at 8 AM or DHEA at 8 PM greater than the 80th percentile of the daily mean (Goodyer et al.,

2000). However, there is a difficulty in evaluating cortisol secretion in adolescence even without the superimposition of psychopathology. Cortisol rhythms follow a diurnal pattern and although there is no change in cortisol response to CRH with pubertal progression, there is normal variation among individuals (Dahl et al., 1992). Regardless of high or low mean diurnal cortisol

685

levels, repeated measurements within and between pubertal stages indicated that an individual remains in his or her cortisol channel throughout pubertal development. Thus, (1) serum cortisol levels do not correlate with either age or gender; (2) there is a large and significant interindividual variability in endogenous mean diurnal cortisol levels; and (3) despite this variability among individuals, there is no correlation between cortisol levels and either body composition or growth rate. This suggests that the variability in cortisol levels is an expression of normal homeostasis rather than pathology (Knutsson et al., 1997). This must be factored into any correlation of cortisol and behavior or mood. An estimated 1.7-5.5% of adolescents have seasonal affective disorders (SAD) (Swedo et al., 1995). Children with SAD displayed dysregulated circadian activity rhythms that were comparable with those reported in nonseasonally depressed children, but different from those observed in adults. GH is also disrupted in stress or depression. GH may be suppressed in a stressful environment to the extent that it mimics GH deficiency and leads to poor growth, as found in psychosocial dwarfism (Jorgensen et al., 1993). Decreased GH secretion to secretagogues is found in children and adolescents with MDD in most studies using insulin as a secretagogue (Puig-Antich et al., 1984c) and growth-hormonereleasing hormone (GHRH) (Dahl et al., 2000) and this hyporesponse remains after recovery from depression (Puig-Antich et al., 1984a), as assessed by the GH response to clonidine and L-Dopa (Jensen and Garfinkel, 1990). A larger study of prepubertal children with MDD also showed decreased GH response to insulin and GHRH, but less so to clonidine (Ryan et al., 1994). Further, there is decreased basal GH and decreased response to GHRH in children and adolescents at risk for depression who have not been diagnosed per se, suggesting that this pattern of GH secretion might be a marker to incipient depression (Birmaher et al., 2000). The cause of these abnormalities in GH secretion in some of these studies is postulated to be stress, which increases CRH and suppresses GH release. Further, there is an increased prevalence of social phobias in adults who were GH deficient as children (Stabler et al., 1996a,b). Indeed a decrease in stature of 1-2 inches was described in girls with anxiety disorders, but not in boys (Pine et al., 1996). These findings may relate

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to the pathogenesis of psychosocial dwarfism (Powell et al., 1967a,b). However, sleep studies show increased GH secretion in some psychopathologies. A 10-year followup of individuals undergoing sleep studies with sequential GH determinations during adolescence demonstrated that a rapid and increased rise in GH in the first hours after falling asleep was predictive of future athymia, depression, and even suicide attempts, whether they appeared at risk during adolescence or were considered normal controls (Coplan et al., 2000). An increase in sleepentrained GH secretion is reported in major depression even after recovery (Puig-Antich et al., 1984b,d). In summary, lower daytime GH and increased sleepentrained GH may be found in depression. There are changes in thyroid function in puberty that vary between adults and children. Children and adolescents with MDD demonstrated lower serum thyroxine (T4) and thyroid-stimulating hormone (TSH) in boys but not girls, although MDD subjects were still euthyroid (Dorn et al., 1996a, 1997). This differs from adults who have some elevation of T4 in depression, although remaining in the euthyroid range. The frequency of attempted suicide increases abruptly during puberty, and suicide now ranks fourth as a cause of death among 15- to 19-year-olds (Michael and Zumpke, 1990; Weiner and del Gaudio, 1977). A retrospective analysis of adolescents committing suicide indicated an onset of their depression in childhood or early puberty, even though the act of attempted suiside occurred later in puberty (Rao et al., 1993).

E Schizophrenia in Puberty Schizophrenia is usually diagnosed no earlier than puberty; childhood-onset schizophrenia is rare. A large epidemiologic study from Germany demonstrated that more boys than girls are diagnosed with isolated (but not familial) schizophrenia starting in the pubertal years, in contrast to adulthood when more women are diagnosed than men. The suggestion is that a protective effect of estrogen raises the threshold for schizophrenia in women until the age of menopause and the elimination of estrogen, at which time more severe cases of depression occur in women; men of the same age have milder cases in general (Hafner et al., 1998).

A longitudinal study of the biological aspects of childhood-onset schizophrenia reports changes in affected children's magnetic resonance imaging (MRI) and positron emission tomography (PET) scans of the CNS (Gordon et al., 1994). The reason for the increased onset of schizophrenia at the age of puberty may have an anatomical explanation related to the prefrontal cortex, an area implicated in the etiology of schizophrenia. Studies of changes in the dorsolateral prefrontal cortrex in monkeys during puberty suggests a (speculative) relationship with the histological study of the brains of human beings with schizophrenia (Lewis, 2000). It is postulated that the remodeling of this area is particularly vulnerable to adverse influence at the time of puberty and that these influences may be implicated in the pathophysiology of schizophrenia. There are other psychological or neurological conditions that usually first appear during puberty such as panic attacks (Hayward et al., 1992) and migraine headaches (Solomon, 1994).

G. Risk-Taking Behavior There are relationships reported with risk-taking behavior and puberty. The age of the onset of cigarette smoking and alcohol use is related to the age of the onset of puberty in girlsmearlier-maturing girls partake earlier; boys may follow the same pattern (Wilson et al., 1994; Tschann et al., 1994). Adolescents that remain at lower levels of cognitive complexity or concrete thinking and have an early onset of puberty have an increase in risk-taking behavior (Orr and Ingersoll, 1995). One study reports a predictive relationship between random salivary testosterone and having ever smoked a cigarette in 12- to 14-year-old boys and a relationship between salivary testosterone and current smoking in 12- to 14-year-old girls. Although the study was controlled for age, no mention of pubertal stage was provided (Bauman et al., 1989).

