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Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Department of Pediatrics (J.N.R.), State University of New York at Buffalo, Buffalo, New York 14214-3000; Departments of Pediatrics and Internal Medicine (E.J.R., A.D.R.), General Clinical Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22903; Pennington Biomedical Research Center (J.C.L.), Baton Rouge, Louisiana 70808; Division of Endocrinology (M.S.-M.), Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Department of Pediatrics (N.M.), Nemours Children’s Clinic, Jacksonville, Florida 32207; and Division of Endocrinology and Metabolism (C.Y.B.), Department of Internal Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112
Correspondence: Address all correspondence and requests for reprints to: Johannes D. Veldhuis, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu
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 Top Abstract I. Timing and Tempo...II. Measurement of Body...III. Sex-Steroid and GH...IV. Energy Expenditure in...V. SummaryReferences |
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I. Timing and Tempo of Normal Human Growth |
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TopAbstractI. Timing and Tempo...II. Measurement of Body...III. Sex-Steroid and GH...IV. Energy Expenditure in...V. SummaryReferences |
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Although normative isobars are widely used for comparisons of static height, the endocrinologist and pediatrician should also evaluate the velocity of linear growth velocity (annual increment in height), chronological and apparent biological age, pubertal status, family history, and psychosocial adjustment. From a clinical perspective, biological age is often assessed indirectly as radiographic bone age.
The velocity of in utero linear growth is maximal at about 18 wk of gestational age in the human. At this time, the fetus grows four times more rapidly than at any time postnatally. Increases in body weight follow a similar temporal pattern, except that the zenith occurs at about 34 wk. The growth rate declines sharply during the last weeks of gestation. The maternal-placental environment dictates the infant’s birth weight more than the fetal genotype (1). In the newborn, height velocity adjusts toward the genetically predicted trajectory. Linear growth averages approximately 25 cm in the first year and 12.5 cm in the second year of life (see Refs.2 and 3 for distributional estimates). The annual height velocity decreases to 8 cm (ages 2–4 yr) and 6 cm (ages 4–6 yr) during childhood. A plateau-like phase emerges in midchildhood, wherein height velocity approaches 5.5 cm/yr before puberty. Especially in the male, there is an incompletely understood decline in height velocity before onset of the pubertal growth spurt.
1. Sex differences in the fetal period.
Unborn humans exhibit two gender-related auxological distinctions: 1) males exhibit more rapid linear growth than females early in utero; and 2) girls manifest greater skeletal maturation than boys after 15 wk of gestational development. For example, the crown-rump length in boys exceeds that in girls by 1.0 mm at 8 wk and by 2.6 mm at 14 wk gestation (4). Ultrasonographic records of fetal head circumference show an analogous gender difference early in development. At term, the foregoing sex-related distinctions approach 2% of the population mean. Conversely, skeletal maturation (e.g., defined by radiological bone age) proceeds more rapidly in the female than male fetus, which disparity yields a bone age advance of 1.5 wk in girls by the early third trimester of pregnancy (5). Weight diverges in the sexes at approximately 24 wk of gestational age, such that boys weigh 70 g more than girls at 30–32 wk of in utero life. The absolute male-female weight difference approximates 130 g (4% of the mean) at birth.
2. Sex differences in the postnatal period.
Figure 1
presents population-based projections of linear growth velocity by gender in North American children. Healthy cohorts are heterogeneous in genetic background, biological development, nutrition, exercise, and psychosocial adaptation. Accordingly, in an effort to incorporate expected genetic nonuniformity in height trajectories, normative data include observations in children destined to become relatively tall or short as adults.
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Girls attain a peak height velocity of 8.3 cm/yr at an average chronological age of 11.5 yr. This growth milestone corresponds to pubertal Tanner breast stages 2 and 3. Boys gain height at a prepubertal rate until age 11 (instead of 9), when testis volume begins to increase beyond 7–10 ml. Adolescent males then achieve a peak height velocity of 9.5 cm/yr at about 13.5 yr of age. The latter chronology coincides with pubertal genital stages 3 and 4. Maximal height velocity, but not total duration of linear growth, tends to be greater in youths who mature early. In both sexes, the pubertal growth rate declines rapidly after the gender-specific zenith; e.g., girls gain 1 cm/yr or less in height after age 14.5 yr, and boys gain 1 cm/yr or less after age 17 yr. The net pubertal increment in stature in the male exceeds that in the female by 3–5 cm in Western cultures. Accordingly, the mean adult height difference of 13 cm between the sexes primarily reflects the gain of an additional 8–11 cm during a more prolonged prepubertal interval (
2 additional years) in boys.
