Pediatric Annals

Sexual Precocity

Werner Blunck, MD

Abstract

1. Tanner, J. M. Growth and Endocrinology of the Adolescent. L.I. Gardner, ed. In Endocrine and Genetic Disorders of Childhood. Philadelphia and London: W. B. Saunders Co., 1969, 19.

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

3. Tanner, J. M., Whltehouse, R. H., and Healy, M. J. R. A New System for Estimating Skeletal Maturity from the Hand and Wrist with Standards Derived from a Study of 2600 Healthy British Children. Paris: Centre International de l'enfance, 1962.

4. Kelch, R. P., Kaplan, S. L.. and Grumbach, M. M. Suppression of plasma and urinary gonadotropins by exogenous estrogens in prepubertal and pubertal children. American Pediatric Society, Washington. May 1972. Abstract In Ped. Res. 6 (1972), 354.

5. Werff ten Bosch, J.J. van der. Control of Puberty by Endocrine and Other Factors. Proceedings Second International Congress Endocrinology (London) Part 2. 833. Internat. Congr. Ser. N. 83. Amsterdam and New York: Excerpta Medica Foundation, 1965.

6. Driggs, M. and Spatz. H. Virchows Arch. Path. Anat. 305 (1939), 567.

7. Bierich, J. R., Blunck, W., and Schönberg, D. Über Frühreife II. Frühreife bei cerebralorganischen Erkrankungen. Mschr. Klnderheilk. 115 (1967), 509.

8. Beas, F., ZurbrUgg, R. P., Leibow, S. G., Patton, G. R., and Gardner, L. I. Familial male precocity: report of the eleventh child found, with observations on blood group linkage and urinary Cig-steroid excretion. J. Clin. Endocrin. 22(1962), 1095.

9. Blunck, W., Bierich, J. R., and Bettendorf, G. Über Frühreife III. Idiopathische Pubertas praecox, temporäre Frühreife und praemature Thelarche. Mschr. Kinderheilk. Î5(1967), 555.

10. Kuppermann, H. S. and Epstein, J. A. Medroxyprogesterone acetate in the treatment of constitutional sexual precocity. J. Clin. Endocrin. 22 (1962). 456.

11. Kaplan, S.A.. Ling, Sh. M., and Irani, N. G. Idiopathic isosexual precocity-therapy with medroxyprogesterone. Amer. J. Dis. Childh. 116 (1968). 591.

12. Werder, E. A., MUrset, G., Zachmann, M., Brook, C. G. D., and Prader, A. Treatment of precocious puberty with cyproterone acetate. Pediat. Res. 8 (1974), 248.…

For many parents, even normal puberty in their children creates a change of attitude and behavior towards the children. Parents of patients with precocious puberty often are more disturbed and afflicted than would be expected for the importance of the disorder. In contrast, the patients are normally just as childlike and unaffected as other children of the same chronologic age. Sometimes they even seem to be a bit too boisterous. This could be due to their physical superiority to other children of the same age group. This discrepancy in the behavior of the parents and the children is typical when a patient with precocious puberty is seen in the physician's office.

NORMAL PUBERTAL DEVELOPMENT

In general terms, precocious puberty means that a patient passes through sexual maturation earlier and more quickly than other children. The symptoms of the disorder are the signs of normal pubertal development. This normal course may be altered or complicated in special forms, which will be discussed later.

As a basis for better understanding it is necessary to review some of the essentials of normal sexual maturation:

1. Pubertal physical development (growth spurt, increase in muscle size, development of breasts and pubic hair, as well as menarche) is affected by increasing levels of sex steroid hormones in the blood.

2. The increased production of estrogens and androgens in the gonads and the adrenal gland is promoted by increasing levels of gonadotropins, which are protein hormones produced by the anterior lobe of the pituitary gland.

3. This increase in gonadotropin production is due to enhanced stimulation of the gonadotropin-producing cells by gonadotropin releasing hormone(s), which reach the pituitary gland from the median eminence of the hypothalamus via special portal vessels along the stalk of the pituitary gland.

4. It is not known why at a certain stage of maturation an increase in the production of hypothalamic gonadotropin hormone(s) occurs. A number of interesting results of research in this field allow speculations regarding the control of sexual maturation or, vice versa, the "preservation of childhood."

PHYSICAL SIGNS OF PUBERTY

Thelarche and pubarche. The normal course of pubertal development is illustrated in Figure 1. We prefer this type of wedge graph because the wedges demonstrate best that sexual maturation is primarily a continuous development that lasts for three to four years until a preliminary final stage is reached. Photographic examples of the different stages of breast and pubic hair development are shown in Tanner.1 Three to four years after the first signs of pubarche 90 per cent of all girls have a pubic hair development comparable to stage 5 according to Tanner. In stage 5 the pubic hair forms a horizontal upper line, in contrast to the male type of distribution, which extends to the naval (= type 6). Thelarche and pubarche are fixed events but represent a long-term developmental process.

