Jeremi M. Carswell
Diane E. J. Stafford
Accelerated growth, maturation of sexual characteristics, and the attainment of adult height and body proportions are the physical hallmarks of adolescence. Underlying these changes are the complicated activation and interplay of several hormonal axes that have been previously quiescent. The teenage years also involve significant developmental changes in the psychosocial area (see Chapter 2). This chapter provides an overview of the normal pubertal process and highlights the wide variation in the onset and duration of puberty in healthy adolescents and between male and female adolescents. Understanding these variations will provide the health care provider a framework for differentiating normal variations from abnormal pubertal development. The focus of Chapter 8 is abnormalities in growth and pubertal development.
The Major Endocrine Axes Affecting Growth and Development
Although there is activity and change in most hormonal systems during adolescence, there are three primary hormonal axes that influence the physical changes observed. These are the hypothalamic-pituitary-gonadal (HPG) axis, the hypothalamic-pituitary-adrenal (HPA) axis, and the growth hormone (GH) axis.
The HPG axis is responsible for the release of estradiol (E2) from the ovary and testosterone (T) from the testes and ultimately responsible for secondary sexual characteristics, menarche (onset of menses), and thelarche (onset of breast development). The initial signal originates from the hypothalamus in the form of gonadotropin-releasing hormone (GnRH) (also called luteinizing hormone–releasing hormone, or LHRH) from the so-called GnRH pulse generator, which signals the release of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating-hormone (FSH) from the pituitary gland. Although the exact pubertal triggers are incompletely understood, it is release of inhibition by the central nervous system (CNS) through neurotransmitters that allows the initiation of a positive feedback loop that characterizes pubertal maturation within this system. Figure 1.1 depicts this system diagrammatically, whereas Figure 1.2 illustrates how the CNS and gonadal steroids influence GnRH pulsatility.
FIGURE 1.1 The hypothalamic-pituitary-gonadal and the hypothalamic-pituitary-adrenal axes. CRH, corticotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle-stimulating-hormone.
Androgens secreted from the adrenal glands are under the control of the HPA axis and are independent of the changes occurring in the HPG axis. The two primary hormones are dehydroepiandrosterone (DHEA) and its sulfate ester, dehydroepiandrosterone-sulfate (DHEA-S), both produced in the zona reticularis of the adrenal gland. These hormones exert their effects by acting as precursors for the more potent androgens, testosterone and dihydrotestosterone, as DHEA and DHEA-S do not appear to activate the androgen
receptors themselves. The primary physical manifestations of the rise in adrenal hormones (adrenarche) are as follows:
FIGURE 1.2 Postulated influences of the central nervous system and gonadal steroids on gonadotropin-releasing hormone (GnRH) pulsatility and the changes with puberty. Interrupted arrows indicate inhibition. Note the action of both components during the prepubertal phase. CNS, central nervous system; LHRH, luteinizing hormone releasing hormone; MBH, medial basal hypothalamus; FSH, follicle-stimulating-hormone; LH, luteinizing hormone. (Copied with permission from: Grumbach MM, Styne DM. Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Larsen RM, Wilson JD, Foster DW, et al. eds. Williams textbook of endocrinology, 10th ed. Philadelphia: © 2003 WB Saunders, 2003:1161.)
Growth Hormone Axis
The key hormone influencing growth is GH. Pituitary secretion of this hormone is regulated by growth hormone–releasing hormone (GHRH) and somatostatin, as shown in Figure 1.3. GH secretion is increased by GHRH and decreased by somatostatin. GH is released in a pulsatile manner, with maximum rates at the onset of slow wave sleep. There is negative feedback of GH secretion through GH itself and the insulin-like growth factors (IGFs).
The effects of GH are primarily modulated through the IGFs. The two major types are IGF-I (formerly somatomedin-C) and IGF-II. As the term implies, these hormones have qualitative biological effects that are similar to those of insulin. The major mechanism for growth appears to be through stimulation of IGF-I by GH, which affects bone growth. Serum levels of IGF-I increase with age and pubertal development. However, levels vary widely from individual to individual.
At puberty, both sex steroids and GH participate in the pubertal growth spurt. This is best illustrated by the fact that children with isolated GH deficiency grow throughout puberty, but lack a definitive growth spurt. The cessation of the growth spurt is secondary to epiphyseal closure, due to the action of the sex steroids.