3. Interindividual auxological variations.
Height isobar projections (static distance curves) are shown for both sexes in Figure 2. Such population-defined data belie significant nonuniformities among individual children in the timing (onset) and tempo (rate) of sexual maturation and attendant physical development. Known genetic and environmental factors predispose to pubertal pathophysiology (6, 7, 8, 9, 10, 11, 12). However, precisely how heredity and environment control normal variations in physical maturation in healthy individuals is less well understood (13). Mechanistic considerations include mutations or microsequence polymorphisms of genes encoding (at least) the LH ß-subunit, the aromatase enzyme, and the GH, LH, leptin, glucocorticoid, estrogen, and androgen receptors (14, 15, 16, 17, 18, 19). Additional studies will be important to elucidate the impact of molecular diversity on physical, sexual, and psychological phenotypes.
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Normative weight trajectories are illustrated in Figure 3. Newborns lose approximately 10% of birth weight over the first 7–10 d of life. The exact adaptive processes that mediate evident extracellular fluid loss and inferred tissue catabolism at this time have not been articulated fully, but presumptively entail combined nutritional and endocrine factors. Healthy neonates overcome the expected weight deficit within several weeks, and then gain approximately 30 g/d during the first 3 months of life. The latter mean increment declines to 20, 15, and 12 g/d over successive quarterly intervals until age 1 yr.
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B. Body composition in childhood and puberty
Extended, prospective, ethnicity-specific, and population-based normative body composition data stratified by gender in childhood are lacking. However, important (albeit longitudinally delimited and/or cross-sectional) observations are available in the fetus, neonate, child, and adolescent (22, 23, 24, 25, 26, 27, 28). Comprehensive body-compositional investigations will require the use of validated quantitative procedures, minimal (if any) radiation exposure, high procedural reproducibility, and repeated application in randomly selected cohorts of healthy children.
Accurate estimates of and (population-based) statistical boundaries for fat mass (FM) are crucial to classify children accurately as lean, normal, overweight, or obese. Analogously, reliable quantitation of fat-free mass (FFM) is important to identify relative or absolute sarcopenia and osteopenia. Valid measures of regional adiposity (e.g., sc and visceral fat) are essential to elucidate the pathophysiological basis and clinical impact of hyposomatotropism, insulin resistance, dyslipidemia, obesity, and cardiovascular morbidity (see Section II.A).
1. FM and FFM accrual.
Projections of the gender-specific evolution of FM, FFM, and percentage body fat in Caucasian children are given in Fig. 4. These predictions aggregate the results of accurate multicompartmental analyses performed cross-sectionally at selected stages in infancy, childhood, puberty, and early adulthood (22, 29, 30). Interpolations are required to supplement incomplete body-compositional data in midchildhood and early adolescence. Although ethnic comparisons are limited, one pediatric investigation compared FM and FFM estimates among African-, European-, and Mexican-American children at or over the age of 4 yr (31) (Fig. 5). This analysis like several recent other studies reported a higher mean FM value than that typically observed earlier in children (32). Whether the latter (possible) increase in absolute FM reflects de facto historical trends, population selection, and/or technical differences is not clear.
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13%), compared with the female (15%), and the male’s higher birth weight. FM increases to 25–30% of total body weight by age 6 months. Thereafter, FFM begins to accumulate preferentially. For example, 85% of the total weight gain over the second 6 months of life comprises FFM. Although fractional FFM remains comparable by gender across midchildhood, boys accrue about 1 kg more absolute FFM than girls before puberty (22, 29, 30). In puberty, boys acquire FFM at a greater rate (kilograms per year) and for a longer period than girls. In one analysis, stable (adult) values of FFM were attained by approximately 15–16 yr of age in girls and 2–3 yr later in boys (35). In absolute terms, FM (kilograms) is comparable by sex in children ages 3–5 yr. Girls accumulate FM more rapidly than boys in midchildhood, such that 10-yr-old females have approximately 2 kg (6%) more FM than males. In adolescence, girls gain absolute FM at an average annual rate of 1.14 kg, whereas boys maintain a relatively fixed absolute FM. Hence, percentage body fat declines in pubertal boys (27).
2. Water, protein, and mineral accrual.
Primary components of FFM (water, protein, and mineral) vary markedly in infancy and adapt further in childhood and adolescence (Fig. 6). The percentage of total body water (TBW) normalized to FFM (TBW/FFM) exceeds 80% at birth. The latter value decreases by 1% over the first year of life. TBW/FFM falls to 77% in boys and 78% in girls in early childhood and to 76% by age 10 in both sexes (22, 25, 29).
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Mineral comprises primarily (82%) bone salts. The mineral fraction in FFM remains stable in infancy and early childhood, and then rises disproportionately (over protein and water) in midchildhood and early puberty (22, 25, 29). Bone mineral density (BMD) determined at near-peak height velocity is greater in boys than girls (25, 29, 30). BMD is higher in African-American than Caucasian individuals before and after puberty in both sexes (36, 37). The precise endocrine determinants of this consistent ethnic difference are not known. Nonendocrine genetic and environmental factors may contribute to some differences. One analysis revealed higher (overnight) serum concentrations of GH and estradiol in African-American than Caucasian men, which levels correlated positively with BMD (36). No comparable distinction was evident before puberty or in women (37). Other clinical studies have reported ethnic contrasts in plasma IGF-I/IGF binding protein (IGFBP) concentrations in the female (37, 38, 39). The foregoing epidemiological observations highlight the need to better understand the specific mechanisms by which ethnicity, gender, and developmental age modulate the endocrine control of human growth and body composition (40).
