Associate Editor, ' ~

Transcription

1 FERTILITY AND STERILITY Copyright 1976 The American Fertility Society *lliw*w*<''*0mf'w*-'*-~:dwall;;h, M~ Associate Editor, ' ~ Vol. 27, No.7, July 1976 Printed in U.SA. EVALUATION AND MANAGEMENT OF THE CHILD WITH DELAYED PUBERTAL DEVELOPMENT* ALLEN W. ROOT, M.D., AND EDWARD 0. REITER, M.D. Department of Pediatrics, University of South Florida College of Medicine, Tampa, Florida 33612, and Ed Wright Pediatric Endocrinology Research Laboratory, All Children's Hospital, St. Petersburg, Florida The physical and hormonal changes of puberty are presented and the wide range of ages at which the pubertal process may begin is emphasized. The great variability in the timing of onset of adolescence, its rate of progression, and the age of completion are detailed. The causes of delayed adolescence in males and females are considered. The most common form of delayed adolescent development is termed constitutional delay in growth and development, which may occur sporadically, or may be the familial pattern of growth and development or may reflect a suboptimal nutritional environment. The evaluation of such children, including appropriate historical review, physical examination, and laboratory assessment, is outlined. In most patients with constitutional delay in growth and development, strong reassurance is sufficient therapy. In other subjects, treatment with androgens (boys) or estrogens (girls) may be indicated. In patients with primary systemic diseases associated with delayed maturation, specific treatment which eradicates the illness will often be followed by resumption of growth and development. In subjects with primary disorders of the hypothalamus, pituitary, or gonads, replacement therapy with androgens or estrogens is indicated. If gonadal function is intact, these patients may eventually become fertile with appropriate use of hypothalamic and/or pituitary hormones. Pubertyt is the transitional period between the immature state of sexual development and adult sexual maturation with attainment of reproductive capability. Failure to achieve sexual maturation at an age and time similar to that of one's peers is often accompanied by significant concern and occasionally by real anxiety which sometimes interferes with the child's ability to progress Received May 20, *Supported by National Foundation-March of Dimes Grant 1-323, C-199, and tthe terms puberty and adolescence are used interchangeably to indicate the process(es) of sexual maturation. effectively within his peer group. Although delayed puberty is usually a manifestation of the heterogeneity of the timing of the developmental processes, occasionally it signifies a more serious underlying systemic or endocrinologic disorder. It is the purpose of this paper to describe briefly the normal somatic and hormonal changes of puberty, to discuss abnormalities of this process, and to outline a rational plan for the evaluation and management of children with delayed puberty. Delayed adolescence occurs in 25/1000 children and is thus a problem of considerable frequency. In 2.5% of normal males the onset of sexual development will be delayed more than 2 745

2 746 ROOT AND REITER July 1976 years after the usual age of initiation, and in 0.1% the delay will be more than 3 years. 1 NORMAL PUBERTY Table 1 lists the stages of male genital development as described by Tanner 2 and the mean age and age range at which each developmental stage is achieved. Tables 2 and 3 list similar data for female breast development and pubic hair growth, respectively.2-6 The initial manifestation of male pubertal development is enlargement of the testes to a length greater than 2 em, whereas in the female acceleration of Stage 3 I II III IV v TABLE 1. Stages of Male Genital Development Description Prepubertal: testicular length < 2 em Testicular length >2 em <3.2 em; enlargement, thinning, and reddening of scrotal skin Testicular length >3.3 em <4.0 em; further enlargement and thinning of scrotum Testicular length >4.1 em <4.9 em; darkening and enlargement of scrotum; increase in penile width, length, and glan size Adult: testicular length > 5 em; scrotum pigmented and thickened; penis adult in size and configuration Age at onset 3 " 6 Mean Range yr Stage 2 TABLE 2. Stages of Female Breast Development Description Mean Age at onset Range I II III IV v Prepubertal Areolar widening, pigmentation; subareolar breast tissue Further breast enlargement Further breast enlargement with mounding of areola above plane of breast" Adult (variable size) yr a May not occur in all individuals. TABLE 3. Stages of Pubic Hair Growth Age 0 at onset3 6 Stage' Description Male Female Mean Range Mean Range yr I Prepubertal (hair absent) II Sparse, long, slightly curly and pigmented (13.4) ( ) (11.7) ( ) hair at base of phallus or scrotum (M) or on labia majora or mons veneris (F) III Increased quantity of coarsely pigmented, curled hair on mons veneris IV Curled, coarse hair covering mons veneris v Hair of adult quality and quantity covering entire mons veneris and medial aspect of thighs VI Extension of hair growth up linea alba (M) "Values in parentheses possibly are too high owing to error in experimental observations.