H. Aggression and Puberty Testosterone is generally considered to be related to aggressive activity in males and females, in ungulates and lower mammals, although the effect is less prominent in primates (Bouissou, 1983). However, in spite of common wisdom, there is little hard evidence to

76. Puberty in Boys and Girls support the concept that testosterone is related to aggression in humans. Studies of adolescents usually suffer from a limited number of subjects, lack of prospective design, or insufficient change in characteristics in normal subjects to allow meaningful correlations. Further, the difficulty in determining which comes first, testosterone causing aggression or aggressive behavior stimulating the adrenal glands or even the testes to raise serum testosterone concentrations, weakens the link even if one can be established. In aggression, as in other behaviors, hormones may act as organizational agents on the CNS during fetal life, which causes behavior that is manifest later in life, or hormones can work as activating agents contemporaneously exerting effects on the differentiated brain (Rubin et al., 1981; Goy and Phoenix, 1972); thus, a passage of over 10 years may separate a cause and an effect. Last, in boys with delayed puberty or Klinefelter syndrome, in which serum testosterone levels are low, increased aggressiveness may serve as a compensatory mechanism for real or perceived slights from peers (Johnson et al., 1970). The study of unselected, normal adolescents is the best way to evaluate evidence of a link between aggression and testosterone. The results are mixed. Several studies do suggest that aggressive behavior in adolescents may be related to the changes in gonadal steroid levels (Michael and Zumpke, 1990; Susman etal., 1987; Warren and Brooks-Gunn, 1989; Udry et al., 1985). Normal boys experience increasing serum testosterone concentrations during pubertal development, but do not display increased aggressiveness. Indeed, aggressive behavior usually appears to decrease with progression through puberty, although, of course, there are groups of adolescents that retain such tendencies throughout their development (see Tumutuous group above). However, several studies could not demonstrate a relationship between the serum concentrations of testosterone, sex-hormone-binding globulin, DHEAS or DHEA, and violent, unmanageable behavior (conduct disorders) (Finkelstein et al., 1994; Constantino et al., 1993; Halpern et al., 1993a). This stands in contrast to earlier studies that were able to link serum testosterone concentrations and aggressive behavior, although no link between pubertal status and aggression occurred (Olweus et al., 1980). Boys and girls, 10 to 14 years old, were rated on several behavioral measures and the results correlated

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with serum LH, FSH, testosterone, DHEA, DHEAS, androstenedione, and estradiol (Susman et al., 1987a). Levels of aggressiveness and nasty tendencies were similar in boys and girls and although there were some positive relationships demonstrated between androgen levels and behavior in boys, there was no relationship between hormones and behaviors in girls. Serum testosterone was not related to aggressiveness in boys or girls. Higher serum androstenedione and lower levels of estradiol, the testosterone/estradiol ratio, sex-hormonebinding globulin, and DHEAS were related to higher levels of acting-out behavior problems in boys. However, sex-hormone-binding globulin was negatively related to a sad affect and delinquent behavior. That sexhormone-binding globulin is negatively related to the testosterone concentration suggests an indirect relationship with testosterone. The adrenal androgen precursors DHEA and DHEAS and androstenedione were related to sad affect and delinquent and rebellious behavior; adrenal hormones had been previously established to change in response to variations in mood, so cause and effect cannot be determined. The pubertal stage itself did not relate to behavior in the study. Thus, boys but not girls show a relationship, albeit not as strong one, between some agressive behaviors and androgens. However, results of other studies indicate that a relationship in the short term may change with longitudinal followup. A cross-sectional study of 12- to 13year-olds revealed a correlation between testosterone and sexual activity and self-reported aggression, dominance, and antisocial acts even when the effect of pubertal stage was removed. But when the study was extended to the time that the subjects reached 1516 years, there was no relationship remaining between testosterone and behavior. The conclusion of the authors is that testosterone may cause the physical changes of puberty leading to a change in appearance that acts on social factors that ultimately affect behavior. However, testosterone does not itself affect this behavior (Halpern et al., 1993a). This is further supported by longitudinal and cross-sectional studies that demonstrated no correlation of serum testosterone and problem behavior over a 3-year period in boys. Testosterone levels in early adolescence may serve as a marker for the progression of physical maturation, but testosterone concentration did not serve as

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a marker for problem behavior (Drigotas and Udry, 1993). Social factors can change the hormonal milieu and thereby affect behavior. A novel or stressful environment caused a rise in cortisol and androstenedione in boys and tended to lower testosterone values. Behavior reflecting the stress was manifest at first, but after a period of time the behavior waned while the elevated cortisol remained. Thus, there was a physiologic effect of stress without outward manifestations. This has clinical relevancema stressed adolescent might receive less support in the absence of manifestations because a peer or parent might not know to respond, leading to more physiological stress. The authors of this study further postulated that chronic stress might decrease gonadal function and that delayed puberty might result from such chronic stress (Susman et al., 1988b). The elevated cortisol that correlates with depression in some studies is discussed previously, but in contrast cortisol might be low in aggressive or antisocial adults (Virkkunen, 1985). Salivary cortisol was found to be low in boys with conduct disorder symptoms and lower still in those whose fathers had conduct disorders as children and retained aggressive behavior (Vanyukov et al., 1993). Further, boys with conduct disorder symptoms but no coexisting anxiety disorders had lower salivary cortisol than those with both (McBurnett et al., 1991, 2000). In a longitudinal study of boys ages 712 years, salivary cortisol was lower the greater the conduct disorder symptoms, the greater the aggression, and the earlier the onset of those symptoms; in contrast, salivary cortisol did not change with covert conduct disorder (McBurnett et al., 1996). A restricted, low range of cortisol values was found in the most aggressive boys of one study (McBurnett et al., 1996). Boys considered at high risk for substance abuse demonstrated low levels of salivary cortisol, suggesting that this might be a marker for anticociality and psychoactive substance abuse (Moss et al., 1995). The hypothesis that stress brings out the relationship between aggression and hormones is supported by a study of 30 male peripubertal junior high school adolescents who were administered psychologically stressful tests (Mental Arithmetic, Stroop Color Word Interference task, and Trial Social Stress tests). Serum samples were analyzed for various hormones before and after the test. High-normal levels of aggressiveness were

associated with significantly higher basal concentrations of norepinephrine, ACTH, prolactin, and testosterone and with a significant increase of GH responses to the stressful stimuli (Gerra et al., 1998). Higher cortisol response to a parent-child conflict discussion task was related to social withdrawal anxiety and somatic complaints (Granger et al., 1994). The determination of salivary testosterone reflects the serum testosterone concentration and reduces the difficulty of collecting samples, including multiple samples, in a population. A study of salivary testosterone in 13yea>old boys who were rated by peers, teachers, and also by a historical evaluation of their behavior over the preceding 6 years revealed contradictory results reflecting the complexity of such an analysis (Schaal et al., 1996). High salivary testosterone levels in adolescent boys were associated with ratings for toughness and leadership by other boys of the same age who had not previously known the subjects. In contrast, low salivary testosterone was found in those with a stable history of previous aggression who did not demonstrate leadership skills. Thus, high salivary testosterone may reflect social well-being and may be a marker of social success rather than of social maladjustment as previously suggested (Buchanan et al., 1992). This is supported by studies in adult males. Testosterone rises in the face of a challenge and rises after success, but falls in the face of loss (Ma7ur and Booth, 1998). Thus, testosterone, no matter what role it has in causing behavior, appears to respond to behavior itself. The study of the effects of exogenous sex steroids may provide further information on the relationship between sex steroids and aggression. Adolescents with delayed puberty were treated with sex steroid replacement at three dosages intermixed with periods of placebo treatment; testosterone was given intermuscularly in boys and estradiol was given orally in girls (Kulin et al., 2000). Serum steroid values were determined to assure that the intended levels were reached at each dosage level of sex steroids. Using six measures of aggression, scores for physical aggression and aggressive impulses (but not in verbal aggressiveness) increased in the low and mid-dosage ranges, but not in the high-dosage cohort (Finkelstein et al., 1997). Because the results followed similar patterns for girls and boys, the question of whether the effects of testosterone occur through estrogen derived from aromatization of testosterone rather