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II. Measurement of Body Composition |
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TopAbstractI. Timing and Tempo...II. Measurement of Body...III. Sex-Steroid and GH...IV. Energy Expenditure in...V. SummaryReferences |
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Primary estimates of body composition were derived by chemical analyses of adult cadaveric tissues (27, 31). Such data, albeit limited, provide validation for secondary estimates based on densitometry (e.g., underwater weighing), dual-energy x-ray absorptiometry (DEXA), isotope dilution, bioelectrical impedance, BMI, and skinfold thickness (22, 24, 26, 27, 29, 31, 46, 47, 51, 52).
A. Body mass index
Height (meters) and weight (kilograms) are simple anthropological attributes. Algebraic combinations of these two measures are used to compute the BMI (kilograms per square meter), ponderal index (kilograms per cubic meter) or Benn index (kilograms per meter) (53). BMI has been applied to categorize children as lean, normal, overweight, or obese (54, 55). However, this metric varies with developmental age, gender, and ethnicity (27, 55, 56, 57, 58). For example, BMI is high in the first year of life, decreases in early childhood (ages 2–5 yr), and then increases in puberty (54, 59). Accordingly, BMI should be compared via age-stratified standardized z-scores (or percentiles) defined in healthy populations, e.g., as reported in North America, Holland, United Kingdom, France, and China (60, 61, 62, 63).
BMI does not quantitate body composition. Indeed, this metric amalgamates frame size (mineral content), total FM (visceral and sc) and lean tissue (27, 28, 30, 52, 64). Thus, a short, muscular adolescent could be assigned a high BMI spuriously suggestive of obesity (47, 59). Moreover, treatment with recombinant human (rh) GH often reduces FM by 2–3 kg and increases lean body mass comparably in the hypopituitary adult, while leaving BMI unchanged (65).
Indices like BMI also do not monitor the regional fat distribution (e.g., visceral vs. sc) (57, 66, 67, 68). This distinction is significant epidemiologically, because visceral fat accumulation predicts higher risk of peripheral insulin resistance, dyslipidemia, adult cardiovascular disease, hypoandrogenemia, elevated free (salivary) cortisol, reduced concentrations of SHBG, IGFBP-1, LH, and high-density lipoprotein, and impoverished daily GH production (22, 26, 28, 69, 70, 71, 72, 73, 74, 75, 76). Recent investigations suggest that deficiency of intrauterine growth factors, degree of fetal stress, low birth weight, relative hypercortisolemia, impaired glucose disposal in midchildhood, and premature adrenarche further forecast greater risk of insulin resistance, cardiovascular disease, dyslipidemia, and abdominal obesity in adulthood (39, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86).
B. Two-compartment models
1. Densitometry.
Densitometric methods partition body composition into two mutually exclusive compartments, viz., FM and FFM. Calculations relate whole-body density (weight divided by volume) to FM and FFM by way of average tissue-density constants (24, 87). To estimate whole-body density, weight is quantitated accurately on a dry scale, and volume is estimated by underwater weighing, clinical volumetry, or air plethysmography (26).
Water-displacement procedures are based on the principle of Archimedes, and thus require: 1) complete submersion of the volunteer in a suitable water-filled chamber to record underwater weight (hydrodensitometry) or quantitate water overflow into a burrette (clinical volumetry); and 2) accurate measurement of functional residual lung capacity by nitrogen washout to correct for the thoracic gas space. The latter determination introduces the majority of technical variability into the final estimate of percentage body fat. Within-subject coefficients of variation are approximately 3–4% of total body weight (26, 88). Limitations of hydrodensitometry include the requirement for a water tank, variable subject reluctance, and multiple (up to 10) submersions to ensure technical reproducibility.
Air-displacement plethysmography provides a complementary volumetric approach based on Boyle’s law of the partial pressure of gases. This procedure may be less stressful to the subject than repeated immersion in a water chamber (89, 90). One plethysmographic unit comprises a sealed fiberglass capsule (or pod). The volunteer enters the chamber wearing a tightly fitting swimsuit and swim cap, views the room through a small window, and breathes quietly for several minutes while an internal diaphragm is oscillated to generate small changes in air pressure. The air-displacement estimate is also corrected for thoracic gas volume (above). Cross-validating analyses indicate that air- and water-displacement methods perform comparably in young adults. However, air plethysmography may underestimate percentage body fat by 2–7% of total body weight (2–6 kg absolute FM) in children and older individuals (45, 52, 89, 90, 91).