3 Vol. 27, No. 7 DELAYED PUBERTAL DEVELOPMENT linear growth velocity is the first physical indication of puberty. The peak height velocity in boys is reached at 14 years and in girls at 12 years. Normally there is areolar enlargement during male adolescence. A large number of boys (70%) will also develop subareolar breast tissue (benign adolescent gynecomastia) during puberty; in the majority of instances it will disappear within 6 to 18 months. Axillary hair usually appears 2 years after the onset of pubic hair growth. In males the onset of facial hair growth coincides with stage 3 of pubic hair development. As is indicated in the tables, there is a wide range of ages at which the physical signs of puberty may begin and at which the various stages of development are achieved. It should be pointed out that data cited in Tables 1 to 3 are derived from extensive English studies. 4 6 Although similar investigations in America have not been as extensive, available data suggest that the mean age of achievement of these milestones in American children is approximately 1 year eariler than in English children. 6 The mean age of menarche in English girls is 13.5 years, in white American girls is 12.8 years, and in black American girls 12.5 years. 7 The duration of each stage of male genital growth is variable. In general, adult male genital development is attained within 3.0 years after it is initiated. Pubic hair growth, in contrast, is usually complete within 1.6 years after initiation, although as many as 2. 7 years may elapse in some individuals before the attainment of stage 5 of pubic hair growth. If male genital development has not begun by 14 years, if it is incomplete more than 4.7 years after initiation, or if genital stage 5 has not been reached by 17.1 years of age, evaluation is required to be certain that systemic or endocrinologic disease does not exist. The stages of genital growth and pubic hair development in males are correlated to some extent. Thus 72% of boys will achieve genital stage 2 and 16% genital stage 3 before pubic hair growth begins. In only 2% of boys will pubic hair growth appear before genital enlargement. If this should occur, consideration should be given to primary disorders such as premature adrenarche or abnormalities of adrenal or gonadal function. In 75% of boys the peak height velocity coincides with genital stage 4, and so, in contrast to the female, is a later event of puberty. In the female, breast growth is usually complete 4.0 years after initiation, but as many as 9.0 years may elapse. Pubic hair growth is usually complete within 2.5 years, but 3.1 years may elapse. Sixteen per cent of girls may develop pubic hair before breast growth begins, but rarely is stage 3 or 4 of pubic hair growth achieved without breast development. Peak height velocity in girls coincides with stage 3 of breast growth and stages 2 and 3 of pubic hair development. Menarche occurs after the time of peak height velocity has passed. There is a significant correlation between age at menarche and body weight and, more important, body fat composition. The menarche is achieved at a mean weight of 47 kg. 8 Menarche coincides with breast stage 2 in 5%, stage 3 in 25%, stage 4 in 60%, and stage 5 in 10%. In 99% of females, menarche occurs within 5 years after onset of breast growth. HORMONAL CHANGES OF ADOLESCENCE The earliest hormonal changes of adolescence in both sexes involve secretion of the adrenal androgens--<lehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHAS) In the male, plasma levels of DHEA and DHAS begin to rise by 10 years of chronologie age; when correlated with bone age, DHEA levels increase by 7

