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Delayed puberty: When to wake the bugler
EDITORIALS
D
THE JOURNAL OF PEDIATRICS DECEMBER 1998
Delayed puberty: When to wake the bugler If the initial physical changes of puberty are not present by age 13 in girls or age 14 in boys, evaluation should be considered for possible causes for the lack of development. Likewise, an abnormality may be present if pubertal development has begun in orderly fashion but does not progress appropriately. Therefore an evaluation may be indicated if more than 5 years have elapsed between the first signs of puberty and menarche in girls or the completion of genital growth in boys.1 The differentiation between delayed puberty caused by constitutional delay of growth and/or puberty and a hypothalamic-pituitary defect (hypogonadotropic states) or primary gonadal failure (hypergonadotrophic states) has been a conundrum puzzling clinical endocrinologists for many years. Unfortunately, there is still no foolproof test with a sufficiently high degree of sensitivity and specificity that would allow one to dif-
J Pediatr 1998;133:724-6. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/18/95200
724
ferentiate between benign variants of pubertal development, such as constitutional delay, and more serious afflictions.
See related article, p. 745. Although the onset of puberty is influenced by both genetic and environmental factors, an important trigger for puberty is related to fat mass. 2-4 Moderately obese girls have long been known to enter puberty earlier than girls of normal weight, and conversely, girls with malnutrition do not have normal pituitary ovarian function. Moderate obesity (up to 30% above normal weight for age) is associated with earlier menarche, whereas menarche may be delayed with pathologic obesity.4 One hypothesis to explain the relation between fat mass and menstruation is that fat cells (in a state of high fat storage) secrete an as-yet elusive neuroregulatory hormone into the blood, analogous to the appetite-regulating fat cell–derived protein hormone leptin.5 If leptin is the signal that connects energy storage in
the adipose tissue with the central nervous system, it seems plausible that obtaining a characteristic store of body fat mass may contribute to triggering puberty.6,7 There appears to be a sexual dimorphism in the role of leptin in that rising leptins may signal the onset of puberty in both sexes; there is a continued increase in girls, whereas there is a decline in boys, suggesting that androgens may suppress leptin gene expresCDP Constitutional delayed puberty SHBG Sex hormone binding globulin
sion, and subsequently, circulating plasma leptin concentrations.8 Recent observations that plasma leptin levels in patients with central precocious puberty are not elevated at the onset of the premature development again cast doubt on the causal relationship between leptin and pubertal onset. Increases in leptin paralleled the increases in body mass index in that study.9 In our experience the overweight child is commonly tall for age. This is further
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 6 associated with an advanced gonadal maturity and bone age and earlier onset of puberty. Thus premature adrenarche is common in these children. Surprisingly, lean body mass and fat free mass are often increased in obese children.10,11 Data on puberty in obese boys are more scanty than that for girls. Nonetheless, similar principles operate. It is therefore surprising that Kaplowitz12 encountered the relatively large number of boys with obesity and pubertal delay described in this issue. The association of exogenous obesity and early maturation is so characteristic that the child with obesity and short stature should always be evaluated for underlying disease such as growth hormone deficiency, Cushing’s syndrome, and hypothyroidism.13 Several studies have shown that in boys a positive relation exists between the age of pubertal onset and the body mass index. This correlation has not always been equally strong in girls. Finding a tight correlation between body fat mass as a characteristic of pubertal onset in both sexes, particularly in boys, does again suggest a tight link between energy stores in the form of adipose tissue and the triggering of puberty.14 Increases in leptins signaling pubertal elevations of follicle-stimulating hormone (observed in 7- to 9-year-old girls without changes in luteinizing hormone) may be responsible for earlier puberty in tall and overweight children with advanced skeletal age. An additional factor may be the relationship between degree of adiposity and the level of sex hormone binding globulin. In general, abnormalities in SHBG correlate with the degree of obesity; decreased binding occurs in the obese state (with an accompanying increase in the bioavailability of sex steroids), and increased binding occurs in the lean state. This is usually due to a decrease in SHBG, which results in a higher fraction of free or unbound sex steroids, and thus increased bioavailability in the lean state. In general, the SHBG abnormalities correlate with the degree of obesity and are reversed with weight loss. It has been found that obese adolescent boys appear to have an attenuated testicular response to human chorionic gonadotropin, but this is prob-
EDITORIALS
