Pediatric Annals

Delayed Adolescence

Ruth Illig, MD

Abstract

1. Tanner. J. M. Growth and Adolescence. Oxford and Edinburgh: Blackwell Scientific Publications, 1962.

2. Van Wieringen. JC, Wafelbakker. F.. Verbrugge, H. P., and de Haas, J. H. Groeidiagrammen Nederland 1965. Groningen: Wolters-Noordhoff n.v.. 1968.

3. Andersen, E. Skeletal maturation of Danish school children in relation to height, sexual development, and social conditions. Ac fa Paedit. Scand. 57 (1968).

4. Marshall, W. A. and Tanner, J. M. Variations in the pattern of pubertal changes in boys. Arch. Dis. Childh. 45 (1970). 13.

5. Martin. L.G.. Clark, J. W., and Connor. T.B. Growth hormone secretion enhanced by androgens. J. Clin. Endocr. M e tab. 38 (1968). 425.

6. Deller. JJ. . Boulis, M.W.. Harrlss. W. E., Hutsell, T. C, Garcia, J. F., and Linfoot, J. A. Growth hormone response patterns to sex hormone administration in growth retardation. Amer. J. Med. Sci. 259 (1970). 1366.

7. Illig, R. and Prader, A. Effects of testosterone on growth hormone secretion in patients with anorchia and delayed puberty. J. Clin. Endocr. Metab. 30 (1970). 615.

8. Greulich, W. W. and PyIe, S.I. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford: Stanford University Press, 1959.

9. Bayiey, N. and Pinneau. S. R. Tables for predicting adult height from skeletal age: Revised for use with the Greulich-Pyte hand standards. J. Ped. 40(1952). 432.

10. HIIg, R., Pluznik, S.. Werner, H.. and Prader, A. The effect of synthetic LHRH on plasma LH and FSH in 92 children and adolescents with delayed, disturbed or deficient sexual maturation. Metabolic. Horm. Res. In press.

TABLE 1

COURSE OF PUBERTY IN BOYS

Figure 5. Effect of testosterone on growth hormone response to insulininduced hypoglycemia. In a boy with delayed adolescence the equivocal growth hormone response was normalized already, two days after one injection of 500 mg. Depo-testosterone and became even higher after three months of testosterone therapy.

In the patient with growth hormone deficiency no growth hormone response was seen either before or during testosterone therapy.

TABLE 2

DELAYED ADOLESCENCE WITH FAMILIAL OCCURRENCE…

Today, concern about lack of sexual maturation and slow growth occurs at a relatively early age. This may be due to common knowledge about the secular trend towards earlier maturation and accelerated growth rate and overaccentuation of sexuality. In consequence, many boys between 14 and 16 years of age, but rarely girls, seek medical advice.

In most of these cases, the past and present history of the patient and the family, the physical examination, and the skeletal age derived from a hand and wrist roentgenogram reveal a benign retardation of physical development - benign because there is a delay, rather than any defect of, growth and maturation, associated with a late onset of puberty.

Figure 1. Diagram of sequence of events at adolescence in boys. An average boy is represented. The range of ages within which each event charted may begin and end is given by the figures placed directly below its start and finish.

Figure 1. Diagram of sequence of events at adolescence in boys. An average boy is represented. The range of ages within which each event charted may begin and end is given by the figures placed directly below its start and finish.

Figure 2. Diagram of sequence of events at adolescence in girls. An average girl is represented. The range of ages within which some of the events may occur is given by the figures placed directly below them.

Figure 2. Diagram of sequence of events at adolescence in girls. An average girl is represented. The range of ages within which some of the events may occur is given by the figures placed directly below them.

In order to establish the diagnosis of this benign form of retarded maturation, commonly called delayed adolescence, it is necessary to know the normal events of puberty; to consider the wide variation in normal maturation; to evaluate the relations between chronologic age, skeletal maturation, growth rate, and developmental rating of puberty; and finally, to exclude metabolic, endocrine, or other causes of lack of sexual maturation and delay of growth.

NORMAL EVENTS OF PUBERTY

In boys, the first perceptible sign of puberty (though frequently not noticed) is growth of the testes and scrotum. This is followed, usually one year later, by the appearance of pubic hair and the enlargement of the penis (Figure I).1 In girls, the appearance of pubic hair and breast development usually precede the menarche by more than one year (Figure 2).