Endocrine Axes through the Life Span
In fetal life, GnRH, LH, FSH, estrogen, and testosterone (in the male) are detectable by a gestational age of 10 weeks, with hormone levels rising between 10 and 20 weeks. GnRH secretion is intermittent, causing pulsatile LH secretion. After the withdrawal of placental sex steroids, there is an initial fall in sex-steroid levels, but LH and FSH concentrations then rise to midpubertal levels for several months, exhibiting a pattern that is consistent with a mature differentiated hypothalamic-pituitary unit.
Both testosterone levels and estradiol levels also rise. This period has been referred to as “mini-puberty” and provides a window of opportunity to study the HPG axis to determine whether abnormalities exist that will affect future pubertal/sexual maturation. This period usually ends by age 9 months to 1 year in the male and by 2 years of age in the female, by when the levels of sex hormones have fallen to prepubertal levels in both boys and girls.
FIGURE 1.3 Simplified diagram of growth hormone–insulin-like growth factor I (GH-IGF-I) axis involving hypophysiotropic hormones controlling pituitary GH release, circulating GH-binding protein and its GH receptor source, IGF-I and its largely GH-dependent binding proteins, and cellular responsiveness to GH and IGF-I interacting with their specific receptors. FFA, free fatty acids; GHRH, growth hormone–releasing hormone. (From Rosenbloom AL, Guevara-Aguirre J, Rosenfield RG, et al. Trends in endocrinology and metabolism; vol 5. Growth in growth hormone insensitivity. New York: Elsevier Science, 1994:296, with permission.)
Growth during infancy is at a higher velocity than at any other time during the life span, with infants growing 25 cm/year on average. It is worth noting that much of the rapid growth seen during infancy is not GH dependent, but nutritionally driven via the effects of insulin. Therefore one cannot make predictions about final height based on an infant's growth curve.
During childhood, GnRH pulsatility and the HPG system is restrained, a likely result of tonic inhibition by the CNS from neurotransmitters acetylcholine, γ-aminobutyric acid (GABA), and others. During this quiescent phase, however, both the pituitary gland and the gonads are capable of mature function after appropriate stimulation. FSH concentrations are relatively higher than LH levels during this time, especially in girls (Apter et al., 1993; Goji, 1993; We et al., 1991), and stimulation of the axis will result in a characteristic FSH-dominant response.
Height velocity during childhood is relatively constant, falling rapidly after the first year of life before increasing during adolescence. On average, children grow 10 cm/year in the second year of life, followed by 8 cm/year and 7 cm/year in the third and fourth years of life, respectively. During the ages of 5 to 10 years, height velocity is at its lowest at 5 to 6 cm/year. It is also important to note that many boys experience a slowing in height velocity before the rapid acceleration seen in puberty. This may be a source of concern to many parents and preteens.
Maturation of the Hypothalamic-Pituitary-Gonadal Axis
The target tissues of LH and FSH are the ovaries and testes, which produce estradiol (E2) and testosterone (T), respectively. Leydig cells in the testes also produce, but to a much
lesser extent, androstenedione, dihydrotestosterone, and estradiol.
Estradiol (E2) from the ovary accounts for most of the circulating estrogens, although there is a small amount of extra-ovarian conversion from androstenedione and testosterone. In addition to stimulating breast growth and maturation of the vaginal mucosa, estrogen has been found to have a major impact on the skeleton, being the primary hormone responsible for epiphyseal closure.
Although the testes represent the primary source of this hormone, a small amount comes from extra-testicular conversion of the adrenal hormone androstenedione in both males and females. Testosterone is the primary hormone responsible for the voice change in males and the attainment of male body habitus, but it is dihydrotestosterone, the product of conversion of testosterone by 5α-reductase, which causes growth of the phallus and prostate.
Gonadotropin-Releasing Hormone Pulse Generator
At the time of puberty, GnRH is secreted from the GnRH pulse generator in the hypothalamus in a pulsatile manner, leading to the secretion of LH and FSH from the pituitary and subsequent secretion of estradiol (E2) from the ovaries or testosterone (T) from the testes. Although the exact triggers are poorly understood, there are three distinct changes that are observed in the hypothalamic-pituitary unit.
In addition, recent research has elucidated new potential regulators and key players in the awakening of this system.
GPR54, a G-protein–coupled receptor, and its ligand, derived from the KiSS-1 gene, have been recently implicated as regulators of puberty. This was first discovered by examination of a kindred with multiple members with delayed puberty from idiopathic hypogonadotropic hypogonadism, later found to have a mutation in the GPR54 gene (Seminara et al., 2003). Studies with GPR54 knockout mice confirmed a role for this receptor and its ligand in pubertal development (Seminara et al., 2003; Funes et al., 2003). KiSS-1 encodes the ligands for the GPR54 receptor called kisspeptins. Kisspeptins appear to stimulate LH through GnRH at the hypothalamic level. This stimulation is both dose- and time-dependent, with effects seen within 10 minutes of administration of minimal doses. Kisspeptins also stimulate FSH, but to a lesser degree (Navarro et al., 2005).