ably an artifact caused by decreased SHBG. Free and total testosterone levels may be diminished in moderately obese boys. This is commonly associated with decreased gonadotropin levels, suggesting some degree of hypogonadism. These alterations in pituitary and gonadal hormones return to the normal range with weight loss.14-17 Fortunately, boys, as well as girls, with constitutional delayed puberty eventually enter puberty and achieve normal final heights. Several authors have extolled the salutary effects of a brief course of androgen therapy, which provides a booster start in physical growth and development and leads to the onset of spontaneous pubertal development. If sex hormones are used prudently, this is generally achieved without loss in final height18-20 and will lead to some decrease in fat mass.21 We agree with the final assessment of Kaplowitz that because no single test reliably discriminates between the 2 diagnoses, CDP and hypogonadotropic hypogonadism, a brief course of testosterone may be indicated for those who do not show any pubertal development by the age of 14 years. It is not surprising that Kaplowitz finds a similar response in obese boys with pubertal delay as he finds in boys with classic CDP. This consensus of providing testosterone therapy to boys showing signs of CDP is attributable to its evident safety, low treatment burden for the patient and family, and proven efficacy in accelerating pubertal tempo without sacrificing adult height potential. It is reassuring to note that the testosterone therapy in the obese boys with CDP did not further exacerbate their obesity as a result of increased appetite. The rationale for treating this group is to normalize physical appearance so that psychosocial development can proceed at presumably lower risk. Although there is ample evidence that boys with CDP (with or without short stature) likely experience stigmatization and juvenilization related to physical status, Kaplowitz’s generalization that boys with CDP “often have emotional problems”12 is an overstatement. It is important to keep in mind that the experience of psychosocial stress is not equivalent to the individual’s psychoso-
cial adaptation. Children and adolescents with CDP may be experiencing social stress, but the more recent literature on this topic suggests that most are coping rather well. This conclusion is based on studies of both clinically referred and community samples of children with short stature. Parents would benefit from the knowledge that social stress related to pubertal and/or height deviations is not incompatible with a healthy psychosocial adaptation. This awareness would potentially alleviate some of the distress they experience in arriving at a treatment decision, whether it be shortterm testosterone administration or watchful waiting.22-24 In one recent placebo-controlled study exploring the psychosocial benefit of treatment of constitutional delay, Brown et al25 came to the sobering conclusion that there was improvement in only 1 of 5 self-perception domains, namely, behavioral conduct, after testosterone therapy. There were, however, no changes in scholastic competence, social acceptance, athletic competence, physical appearance, or global self worth.25 There were no significant differences for the placebo group, and the teacher’s rating scale of the child’s actual behavior did not detect any significant differences in the treated group or the placebo group. Might testosterone therapy in CDP then just be another therapy that primarily treats the concerned physician and the vociferous parent? Maybe we should leave the testosterone syringe in the medicine cabinet and better focus our intervention and anticipatory guidance on the second adjective in Kaplowitz’s article, the obesity. Well-designed studies from Scotland have shown that it is often already over well before the fat teenager sings. In overweight, short adolescents, earning capacity in young adulthood was adversely affected by height and obesity.26 Paul Saenger, MD The Division of Pediatric Endocrinology Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY 10647 David E. Sandberg, PhD Pediatric Psychiatry Children’s Hospital of Buffalo and University of Buffalo, SUNY Buffalo, NY 14222
725
EDITORIALS
THE JOURNAL OF PEDIATRICS DECEMBER 1998
REFERENCES 1. Lee PA. Disorders of puberty. In: Lifschitz F, editor. Pediatric endocrinology. 3rd ed. New York: Marcel Dekker; 1996. p. 175-95. 2. Frisch RE. Fatness, menarche, and female fertility. Perspect Biol Med 1985;28:611-33. 3. Frisch RE. Body fat, menarche, fitness and fertility. Prog Reprod Biol Med 1990;14:1-26. 4. Hartz AJ, Barboriak PN, Wong A, et al. The association of obesity with infertility and related menstrual abnormalities in women. Int J Obes 1979;3:57-73. 5. Reichlin S. Neuroendocrinology. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, editors. William’s textbook of endocrinology. 9th ed. Philadelphia: WB Saunders; 1998. p. 215. 6. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-9. 7. Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and physical alteration during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab 1997;82:1066-70. 8. Zhang Y, Leibel RL. Molecular physiology of leptin and its receptor. Growth, Genetics and Hormones 1998;14:17-26. 9. Heger S, Partsch CJ, Peter M, Blum WF, Kiess W, Sippell WG. Plasma leptin levels in patients with central precocious puberty [abstract]. Horm Res 1998;50(suppl 3):122.