The development of the reproductive system is associated with quantitative and morphologic changes of muscles, skeleton, and subcutaneous fat which are very different in boys and girls. Inherent to both sexes is the accelerated growth rate.

The so-called adolescent (circumpubertal) growth spurt - like the other events of puberty - closely follows a known sequence of events independent of the patient's age at the beginning of puberty. It is helpful to know that in individual boys, of whatever age, the growth spurt begins one year after the onset of testicular growth and about simultaneously with the enlargement of the penis. In individual girls, there is a close relationship between the beginning of the growth spurt and breast development. The peak of growth spurt usually has passed when menarche occurs.

VARIATION IN NORMAL MATURATION

The ages at the onset of puberty and at the appearance and full development of secondary sex characteristics in boys are given in Table 1. These figures represent the mean obtained by three European study groups (Holland,2 Denmark,3 and Great Britain4).

The so-called normal range (which includes the mean +2 S.D. or 95 per cent of all boys) therefore includes a period of four years. This means that the onset of puberty in boys (beginning of growth of the testes) between 9Vi and 13 Vi years of age can be considered normal. Five per cent of all boys fall outside this normal range. In half of them (2.5 per cent) puberty is more than two years late, and in 0.1 per cent of them puberty is even more than three years retarded (compared to the normal mean). The occurrence of delayed onset of puberty in 25 among 1,000 children explains why physicians are rather frequently confronted with this situation.

Table

TABLE 1COURSE OF PUBERTY IN BOYS

TABLE 1

COURSE OF PUBERTY IN BOYS

Figure 3. Growth chart of a boy with delayed adolescence. The flattening o1 the growth curve leads to the suspicion of acquired growth hormone deficiency but the growth spurt associated with the appearance of pubertal signs proves the diagnosis of delayed adolescence.

Figure 3. Growth chart of a boy with delayed adolescence. The flattening o1 the growth curve leads to the suspicion of acquired growth hormone deficiency but the growth spurt associated with the appearance of pubertal signs proves the diagnosis of delayed adolescence.

Figure 4. Growth velocity curve of the same patient with delayed adolescence as in Figure 3.

Figure 4. Growth velocity curve of the same patient with delayed adolescence as in Figure 3.

TIME COURSE OF GROWTH

One of the main complaints of patients with delayed adolescence (and in younger boys sometimes the only one) is their small stature. Because their adolescent growth spurt, which causes them to grow around 20 cm. (7.9 in.) within two to three years, occurs (on the average) two or more years later than it occurs in their peers, the height difference may be considerable. The variation of age at the onset of the pubertal growth spurt explains the wide range of normal height during this period of life (in 14-year-old boys, 1 S.D. of height = 8.3 cm. or 3.3 in.).

Statistical tables and percentile curves of normal growth based on cross-sectional studies of a population which is heterogenous with respect to pubertal development therefore contribute little to the evaluation of the growth delay of these children. Of more value is the analysis of individual growth curves- which usually show a characteristic pattern in patients with delayed adolescence.

Figures 3 and 4 show the growth chart and the growth velocity curve of a boy who was admitted because of small stature. His growth rate before the onset of puberty was less than 4 cm. /year (1.6 in. /year), his growth curve dropped below the third percentile at a time when an increase of testicular volume was already noticeable. At the age of 15 years, simultaneously with the appearance of pubic hair, his growth started to speed up to a peak growth velocity of 10 cm. /year (3.9 in. /year), and at the age of 18 his height DIFFERENTIAL DIAGNOSIS

Not infrequently, constitutional small stature is associated with delayed adolescence. The growth curves of these patients lie below the third percentile but follow it side by side. Towards the age of puberty, however, they deviate more and more from the third percentile of normal height, resembling growth curves of patients with isolated growth hormone deficiency. Growth hormone (GH) stimulation tests may give equivocal results;5'6 repetition of these tests after a single injection of testosterone for diagnostic reasons leads to a normalization of the growth hormone response (Figure 5). Therefore, androgen administration allows the differentiation between isolated GH deficiency and delayed puberty in patients with constitutional small stature.7

Table

Figure 5. Effect of testosterone on growth hormone response to insulininduced hypoglycemia. In a boy with delayed adolescence the equivocal growth hormone response was normalized already, two days after one injection of 500 mg. Depo-testosterone and became even higher after three months of testosterone therapy.In the patient with growth hormone deficiency no growth hormone response was seen either before or during testosterone therapy.

