*lliW*w* 10%) than the mean weight for height and body build. The diagnosis of constitutional delay in growth and sexual maturation is established by excluding nutritional, endocrinologic, or systemic disease and retrospectively by the normal pattern of growth and development which these children ultimately pursue. Therefore, it is necessary to follow these children periodically in order to be certain that the anticipated patterns of growth and development ensue. Should the patient not grow and undergo sexual maturation as the bone age matures and reaches 12 to 13 years, fur-

752

ROOT AND REITER

TABLE 5. Evaluation of Delayed Adolescence History Patient: gestation, birth, nutrition, growth, illnesses Family: maturational patterns Physical examination General appearance, vital signs Height, weight Fundoscopy, visual fields Stage of maturation Laboratory investigation Roentgenographic: bone age, skull Gonadotropins: serum or urine LH, FSH Gonadal hormones: testosterone, estradiol Adrenal hormones: DHEA, DHAS Gn-RH response hCG response Buccal smear, chromosome analysis

ther evaluation is indicated (Table 5). In the patient who is 14 to 15 years of age when initially examined or whose height is more than 2 SD below the mean for age or in whom the process of sexual development has not progressed at an appropriate rate or has even been arrested, evaluation beyond the historical review, physical examination, and survey of skeletal maturation is usually indicated. Roentgenograms of the skull may identify enlargement of the sella turcica, intracranial calcifications, or increased intracranial pressure. Hemogram and urinalysis, sedimentation rate, and thyroxine, creatinine, albumin, and electrolyte levels are determined in order to identify a chronic systemic disease. In patients with inflammatory bowel disease the sedimentation rate is high and the serum albumin concentration is low. Plasma zinc concentration may be measured in those children with evidence of malnutrition (underweight for height). In children of pubertal age, determination of serum and urinary levels of LH and FSH will separate patients with primary gonadal disorders from those with delayed normal puberty or hypogonadotropic hypogonadism due to diseases of the central nervous system, hypothalamus, and pituitary. Determination of the gonadotrope secretory response to Gn-RH in many instances

July 1976

will distinguish the child with constitutional delay in growth and development from the subject with hypogonadotropic hypogonadism. In the former group, the Gn-RH-evoked LH and FSH secretion should be appropriate for the normal prepubertal state if there is no physical evidence of sexual development or should approximate the early pubertal response if there is even slight clinical suggestion of pubertal changes; in the latter group, LH and FSH secretion following Gn-RH administration may be markedly attenuated. However, there is considerable variability in the normal prepubertal response to Gn-RH, and, therefore, this test may not distinguish between these entities at all times. The short-term urinary LH and FSH responses following Gn-RH administration may be more revealing than the study of changes in serum LH and FSH levels. 24 • 25 Testosterone levels increase after Gn-RH administration in pubertal but not in prepubertal males. Evaluation of the secretion of other anterior pituitary hormones (growth hormone, adrenocorticotrophic hormone, prolactin) is indicated in the subject with hypogonadotropic hypogonadism. Clomiphene, an antiestrogen with weak estrogenic properties, stimulates the hypothalamus to cause release of GnRH and subsequently LH and FSH in adult and late pubertal subjects. The administration of 100 mg of clomiphene daily for 7 days is followed by an increase in serum levels of LH and FSH in adults and late pubertal adolescents. In prepubertal subjects the weak estrogenic effects of clomiphene predominate and cause a decline in urinary gonadotropin excretion. 26 Determination of serum or plasma gonadal hormone levels provides data concerning gonadal function. In boys, plasma testosterone values increase sequentially as adolescence advances. 6 • 11 In males with anorchia, LH and FSH values