Neuroendocrine glial cells may influence neurons to produce LHRH in an autocrine/paracrine manner using prostaglandin E2 (PGE2) (Ojeda and Terasawa, 2002). Mice with a specific mutation in the glial receptors erbB-1 and erbB-4 have delayed sexual maturation and diminished reproductive capacity in early adulthood (Prevot et al., 2005).
Recent research has focused on the role of leptin, a product of the ob gene produced by fat cells, in pubertal development (Zhang et al., 1994). Leptin was discovered to play a key role in the regulation of appetite, food intake, and energy expenditure, providing a signal to the CNS regarding satiety and the amount of energy stored in adipose tissue (Pellymounter et al., 1995; Halaas et al., 1995; Campfield et al., 1995). Animal studies have shown that leptin is also implicated in the control of pubertal development and reproductive function. Mice lacking leptin are obese and infertile, and leptin replacement reverses their obesity and reproductive failure (Chehab et al., 1996).
Although leptin originally was thought to be produced only in white adipose tissue, it has also been shown to be expressed in the hypothalamus and pituitary, among other tissues. Leptin receptors have been found throughout the HPG axis. In vitro, it has been found to accelerate GnRH pulsatility and stimulate GnRH release. (Moschos et al., 2002). Leptin may also have direct stimulatory effects on LH release by gonadotrophs.
The link between adequate nutrition and the timing of puberty has long been recognized. The theory that leptin could be the initiator of puberty was attractive, as researchers had hypothesized that a critical body weight and fat mass were necessary for puberty (Frisch and Revelle, 1970; Frisch, 1984; Johnston et al., 1971). However, there has been an absence of a molecular mechanism to link activation of the HPG axis to adipose cell mass or function. Recent experimental evidence suggests that leptin may play a role in this respect.
There is a significant change in leptin levels during pubertal development and a distinct sexual dimorphism is exhibited. Serum leptin levels peak in boys just before or during early puberty, followed by a decrease to baseline as testosterone levels rise (Mantzoros et al., 1997; Blum et al., 1997; Clayton et al., 1997; Garcia-Mayor et al., 1997; Horlick et al., 2000). In girls, there is a steady rise in leptin levels throughout puberty (Fig. 1.4). The exact interplay between leptin and other hormones, and its effect on the release of the “brake” which results in activation of the HPG axis remains unclear and is an area of active research.
Gonadotropin Secretion in Adults
Pulsatile secretion of GnRH from the hypothalamus continues into adulthood. As is seen during puberty, the frequency and amplitude of the GnRH pulses are critical to the secretion of gonadotropins, as a minor change may inhibit secretion. The control of GnRH secretion is not well understood, but is likely under the influence of a variety of neurotransmitters such as catecholamines (dopamine and norepinephrine), serotonin, and endogenous opioid
peptides (endorphins and enkephalins). Sex steroids generally have a negative influence on the production of gonadotropins. This negative feedback may occur at the level of the hypothalamus or pituitary, or both. An estradiol level of approximately 200 pg/mL or greater generates positive feedback leading to a surge of gonadotropin secretion and ovulation in the mature female.
FIGURE 1.4 Standard Error of the Mean (SEM) leptin/Fat Mass (FM) in females and males. *, p < 0.05 compared with same-sex subjects at Tanner stage 1; +, p < 0.05 compared with girls at the same Tanner stage. (From Horlick MB, Rosenbaum M, Nicolson M, et al. Effect of puberty on the relationship between circulating leptin and body composition. J Clin Endocrinol Metab 2000;85:2509, with permission.)
Sexual Development in Puberty
What is commonly thought of as pubertal secondary sexual characteristics should be separated into gonadarche and adrenarche, arising from the HPG axis and the HPA axis, respectively. In girls, gonadarche is represented by thelarche (the onset of breast budding), and in boys it is represented by testicular enlargement to 4 mL and above, or 2.5 cm in the longest axis. Pubarche, or the growth of terminal sexual hair in girls, is mainly the result of adrenarche. In boys, both testicular and adrenal androgens contribute. Health care providers should feel comfortable in dealing with the multitude of questions that may arise from adolescents and their parents regarding not only sexual maturation but also the issues of arising sexuality.