4 748 ROOT AND REITER July 1976 i 16 ::l ] 12 J:...1 "'C iii 8 J: en u.. II Ill IV v STAGES OF PUBERTY T 600 LH ADULT 500 "'E 0 '" w 400..s z a: w 1- en 0 200!i; w FIG. 1. Sequential changes in peripheral concentrations of LH, FSH, and testosterone (T) during male adolescence. 11 ] 16 ::l ] J: 12...J "'C ""' J: 8 en u.. 4 II Ill IV V ADULT STAGES OF PUBERTY 70] c. "' 60 ::; 50 Q 0 40 ~ 1-30 ~ FIG. 2. Sequential changes in peripheral concentrations of LH, FSH, and estradiol (E 2 ) during female adolescence. 11 years. Testosterone concentrations increase slightly but significantly by 11 years (10 years bone age). 10 Although serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increase slowly between 5 and 10 years, concentrations of LH may not increase significantly until mean bone age 11, and FSH levels may not be significantly higher than prepubertal values until bone age 13 years.r;, 10 Plasma concentrations of DHEA and testosterone continue to increase during puberty until adult values are achieved. LH concentrations reach adult levels in late puberty, while FSH values are near adult level in midpuberty 11 (Fig. 1). In girls, plasma levels of DHEA increase by 8 years of chronologie age and by 7 years of bone age, with further increases throughout adolescence. 10 Testosterone values increase slightly but significantly with advancing (chronologie and bone) age. FSH values increase at bone age 12 and plateau by midpuberty. Estradiol and LH levels continue to increase until late puberty 11 (Fig. 2). In addition to the changes in the adrenal, gonadal, and pituitary hormone levels cited, alterations in the secretory dynamics of the pituitary gonadotropins and gonadal hormones also occur. In early, mid-, and late adolescence in both sexes, but not in prepubertal or adult subjects, there is a sleep-associated nocturnal rise in serum levels of LH and FSH (and testosterone in males)y Episodic secretion of LH, FSH, and testosterone is demonstrable in pubertal and adult subjects. 13 Cyclic secretion of gonadotropins occurs in girls in early to midpuberty. 14 In addition to basal changes in gonadotropin and gonadal hormone secretion, and alteration in the secretory dynamics of these hormones, puberty is accompanied by changes in pituitary ganadotrope secretory responsiveness to the hypothalamic decapeptide, gonadotropinreleasing hormone (Gn-RH). 15 In the prepubertal male, LH and FSH secretion following administration of Gn-RH by intravenous bolus or infusion or by intramuscular or subcutaneous injection is quite low and increases during puberty and still further in adulthood. In prepubertal girls the LH release after Gn RH administration is low, but FSH secretion is enhanced. During puberty and adulthood the LH response increases and the FSH response declines. In the cycling female, Gn-RH-induced LH secretion is maximal at midcycle. 16

5 Vol. 27, No. 7 DELAYED PUBERTAL DEVELOPMENT 749 The mechanism by which puberty occurs is unknown. It is currently hypothesized that increasing secretion of gonadotropins and gonadal hormones is accompanied by decreasing sensitivity of the centers within the hypothalamus which regulate the inhibitory effects of the sex hormones upon hypothalamicpituitary gonadotropin secretion. As a consequence of waning inhibitory sensitivity there is increased production of gonadotropin-releasing hormone, increased pituitary gonadotropin secretion, and increased gonadal sex hormone production. This process continues until the "adult" relationship within this system is achieved. In addition, in the female the anterior hypothalamic center or centers that regulate the cyclic discharge of gonadotropin also mature, and the "positive" feedback response to estrogens develops. The manner in which hypothalamic inhibitory sensitivity to gonadal hormones declines remains enigmatic. It is possible that alteration in adrenal androgen synthesis may be involved in this process The role of the pineal gland or of other central nervous system components in the maturational process remains speculative.6 ETIOLOGY OF DELAYED ADOLESCENCE Causes of delayed puberty are presented in Table 4. Constitutional delay in growth and development is by far the most common form of delayed adolescent growth and maturation encountered. The age range at which puberty may begin is extremely broad. Children with constitutional delay in growth and development represent those subjects whose timing of pubertal events is shifted to later years. This pattern of growth and maturation is often familial, and a similar history may be elicited from one or both parents, grandparents, aunts or uncles, or siblings. On oc- TABLE 4. Causes of Delayed Adolescence Constitutional delay in growth and development Malnutrition Anorexia nervosa Zinc deficiency Hypogonadotropic hypogonadism Disorders of hypothalamus and central nervous system Congenital Absence of gonadotropin releasing hormone Isolated Compound With anosmia (Kallmann's syndrome) With septo-optic dysplasia Sporadic Familial Other syndromes (Laurence-Moon-Biedl, Prader-Willi, Friedreich's ataxia) Acquired Postencephalitis Trauma Tumor Craniopharyngioma Cysts, gliomas of the hypothalamus Pinealoma Histiocytosis Granulomatous disease-sarcoidosis, tuberculosis Suppression by exogenous hormones Pyschologic trauma Systemic diseases Cardiovascular-congenital, acquired Respiratory-asthma Gastrointestinal-regional enteritis, ulcerative colitis Renal-renal failure, renal tubular acidosis Endocrine-hyperthyroidism, hypothyroidism, uncontrolled diabetes mellitus Collagen-vascular-lupus erythematosus, rheumatoid arthritis Disorders of pituitary Congenital Hypoplasia, aplasia Isolated deficiency of gonadotropes Acquired Hypophysitis Granulomatous disease Trauma Vascular insufficiency Neoplasm Primary-chromophobe, acidophil adenoma Metastatic carcinoma Histiocytosis Hypergonadotropic hypogonadism Disorders of ovaries Congenital Gonadal dysgenesis (45/X, XO/XX, XX, "pure") 17a-Hydroxylase deficiency Acquired Oophoritis, isolated; with hypoparathyroidism, thyroiditis, hypoadrenalism, and pernicious anemia