Vol. 27, No. 7

DELAYED PUBERTAL DEVELOPMENT

are high, whereas testosterone levels may be low or normal. In the latter case testosterone may be secreted by clusters of Leydig cells scattered along the course of normal testicular descent. In prepubertal patients with testicular dysgenesis (Klinefelter's syndrome) serum levels of LH and FSH are appropriate for age, and the response to Gn-RH is a normal prepubertal one. In postpubertal subjects with testicular dysgenesis there is often gynecomastia and a eunuchoid habitus, and LH and FSH levels are elevated. The gonadotrope secretory response is exaggerated, while plasma concentrations of testosterone may be low or normal.2 7 Buccal smear reveals a sex chromatin-positive pattern in most subjects with testicular dysgenesis; occasionally, sex chromosome mosaicism (XY/XXY) may be associated with a normal male sex chromatin (negative) pattern. Responsiveness of Leydig cell secretion of testosterone may be evaluated by administration of human chorionic gonadotropin (hCG.) 11 In prepubertal subjects there is a severalfold increase in testosterone levels after administration of hCG, 2000 U intramuscularly daily for 3 days. Sex chromatin (buccal smear) should be determined in all females with delayed puberty, because gonadal dysgenesis is not infrequently found in girls with poor growth and delayed maturation. In many such children the classic stigmata of 45/XO gonadal dysgenesis may not be present, and one must be alert for children with sex chromosome mosaicism (XO/XX, XO/XY) and/or structural aberrations of the X chromosome. Therefore, in all doubtful instances, the sex chromosome karyotype should be determined. In phenotypic females with normal breast development, absence of pubic or axillary hair, and primary amenorrhea, one should consider the possibility of testicular feminization, an inborn error of andro-

753

gen sensitivity inherited either as an Xlinked recessive trait or as an autosomal sex-limited dominant characteristic.20 Other local, non-endocrine causes of primary amenorrhea in girls with normal breast growth include imperforate hymen and congenital absence of uterus or vagina. MANAGEMENT OF THE CHILD WITH DELAYED PUBERTY

In general, the child with constitutional delay in growth and development and the parents should be reassured that his (her) developmental pattern is simply a variant of normal. The processes of growth and development should be carefully explained and the wide range of normal fully stated. Visual demonstration of selected materials may help to reassure the child about himself (herself). The majority of children will be reassured by the physician's explanation. Thereafter the patient should be observed at 6-month intervals to be certain that the expected patterns of growth and development ensue. In some patients with constitutional delay in growth and development, treatment may be indicated in order to accelerate the rates of growth and sexual maturation. Such a patient is usually, but not always, a boy with marked psychosocial-educational difficulties attributable to the difference between his immature body image and that of his more mature peers. In these children, treatment (begun after chronologie age 13) which accelerates growth and sexual development may be associated with significant improvement in the child's sense of well-being and in his interpersonal relationships. Although hCG has been used to stimulate interstitial cell maturation and testosterone production, we prefer to use a long-acting intramuscular preparation of testosterone

754

ROOT AND REITER

in a dosage of 50 to 200 mg/month for 4 to 6 months. Oral methyltestosterone is not used because of its association with cholestasis. The synthetic androgens such as fluoxymesterone and oxandrolone are not used because the virilizing effects of testosterone, as well as its growth-promoting qualities, are desired. Treatment should be interrupted by periods without hormone equal to the duration of treatment, because the effects of testosterone are often prolonged far beyond the period of therapy. Physical examination should be performed at least twice yearly and skeletal maturation assessed yearly. The course of testosterone may be repeated as necessary, but therapy is discontinued as soon as testicular enlargement is noted, indicating activation of the endogenous hypothalamic-pituitary-testicular axis. Boys with anorchia, Klinefelter's syndrome, and hypogonadotropic hypogonadism require replacement therapy with androgens in order to avoid the eunuchoidal habitus. In males with hypogonadotropic hypogonadism, treatment with gonadotropins or Gn"RH may restore fertility. In the girl with constitutional delay in growth and development, reassurance and observation are usually sufficient. Rarely, treatment with estrogens may be indicated in order to accelerate the rate of breast growth and to initiate menses. We have used ethinyl estradiol, 0.02 mg daily for 21 days of a 28-day cycle, or conjugated estrogens, 0.6 to 2.5 mg daily in a similar cycle, for such purposes. In this instance therapy should be discontinued when a bone age of 13 years is achieved, because this is the degree of skeletal maturation at which endogenous mechanisms should be active. In girls with gonadal dysgenesis, treatment with estrogens is indicated beginning at 12 to 14 years of age, depending upon individual circumstances.

July 1976

Patients with other endocrinopathies (such as hypothyroidism, hyperthyroidism, and diabetes mellitus), chronic systemic disease, or nutritional deprivation (e.g., anorexia nervosa and zinc deficiency) must be treated specifically for the disease state. Normal hypothalamic-pituitary-gonadal function may be expected to follow successful therapy. Acknowledgments. The authors thank Mrs. V. Hofmann for competent secretarial assistance in the preparation of the manuscript.