Figure 5. Effect of testosterone on growth hormone response to insulininduced hypoglycemia. In a boy with delayed adolescence the equivocal growth hormone response was normalized already, two days after one injection of 500 mg. Depo-testosterone and became even higher after three months of testosterone therapy.

In the patient with growth hormone deficiency no growth hormone response was seen either before or during testosterone therapy.

HEREDITARY FACTOR

The mechanism by which puberty is induced is not yet clearly understood but there is little doubt that socioeconomic and hereditary factors play a role in the variability of the beginning of puberty. The familial occurrence of late onset of puberty and retarded growth is well known and is an important factor in establishing the diagnosis of delayed adolescence. There are two relatively reliable criteria for the timing of puberty in family members - the age of menarche in the females and the difference between present adult height and the height measured at recruitment for military service in males. Menarche at the age of 15 years or later and growth after the age of 18 to 20 are in agreement with the diagnosis of benign delay of growth and maturation.

Figure 6. Extremely delayed adolescence with familial occurrence in a patient at the age of 163/12 (left) and 219/12 years (right).

Figure 6. Extremely delayed adolescence with familial occurrence in a patient at the age of 163/12 (left) and 219/12 years (right).

The boy in Figure 6 is an example of extremely delayed adolescence with familial occurrence. At the age of 16 he was small and showed no signs of beginning puberty; at the age of 23 he has attained normal adult height and complete sexual maturation (Table 2). His grandfather, father, and one of his brothers were also extremely small at the age of 19 and had grown considerably thereafter.

SKELETAL MATURATION

Skeletal maturation and puberty are more closely correlated than puberty and chronologic age. At the onset of puberty in normal children the variation of the so-called bone age is considerably smaller than the variation of chronologic age.1 Therefore, an x-ray examination of the hand and wrist for bone age is a useful indicator for evaluating maturity and biologic age. It allows the prediction of the onset of puberty, which is marked by the appearance of the sesamoid bone (in normal girls at 11 years of age, in normal boys at 13 years of age).

In patients with delayed adolescence skeletal maturation is always delayed by one year or more. If skeletal and chronologic age are alike, or if bone maturation is accelerated, delayed adolescence can be excluded.

Table

TABLE 2DELAYED ADOLESCENCE WITH FAMILIAL OCCURRENCE

TABLE 2

DELAYED ADOLESCENCE WITH FAMILIAL OCCURRENCE

The determination of the bone age according to Greulich and PyIe* also allows the prediction of the adult height by using the tables of Bayley and Pinneau.9

DIAGNOSIS

A carefully taken family and personal history, a thorough examination of the patient, the developmental rating of puberty,1 analysis of the growth curve, and a roentgenogram of the hand and wrist usually allow the exclusion of known metabolic, organic, or endocrine causes of delayed puberty and small stature without further laboratory tests. In some cases with extreme growth retardation, growth hormone determinations may be necessary (see above).

The discovery of the hypothalamic luteinizing hormone-releasing hormone (LH-RH) and its purification, structural elucidation, and synthesis have added a new tool for the diagnostic work-up of patients with lacking sexual maturation and small stature at the age of puberty. The determination of plasma luteinizing hormone (LH) and follicle - stimulating hormone (FSH) after stimulation with LH-RH has proved to be of great value in differentiating patients with isolated gonadotropin deficiency without release of LH and FSH; children with delayed adolescence with a normal rise of LH and FSH; and patients with primary gonadal failure such as anorchia, Turner's syndrome, etc., with an excessive increase of LH and FSH.10 Until recently, isolated gonadotropin deficiency and delayed adolescence could be distinguished only by clinical observation over a long period of time. The basal values of plasma and urinary LH and FSH were of little help because of the overlap of normal and decreased values at this age. With the help of the LH-RH test it is possible to establish the correct diagnosis and to predict the spontaneous occurrence of puberty.