6 750 ROOT AND REITER July 1976 TABLE 4. Causes of Delayed Adolescence (Cont.) Trauma Neoplasms Oophorectomy secondary to neoplasms; ovarian torsion, etc. Radiation Disorders of vagina and uterus Congenital Absence of uterus and/or vagina Imperforate hymen Testicular feminization Disorders of testes Congenital Anorchia Testicular dysgenesis (XXY and mosaics) Deficiency of testicular enzymes (17, 20-lyase, 17,8-reductase, 3,8-hydroxysteroid dehydrogenase) Male pseudohermaphroditism Weinstein's, Reifensten's syndromes Male Tumer's syndrome Myotonia dystrophica Acquired Orchitis-mumps, gonorrhea, tuberculosis Torsion Trauma Orchiectomy Toxins Neoplasms Radiation Postorchiopexy Miscellaneous True hermaphroditism Functional ovarian tumors casion the growth pattern is the result of nutritional deprivation (vide infra) or it may occur spontaneously in some children. Although this pattern of maturation probably occurs with equal frequency in both sexes, many more boys than girls seek medical attention, possibly because of increased social pressures upon the male. Delay in growth and sexual maturation occurs in children with suboptimal nutrition. When the reproductive endocrine system matures and the secretion of gonadal hormones increases, the growth-promoting properties of these hormones are not expressed optimally because of the malnourished state. The skeleton-maturing effects of the gonadal steroids are normal, however, and thus bone age advances but the expected growth spurt does not occur. The malnourished subject completes his adolescence with fused epiphyses without achieving his (genetically) endowed height potential. In patients with severe malnutrition (anorexia nervosa), adolescent development may be markedly delayed. If puberty has occurred prior to the onset of this illness, primary and secondary sexual characteristics frequently regress, and the female patient becomes amenorrheic. Menses may not resume until weight exceeds by 5 to 10 pounds the weight at which the patient experienced her last menstrual periody In patients with marked deficiency of zinc, growth and sexual maturation may also be retarded. 18 Diseases that delay sexual maturation may involve either the hypothalamicpituitary axis, and are thus associated with decreased secretion of LH and FSH (hypogonadotropic hypogonadism), or the gonads, resulting in a compensatory increase in secretion of LH and FSH because the inhibitory feedback effects of the sex hormones have been removed (hypergonadotropic hypogonadism).! Occasionally, both decreased secretion of gonadotropins and end-organ insensitivity to gonadotropin are associated with other neurologic abnormalities (e.g., anosmia)y Disorders primarily affecting secretion of LH and/or FSH are associated with abnormalities of either the hypothalamus or pituitary. With the use of Gn RH it is possible to begin to determine which of these two areas is the primary site of disease. Hypothalamic abnormalities may be due to congenital factors, including absence of Gn-RH, synthesis of an abnormal, inactive Gn-RH, congenital malformations, in utero infections, perinatal hypoxia, or hemorrhage, or to acquired abnormalities such as encephalitis, meningitis, head trauma, or neoplasms. Primary abnormalities of the pituitary gland also interfere with secretion of LH and FSH. Patients with isolated deficiency of growth hormone