76. Puberty in Boys and Girls

than resulting directly from testosterone directly must be considered (as occurs in the effects of estradiol on bone maturation discussed above). Focusing on delinquent or criminal youth could provide information supporting a link between aggression and testosterone. However, even if established, such a correlation would be suspect unless confirmed in an unselected population. Prepubertal boys have testosterone secretion, albeit much less than in puberty or adulthood; highly sensitive assays must be used to measure testosterone secretion at these ages. A study of 18 highly aggressive prepubertal boys found no relationship between activity and testosterone (Constantino et al., 1993). Thus, in this select group there was no contemporaneous relationship between testosterone and behavior. A study of a group of disruptive children between 7 and 14 years of age demonstrated moderate relationships between salivary testosterone and staff-observed aggression and between salivary cortisol and parentreported emotional behaviors such as internalizing tendencies (Scerbo and Kolko, 1994). There was a negative relationship between cortisol and hyperactive behavior, but cortisol did not moderate the testosteroneaggression relationship in this population. A study of 14- to 19-year-old delinquent boys in an institution found serum testosterone to be higher but not significantly higher than in age-matched nondelinquent boys (Olweus et al., 1988). The analysis of measures of aggression mainly demonstrated that the delinquent boys' actions most closely correlated with a response to provocation; these results are similar to the study noted previously that suggested a link between stress and aggression in normal boys. An evaluation of 17- to 18-year-old male prison inmates demonstrated higher salivary testosterone concentrations in those inmates who had committed more violent crimes and who had infractions in prison; if only individuals with a decreased salivary cortisol concentration were considered, the level of violence was greater, suggesting to the authors that cortisol moderated the effects of testosterone. Alternatively, the low cortisol might simply be a reflection of the previously presented relationship between low cortisol of aggression in the absence of anxiety. The study had no comparison group and the actual time of sampling saliva

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was unclear enough to cloud the results (Dabbs et al., 1991). A relationship between salivary testosterone and criminal violence and aggressive dominance in women in prison was reported. There was a decrease in these behaviors with age, which correlated with a decline in testosterone; the authors suggested that testosterone could serve as a marker for this behavior in women (Dabbs and Hargrove, 1997). In summary, there is some evidence that endogenous testosterone exerts effects on violent behavior in boy and girls, but the data are imperfect. There is a relationship between serotonergic factors and aggression or depression. Serotonergic pharmacological agents are used more successfully for the treatment of depression in adolescents (Emslie et al., 1997), in contrast to lesser effects of tricyclic antidepressives (Hazell et al., 1995). There is neuroendocrine support for mechanisms for such agents to function. A blunted cortisol response in boys and girls with major depression was found as well as an augmented prolactin response in the girls after infusion of k-5hydroxytryptophan (a precursor of serotonin) after carbidopa preloading (Ryanet al., 1992). Remarkably, this same result was found in children with a strong family history of depression but who did not yet show such signs, suggesting that these responses might provide a biological marker for the prediction of the later onset of depression (Ryan et al., 1992). The amount of prolactin and cortisol released after the administration of the indirect serotonin agonist fenfluramine did not correlate with aggression rating scores in prepubertal humans and adolescents with disruptive behavior disorders and did not differ significantly between adolescent DBD patients and normal control subjects (Stoff et al., 1992). However, another pair of studies did demonstrate augmented prolactin release after fenfluamine in AD/HD aggressive boys compared to AD/HD nonaggressive boys if they were younger (the age of 9.1 years was analyzed) but not if they were older (Halperin et al., 1994, 1997b). Remarkably, those boys with a parental history of aggression had lower responses to fenfiuramine than did AD/HD boys without aggression, whereas boys without a parental history of aggression had elevated levels such as were noted in the preceeding studies (Halperin et al., 1997a). Younger brothers of convicted delinquents,

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when demonstrating aggressive tendencies or when raised in an environment conducive to the development of such tendencies, had an increased prolactin response to fenfluramine (Pine et al., 1997). The body of evidence indicates that there is disordered serotonergic function in aggression or depression that may be developmentally regulated. I. B e h a v i o r in V a r i a t i o n s of t h e N o r m a l Age of O n s e t of P u b e r t y The timing of the onset of puberty has an effect on psychosocial development in puberty. Considering only those children who progress through puberty at the normal limits of pubertal development previously described, early-maturing girls and late-maturing boys have the greatest prevalence of adjustment reactions in puberty and thereafter (Graber et al., 1997). In general, early-developing a boys are perceived to be more mature and are given more leadership roles, are accepted as more attractive and smarter by their peers. Late-developing boys, however, are more insecure, more susceptible to lower levels of self-esteem and body image (Blyth et al., 1981), and more vulnerable to peer pressure, especially in working class and minority groups. Much of the problem of late maturation is said to focus on the decreased height of the individual rather than the lack of sexual development (Apter et al., 1994). Social maturation is said to lag behind even after androgen treatment is administered in severe constitutional delay in puberty (Lewis et al., 1977). On the other hand, early-maturing girls tend to experience more difficulty, especially in the junior high school setting, where they may attract the attention of older, more mature boys. Girls with early puberty had a higher prevalence of internalizing symptoms and even internalizing disorders (Hayward et al., 1997). Early puberty may lead to negative body image in girls, in contrast to boys in whom the effect is positive. Early pubertal maturation in girls may be related to a small IQ advantage over late-maturing girls, but there is no support for differences in specific areas of cognitive abilities (Newcombe and Dubas, 1987). Late-maturing girls are often more comfortable, remaining with the support of their families longer and are less often brought to medical attention than late-maturing boys (Hamburg, 1992).