10. Forbes GB. Influence of nutrition. In: Forbes OB, editor. Human body composition: growth, aging, nutrition and activity. New York: Springer Verlag; 1987. p. 209-47. 11. Forbes GB. Nutrition and growth. J Pediatr 1977;91:40-6. 12. Kaplowitz P. Delayed puberty in obese boys: Comparison with constitutional delayed puberty and response to testosterone therapy. J Pediatr 1998;133:745-9. 13. Rosenfeld R. Disorders of growth hormone and insulin-like growth factor secretion and action. In: Sperling MA, editor. Pediatric endocrinology. Philadelphia: WB Saunders; 1996. p. 117-65. 14. Genazzano AR, Pintor C, Corda R. Plasma levels of gonadotropins, prolactin, thyroxine, and adrenal and gonadal steroids in obese prepubertal girls. J Clin Endocrinol Metab 1978;47:974-9. 15. Dunkel L, Sorva R, Voutilainen R. Low levels of sex hormone-binding globulin in obese children. J Pediatr 1985;107:95-7. 16. Stanik S, Dornfeld LP, Maxwell MH, Viosca SP, Korenman SO. The effect of weight loss on reproductive hormones in obese men. J Clin Endocrinol Metab 1981;53:828-32. 17. Strain GW, Zumoff B, Kream J, et al. Mild hypogonadotropic hypogonadism in obese men. Metabolism 1982;31: 871-5. 18. Rosenfeld RO, Northcraft GB, Hintz RL. A prospective, randomized study of testosterone treatment of constitutional delay of growth and adolescence in male adolescents. Pediatrics 1982;69:681-7. 19. Richman RA, Kirsch LR. Testosterone treatment of adolescent boys with consti-
20.
21.
22.
23.
24.
25.
26.
tutional delay in growth and development. N Engl J Med 1988;319:1563-70. Tse W, Buyukgebiz A, Hindmarsh PC, Stanhope R, Preece MA, Brook CGD. Long-term outcome of oxandrolone treatment in boys with constitutional delay of growth and puberty. J Pediatr 1990;117:588-91. Arslanian S, Suprasongsin C. Testosterone treatment in adolescents with delayed puberty: changes in body composition, protein, fat, and glucose metabolism. J Clin Endocrinol Metab 1997;82:3213-20. Sandberg DE. Short stature: intellectual and behavioral aspects. In: Lifshitz F, editor. Pediatric endocrinology. 3rd ed. New York: Marcel Dekker; 1996. p. 149-62. Sandberg DE, Michael P. Psychosocial stresses related to short stature: Does their presence imply psychiatric dysfunction? In: Drotar D, editor. Assessing pediatric health-related quality of life and functional status: implications for research, practice and policy. (NJ): Lawrence Erlbaum; 1998. p. 287-312. Downie AB, Mulligan J, Stratford RJ, Betts PR, Voss LD. Are short normal children at a disadvantage? The Wessex Growth Study. Br Med J 1997;314: 97-100. Brown DC, Kelnar CJH, Wu FCW. Self-perception of boys with constitutional delay of growth and puberty treated with testosterone undecanoate [abstract]. Horm Res 1998;(suppl 3):123. Sargent JD, Blanchflower DG. Obesity and stature in adolescence and earnings in young adulthood. Arch Pediatr Adolesc Med 1994;148:681-7.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of The Journal of Pediatrics for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted, at a cost of $13.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.