Sexual Maturity Rating Scales
Sexual maturity rating (SMR) scales (also called Tanner staging) as developed by Marshall and Tanner (Marshall and Tanner, 1969; Marshall and Tanner, 1970) allows for accurate classification of physical pubertal maturation. For both boys and girls there are five stages categorizing secondary sexual characteristics (pubic hair and breast development in females and pubic hair and genitalia in males). These stages are described as follows and are shown both in photographs and drawings in Figures 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11.
FIGURE 1.5 Stages of breast development. (From Tanner JM. Growth at adolescence, 2nd ed. Springfield, IL: Blackwell Scientific Publications, 1962, with permission. Copyright © 1962 by Blackwell Scientific Publications.)
Males (testicular volumes as measured by a Prader Orchidometer)
Male and Female: Pubic hair
FIGURE 1.6 Stages of female pubic hair development. (Reproduced from Tanner JM. University of London, Institute of Child Health, with permission.)
FIGURE 1.7 Stages of male pubic hair development. (Reproduced from Tanner JM. University of London, Institute of Child Health, with permission.)
FIGURE 1.8 Stages of male genital development. (Reproduced from Tanner JM. University of London, Institute of Child Health, with permission.)
Importance of Sexual Maturity Ratings
SMRs should be recorded yearly, as this provides critical information in the identification of an abnormal pubertal progression and also reassurance to the health care provider and the teenager that puberty is progressing normally. The SMR is also critical in evaluating issues such as hematocrit (Fig. 1.12), alkaline phosphatase values (Table 1.1), and menarche (Fig.1.13).
Female Pubertal Changes
FIGURE 1.9 Female pubic hair development. Sexual maturity rating 1 (SMR 1): Prepubertal; no pubic hair. SMR 2: Straight hair is extending along the labia and, between ratings 2 and 3, begins on the pubis. SMR 3: Pubic hair has increased in quantity, is darker, and is present in the typical female triangle but in smaller quantity. SMR 4: Pubic hair has increased in quantity, is darker, and is more dense, curled, and adult in distribution but less abundant. SMR 5: Abundant, adult-type pattern; hair may extend onto the medial aspect of the thighs. (From Daniel WA, Palshock BZ. A physician's guide to sexual maturity rating. Patient Care 1979;30:122, with permission. Illustration by Paul Singh-Roy.)
FIGURE 1.10 Female breast development. Sexual maturity rating 1 (SMR 1), not shown: Prepubertal; elevations of papilla only. SMR 2: Breast buds appear; areola is slightly widened and projects as small mound. SMR 3: Enlargement of the entire breast with protrusion of the papilla or of the nipple. SMR 4: Enlargement of the breast and projection of areola and papilla as a secondary mound. SMR 5: Adult configuration of the breast with protrusion of the nipple; areola no longer projects separately from remainder of breast. (From Daniel WA, Paulshock BZ. A physician's guide to sexual maturity rating. Patient Care 1979;30:122, with permission. Illustration by Paul Singh-Roy.)
also influences age at menarche, although controversy exists whether there is a necessary amount of adipose mass needed at the time of menarche. For a large population, there appears to be a relationship between height and weight and menarche (Fig. 1.14). This relationship is less meaningful in evaluating a single adolescent.
FIGURE 1.11 Male genital and pubic hair development. Ratings for pubic hair and for genital development can differ in a typical boy at any given time, because pubic hair and genitalia do not necessarily develop at the same rate. Sexual maturity rating 1 (SMR 1): Prepubertal; no pubic hair. Genitalia unchanged from early childhood. SMR 2:Light, downy hair develops laterally and later becomes dark. Penis and testes may be slightly larger; scrotum becomes more textured. SMR 3: Pubic hair has extended across the pubis. Testes and scrotum are further enlarged; penis is larger, especially in length. SMR 4: More abundant pubic hair with curling. Genitalia resemble those of an adult; glans has become larger and broader, scrotum is darker. SMR 5: Adult quantity and pattern of pubic hair, with hair present along the inner borders of the thighs. The testes and the scrotum are adult in size. (From Daniel WA, Paulshock BZ. A physician's guide to sexual maturity rating. Patient Care 1979;30:122, with permission. Illustration by Paul Singh-Roy.)
Earlier menarche is usually correlated with shorter adult height, although this depends upon the degree of estrogen stimulation before menses. Girls with higher or prolonged estrogen levels tend to grow less after menarche. On an average, girls grow 4 to 6 cm after menarche. The sequence of pubertal events in females is found in Figures 1.13 and1.15B. The age at menarche has gradually decreased during the last century, as illustrated in Figure 1.16. However, this trend has slowed significantly in the past few decades.