In densitometric techniques, one calculates percentage body fat from the density estimate using an empirical regression model, such as that of Brozek et al. (51) or Siri (92). Both sets of equations assume a nominal adult tissue density of 0.9 g/ml for fat and 1.1 g/ml for FFM (24, 31). However, the use of adult tissue-density constants forces an overestimate of percentage body fat in children (Fig. 7). This artifact arises because the true density of FFM is as low as 1.063 g/ml in early childhood, whereas the contribution of water (density, 0.9937 g/ml) and mineral (density, 3.0 g/ml) to body density is higher and lower, respectively (27, 30). Accordingly, Lohman and colleagues suggest the use of age-specific tissue-density constants in the Siri model (24, 27). This adjustment obviates systematic overestimation bias in younger subjects. However, compared with multicompartmental methods (below), densitometry may yield inconsistent individual predictions (random procedural bias) (30).
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C. Four-compartment models
Multicompartmental models are used to quantitate FM and the principal components of FFM (water, mineral, and protein) (29, 30, 59, 93, 94, 95, 96, 97, 98, 99). For example, one method determines TBW by isotope dilution (above) and quantitates FM and mineral mass by DEXA. Some compartmental models include the determination of body cell mass (e.g., appraised by nonradioactive potassium spectrometry) or total body nitrogen and calcium (e.g., assessed by whole-body neutron activation analysis) (100, 101, 102, 103, 104, 105).
D. Two- and three-compartment models
Two-compartment analyses of body composition use several means to evaluate the components of FFM (26, 46). In the water-density model, TBW is quantitated first to calculate FM (total weight minus TBW). Protein and mineral content of FFM are estimated secondly from age- and gender-specific prediction equations. In the mineral-density model, bone mineral content is determined so as to compute summed water and protein (mineral-free lean tissue) and FM (29). The water-density model performs more reliably in pediatric age groups, because water represents 73–80% (and mineral only 5%) of FFM in children (30). The mean bias of the water-density calculation of FM is approximately 0.75% when calibrated against four-compartment methods. On the other hand, the mineral-density model may overestimate percentage body fat by as much as 5–7.5% in individual children and adolescents (Fig. 8).
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DEXA precision is higher when applied to calibration phantoms than to the human skeleton or the whole body (96, 106). In adults, the reproducibility of DEXA-based quantitation of BMD averages 0.7% or 0.01 g/cm2; and, the absolute error in percentage body fat approaches ± 1.4% of body weight. The latter precision compares well with a value of ±1% in predicting absolute FM by four-compartment models (96, 107). In adults, estimates of percentage body fat based on DEXA usually fall within 3% of those determined by more complex models. Discrepancies typically reflect technical uncertainty in the DEXA calculation of body weight (which should agree with the scale weight within 1 kg) and/or errors in the isotopic determination of TBW.
DEXA scanning tends to predict falsely high percentage body fat in children (and older adults) (30, 95) (Fig. 8
). DEXA likewise overestimated FM in two recent primary validation studies using the whole carcass of immature swine (108, 109). Practical limitations include equipment and technician costs and low-dose radiation exposure (1–3 mrad, or less than that contributed by cosmic background during a single 4000-km air flight). Nonetheless, DEXA technology offers a valuable means to estimate body composition. Additional important insights are achievable by way of computed tomography (CT) and magnetic resonance imaging (MRI), because these techniques allow one to appraise the regional distribution of fat.
E. Fat topography
Intraabdominal fat is a key epidemiological determinant of insulin resistance and cardiovascular risk (110). CT provides one well-validated means to quantitate intraabdominal adiposity. CT is technically precise in discriminating adipose tissue and affords a brief scan time that obviates motion artifact (111). To estimate abdominal fat, the CT examination is performed at the level of the fourth or fifth lumbar vertebrae, the corresponding intervertebral disc space, or (somewhat less reliably) the umbilicus. Data are expressed as the cross-sectional area (square centimeters) of a demarcated region of adipose tissue, such as visceral (mesenteric, pericolic, and perirenal), retroperitoneal, and sc fat (112, 113). A recent distinction between superficial and deep sc FM suggests that the latter may also predict increased cardiovascular health risk (114). MRI offers a complementary method to quantify regional FM that does not require x-ray exposure. Although not evaluated exhaustively in children, MRI outcomes correlate with those of CT (115). Table 1 summarizes available CT and MRI data in children as distinguished by peripubertal age, gender, and ethnicity in cross-sectional analyses. However, appropriately stratified longitudinal comparisons will be required to definitively assess the transpubertal control of regional fat distribution in girls and boys. Concomitant metabolic implications of visceral and sc accumulation and dissipation (e.g., peripheral insulin sensitivity and lipoprotein composition) will be important to quantitate so well as practicable in pediatric populations. Finally, anatomic and metabolic adaptations across puberty need to be correlated with changing hormone outflow (viz., GH, testosterone, estradiol, IGF-I, insulin, and leptin) or resting energy expenditure.
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). However, anthropometric assessments may exhibit significant inter- and intraindividual variability (random bias), and bioelectrical impedance estimates may manifest marked (>25%) systematic bias compared with multicompartmental analyses (34, 75, 119, 120, 121).