726
D
THE JOURNAL OF PEDIATRICS DECEMBER 1998
Delayed puberty: When to wake the bugler If the initial physical changes of puberty are not present by age 13 in girls or age 14 in boys, evaluation should be considered for possible causes for the lack of development. Likewise, an abnormality may be present if pubertal development has begun in orderly fashion but does not progress appropriately. Therefore an evaluation may be indicated if more than 5 years have elapsed between the first signs of puberty and menarche in girls or the completion of genital growth in boys.1 The differentiation between delayed puberty caused by constitutional delay of growth and/or puberty and a hypothalamic-pituitary defect (hypogonadotropic states) or primary gonadal failure (hypergonadotrophic states) has been a conundrum puzzling clinical endocrinologists for many years. Unfortunately, there is still no foolproof test with a sufficiently high degree of sensitivity and specificity that would allow one to dif-
J Pediatr 1998;133:724-6. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/18/95200
724
ferentiate between benign variants of pubertal development, such as constitutional delay, and more serious afflictions.
See related article, p. 745. Although the onset of puberty is influenced by both genetic and environmental factors, an important trigger for puberty is related to fat mass. 2-4 Moderately obese girls have long been known to enter puberty earlier than girls of normal weight, and conversely, girls with malnutrition do not have normal pituitary ovarian function. Moderate obesity (up to 30% above normal weight for age) is associated with earlier menarche, whereas menarche may be delayed with pathologic obesity.4 One hypothesis to explain the relation between fat mass and menstruation is that fat cells (in a state of high fat storage) secrete an as-yet elusive neuroregulatory hormone into the blood, analogous to the appetite-regulating fat cell–derived protein hormone leptin.5 If leptin is the signal that connects energy storage in
the adipose tissue with the central nervous system, it seems plausible that obtaining a characteristic store of body fat mass may contribute to triggering puberty.6,7 There appears to be a sexual dimorphism in the role of leptin in that rising leptins may signal the onset of puberty in both sexes; there is a continued increase in girls, whereas there is a decline in boys, suggesting that androgens may suppress leptin gene expresCDP Constitutional delayed puberty SHBG Sex hormone binding globulin
sion, and subsequently, circulating plasma leptin concentrations.8 Recent observations that plasma leptin levels in patients with central precocious puberty are not elevated at the onset of the premature development again cast doubt on the causal relationship between leptin and pubertal onset. Increases in leptin paralleled the increases in body mass index in that study.9 In our experience the overweight child is commonly tall for age. This is further
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 6 associated with an advanced gonadal maturity and bone age and earlier onset of puberty. Thus premature adrenarche is common in these children. Surprisingly, lean body mass and fat free mass are often increased in obese children.10,11 Data on puberty in obese boys are more scanty than that for girls. Nonetheless, similar principles operate. It is therefore surprising that Kaplowitz12 encountered the relatively large number of boys with obesity and pubertal delay described in this issue. The association of exogenous obesity and early maturation is so characteristic that the child with obesity and short stature should always be evaluated for underlying disease such as growth hormone deficiency, Cushing’s syndrome, and hypothyroidism.13 Several studies have shown that in boys a positive relation exists between the age of pubertal onset and the body mass index. This correlation has not always been equally strong in girls. Finding a tight correlation between body fat mass as a characteristic of pubertal onset in both sexes, particularly in boys, does again suggest a tight link between energy stores in the form of adipose tissue and the triggering of puberty.14 Increases in leptins signaling pubertal elevations of follicle-stimulating hormone (observed in 7- to 9-year-old girls without changes in luteinizing hormone) may be responsible for earlier puberty in tall and overweight children with advanced skeletal age. An additional factor may be the relationship between degree of adiposity and the level of sex hormone binding globulin. In general, abnormalities in SHBG correlate with the degree of obesity; decreased binding occurs in the obese state (with an accompanying increase in the bioavailability of sex steroids), and increased binding occurs in the lean state. This is usually due to a decrease in SHBG, which results in a higher fraction of free or unbound sex steroids, and thus increased bioavailability in the lean state. In general, the SHBG abnormalities correlate with the degree of obesity and are reversed with weight loss. It has been found that obese adolescent boys appear to have an attenuated testicular response to human chorionic gonadotropin, but this is prob-
EDITORIALS