Several investigators have examined data from the Third National Health and Nutrition Examination Survey (NHANES III) conducted from 1988 to 1994 (Wu et al., 2002; Sun et al., 2003; Chumlea et al., 2003; Anderson et al., 2003). One study (Anderson et al.) compared data from an earlier U.S. survey 25 years previous to the NHANES III data and found that the average age at menarche had declined only minimally (i.e., by approximately 2.5 months, from 12.8 years to 12.5 years). Another study cited up to a 4-month decrease in age at menarche (Chumlea et al., 2003). All studies that have examined the race have demonstrated that African-American girls reach menarche the earliest, followed by Mexican-American and white girls.
Male Pubertal Changes
throughout and beyond puberty into adulthood, the amount and distribution being quite variable and dependent on ethnicity and family patterns. The average length of time for completion of puberty is 3 years, but it can range from 2 to 5 years. The sequence of events for an average male is shown in the following text in Figures 1.17 and 1.15B. Table 1.3lists male genital size by age and Table 1.4 lists testicular volume by SMR.
FIGURE 1.12 Hematocrit values for African-American and white boys (A) and girls (B) during puberty. (From Daniel WA. Hematocrit: maturity relationship in adolescence.Pediatrics 1973;52:388, with permission.)
FIGURE 1.13 Biological maturity in girls. (From Tanner JM. Growth at adolescence, 2nd ed. Springfield, IL: Blackwell Scientific Publications, 1962, with permission. Copyright © 1962 by Blackwell Scientific Publications.)
In both sexes, consequences of earlier maturation with regard to teen behavior, sexual activity, and pregnancy need to be addressed with age-appropriate interventions during middle childhood and the preteen years. In addition, the lifetime health consequences of early sexual maturation merit further study.
The increased secretion of androgens from the adrenal gland, called adrenarche, in the prepubertal and pubertal periods is independent of HPG changes. The two events are temporally related, with the increase in adrenal hormones preceding that of the gonadal sex steroids (Ducharme et al., 1976), although the effects are evident later. It is important to note, however, that adrenal androgens are not necessary for pubertal development or the adolescent growth spurt. It is widely believed that adrenarche begins in midchildhood, at around the age of 6 years (de Peretti and Forest, 1976),
and levels continue to rise until the age of 20 to 30 years. Recent evidence, however, has suggested that the rise of DHEA-S is a more gradual process and occurs as early as the preschool years (Palmert et al., 2001; Remer and Manz, 1999; Remer et al., 2005).
FIGURE 1.14 The weight for height at which menarche is likely to occur (solid line) and the weight for height at which regular ovulatory menstrual periods are likely to be maintained (dashed line). (From Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset.Science 1974;185:949, with permission. Copyright 1974 by American Association for the Advancement of Science.)
Local conversion of DHEA-S to testosterone, then to dihydrotestosterone is responsible for hair growth in the androgen-dependent areas (face, chest, pubic area, axilla). Axillary and pubic areas are most sensitive to the effects of androgens, which is why these areas are the first to develop sexual hair. In addition, local conversion of DHEA-S within the apocrine glands of the axillae causes body odor, and conversion within sebaceous glands is responsible for the development of acne.
Physical Growth During Puberty
One of the most striking changes in adolescents is their rapid growth velocity. This height spurt is dependent primarily upon GH and the insulin-like growth factors, but many other hormones may influence growth as well, especially the sex steroids. Premature or delayed puberty without prompt recognition and treatment may have marked effects on height.
Growth Hormone during Puberty
Most linear growth is dependent upon GH and its feedback loop, shown graphically in Figure 1.3. As shown, GH secretion is increased by GHRH, and decreased by somatostatin from the hypothalamic arm of the loop. GH concentrations have been shown to double during the pubertal growth spurt. As with many hormones, GH
is secreted in a pulsatile manner, with maximum rates at the onset of slow-wave sleep. It has been shown that the increased available GH is due to higher pulse amplitude and amount per pulse, as opposed to increased frequency or decreased clearance (Martha et al., 1989; Martha et al., 1992). It is this pulsatile secretion which renders random GH testing unhelpful. GH exerts its effects through insulin-like growth factors, or IGFs, mainly IGF-I (or somatomedin-C) and IGF-II. Serum IGF-I levels increase slowly and steadily during the prepubertal years, rise more steeply during puberty (Juul et al., 1994), and remain elevated 1 to 2 years past the pubertal growth spurt. IGF levels among males and females must be interpreted with regard to pubertal stage and age.