7 Vol. 27, No. 7 DELAYED PUBERTAL DEVELOPMENT 751 secretion have markedly delayed sexual maturation and (in males) small external genitalia. Primary gonadal abnormalities may be due to congenital factors. In "anorchic" males testicular function at the period of genital formation must be presumed, because the internal and external genitalia of these boys are normal.19 Sometime after the first trimester the testes must have involuted, and pockets of Leydig cells occasionally may be found in the normal testicular pathway of descent in these children. Boys with bilateral cryptorchidism not surgically repaired undergo normal secondary sexual maturation, but spermatogenic maturation is impaired because of the elevated intra-abdominal temperature. Patients with Klinefelter's syndrome may be suspected prepubertally because their testes are smaller than appropriate for the prepubertal state. In older boys there is gynecomastia, a enuchoid habitus, and often desultory sexual development. In patients with selective abnormalities of germinal tissue, normal secondary sexual development occurs with azoospermia or oligospermia. Classic gonadal dysgenesis (Turner's syndrome) in the female is associated with the 45/XO karotype, but in some females with gonadal dysgenesis, chromosome constitution and consequent phenotype may -be atypical. In the female, deficiency of gonadal and adrenal 17a-hydroxylase is characterized by sexual immaturity, hypertension, and hypokalemic alkalosis. 23 The testes or ovaries may also be injured during childhood by inflammatory, toxic, infectious, traumatic, neoplastic, hormonal, radiation, and surgical insults. Many systemic diseases may also delay or inhibit normal sexual maturation, primarily by inhibiting hypothalamic-pituitary maturation. The role of impaired nutrition and poor weight gain in these patients is probably of greatest importance. EVALUATION AND DIAGNOSIS Evaluation of the child with delayed adolescence may be undertaken when there is parental or patient concern no matter what the age of the patient. However, evaluation should be initiated in boys if no sign of sexual development (testicular enlargement) has occurred by 14 years and in girls if there is absence of breast budding at 13 years of age. In younger subjects it is usually sufficient to review the personal and family history, to examine the patient thoroughly, and to determine the bone age. In most patients with constitutional delay in growth and development the medical history (including gestational and birth histories, nutrition, and illnesses) is unremarkable, and past measurements reveal a youngster with a normal growth velocity whose height has been maintained at or very near the lower limits of normal. Physical examination is normal except for immaturity, and height age is less than 2 SD below the mean for age. The child in whom nutritional deprivation is of importance in the genesis of the delayed pattern of growth and development may be identified by the observation that his weight is considerably less (> 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-

8 752 ROOT AND REITER July 1976 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 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 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 Gn RH 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 In males with anorchia, LH and FSH values

9 Vol. 27, No. 7 DELAYED PUBERTAL DEVELOPMENT 753 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 androgen sensitivity inherited either as an X linked 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

10 754 ROOT AND REITER July 1976 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. 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, 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 Barnes HV: Physical growth and development during puberty. Med Clin North Am 59:1305, Marshall WA, Tanner JM: Variations in pattern of pubertal change in girls. Arch Dis Child 44: Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13, Root AW: Endocrinology of puberty. I. Normal sexual maturation. J Pediatr 83:1, MacMahon B: Age at Menarche. United States. Department of Health, Education and Welfare Publication No. HRA 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 Hopper BR, Yen SSC: Circulating concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate during puberty. J Clin Endocrinol Metab 40:458, 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

11 Vol. 27, No. 7 DELAYED PUBERTAL DEVELOPMENT Reiter EO, Root AW: Hormonal changes of adolescence. Med Clin North Am 59:1289, 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, 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, Hansen JW, Hoffman HJ, Ross GT: Monthly gonadotropin cycles in premenarcheal girls. Science 190:161, 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 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, Frisch RE, McArthur JW: Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 185:949, Ronaghy HA, Halsted JA: Zinc deficiency occurring in females. Report of two cases. Am J Clin Nutr 28:831, Root AW: Endocrinology of puberty. II. Aberrations of sexual maturation. J Pediatr 83:187, Price WH: Delayed puberty. Br Med J 1:790, Bardin CW, Ross GT, Rifkind AB, Cargille CM, Lipsett MB: Studies of the pituitary Leydig cell axis in young men with hypogonadotropic hypogonadism and hyposmia. Comparison with normal men, prepubertal boys and hypopituitary patients. J Clin Invest 48:2046, Barnes HV: The problem of delayed puberty. Med Clin North Am 59:1337, Biglieri EG, Herron MA, Buist N: 17-hydroxylation deficiency in man. J Clin Invest 45:1946, Westphal! 0: Hypothalamic releasing factors. Pediatr Ann 3:10, 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, Kulin HE, Grumbach MM, Kaplan SL: Changing sensitivity of the pubertal gonadal hypothalamic feedback mechanism in man. Science 166:1012, 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