ably an artifact caused by decreased SHBG. Free and total testosterone levels may be diminished in moderately obese boys. This is commonly associated with decreased gonadotropin levels, suggesting some degree of hypogonadism. These alterations in pituitary and gonadal hormones return to the normal range with weight loss.14-17 Fortunately, boys, as well as girls, with constitutional delayed puberty eventually enter puberty and achieve normal final heights. Several authors have extolled the salutary effects of a brief course of androgen therapy, which provides a booster start in physical growth and development and leads to the onset of spontaneous pubertal development. If sex hormones are used prudently, this is generally achieved without loss in final height18-20 and will lead to some decrease in fat mass.21 We agree with the final assessment of Kaplowitz that because no single test reliably discriminates between the 2 diagnoses, CDP and hypogonadotropic hypogonadism, a brief course of testosterone may be indicated for those who do not show any pubertal development by the age of 14 years. It is not surprising that Kaplowitz finds a similar response in obese boys with pubertal delay as he finds in boys with classic CDP. This consensus of providing testosterone therapy to boys showing signs of CDP is attributable to its evident safety, low treatment burden for the patient and family, and proven efficacy in accelerating pubertal tempo without sacrificing adult height potential. It is reassuring to note that the testosterone therapy in the obese boys with CDP did not further exacerbate their obesity as a result of increased appetite. The rationale for treating this group is to normalize physical appearance so that psychosocial development can proceed at presumably lower risk. Although there is ample evidence that boys with CDP (with or without short stature) likely experience stigmatization and juvenilization related to physical status, Kaplowitz’s generalization that boys with CDP “often have emotional problems”12 is an overstatement. It is important to keep in mind that the experience of psychosocial stress is not equivalent to the individual’s psychoso-
cial adaptation. Children and adolescents with CDP may be experiencing social stress, but the more recent literature on this topic suggests that most are coping rather well. This conclusion is based on studies of both clinically referred and community samples of children with short stature. Parents would benefit from the knowledge that social stress related to pubertal and/or height deviations is not incompatible with a healthy psychosocial adaptation. This awareness would potentially alleviate some of the distress they experience in arriving at a treatment decision, whether it be shortterm testosterone administration or watchful waiting.22-24 In one recent placebo-controlled study exploring the psychosocial benefit of treatment of constitutional delay, Brown et al25 came to the sobering conclusion that there was improvement in only 1 of 5 self-perception domains, namely, behavioral conduct, after testosterone therapy. There were, however, no changes in scholastic competence, social acceptance, athletic competence, physical appearance, or global self worth.25 There were no significant differences for the placebo group, and the teacher’s rating scale of the child’s actual behavior did not detect any significant differences in the treated group or the placebo group. Might testosterone therapy in CDP then just be another therapy that primarily treats the concerned physician and the vociferous parent? Maybe we should leave the testosterone syringe in the medicine cabinet and better focus our intervention and anticipatory guidance on the second adjective in Kaplowitz’s article, the obesity. Well-designed studies from Scotland have shown that it is often already over well before the fat teenager sings. In overweight, short adolescents, earning capacity in young adulthood was adversely affected by height and obesity.26 Paul Saenger, MD The Division of Pediatric Endocrinology Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY 10647 David E. Sandberg, PhD Pediatric Psychiatry Children’s Hospital of Buffalo and University of Buffalo, SUNY Buffalo, NY 14222
725
EDITORIALS
THE JOURNAL OF PEDIATRICS DECEMBER 1998
REFERENCES 1. Lee PA. Disorders of puberty. In: Lifschitz F, editor. Pediatric endocrinology. 3rd ed. New York: Marcel Dekker; 1996. p. 175-95. 2. Frisch RE. Fatness, menarche, and female fertility. Perspect Biol Med 1985;28:611-33. 3. Frisch RE. Body fat, menarche, fitness and fertility. Prog Reprod Biol Med 1990;14:1-26. 4. Hartz AJ, Barboriak PN, Wong A, et al. The association of obesity with infertility and related menstrual abnormalities in women. Int J Obes 1979;3:57-73. 5. Reichlin S. Neuroendocrinology. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, editors. William’s textbook of endocrinology. 9th ed. Philadelphia: WB Saunders; 1998. p. 215. 6. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-9. 7. Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and physical alteration during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab 1997;82:1066-70. 8. Zhang Y, Leibel RL. Molecular physiology of leptin and its receptor. Growth, Genetics and Hormones 1998;14:17-26. 9. Heger S, Partsch CJ, Peter M, Blum WF, Kiess W, Sippell WG. Plasma leptin levels in patients with central precocious puberty [abstract]. Horm Res 1998;50(suppl 3):122.