FIGURE 1.15 A: Sequence of pubertal events in males. B: Sequence of pubertal events in females. PHV, peak height velocity. (From Root AW. Endocrinology of puberty. J Pediatr 1973;83:1, with permission.)
FIGURE 1.16 Secular trend in age at menarche. (From Tanner JM. Fetus into man. Cambridge, MA: Harvard University Press, 1978, with permission. Copyright 1978 by Harvard University Press, Cambridge, MA.)
FIGURE 1.17 Biological maturity in boys. (From Tanner JM. Growth at adolescence, 2nd ed. Springfield, IL: Blackwell Scientific Publications, 1962, with permission. Copyright © 1962 by Blackwell Scientific Publications.)
Height velocity during the pubertal growth spurt is at its highest levels outside of infancy (Fig. 1.18). It should be noted that when calculating height velocity, it is important to use an interval of 6 to 12 months, as height growth is greatest during the spring and summer months. Although males and females are roughly the same height upon entry into puberty, males emerge taller by 13 cm on average. This is primarily due to the boys' 2-year lag behind girls in
attainment of their peak height velocity, but a small amount of height may be accounted for by the higher peak velocity (Figs. 1.17 and 1.18). Girls gain their peak height velocity of 8.3 cm/year at an average age of 11.5 years and at Tanner stages B2 to B3 whereas boys do not have their peak height velocity of 9.5 cm/year until the age of 13.5 years, at Tanner genital stages 3 to 4. Although there is great inter-individual variation for height, one trend is for the peak height velocity to be higher, but not more sustained, in those who mature early. Therefore, there may not be a difference in final height. There are also curves available for early and late maturers (Figs. 1.19 and 1.20).
FIGURE 1.18 Typical individual velocity curves for height in boys and girls: height-attained growth curve (top) and growth velocity curve for height (bottom). (From Hill DE, Fiser RH. Chronic disease and short stature. Postgrad Med 1977;62:103, with permission.)
Prediction of Final Height
Predicting final height is a difficult task, and it should be emphasized that the methods available provide a general estimate. One method of predicting a general range for adult height is by the average of parental heights, accounting for the height difference of 13 cm (or 5 inches) between men and women. This is referred to as the midparental target height. One standard deviation from midparental height is 2 inches. As a result, 4 inches around the midparental height is within two standard deviations of the mean. For girls:
The Bayley-Pinneau method uses the bone age to predict final height. This is based on attainment of a bone age, or x-ray of the left hand and wrist that is then matched to standards. Because sex steroids are known to cause bony maturation and epiphyseal fusion, this method is based on the percentage of final height as assessed by bony maturation. In addition, various computer models have used these data to predict adult height. With these programs, basic information (e.g., height, weight, skeletal age) is entered, and the program calculates adult height using several methodologies, including that of Bayley and Pinneau. See Table 1.5 for calculations of estimated final predicted height with this method.
The Role of Sex Steroids
Gonadal steroids contribute to the growth spurt by inducing an increase in GH secretion and by stimulating local production of IGF-I in cartilage and bone directly (Grumbach, 2000;Attie et al., 1990; Van Wyk and Smith, 1999; Rogol, 1994).
Estrogen is the hormone that is most involved with the growth spurt through its effects on bone and cartilage, in both men and women. Estradiol concentration correlates with the pubertal growth spurt; girls have an estradiol increase, and the corresponding peak height velocity is earlier than boys. Boys' peak estradiol levels also correlate with peak height velocity (Klein et al., 1996). At higher doses, estrogen causes epiphyseal fusion and thereby termination of linear growth. The importance of this hormone in men was underscored by three different case studies: one sexually mature male who had a mutation in the estrogen receptor (Smith et al., 1994), and two cases of men with mutations in CYP19 gene that encodes aromatase,
which converts testosterone to estrogen (Morishima et al., 1995; Morishima et al., 1997; Carani et al., 1997). All had tall stature, eunuchoid proportions, osteopenia, and unfused epiphyses. Treatment with estrogen in the men with aromatase deficiency caused epiphyseal closure and an increase in bone mineralization within 6 to 9 months (Bilezikian et al., 1998). The mechanisms by which this end result is accomplished are manifold, but primarily, estrogen stimulates chondrogenesis in the epiphyseal growth plate, which acts to increase linear growth (Weise et al., 2001).
FIGURE 1.19 Height attained for American girls. (From Tanner JM, Davies PW. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;107:317, with permission.)