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III. Sex-Steroid and GH Interactions on Target Tissues in Puberty |
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TopAbstractI. Timing and Tempo...II. Measurement of Body...III. Sex-Steroid and GH...IV. Energy Expenditure in...V. SummaryReferences |
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Clinical treatment of precocious puberty highlights the inference that stimulatory effects of gonadal sex steroids on the GH/IGF-I axis are reversed in part when ovarian or testicular secretion is decreased medically (40, 146, 147). In particular, therapy with a GnRH analog suppresses concentrations of estradiol and testosterone profoundly and those of GH, IGF-I, and IGFBP-3 significantly, but does not affect measurements of cortisol or adrenal androgens (148, 149). Gonadal-axis down-regulation may thereby obviate rapid skeletal maturation not only by sex-steroid depletion but also by secondary inhibition of the somatotropic axis (150). Albeit originally hypothesized as a means to stimulate growth in the face of bone-age delay, combining rh GH supplementation with GnRH agonist therapy in children with sexual precocity may enhance predicted final stature (147, 151, 152).
From a simplified viewpoint, the timely onset and effectual progress of puberty would require, at a minimum, interaxis coordination of GH/IGF-I and GnRH/LH/sex-steroid production. Several mechanistic insights are relevant to this network-like concept. First, IGF-I and/or insulin act in an apparently species-specific manner to: 1) enhance hypothalamic GnRH outflow in vivo in the juvenile female monkey and rat and stimulate GnRH secretion in vitro by murine GT1–7 cells; 2) promote normal reproductive hormone secretion in the male and female mouse in part via the central nervous system insulin receptor substrate-2 signaling pathway; 3) potentiate GnRH-stimulated LH release in vitro; and 4) synergize with LH and FSH in stimulating ovarian and testicular steroidogenesis in vitro and in vivo (12, 132, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163). Second, endogenous gonadal sex steroids amplify the synthesis of GH and IGF-I and regulate the availability of IGFBPs and cognate proteases (90, 131, 132, 133, 164, 165, 166, 167, 168, 169, 170). Third, GH, IGF-I, IGF-II, insulin, and sex steroids interact via complex heterologous control of receptor-effector signaling pathways (135, 165, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182). And, fourth, sex steroids and insulinomimetic peptides act in combination to govern appetite, thermoregulation, behavior, and energy expenditure via central and peripheral pathways (183, 184, 185, 186). Comprehensive formal integration of the foregoing multivalent mechanisms is not yet possible.
B. Actions of androgen, estrogen, GH, and IGF-I on bone
1. Hypogonadism overview.
Prolonged deprivation of sex-steroid hormones at or after the time of expected puberty predisposes to reduced peak bone mass, attendant osteopenia, osteoporosis, and major fractures in the adult (56, 187, 188, 189, 190). Cross-sectional epidemiological analyses demonstrate that total and bioavailable (non-SHBG-bound) estradiol concentrations predict bone mass in women and men more accurately than total or bioavailable testosterone concentrations (188, 191, 192, 193, 194). Data from four longitudinal investigations corroborate the fundamental association between peripheral estrogen concentrations and bone mass in the aging individual (56, 188). Testosterone, GH, IGF-I, and (in some studies) leptin concentrations also correlate with TBW in some analyses (195, 196). Albeit incompletely defined, heterogeneous genetic factors are prominent determinants of bone mass in healthy individuals (197, 198). In addition, ethnicity may influence bone density by as much as 6–11% (199).
2. Male hypogonadism.
Testosterone replacement in hypogonadal boys and men increases TBW incrementally in proportion to the degree of androgen deficiency at presentation (168, 200, 201, 202). The anabolic effects of testosterone in vivo are not fully understood but are associated with augmentation of at least: 1) pulsatile GH secretion, which drives longitudinal bone growth (166, 169, 170, 203, 204); 2) IGF-I synthesis in both liver and bone cells (169, 170, 205, 206, 207); 3) gastrointestinal absorption and skeletal retention of calcium and magnesium (201, 208, 209, 210, 211, 212, 213, 214, 215); 4) muscle mass, mechanical loading, and energy expenditure, which in turn correlate with bone mineral content and density (90, 162, 164, 165, 168, 216, 217, 218, 219, 220); 5) biochemical markers of osteoblastic activity, such as osteocalcin (221); and 6) epiphyseal growth-plate maturation, which culminates in mineralization-dependent cessation of skeletal elongation (15, 222, 223, 224). In vitro studies affirm these inferences and further illustrate that (in rodent species) testosterone and 5
-DHT can stimulate osteoblastic activity, inhibit apoptosis of osteoblasts and osteocytes, suppress osteoclastogenesis, and promote cortical (periosteal) bone apposition (225, 226, 227, 228). Androgen- and estrogen-dependent stimulation of epiphyseal mineralization underscores the clinical challenge of tailoring sex-hormone replacement in hypogonadal children to optimize total skeletal growth without inducing premature fusion of the growth plate (229, 230, 231, 232, 233, 234).