A cross-sectional study of boys and girls of 9-14 years in which multiple gonadal, adrenal, and pituitary hormones were measured relates to differences in behavior with delay in puberty (Nottelmann et al., 1987). There was an association of adjustment problems in boys with relatively low gonadal steroids, lower pubertal-stage attainment, and higher serum androstenedione values (from adrenal activity) with older chronological age; this pattern is suggestive of stress occurring in latermaturing boys who are still within the upper limits of development. Further, adjustment problems in girls were related to relatively high levels of circulating gonadotropins and low levels of DHEAS (derived from the adrenal gland), although the association was less clear than in boys and the girls did not necessarily have a pattern of delayed puberty. Both boys and girls showed a relationship between adjustment problems and higher levels of androstenedione, a hormone raised in stress. The suggestion of the study is that later maturation may provoke a stress response that may derive from social interactions affected by the delayed physical maturation itself or, alternatively, that the stress may be a concomitant of the late maturation. Stress and the administration of glucocorticoids are reported to suppress gonadal function in both humans and other animals (Sakakura et al., 1975; Sowers et al., 1979; Schaison et al., 1978; Selye, 1976). Other effects of stress on human endocrine systems are reflected in the delayed menarche found in anorexia nervosa (Gold et al., 1986) (irrespective of the degree of weight loss); in excessive exercise, such as in ballet dancers (Warren, 1980) (related more to severe exercise than to weight loss), and in the growth failure and temporary GH deficiency in psychosocial dwarfism (Powell et al., 196?). It may be, according to these studies, that stress helps delay puberty, which itself leads to more stress in a vicious cycle (Susman et al., 1988a). The delay in menarche due to stress or decreased weight may be further analyzed. Menarche is delayed in lean ballet dancers compared to a control group of adolescent girls the same age and compared to their own mothers (Brooks-Gunn and Warren, 1988). The dancers studied were less likely to date than their agematched peers and, although menarcheal status had no effect on the dating behavior in nondance controls, the dancers who did achieve menarche were more likely to date (Brooks-Gunn, 1987). Thus, lower body weight

76. Puberty in Boys and Girls

or energy expenditure seems to delay dating as well as to the well-known impairment of menstruation.

j. Behavior in Disorders of Pubertal Development Girls with central or true precocious puberty manifest an increased prevalence of positive scores on the Total Behavior Problem scale, the internalizing (or overcontrolled symptom) and externalizing (or undercontrolled symptom) score and on the social withdrawal scale (Sonis et al., 1985). These symptoms were related more to the physical changes of central precocious puberty than to the abnormal hormonal milieu. The psychiatric sequelae of the precocious puberty include an increase in minor psychopathological symptoms and advancement in sociosexual milestones, albeit mostly within the normal range for adolescents. Although IQ is not different from controls in subjects with central precocious puberty, school achievement was accelerated during childhood. In addition, girls with idiopathic true precocious puberty had lower spatial perception scores than controls (Ehrhardt et al., 1987; Ehrhardt and Meyer-Bahlburg, 1994). Mood may change with the treatment of true precocious puberty in girls with gonadotropin-releasing hormone agonist to suppress gonadotropin secretion. As a consequence of the inhibition of FSH and LH secretion, ovarian estrogen synthesis is suppressed and the concentration of serum estradiol falls; some affected girls may experience mood changes characteristic of menopause. Boys with true precocious puberty often masturbate, and this activity decreases with therapy. Because neither boys nor girls have increased social milestones solely due to precocious puberty, spontaneous heterosexual activity does not occur, although affected children may be the target of illict advances. Thus, precocious puberty exerts some effects on psychological function and successful treatment improves this tendency. Premature adrenarche is the early appearance of pubic hair or axillary hair and often some degree of comedone development. It is self-limited and does not affect the ultimate age of puberty onset, but it can be confused with the more significant diagnoses of nonclassic congenital adrenal hyperplasia or even virilizing adrenal tumors. Little is known of the psychological

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effects of the elevation of adrenal hormones DHEA and DAEAS, which arises largely from the developing zona reticularis of the adrenal. A pilot study demonstrated a difference between children with premature precocious adrenarche and control children, with the former exhibiting a 44% prevelance of scores for psychological disorders on the diagnostic inteview schedule for children and more self-reported depressive symptoms, more behavior problems, and lower cognitive function when the study was controlled for socioeconomic status (Dorn et al., 1999). Although this is a small and selected study, it bears followup in this group of children with a supposed benign disorder. A prospective study of the intramuscular administration of long-acting testosterone preparations to boys with delayed puberty, ages 14-17 years, revealed an effect on mood (Rosenfeld et al., 1982). The boys were randomly assigned to a course of 200 mg testosterone enanthate, administered intramuscularly four times at 3-week intervals or to no treatment. At the 1-year followup all the boys in the testosterone group exhibited excellent growth in stature, whereas growth in the controls was significantly lower than that of the testosterone group. Both groups showed improved selfimage; the treated subjects also exhibited notable increases in both school-related and extracurricular social activities. Thus a relatively brief course of testosterone enanthate had beneficial effects on growth and in inducing or advancing pubertal maturation, which was related to improved social function, over that achieved simply by the passing of i year. In contrast, however, a study of psychological tests in boys and girls with delayed puberty due to mixed causes, including constitutional delay, treated with periods of three doses of sex steroid alternating with no treatment (see above; Susman et al., 1998) demonstrated an increase in withdrawn behavior problems during the administration of low-dose estrogen in girls, but both boys and gilrs scored higher on social competency measures (see previous discussion for the effects of this treatment schema on sexuality). Thus, the administration of sex steroids can exert a positive effect on social function or at least on social competency.

1. Turner Syndrome Turner syndrome of gonadal dysgenesis classically occurs in a phenotypic girl with a 45,X karyotype.

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IV Development of Hormone-Dependent Neuronal Systems

The loss of the X chromosome (and the SHOX gene) leads to many manifestations, including short stature, ovarian failure (degeneration of the ovaries by birth), lymphedma, left-sided heart disease, abnormal kidney shape, and a host of physical changes of the face, thorax, and extremities. Girls with Turner syndrome have a normal verbal IQ (VIQ), but a discrepancy between verbal IQ and performance IQ (PIQ), with the latter approximately 1 SD below the mean value. Turner syndrome is associated with impaired visual-spatial (in most studies) or visual-perceptual abilities in association with executive dysfunction and decreased attention span; these can lead to learning difficulties (Ross et al., 1995, 1996). However, in another study girls with Turner sydrome had difficulties in visuoperceptual tasks and on visuoconstructional tasks, but did not have specific deficits in visuospatial or tactospatial tasks, Temple and Carney