Androgens seem to have little direct effects on pubertal bone growth, as evidenced by the case studies presented in the preceding text, although androgen receptors can be found on developing and mature osteoblasts (Colvard et al., 1989). It is clear that androgens have a role in the sexual dimorphism of the skeleton (Orwoll, 1996; Bellido et al., 1995; Kasperk et al., 1997; Vanderschueren, 1996; Hofbauer and Khosla, 1999) and are likely responsible for the greater increase in periosteal bone deposition and bone strength in men compared with women (Schoenau et al., 2001). As an example, patients with complete androgen insensitivity syndrome (CAIS) who are karyotype 46XY females have a normal growth spurt and a bone density comparable to normal XX women (Munoz-Torres et al, 1995).
FIGURE 1.20 Height attained for American boys. (From Tanner JM, Davies PW. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;107:317, with permission.)
Pubertal Changes in Body Composition
During childhood, boys and girls have relatively equal proportions of lean body mass, skeletal mass, and body fat. By the end of puberty, however, men have 1.5 times more lean body mass and skeletal mass than women, and women have double the fat mass. Table 1.6 shows the effects of GH and the sex steroids on different aspects of body composition. The skeleton also undergoes epiphyseal maturation under the influence of estradiol (E2) and testosterone (T), as reviewed in the preceding text.
Lean Body Mass
The lean body mass decreases from approximately 80% of body weight in early puberty to approximately 75% at maturity. The lean body mass increases in total amount, but decreases in percentage because adipose mass increases at a greater rate.
The lean body mass increases from 80% to 85% to approximately 90% at maturity. This primarily reflects increased muscle mass from circulating androgens.
The percentage of body fat increases in females during puberty and decreases in adolescent males. Changes in body composition stem from hormonal fluctuations that are part of normal adolescence (Table 1.7).
FIGURE 1.21 Weight-for-age percentiles for girls, 2 to 20 years of age. (From CDC. Growth charts: United States—advance data. From vital and health statistics of the Centers for Disease Control and Prevention. Natl Center Health Stat 2000;314:1.)
Pelvic Remodeling in Women
During puberty, the female pelvis widens more rapidly than it increases in the anteroposterior dimension. The forepart of the pelvis also widens and becomes more rounded.
Changes in bone mass, or bone mineral density (BMD), parallel the alterations in lean body mass, body size, and muscle strength. Major determinants of BMD are physical activity level, heredity, nutrition, endocrine function, and other lifestyle factors. The accretion of skeletal bone mass during puberty is critical. Peak bone mass is acquired by early adulthood, serving as the “bone bank” for the remainder of life (Bachrach, 2000). Skeletal bone mass has been affected by the following:
there is a consensus that adequate consumption of both of these nutrients is important for optimal bone mineral accrual. For example, one Swiss study found that supplementing healthy breast-fed infants with vitamin D resulted in higher bone mass later in childhood among girls (Zamora et al., 1999). Several studies have documented that increased calcium intake during childhood and adolescence results in higher peak bone mass (Matkovic et al., 1990; Johnston et al., 1992; Lloyd et al., 1993; Lee et al., 1994; Lee et al., 1995; Lloyd et al., 1996; Bonjour et al., 1997; Nowson et al., 1997; Dibba et al., 2000). A recent study followed a cohort of 144 girls randomized during the prepubertal years to receive either calcium supplementation of 850 g/day or placebo for 1 year (Chevalley et al., 2005). Postmenarchal follow-up showed that even this relatively brief intervention resulted in sustained increases in bone density in those girls who had earlier than average menarche, raising the question of whether higher calcium intake prepubertally may advance menarche. It appears that calcium intakes of between 1,200 and 1,800 mg/day result in maximal calcium absorption for children between age 9 and 18 years (Baker et al., 1999; Abrams and Stuff, 1994; Jackman et al., 1997; Matkovic and Heaney, 1992; Andon et al., 1994; NIH Concensus Conference, 1994; Institute of Medicine, Food and Nutrition Board, 1997).
FIGURE 1.22 Stature-for-age percentiles for girls, 2 to 20 years of age. (From CDC. Growth charts: United States—advance DATA. From vital and health statistics of the Centers for Disease Control and Prevention. Natl Center Health Stat 2000;314:1.)
strength, but results have been less promising regarding the effects of exercise on postmenarcheal girls (for review see MacKelvie et al., 2002). In one study, a jumping program integrated into gym class resulted in greater femoral cross-sectional area, reduced endosteal expansion, and greater bending strength in both prepubertal and early pubertal (Tanner stages 2 and 3) girls compared with controls (MacKelvie et al., 2001).