REFERENCES 1. Illig R: Delayed adolescence. Pediatr Ann 3:17,

1974 2. Tanner JM: Growth and endocrinology of the adolescent. In Endocrine and Genetic Diseases of Childhood, Vol 2, Edited by LI Gardner. Philadelphia, WB Saunders Co, 1975, p 14 3. Barnes HV: Physical growth and development during puberty. Med Clin North Am 59:1305, 1975 4. Marshall WA, Tanner JM: Variations in pattern of pubertal change in girls. Arch Dis Child 44:291-1969 5. Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13, 1970 6. Root AW: Endocrinology of puberty. I. Normal sexual maturation. J Pediatr 83:1, 1973 7. MacMahon B: Age at Menarche. United States. Department of Health, Education and Welfare Publication No. HRA 74-1615. Washington DC, United States Government Printing Office, 1973, p 1 8. Frisch RE: Critical weight at menarche, initiation of the adolescent growth spurt, and control of puberty. In The Control of the Onset of Puberty, Edited by MM Grumbach, GG Grave, FE Mayer. New York, John Wiley and Sons, 1974, p 403 9. Hopper BR, Yen SSC: Circulating concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate during puberty. J Clin Endocrinol Metab 40:458, 1975 10. Sizonenko PC, Paunier L: Hormonal changes in puberty. III. Correlation of plasma dehydroepiandrostereone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison's disease or hypogonadism or with premature or late adrenarche. J Clin Endocrinol Metab 41:894, 1975

Vol. 27, No. 7

DELAYED PUBERTAL DEVELOPMENT

11. Reiter EO, Root AW: Hormonal changes of adolescence. Med Clin North Am 59:1289, 1975 12. Boyar RM, Rosenfeld RS, Finkelstein JW, Kapen S, Roffwarg HP, Weitzman EO, Hellman L: Ontogeny of luteinizing hormone and testosterone secretion. J Steroid Biochem 6:803, 1975 13. Parker DC, Judd HL, Rossman LG, Yen SSC: Pubertal sleep-wake patterns of episodic LH, FSH and testosterone release in twin boys. J Clin Endocrinol Metab 40:1099, 1975 14. Hansen JW, Hoffman HJ, Ross GT: Monthly gonadotropin cycles in premenarcheal girls. Science 190:161, 1975 15. Grumbach MM, Roth SC, Kaplan SL, Kelch RP: Hypothalamic-pituitary regulation of puberty in man: evidence and concepts derived from clinical research. In The Control of the Onset of Puberty, Edited by MM Grumbach, GG Grave, FE Mayer. New York, John Wiley and Sons, 1974, p 115 16. Yen SSC, VandenBerg G, Rebar R, Ehara Y: Variation of pituitary responsiveness to synthetic LRF during different phases of the menstrual cycle. J Clin Endocrinol Metab 35:931, 1972 17. Frisch RE, McArthur JW: Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 185:949, 1974 18. Ronaghy HA, Halsted JA: Zinc deficiency occurring in females. Report of two cases. Am J Clin Nutr 28:831, 1975

755

19. Root AW: Endocrinology of puberty. II. Aberrations of sexual maturation. J Pediatr 83:187, 1973 20. Price WH: Delayed puberty. Br Med J 1:790, 1972 21. Bardin CW, Ross GT, Rifkind AB, Cargille CM, Lipsett MB: Studies of the pituitaryLeydig cell axis in young men with hypogonadotropic hypogonadism and hyposmia. Comparison with normal men, prepubertal boys and hypopituitary patients. J Clin Invest 48:2046, 1969 22. Barnes HV: The problem of delayed puberty. Med Clin North Am 59:1337, 1975 23. Biglieri EG, Herron MA, Buist N: 17-hydroxylation deficiency in man. J Clin Invest 45:1946, 1966 24. Westphal! 0: Hypothalamic releasing factors. Pediatr Ann 3:10, 1976 25. Reiter E, Duckett G, Root A: Effect of constant infusion of gonadotropin releasing hormone (Gn-RH) upon excretion of LH and FSH in children. Pediatr Res 10:343A, 1976 26. Kulin HE, Grumbach MM, Kaplan SL: Changing sensitivity of the pubertal gonadal hypothalamic feedback mechanism in man. Science 166:1012, 1969 27. De Bahar BR, Mendilaharzu H, Rivarola MA, Bergada C: Gonadotropin secretion in prepubertal and pubertal primary hypogonadism: response to LH-RH. J Clin Endocrinol Metab 41:1070, 1975

Evaluation and management of the child with delayed pubertal development.

*lliW*w* 10%) than the mean weight for height and body build. The diagnosis of constitutional delay in growth and sexual maturation is established by...
1MB Sizes 0 Downloads 0 Views