Androgen receptors are expressed in human osteoblastic cells and mature osteocytes (235). A normal linear growth spurt is described in 46XY patients with complete androgen insensitivity (testicular-feminization syndrome) due to inactivating mutation of the cognate receptor (145, 236). Nonetheless, loss of androgen-receptor function limits adult height and skeletal volume (bone size) in the genotypic male to values intermediate between those of the unaffected male and female (237). A reduction in bone mineral content is reported in some (but not other) patients with testicular feminization syndrome. Low bone mineral content may reflect: 1) a younger age at prophylactic orchidectomy; 2) suboptimal estrogen replacement; 3) the postgonadectomy fall in IGF-I availability; 4) a role for the androgen receptor in early bone development; 5) reduced supplementation with aromatizable androgens, which provide substrate for estrogen synthesis in situ; and/or 6) more severe inactivation of androgen-receptor function (135, 223, 238, 239, 240).
Supraphysiological amounts of aromatizable and nonaromatizable androgens stimulate osteoblast proliferation, antagonize the osteoclast-activating effect of PTH, and elevate markers of bone growth (228, 241, 242, 243, 244). In experimental animals, 5-DHT especially stimulates periosteal (appositional) skeletal growth and thereby increases cortical bone formation (228, 245, 246, 247). However, available data are not facile to interpret, because 5-reduced products of testosterone activate the androgen receptor and simultaneously impede estrogen action in some tissues (248, 249, 250). In the human, the androgen receptor may mediate up to 30% of sex steroid-induced skeletal remodeling, as inferred by combined administration of a down-regulating dose of a GnRH agonist, testosterone, and placebo, or an aromatase-enzyme inhibitor in healthy older men. In the sex steroid-depleted setting, transdermal repletion of testosterone or estradiol alone suppressed indices of bone resorption, increased markers of bone formation, and stimulated production of osteoprotegerin, a potent inhibitor of osteoclastogenesis (below). Each of the effects of testosterone was blunted by pharmacological aromatase blockade, with the exception of increased synthesis of osteocalcin, a marker of osteoblast function. Comparable mechanistic investigations of sex steroid-specific control of skeletal development are not available in childhood. Moreover, no studies have extended discrete receptor agonist and antagonist analyses over prolonged intervals (years) in the human.
3. Estrogenic effects.
Estrogenic steroids repress osteoclastogenesis, promote epiphyseal maturation, stimulate endosteal and trabecular bone formation, augment mineralization, and increase tensile bone strength (136, 137, 211, 240, 251, 252, 253, 254). Selective estrogen receptor (ER) modulators (e.g., raloxifene) appear to act analogously (but not necessarily identically) to enhance overall bone mineral content. Estrogen supplementation also stimulates the intestinal absorption and skeletal retention of calcium, which processes contribute to bone mineralization (255, 256, 257). Estrogens drive proliferation and differentiation of the entire osteoblastic-cell lineage; enhance the anabolic actions of other trophic signals (e.g., PTH, GH, IGF-I, and prostaglandin E2); limit osteocyte apoptosis; inhibit osteoclastic resorption under osteolytic stress (e.g., by PTH, prostaglandin F2, interferon 
, IL-1, and TNF-); and induce osteoblast synthesis of osteoprotegerin. The last-named glycoprotein is a potent inhibitor of osteoclastogenesis and inducer of osteoblast cytodifferentiation (77, 136, 245, 251, 258, 259, 260, 261, 262).
4. ER subtype and aromatase-enzyme expression.
Gene transcripts encoding truncated and full-length ER and ERß are detectable in osteoprogenitor cells, differentiated osteoblasts, and mature osteocytes (259, 263, 264). Expression of ERß predominates in immature bone and wanes with skeletal maturation (265, 266). As highlighted in Table 2, inactivating mutations of ER or the aromatase gene (but not ERß) cause severe osteoporosis and impair epiphyseal mineralization in the human and mouse (10, 237, 240, 243, 244, 246, 267, 268, 269, 270). In several patients with rare inborn aromatase deficiency, repletion of estradiol stimulated prompt epiphyseal maturation and bone mineralization, whereas testosterone supplementation did not (243, 271). Albeit less well studied, certain molecular polymorphisms of the estrogen-receptor gene also predict reduced BMD epidemiologically.