THERAPY

As soon as the diagnosis of delayed adolescence is established, the question of hormone treatment arises. Since the absence of development of secondary sex characteristics and the small stature of these patients are simply caused by the extremely late onset and slow course of their normal maturation, there is no somatic need for a hormonal induction of puberty and growth spurt. Very often an open discussion with the patient alone and together with the parents, as well as the prediction of a normal adult size, help to overcome the problem. It is a rewarding task for a physician to convince a young boy or girl of the benign character of the growth delay and to reassure them about their late but normal maturation.

In some cases, mainly in boys, psychological difficulties and social pressure are so severe that a testosterone therapy is justified. A dosage of 250 mg. testosterone cypionate (DepoTestosterone Cypionate) LM. monthly or 10 mg. methyltestosterone orally per day lead to a dramatic change of physical appearance and of mental behavior. As soon as the skeletal age reaches 13 years therapy can be withdrawn and puberty, once induced, continues spontaneously. Testosterone therapy may lead to some reduction of the final adult height. But sometimes this price has to be paid for the great psychological benefit of the therapy.

SUMMARY

Delayed adolescence occurs in about 25 of 1,000 children and may cause psychosocial problems around the age of puberty. The diagnosis is based on the simultaneous retardation of sexual maturation, bone age, and linear growth in otherwise healthy boys and girls and on the familial occurrence of delayed puberty.

Growth hormone determinations may be necessary to differentiate between delayed adolescence with severe growth retardation and isolated growth hormone deficiency. The determination of plasma LH and FSH after stimulation with LH-RH allows a prompt differentiation between gonadotropin deficiency and delayed adolescence.

Treatment with testosterone is indicated only when serious psychological problems are present.

BIBLIOGRAPHY

1. Tanner. J. M. Growth and Adolescence. Oxford and Edinburgh: Blackwell Scientific Publications, 1962.

2. Van Wieringen. JC, Wafelbakker. F.. Verbrugge, H. P., and de Haas, J. H. Groeidiagrammen Nederland 1965. Groningen: Wolters-Noordhoff n.v.. 1968.

3. Andersen, E. Skeletal maturation of Danish school children in relation to height, sexual development, and social conditions. Ac fa Paedit. Scand. 57 (1968).

4. Marshall, W. A. and Tanner, J. M. Variations in the pattern of pubertal changes in boys. Arch. Dis. Childh. 45 (1970). 13.

5. Martin. L.G.. Clark, J. W., and Connor. T.B. Growth hormone secretion enhanced by androgens. J. Clin. Endocr. M e tab. 38 (1968). 425.

6. Deller. JJ. . Boulis, M.W.. Harrlss. W. E., Hutsell, T. C, Garcia, J. F., and Linfoot, J. A. Growth hormone response patterns to sex hormone administration in growth retardation. Amer. J. Med. Sci. 259 (1970). 1366.

7. Illig, R. and Prader, A. Effects of testosterone on growth hormone secretion in patients with anorchia and delayed puberty. J. Clin. Endocr. Metab. 30 (1970). 615.

8. Greulich, W. W. and PyIe, S.I. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford: Stanford University Press, 1959.

9. Bayiey, N. and Pinneau. S. R. Tables for predicting adult height from skeletal age: Revised for use with the Greulich-Pyte hand standards. J. Ped. 40(1952). 432.

10. HIIg, R., Pluznik, S.. Werner, H.. and Prader, A. The effect of synthetic LHRH on plasma LH and FSH in 92 children and adolescents with delayed, disturbed or deficient sexual maturation. Metabolic. Horm. Res. In press.

TABLE 1

COURSE OF PUBERTY IN BOYS

Figure 5. Effect of testosterone on growth hormone response to insulininduced hypoglycemia. In a boy with delayed adolescence the equivocal growth hormone response was normalized already, two days after one injection of 500 mg. Depo-testosterone and became even higher after three months of testosterone therapy.

In the patient with growth hormone deficiency no growth hormone response was seen either before or during testosterone therapy.

TABLE 2

DELAYED ADOLESCENCE WITH FAMILIAL OCCURRENCE

10.3928/0090-4481-19740701-04

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