10. Forbes GB. Influence of nutrition. In: Forbes OB, editor. Human body composition: growth, aging, nutrition and activity. New York: Springer Verlag; 1987. p. 209-47. 11. Forbes GB. Nutrition and growth. J Pediatr 1977;91:40-6. 12. Kaplowitz P. Delayed puberty in obese boys: Comparison with constitutional delayed puberty and response to testosterone therapy. J Pediatr 1998;133:745-9. 13. Rosenfeld R. Disorders of growth hormone and insulin-like growth factor secretion and action. In: Sperling MA, editor. Pediatric endocrinology. Philadelphia: WB Saunders; 1996. p. 117-65. 14. Genazzano AR, Pintor C, Corda R. Plasma levels of gonadotropins, prolactin, thyroxine, and adrenal and gonadal steroids in obese prepubertal girls. J Clin Endocrinol Metab 1978;47:974-9. 15. Dunkel L, Sorva R, Voutilainen R. Low levels of sex hormone-binding globulin in obese children. J Pediatr 1985;107:95-7. 16. Stanik S, Dornfeld LP, Maxwell MH, Viosca SP, Korenman SO. The effect of weight loss on reproductive hormones in obese men. J Clin Endocrinol Metab 1981;53:828-32. 17. Strain GW, Zumoff B, Kream J, et al. Mild hypogonadotropic hypogonadism in obese men. Metabolism 1982;31: 871-5. 18. Rosenfeld RO, Northcraft GB, Hintz RL. A prospective, randomized study of testosterone treatment of constitutional delay of growth and adolescence in male adolescents. Pediatrics 1982;69:681-7. 19. Richman RA, Kirsch LR. Testosterone treatment of adolescent boys with consti-
20.
21.
22.
23.
24.
25.
26.
tutional delay in growth and development. N Engl J Med 1988;319:1563-70. Tse W, Buyukgebiz A, Hindmarsh PC, Stanhope R, Preece MA, Brook CGD. Long-term outcome of oxandrolone treatment in boys with constitutional delay of growth and puberty. J Pediatr 1990;117:588-91. Arslanian S, Suprasongsin C. Testosterone treatment in adolescents with delayed puberty: changes in body composition, protein, fat, and glucose metabolism. J Clin Endocrinol Metab 1997;82:3213-20. Sandberg DE. Short stature: intellectual and behavioral aspects. In: Lifshitz F, editor. Pediatric endocrinology. 3rd ed. New York: Marcel Dekker; 1996. p. 149-62. Sandberg DE, Michael P. Psychosocial stresses related to short stature: Does their presence imply psychiatric dysfunction? In: Drotar D, editor. Assessing pediatric health-related quality of life and functional status: implications for research, practice and policy. (NJ): Lawrence Erlbaum; 1998. p. 287-312. Downie AB, Mulligan J, Stratford RJ, Betts PR, Voss LD. Are short normal children at a disadvantage? The Wessex Growth Study. Br Med J 1997;314: 97-100. Brown DC, Kelnar CJH, Wu FCW. Self-perception of boys with constitutional delay of growth and puberty treated with testosterone undecanoate [abstract]. Horm Res 1998;(suppl 3):123. Sargent JD, Blanchflower DG. Obesity and stature in adolescence and earnings in young adulthood. Arch Pediatr Adolesc Med 1994;148:681-7.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of The Journal of Pediatrics for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted, at a cost of $13.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.
726