(1996). Normal girls perform better on motor tasks as they get older, a trend that is not found in Turner syndrome. Although one study found diminished lateralization of motor tasks (Robinson et al., 1992), a later study found no difference in lateralization and performance of motor tasks in Turner syndrome subjects vs controls; there was superior performance of the dominant or right hand in contrast to the nondominant or left hand (Ross et al., 1996). Anatomic changes of the brain and neurocognitive changes occur in Turner syndrome. There are consistent MRI abnormalities in the right parietal lobe and the occipital lobes, which show decreased volumes in these areas which are implicated in visuospatial processing. Using PET, Murphy and colleagues showed decreased glucose metabolism in the right parietal and occipital lobes (Reiss et al., 1995; Murphy et al., 1993, 1997). This anatomic data relates to the difficulties in visuospatial skills in girls with Turner syndrome (in most studies) because these problems are most closelylinked to the right parietal region (Voeller, 1986). Turner syndrome girls resemble normal girls in verbal and language skills, but there are frequently difficulties with memory and attention and decreased arithmetic skills due to mistakes in operation and alignment processes (Mazzocco, 1998), with girls with 45,X mosaicism associated with a 46,XX cell line (45,X/46,XX) scoring closer to normal that those with

other types of mosaicisms. However, girls with Turner syndrome can score higher on reading achievement tests than predicted by IQ or age; this hyperliteracy is a strength in many girls with this disorder. Only 3.3% of girls with Turner syndrome have mental retardation if they do not have a variant of Turner syndrome caused by a ring X chromosome (Van Dyke et al., 1992). Because most girls with Turner syndrome lack ovarian estrogen production and are treated during the teenage years with exogenous estrogen hormone replacement therapy (HRT), Turner syndrome provides an opportunity to determine the effects of estrogen on neurocognitive function. There appear to be estrogendependent and estrogen-independent tasks that are affected in Turner syndrome. However, there is controversy over which are estrogen-dependent and which are not. For example, visuospatial perceptual deficits appear to begin in childhood and persist into adult life, unaffected by estrogen treatment according to some studies (Downey et al., 1991; Swillen et al., 1993). However, another group of studies shows that the effects of estrogen are dose- and time-dependent, with untreated patients and those treated with high-dose or long-dose term therapy performing equally poorly (Nyborg, 1994). Thus Turner girls spontaneously improve in their testing on visuospatial abilities when younger than 12 years to older than 15 years of age; the older girls treated with 3-24 months of estrogen therapy improved further. However, those treated for more than 2 years with estrogen had decreased visuospatial ability compared to that of untreated agematched Turner patients. There is a decrease in spatial abilities reported in normal girls going through puberty; it is suggested that this is another example of a biphasic effect of estrogen, whereby low levels, as in prepuberty, foster spatial abil W but higher levels, at the end of puberty and thereafter, suppresses such ability (Nyborg, 1994). Some motor-related skills and nonverbal processing were performed more rapidly in estrogen-treated girls with Turner syndrome (Ross et al., 1998; Romans et al., 1998). The study of event-related potentials in pre- and postteenage Turner syndrome patients compared to age-matched controls demonstrated congenital and age-related abnormalities; the later are ameliorated by estrogen treatment if it is given early enough (Johnson et al., 1993).

76. Puberty in Boys and Girls The results of a double-blind study of estrogen vs placebo treatment for 1-3 years in 7- to 9-year-old girls with Turner syndrome show the direct effects of estrogen and effects of GH. These girls were part of a larger double-blind study to determine the effect of GH and estrogen on final height. GH therapy in Turner syndrome leads to increased growth rate, but in addition the girls felt better about their attractiveness, intelligence, and popularity and they perceived that they experienced less teasing; there was no effect on school performance with GH therapy (Rovet and Holland, 1993). Girls with Turner syndrome younger than 6 years old did not perceive that they had a problem with height, but by 7-12 and especially 13-15 years affected Turner girls have a strong desire for GH therapy and even unrealistic expectations of what GH therapy might accomplish in terms of adult height (they usually reach only the lower limits of the normal growth curve even with GH therapy; Lagrou et al., 1998). GH therapy improved self-esteem even if there remained a significant difference in height between Turner girls and the normal range. GH does not affect the nonverbal neurocognitive defects in Turner syndrome (Ross et al., 1997) nor does it affect IQ or achievement scores (Siegel et al., 1998). With regard to estrogen, placebo-treated girls with Turner syndrome performed less well than either controls or estrogen-treated Turner syndrome individuals in the recall of digit spans backward and the immediate and delayed recall of the children's word list, suggesting that estrogen replacement therapy improves verbal and nonverbal memory. This observation raises the possibility that a prepubertal deficit in estrogen may affect the performance of these tasks and that there is a potential role for low-dose estrogen replacement therapy in late prepubertal girls with Turner syndrome (Ross et al., 2000). These results are similar to the improvement in short- and long-term verbal memory found in postmenopausal or surgically castrated women treated with estrogen replacement therapy (Phillips and Sherwin, 1992a,b). Treatment with estrogen for over 4 years appeared to move the scores for girls with Turner syndrome on self-esteem and psychological well-being toward normal control values as they reached 16 years of age compared to a significant difference documented at 12 years of age. No such change occurred in the

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nonestrogen-treated group, suggesting that the estrogen effects caused the change rather than the passage of years. Thus, it appears that estrogen has effects on visuospatial abilities (perhaps in a biphsic pattern), memory and self-esteem. Two mechanisms are proposed to explain these estrogen effectsmeither (1) estrogen acts as a neuromodulator in a transient time frame or (2) estrogen alters synapse formation, remodeling in a permanent time frame; or both mechanisms may be at work. Thus, estrogen may function as an organizational agent in the brain of the young, but as a stabilizing agent in older individuals. The increase in mental health problems documented in Turner syndrome may be rooted in the increased peer ridicule experienced by girls with Turner syndrome as opposed to being due to a biological abnormality. The teasing can by itself lead to decreased self-image and depression (Rickert et al., 1996). There is an increased risk of impaired social adjustment in Turner syndrome (McCauleyet al., 1987). Girls with fragile X syndrome and those with Turner syndrome have higher ratings of social and attention problems and withdrawn behaviors compared to their own sisters (Mazzocco et al., 1998). The risk is higher if the single X chromosome comes from the mother rather than the father. Individuals with Turner syndrome have difficulty in inferring affective intention from facial appearance. As an explanation for these phenomenon, there appears to be a locus on the X chromosome at Xq or close to the centromere on Xp that escapes X inactivation and affects sociocognition (Lagrou et al., 1998; Skuse et al., 1997; Skuse, 1999). This locus is apparently imprinted and not expressed from the maternally derived X chromosome. If the locus was inherited from the father, the 45,X individuals were significantly better adjusted, with superior verbal and higher-order executive function skills, which mediate social interactions. If expressed only on the paternally derived X chromosome, the existence of this putative locus may explain, in part, why 46,XY males (whose single X chromosome is maternal) are more vulnerable to developmental disorders of language and social cognition, such as autism, than are 46,XX females. Accordingly, in addition to haploinsufficiency and its consequences, sex chromosome imprinting appears to be a factor in the Turner syndrome phenotype.