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Interpretation of target-tissue responses to ostensibly isolated interruption of a single sex-steroid signaling pathway in vivo is not straightforward, as indicated by the following considerations. First, in one analysis, supplementation with testosterone partially restored appendicular skeletal size in the orchidectomized mouse harboring transgenetic inactivation (knockout) of the ER subtype (-ERKO model) (240). In a strict technical context, this novel finding might be explained by androgen-receptor and/or ERß-mediated drive of longitudinal bone growth; confounding by supraphysiological androgen addback; and/or species, gene-dosage, or strain effects inherent in the transgenic model (101, 165, 174, 235, 243, 253, 264, 274). Second, pharmacological muting of sex-steroid negative feedback in the human and rodent stimulates (systemic) testosterone and estradiol secretion by 1.5- to 3-fold, thereby secondarily altering the systemic sex-hormone milieu (275, 276, 277, 278, 279). Third, androgen and estrogen exert both delayed genomic and rapid nongenomic effects on diverse target cells. Such bipartite actions mediate an array of complementary neuronal and extraneuronal effects. For example, in the central nervous system, estrogen acts on membrane receptors that facilitate IGF-I signaling via Akt and MAPK, thereby plausibly altering negative feedback by peripheral IGF-I (280, 281, 282). Fourth, androgens and estrogens regulate sex-steroid metabolism by inducing or inhibiting aromatase, 5- reductase and 17ß-hydroxysteroid dehydrogenase isoenzymes, which interconvert androgens and estrogens. Fifth, age and gender appear to influence the skeletal effects of aromatase deficiency in transgenic murine models (246). Sixth, species modulates neuroendocrine adaptations to the sex-steroid milieu; e.g., estradiol but not 5-DHT in the human (and, conversely, in the rodent) drives GH secretion (127, 128). GH output is significant as a stimulus of both systemic and skeletal synthesis of IGF-I (166). Seventh, inactivation of ER in the mouse depletes systemic IGF-I concentrations (237). Transgenic depletion of blood-borne IGF-I indicates that this peripheral source of growth-factor drive also contributes to adult bone growth (283). Eighth, androgen depletion heightens the capacity of estrogen to stimulate osteoblastic synthesis of the potent osteoclastogenesis-inhibiting peptide, osteoprotegerin (251, 259, 284, 285, 286) (Fig. 10). And, lastly, the relative availabilities of estrogen and androgen can determine promoter-specific gene transcription due to incompletely characterized heterologous interactions among ER, truncated ER, ERß, and the androgen receptor (237, 240, 243, 287, 288, 289, 290, 291, 292). In view of extensive complementation of osteogenic and osteolytic signals, the biological effects of interrupting the action of a single agonist-receptor linkage, such as disabling ER, could reflect nonexclusively: 1) impairment of ER-dependent drive; 2) collateral actions via ERß and/or the androgen receptor; 3) reduced availability of systemic and in situ IGF-I; 4) altered sex-steroid synthesis and metabolism; and/or 5) heterologous receptor-receptor interactions.
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Sex steroids, IGF-II, T4, and glucocorticoids not only modulate the secretion of GH and IGF-I (127, 128), but also impact the direct effects of GH and IGF-I on skeletal growth (146, 147, 310, 311). For example, testosterone stimulates GH and IGF-I production systemically; induces IGF-I synthesis in the skeleton; enhances GH-driven IGF-I accumulation in osteoblasts; promotes epiphyseal cartilage growth; increases mineralization of bone matrix; and, augments net trophic effects of selected IGFBPs (306, 307, 308, 312, 313). Estradiol amplifies GH receptor-mediated signaling in osteocytes, up-regulates osteoblast IGF-I production, down-regulates inhibitory binding proteins (IGFBP-4 and -6), induces the type I IGF receptor in bone, and uniquely stimulates osteoblastic synthesis of osteoprotegerin, a potent antiresorptive signal that is not induced by nonaromatizable androgens (15, 136, 165, 174, 207, 237, 265, 308, 309, 313, 314, 315, 316, 317, 318). Apparently joint trophic roles of GH and estradiol in bone accrual are inferable indirectly in clinical studies. In particular, maximal BMD correlates with 24-h GH concentrations in young men and with overnight GH and estradiol concentrations in the African-American (but not Caucasian) male (36, 37, 221).
Height, weight, and genetic endowment are strong epidemiological determinants of bone mineral content (191, 199). However, height and weight mirror multiple convergent genetic, environmental, and trophic-hormone interactions (319, 320, 321). The rate of skeletal calcium and magnesium accretion is maximal at ages 11–14 yr in girls and 16–18 yr in boys (322, 323, 324). On the other hand, total IGF-I, but not sex-steroid, concentrations reach a zenith 1.5–2 yr later. In young women, 99% of maximal BMD and 99% of total mineral content are attained at ages 22 ± 2.5 yr and 26 ± 3.7 yr, respectively (325). Skeletal mass at age 20, which amalgamates the conjoint impact of height, weight, environment, and genetics, predicts more than 50% of the statistical variability in bone mineral content in later adulthood (326). Nonetheless, some bone growth and mineralization continue in selected skeletal sites into the fourth or fifth decade of life (56, 188, 221, 323, 325, 327).