FIGURE 1.23 Weight-for-age percentiles for boys, 2 to 20 years of age. (From CDC. Growth charts: United States—advance data. From vital and health statistics of the Centers for Disease Control and Prevention. Natl Center Health Stat 2000;314:1.)
Skeletal maturation, as reflected by bone age measurements, can be determined by comparing a radiograph of an adolescent's hand, wrist, or knee to standards of maturation in a normal population. Bone age is an index of physiological maturation, providing an idea of the proportion of the total growth that has occurred. For example, if an adolescent is 15 years old and has a bone age of 12 years, there will be more potential growth than if the same adolescent's bone age were 15 years. The use of skeletal age is discussed further inChapter 8.
The growth of the brain, heart, liver, and kidneys during puberty is less than that of muscle and bone. Therefore, the percentage of body weight represented by the brain, heart, liver, and kidney decreases from approximately 10% to approximately 5% at maturity.
FIGURE 1.24 Stature-for-age percentiles for boys, 2 to 20 years of age. (From CDC. Growth charts: United States—advance data. From vital and health statistics of the Centers for Disease Control and Prevention. Natl Center Health Stat 2000;314:1.)
Body Mass Index
Body mass index (BMI) increases with puberty, although it should be pointed out that BMI does not quantitate body composition. BMI varies with age, gender, and ethnicity. In children and adolescents, BMI must be compared using age-stratified standardized percentiles. Charts and tables for BMI, which should be tracked in all children and teenagers, can be obtained from the National Center for Chronic Disease Prevention and Health Promotion of the CDC (mailing and Web site addresses were listed previously in the section on Weight Growth). See Figures 1.25 and 1.26 to determine the normal BMI for a given age. There is a strong correlation between the timing of puberty and BMI: children with higher mean BMI mature earlier. BMI is determined by the following formula:
The equivalent formula in English units is the following:
The BMI declines from birth and reaches a minimum between 4 and 6 years of age, before gradually increasing through adolescence and adulthood. The upward trend after the lowest point is referred to as the “adiposity rebound.” Children with an earlier rebound are more likely to have an increased BMI.
FIGURE 1.25 Body mass index-for-age percentiles for boys, 2 to 20 years of age. (From CDC. Growth charts: United States—advance data. From vital and health statistics of the Centers for Disease Control and Prevention. Natl Center Health Stat 2000;314:1.)
Concern About Growth and Development
This chapter has discussed most of the features of normal adolescent growth and development. As essential as it is for the health care provider to have a firm grasp of the facts of normal growth and development, a clear understanding and feeling for what these changes mean to the adolescent are also critically important. As their bodies change, adolescents develop tremendous concern about whether their bodies are “normal.” The great variation in the timing of puberty, with resultant differences in physical maturity of similar-aged adolescents, serves to heighten teenagers' worries. Practitioners must be adept at detecting the adolescent's concerns about height, weight, pubic hair growth, or phallus size, for example, even if these concerns are not stated overtly in the initial complaint.
The changes of puberty are a marvel of nature and a testimony to the intricacies and wonders of the human hormonal system. The health care provider must understand these changes and the wide variations of normalcy. He or she must also be able to sense the profound effect these changes have on the adolescent and be prepared to be a source of information, reassurance, and help if abnormalities are detected.
FIGURE 1.26 Body mass index-for-age percentiles for girls, 2 to 20 years of age. (From CDC. Growth charts: United States—advance data. From vital and health statistics of the Centers for Disease Control and Prevention. Natl Center Health Stat 2000;314:1.)
For Teenagers and Parents
http://www.teenwire.com/. What happens during puberty for guys and girls, from Teen Wire.
http://www.youngwomenshealth.org. From Young Women's Health Center at Boston Children's Hospital.
http://www.puberty101.com/. Information site on puberty and other adolescent questions.
http://www.iwannaknow.org/puberty/. Information on puberty from American Social Health Association.
http://www.aap.org/healthtopics/stages.cfm#adol. The American Academy of Pediatrics web site with different nd rotating issues related to teen health.
http://www.plannedparenthood.org/pp2/portal/medicalinfo/teensexualhealth/pub-period.xlm. Information from Planned Parenthood for girls on puberty and menstruation.
http://www.keepkidshealthy.com/adolescent/puberty.html. Teen health site, puberty section.
For Health Professionals
http://www.teachingteens.com/index2.htm. Health education site on teaching teens about puberty.
http://www.cdc.gov/growthcharts. Growth charts on-line.
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