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Iv. Development of Hormone-Dependent Neuronal Systems

The origin of the single X chromosome affects memory performance as well because those with a mate> nally derived X have increased verbal forgetting but normal nonverbal forgetting, whereas those with a paternally derived X chromosome have the opposite pattern of problems (Bishop et al., 2000). 2. Klinefelter S y n d r o m e The Klinefelter karyotype (47,XXY) occurs in 1 in 1000 male births (see Grumbach and Conte, 1998; Hook and Hamerton, 1977). The 47,XXY is associated with advanced maternal age and, thus, it is detected relatively frequently by prenatal cytogenetic diagnosis. The Klinefelter syndrome phenotype in its classic form includes small hyalinized testes after the onset of puberty with azoospermia and resulting infertility. The onset of puberty is not delayed, but dimininished Leydig cell function can reduce testosterone secretion so some affected individuals do not fully masculinize without exogenous testosterone administration (Grumbach and Conte, 1998). Gyneceomastia is common. Neurobehavioral abnormalities, primarily in language and frontal executive functions, are frequent and, some say universal, in Klinefelter syndrome. These problems may be severe enough to lead to evaluation in childhood and the prepubertal recognition of the syndrome. The global IQ in unselected populations of Klinefelter syndrome subjects is normal or near-normal, but VIQ, in contrast to Turner syndrome, is usually lower than PIQ (Rovet et al., 1996). Because patients with clinical or psychological problems are referred more often for evaluation, some studies are skewed to suggest more significant deficits than is prevalent in an unselected population of XXY individuals. Although younger patients with Klinefelter syndrome have a VIQ that is less than their PIQ, there are older adults that have a PIQ less than their VIQ (reviewed in Boone et al., 2001). It was suggested the PIQ drops in late puberty, whereas the VIQ remains stable (Rovet et al., 1995). Further, prepubertal Klinefelter syndrome patients have reduced left-hemisphere specialization for verbal tasks and enhanced righthemisphere specialization for nonverbal tasks. However, these abnormalities tended to normalize after puberty began, suggesting hemispheric reorganization during puberty (Netley and Rovet, 1984). A reduced head circumference and reduced total finger-ridge

count in Klinefelter syndrome is evidence of prenatal slowing of neural cell division and of development, a finding that may be related to the impairment of verbal ability (Netley and Rovet, 1987). It is suggested that slowed development reduces the growth of the left hemisphere, allowing more unrestrained growth of the right hemisphere before and soon after birth (Stewart et al., 1982). Decreasing the PIQ and improving the VIQ are postulated to relate to the relatively low testosterone concentrations and relatively high estrogen concentrations characteristic of some patients with Klinefelter syndrome during puberty, which is reflected physically in the development of gynecomastia. Estrogen is known to enhance verbal skills, whereas reduced androgen levels decrease visuospatial function (Collaer and Hines, 1995). However, the local aromatization of testosterone to estrogen, which is not fully reflected in the serum values of these hormones, and the varying effect of testosterone and estrogen in Klinefelter syndrome on physical features such as gynecomastia and habitus make the detailed interpretation of these cognitive changes difficult. Hypotheses have been advanced supporting the effect of prenatal testosterone on cerebral dominance and language and reading pathology (Geschwind and Galaburda, 1985), but such explanations are unlikely to explain the difficulties faced by Klinefelter patients because androgen deficiency is not apparent until puberty begins. Although there is a growing feeling among parents that testosterone treatment in the early pubertal period improves language, reading, and behavior in boys with Klinefelter syndrome, convincing studies documenting these observations are not at hand (Geschwind et al., 2000). Indeed, the widespread perception of the benefit of testosterone in XXY boys has limited the ability of researchers to carry out a carefully controlled study. One study, however, did report a better mood, less irritability, more energy and drive, less tiredness, more endurance and strength, less need for sleep, better concentration, and better relations with others during testosterone treatment of mid-twenty-yea>old adults with Klinefelter syndrome (Nielsen et al., 1988). Some of these improvements may relate to frontal executive function rather than language. Thus, the Klinefelter syndrome is a model of the effects of abnormal karyotype or abnormal testosterone production on psychoeducational development.

76. Puberty in Boys and Girls 3. Effects of Prenatal Hormones and Intersex States on Later Behavior Although it is well established that in humans testosterone secreted by the fetal testes induces male differentiation of the external genitalia, the role of androgens and other sex hormones in the structural and functional change in the CNS during fetal life and at puberty are not as well defined. Inferences are drawn about the effects of prenatal hormones on childhood and later pubertal behavior in humans from studies in experimental animals. However, important and critical species differences exist and the development of gender identity in humans is a cognitive process that has no counterpart in animal behavior. An understanding of the influence of prenatal hormones in humans must come from human research. Hormone-dependent variations of sexually dimorphic behavior and cognition in childhood can be significant without a change in gender identity occurring in the child. In the past, it was held that if the child's physical appearance is gender adequate and the parental (or other caregivers') rearing style does not interfere with typical gender-role development, there should be no problem with gender identity. It appeared, according to the gender neutral at birth hypothesis of Money and Ehrhardt (1972) and their theory of gender socialization as the major determinant of gender identity, that there was no critical hormonal or genetic effect on identity and that social interactions were of most importance. Decisions about sex assignment and reassignment of intersex patients was based on expected social and sexual functioning. The clinical management of such patients aimed to minimize the risk of ambiguous rearing and of the development of a gender-incongruent physical appearance. This view has now been seriously challenged as its observational support has come under rigorous scrutiny. The factors constituting gender development are gender identity (classic said to be firmly established by 18-24 months of age, but there is increasingly doubt), which is the experience of one's self as male, female, or ambivalent; gender role, which is the behavior or activities indicating to others or self the degree to which one is male, female, or ambivalent; adult sexual orientation or choice of gender of sexual objects; and parenting, which is the desire and capacity for child caretaking (an important trait for the survival of a species) (Baker, 1980).