In hyposomatotropic children and adults, GH replacement therapy facilitates the timely onset of sexual development and therewith increased sex-steroid secretion (140). GH treatment in such patients uniformly elevates biochemical indices of bone remodeling (within weeks), promotes marked (so-called catch-up) linear growth in the first year, augments skeletal mineralization after 1.5 to 2 yr, and (in children) increases final adult stature (97, 241, 298, 328, 329, 330, 331, 332, 333, 334) (Table 3). Albeit less well documented, administration of IGF-I also stimulates bone growth, skeletal remodeling, and mineral deposition in the IGF-I-deficient setting in man and animals. Estrogen blunts the actions of GH on biochemical markers of skeletal remodeling in the hypopituitary female, postmenopausal woman, and male-to-female transsexual patient (335, 336, 337). Estradiol replacement also attenuates the rh GH-induced rise in IGF-I concentrations and decline in visceral FM (127, 337). Whether the foregoing GH/sex-steroid interactions apply equally to other long-term tissue effects is not known.
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6. Multisignal endocrine control.
Sex steroids, GH, IGF-I, cortisol, T4, and other systemic hormones act on bone collaboratively via potent local effector molecules, such as IGF-I/IGFBPs, cytokines, prostaglandins, and osteoprotegerin. This nonexclusive ensemble of in situ regulators directs skeletal growth (increased volume), remodeling, and mineralization (259). The importance of multihormonal trophic control of bone growth and maturation is illustrated in children with Turner syndrome. Osteopenia in this setting is attributable to 3-fold deficiency of estrogen, GH/IGF-I, and androgen along with important but incompletely characterized genetic factors that disrupt bone development. TBW in gonadal dysgenesis is reduced detectably in the third decade, and fracture risk is increased significantly by the fourth decade of life (40, 77, 136, 137, 201, 243, 359, 360, 361, 362, 363). Clinical interventional trials have combined physiological estrogen replacement (based on developmental age), dose-titrated repletion of androgen, and supraphysiological amounts of GH to accelerate height velocity. Final statural gain in Turner syndrome is influenced principally by age at initial treatment, duration of hormonal intervention, doses of GH (higher) and androgen (low), degree of growth failure, and incompletely defined genetic factors (98, 175, 176, 177, 209, 210, 232, 233, 364, 365).
C. Adiposity and sex-steroid hormones
Sex-steroid hormones, GH, insulin, glucocorticoids, and ß-3 adrenergic agonists are dominant determinants of adipocyte mass (Fig. 11). A corollary thesis is that fat topography is controlled by regionalized expression and activity of sex steroid-metabolizing enzymes, growth factors, and cognate receptors (366, 367, 368). For example, estradiol receptors predominate in mammary and gluteofemoral fat, whereas androgen receptors are more abundant in intraabdominal (omental) fat (367). At the level of target cells, GH, ß-3-adrenergic agonists, and testosterone induce greater lipolysis of visceral than sc adipose tissue. In contradistinction, insulin and cortisol stimulate lipogenesis in diverse fat depots (76, 100, 365, 366, 367, 369, 370, 371, 372).
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Estradiol up-regulates its own receptor and that of insulin in fat cells in vitro and in vivo (378, 379). These effects would be consistent with the statistical association between (unopposed) estrogen replacement therapy and intraabdominal adiposity in postmenopausal women (366, 380). However, correlations may be invidious, inasmuch as the route of estrogen supplementation also determines the magnitude of metabotropic effects; e.g., oral compared with transdermal estradiol replenishment inhibits lipid oxidation more (thereby predisposing to fat retention) and blocks glucose disposal less (thus facilitating insulin action and fat synthesis) (98, 381). Conversely, a history of combined use of estrogen and a synthetic progestin postmenopausally predicts less visceral fat accumulation (98, 175, 177, 180, 382, 383). The apparent lipolytic effect of adding a synthetic progestin may be due to weak intrinsic androgenicity of such agents. According to this reasoning, greater availability of androgens in menstruating than ovariprival women may contribute to relatively less intraabdominal (visceral) fat (365, 383, 384). In addition, nonwithdrawal of adrenal androgenic sex steroids during long-term GnRH agonist therapy of precocious puberty may account for some changes in total body fat despite estrogen depletion (73, 385).
Estradiol inhibits proliferation of immature fat cells via ER and stimulates growth of preadipocytes via ERß (366). The foregoing distinction applies in the rodent, inasmuch as transgenetic -ERKO and aromatase knockout induce hyperplasia and hypertrophy of (white) adipocytes with a resultant 80–100% increase in total body fat (368, 386). Conversely, high-dose estradiol administration in the immature mouse, rat, and cow reduces FM. The topography of adipose tissue presumably depends further on (nonexclusively) tissue-specific differences in the expression of - (inhibitory) and ß- (stimulatory) ER, aromatase enzyme, 11-hydroxysteroid dehydrogenase (types I and II), and 17ß-hydroxysteroid dehydrogenase (isotypes 2 and 3) (384). The foregoing enzymes control interconversion of testosterone and estradiol, as well as cortisol and (inactive) cortisone. Understanding how the ensemble of IGF-I, GH, insulin, cortisol, sex steroids, adipocyte topography, gender, and species