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Patients with disorders of sex determination and differentiation come from a wide variety of conditions and diagnoses (Styne, 1996). Thus, some have abnormalities in the synthesis of sex steroids or in the action of these hormones. Phenotype is also variable, as is the tendency to undergo significant physical changes at puberty. The causes of intersexuality and its diagnosis and management have been greatly clarified by clinical research (see Grumbach and Conte, 1999). Some studies have focused on prenatal-hormonetreated patients and their psychological state in childhood or their adult gender roles as a result of this exogenous hormone. Psychological evaluation was carried out on female subjects ages 16-2 7 years with a history of prenatal progestin exposure (synthetic steroids with progestational action, but with testosterone-like effects on the external genitalia of the female fetus) (Money and Mathews, 1982). Eleven cases had virilization of the external genitalia, but the twelfth was an anatomically unaffected sister of one of the other cases. None of the 12 had a history of difficulty in establishing friendships or dating relationships. Although when younger the subjects were called "tomboys" and expressed an avid interest in high school sports, none of the subjects chose sports as a career or major pastime. Five who were older women described only heterosexual sexual imagery or activity. There are useful biological models of prenatal androgen exposure in girls. Virilizing congenital adrenal hyperplasia (CAH) leads to prenatal exposure to androgens due to the production of androgen precursors to cortisol by the fetal adrenal gland. The most common type of virilizing CAH, 21-hydroxylase deficiency is associated with behavior differences when the subjects are compared to their sisters or sex-matched controls. As reviewed in Berenbaum et al. (2000), girls with CAH have more male-typical play (Dittmann et al., 1990); have more male-typical adolescent behavior (Berenbaum, 1999); use physical aggression more often when conflict arises (Berenbaum and Resnick, 1997); demonstrate better spatial ability and are more likely to be left-handed (Nass et al., 1987); express less interest in infants, femininity, motherhood, and marriage (Dittmann et al., 1990); score lower on tests developed to measure empathy, intimacy, maternal and nurturing behavior, and the need for social interaction; and scored more like male subjects for detachment and indirect

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IV. Development of Hormone-Dependent Neuronal Systems

aggression (McCauley et al., 1987; Helleday et al., 1993). Women with CAH have a lower fertility rate than unaffected women. This was in part attributed to endocrine dyregulation affecting ovulation, but more important factors involve a lower prevalence of heterosexual activity, inadequate surgical correction of the ambiguous genitalia, and a decreased interest in childbearing (Meyer-Bahlburg, 1999). Women with CAH are more likely to be aroused by and fantasize about women than their unaffected sisters; in some studies in general, women with the salt-wasting form of 21-hydroxylase deficiency were more severely affected (Zucker et al., 1996; Dittmann et al., 1992; Federman, 1982). However, not all studies confirm a higher degree of homosexual ideation or behavior in CAH (Mulaikal et al., 1987; Kuhnle et al., 1995). Indeed most female subjects with CAH have a female gender identity and are exclusively heterosexual in relation to arousal characteristics and their sexual fantasies (McCauley et al., 1987; Zucker et al., 1996). This suggests that, among other factors, the timing or magnitude of the fetal exposure to androgen in female fetuses with this disorder is different and less than the androgen exposure characteristic of the male fetus. Although there was little indication that behavior in females with CAH is related to the control of androgen production (Dittmann et al., 1990), the question of the relative importance of prenatal androgen exposure in contrast to postnatal androgen excess as the major factor in the characteristic behaviors has been studied. By relating the psychological scores in these various areas to the genital appearance at birth as a reflection of the prenatal environment and by comparing the simple virilizing form to the more severe salt-losing form of 21-hydroxylase deficiency, correlations are made between prenatal androgen excess and behavior. Contrariwise, the degree of postnatal androgen excess can be inferred by determining the bone-age advancement, growth rate, and degree of progressive virilization. By these measures, sex-atypical behavior was significantly associated with prenatal but not postnatal androgen excess (Berenbaum et al., 2000). This reflects the effect of prenatal androgen exposure on the organization of brain structure and function. Aggression could not be reliably related to postnatal androgen excess in this group, as is the case in normal puberty previously discussed (reviewed in Hampson and Kimura, 1992). A1-

though there were early reports of higher intelligence in children affected with CAH and precocious puberty, further critical study eliminated such effects (reviewed in Hampson and Kimura, 1992). In summary, there appear to be measureable, reproducible effects of preanatal androgens in CAH on behavior and parenting, and in some cases there may be effects on sexual orientation, but not gender identity.

4. Change in Gender Role at Puberty There are clinical disorders that lead to a reversal of gender identity from female to male at puberty; for example, children with male pseudohermaphroditism (46XY genotype with ambiguous or female phenotype) assigned a female gender at birth, changed to a male gender role at puberty. Such individuals can provide insight into the biological processes that lead to gender identity. Steroid 5-oe-reductase-2 deficiency, due to a mutation in the iso-enzyme 2, which is predominant prenatally in the urogenital tract and causes the local conversion of testosterone to dihydrotestosterone, is an autosomal recessive disorder that in the XY individual leads to ambiguous differentiation of the external genitalia. At birth the phenotype is female and characterized by pseudovaginal perinoscrotal hypospadius, male genital duct differentiation, a urogenital sinus, and a blind vaginal pouch (Imperato-McGinley et al., 1979; Wilson, 1999). The homozygous female is unaffected. In the Dominican Republic, a region in which this disorder is prevalent, family histories reveal consanguinity and a founder effect. Affected children are called heuvo-doces because of their propensity to experience testicular descent (i.e., eggs are "huevos" in Spanish) at the age of puberty (12 years old). In Papua New Guinea, another site of concentration of cases, most subjects are raised as girls but change to a male gender role at puberty (Her& and Davidson, 1988). Some affected individuals are known as kwalatmala, indicating that they can be raised as boys to ultimately take a male role in society. At puberty, the testes descend, the phallic structure enlarges, and, although the phallus is still bound in chordee (ventral tissue holding the phallus in a ventrally curved position), the individual takes on a male gender role. The majority of reported cases come from areasmthe Dominican Republic, Papua New Guinea, and Saudi Arabia (al Attia, 1996)mwhere it might be presumed that these individuals would prefer a male gender role

76. Puberty in Boys and Girls (Herdt and Davidson, 1988). However, some choose to maintain a female gender role. Seven individuals with 5-oe-reductase-2 deficiency from Mexico were raised unambiguously female and four changed gender to male during or after puberty; the other three appear to have tended toward a change to male gender but, due to intensive psychotherapy, remained female (with one undergoing surgical removal of penis and testes who manifested suicidal depression) (Mendez et al., 1995). In Brazil, of 16 patients, all but one were assigned female gender at birth; three maintained a female gender role and 10 of the 13 of postpubertal age changed to a male gender role; remarkably one patient who retained a female gender role had a sibling who had previously changed to a male gender role (Mendonca et al., 1996). In this disorder, the relative roles of the rising serum testosterone values at puberty (which reach adult male levels), prenatal androgen effects on the brain, and ambiguity in the sex of rearing in causing the high prevalence of a change in gender identity from female to male are uncertain. Affected individuals have a functional 5-o~-reductase-1 isoenzyme that is active in the brain and sebaceous glands and at puberty leads to sufficient conversion of testosterone to dihydrotestosterone to induce penile growth in spite of deficient 5-oe-reductase2. High dose androgen therapy in this disorder and in partial androgen resistance is reported to exert beneficial effects on virilization self image and sexual performance (Price et al., 1984). Individuals with 17-fi-hydroxysteroid dehydrogenase-3 deficiency (the enzyme is normally responsible for the conversion of androstenedione, an androgen precursor to testosterone in the Leydig cell to testosterone, are born with ambiguous genitalia; the sex assignment at birth is usually female (Wilson, 1999). The differentiation of the genital ducts is male; no uterus is present. At puberty, testosterone rises as a consequence mainly of the peripheral conversion of androstenedione to testosterone by other 17-beta-hydroxysteroid dehydrogenases and virilization occurs; with age, the serum testosterone values may reach normal adult levels. Approximately 50% of affected XY individuals change their gender-role behavior from female to male, although some may remain female in the same family as another member with the same genetic defect who does change from female to male. These discordances in the selection of gender role and gender identity within the

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same sibship highlight the complexity of the naturenurture interaction in a given affected individual. Complete androgen insensitivity or resistance due to a mutation on the X-borne gene encoding the androgen receptor is a syndrome of total androgen resistance (testicular feminization). It presents as an unambiguous female phenotype at birth in a 46 XY individual who undergoes unambiguous feminization at puberty. The internal genital duct structures are male, there is regression of the MOllerian structures, and only the lower one-third of the vagina is formed. Despite the development of female secondary sex characteristics at puberty, these individuals have primary amenorrhea. Testosterone production and serum testosterone values are normal or high because the defect is in the intracellular androgen receptor and hence in androgen action. Individuals are unambiguously female in gender role and are satisfied with their female phenotype (Wisniewski et al., 2000); 46,XY individuals with complete androgen resistance are attracted to men. This condition demonstrates the critical role of testosterone action in the development of a male gender role. The fact that 46,XY individuals with an estrogen receptor defect have unambiguously male gender roles indicates that estrogen has little to do with the masculine gender role (Smith et al., 1994; Morishima et al., 1995; Bilezikian et al., 1998; Carani et al., 1997). Further, the fact that females with aromatase deficiency, who cannot convert testosterone to estrogen, have unambiguously female gender roles indicates that, unlike the case in nonprimate species, estrogen does not have a critical role in sex differentiation of the brain (Grumbach and Auchus, 1999). Patients with complete androgen resistance underwent psychological and laboratory tests and were interviewed (Alvarez et al., 1983). Their intellectual achievement was normal, and there was no common profile of psychopathology typical of the group. Psychosexual attitudes showed alterations related to acceptance of body image, fears of being unable to maintain the stability of the couple (if they had a partner), and a lack of a strong maternal drive. The personality profile manifested dominance and shrewdness, the former being remarkably high for a female population and more suggestive of a male role (according to the tests in use at that time). Thus, careful study of these individuals may reveal traits that some attribute to a mild degree of androgenization of the CNS.

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Those individuals with the incomplete form of androgen resistance present a different clinical picture. Sex assignment at birth may vary, but virilization of the phenotype at puberty occurs. If the sex assignment was female, gender reversal to the male gender role has been described during puberty (Gooren and Cohen-Kettenis, 1991). A similar sex reversal at puberty or earlier from male to female is described in individuals with male pseudohermaphroditism with inadequate virilization, in whom the penis is poorly formed and to whom a female sex is assigned in infancy although the production of testosterone and androgen receptors are normal (Wilson, 1999). The common thread in these cases is prenatal exposure to androgens in normal or subnormal levels, with a pubertal rise in testosterone and the decision by the patients to change the child's sex from female to male at puberty or before. Again, the present construct is that prenatal androgen exposure in an XY individual seems a key factor that leads to a reexamination of gender identity in the patients with these disorders in late childhood and adolescence. One case has attracted wide attention in the scientific literature and the media. A surgical accident, ablating the previously normal phallus at birth, eliminated the possibility of reconstructing a penis, so the male child was gender-reassigned as female. However, during puberty the individual successfully reverted to a male gender role (Diamond and Sigmundson, 1997a). Again, the implication is that with a completely normal prenatal and neonatal male endocrine mileu, there is a drive to maintain maleness in spite of a social environment promoting a female gender role, even in the absence of testicular testosterone production. However, in another case of an ablated penis in which the infant was reassigned as a female at 7 months of age, the individual was said to have adapted to this gender identity. As an adult she has a bisexual orientation and is a successful functioning female (Bradley et al., 1998). A study of the case histories of 24 male-assigned male pseudohermaphrodites ages 18 or older investigated gender transpositionmbisexualism, homosexuality, or sex reassignment to live as a female (Money and Norman, 1987). In 20 cases, there was no gender transposition even when the following variables were in evidence: neonatal ambivalence in announcing the sex, cosmetic inadequacy of masculine genital appearance, sitting posture for urination, and feminizing in-

stead of virilizing puberty. In the four who did have a gender transposition, there was a trend toward an association between gender transposition and sitting to urinate and being stigmatized in childhood. Although most did not have gender transposition, some did have suicidal depression, drug and alcohol addiction, marital failure, and death from testicular cancer. A large study from the Netherlands reports a 39% prevelance of psychopathology in 59 children with various intersex conditions and in 13% a gender identity disorder in XY patients with male pseudohermaphrodism (excluding those with complete androgen resistance raised as girls) (Slijper et al., 1998). Only one child underwent a sex transposition, but psychological distress was far more prevalent. W. Reiner, H. E L. Meyer-Bahlburg, and J. Gearhard, personal communications, 2000) studied a group of children with the rare condition cloacal extrophy, an anomaly that consists of defects in the lower abdominal wall, extrophy of the bladder and cloaca, and absent or severely malformed external genitalia structures in affected boys and girls. However, testis development occurs in affected XY boys and ovarian differentiation in the XX girls. Accordingly, the boys are exposed in utero to putatively normal amounts of fetal testicular testosterone. Of 14 genetic males assigned to female gender at birth or in infancy the majority apparently switched to male sex and declared their male gender identity between 6 and 18 years of age. This study reinforces the mounting evidence that male gender identity is associated with exposure of the fetus to normal male fetal amounts of testosterone prenatally. It emphasizes the importance of considering the long-term effects of prenatal androgen on gender identity in the sex assignment and management of XY newborns with ambiguous external genitalia. The sum of the studies of gender change at puberty in XY individuals strongly implies that prenatal androgen exposure and the ability to respond to it instills a tendency toward a male gender role. We can consider prenatal androgen exposure as having a powerful probablistic effect, but, in view of the complexity of genetic and environmental factors, not a deterministic role. This is of practical clinical significance in the assignment of gender to an XY newborn with ambiguous genitalia. A careful consideration of each case, mindful of the possible outcomes years after sex assignment is essential, with involvement of the parents and disclosure

76. Puberty in Boys and Girls

as fundamental and critical features in the decision (Reiner, 1997).

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