Figurs 1. Average liming of sexual maturation.

Figurs 1. Average liming of sexual maturation.

Menarche. During the development of uterus and endometrium, menarche indicates a certain degree of endometrial maturation and cyclic steroid production. The first ovulatory cycles normally occur one to two years later. Although the time of menarche may be influenced by several psychological and nutritional factors, there is a high correlation of menarche with bone maturation.

Longitudinal growth and adolescent growth spurt. The increase in height (growth velocity) steadily decreases during childhood. During their twelfth year of life boys have the slowest growth velocity, on the average of 5 cm. (2.0 in.) per year. The "average boy" of 12 years of age is about 145 cm. (57.1 in.) tall, and his external genitalia are infantile. During the next four years he will grow rapidly, with a maximal growth velocity of about 10 cm. (3.9 in.) per year at the age of 14 years. This increase in growth is known as adolescent growth spurt. Thereafter growth velocity decreases again until a final height of about 175 cm. (68.9 in.) is reached.

If growth velocity is plotted against age (Figure 2), a typical curve is achieved, showing a constant deceleration during childhood and the adolescent growth spurt as a peak. In girls this peak is found two years earlier. Adolescent growth spurt occurs parallel to the development of pubertal hair. It is well accepted that growth spurt in both sexes is induced by androgens, and that the growth hormone serves as a permissive factor.

Figure 2. Typical individual growth velocity curves for supine length or height. These curves represent the velocity of the typical boy and girl at any given instant.

Figure 2. Typical individual growth velocity curves for supine length or height. These curves represent the velocity of the typical boy and girl at any given instant.

Figure 3. The gonadostat as control br sex steroid hormone levels.

Figure 3. The gonadostat as control br sex steroid hormone levels.

Bone maturation. During adolescence both growth hormone and androgens influence the epiphyseal cartilage, so that growth of the legs and arms is pronounced. Radiographs of the epiphyseal lines show an increasing closure. When longitudinal growth is completed, all epiphyseal lines are closed. Usually, a radiograph of the left hand is made to evaluate the stage of bone maturation. The hand is taken as a parameter because of the great number of epiphyseal lines and because the development of the wrist bones and of sesamoid bones give further information.

The evaluation of skeletal maturation usually is performed by comparison of the radiograph with standard radiographs of normally developed children2 or by application of the "skeletal maturity score."3 When an individual x-ray film is compared with standard radiographs, difficulties of interpretation often arise because some centers show more accelerated development while others may be relatively retarded. The maturity score of Tanner3 may provide a more objective evaluation, although its application is much more laborious.

Because of the close correlation between bone maturation and longitudinal growth, a "growth prognosis" can be performed from the child's actual height and bone age. For instance, a girl with bone age of 11 years (at the beginning of growth spurt) and a chronologic age between 10 and 12 years attained 90.6 per cent of her adult height. The greater the difference between chronologic age and bone age, the greater the care that must be taken in interpreting the calculated result. The same is true if there is a greater difference between bone age and stage of sexual maturation.

SEX STEROID HORMONES IN CHILDHOOD AND SEXUAL MATURATION

The results of radioimmunologic estimation of steroid hormones in the plasma of children show that sex steroid hormones are produced, although they have no demonstrable influence on sex-specific target organs. Because the levels of estrogens and androgens are very low it is generally accepted that breast development and pubarche begin when a certain hormonal threshold is crossed. This thesis should not be taken too dogmatically, however, because alterations in the target cell metabolism may influence the mode of action of the hormones. At least, childhood is not life without sexual hormones.

During childhood the production of sex steroid hormones is regulated by a hypothalamic-pituitary feedback mechanism. Hypothalamic centers - in comparison to the function of a thermostat - may be named "gonadostat," although this term is attended with all the risks of oversimplification. During childhood the gonadostat is very sensitive; low levels of sex steroids block further hypothalamic stimulation of the pituitary gland to produce gonadotropins. There is no doubt about the central function of this gonadostat because the gonads of children can produce higher amounts of sex steroid hormones if stimulated by administration of exogenous gonadotropins. In addition, the infantile pituitary gland can produce higher amounts of gonadotropins if stimulated by administration of a gonadotropin releasing hormone such as luteinizing hormonereleasing hormone (LH-RH).

Figure 4. Positive influences on sex steroid hormone production: hypothalamus→pituitary gland = gonadotropin releasing hormones. Pituitary gland→gonad: gonadotropins.

Figure 4. Positive influences on sex steroid hormone production: hypothalamus→pituitary gland = gonadotropin releasing hormones. Pituitary gland→gonad: gonadotropins.

Figure 5. Survey of the different forms of precocious sexual development.

Figure 5. Survey of the different forms of precocious sexual development.

The function of the gonadostat in children was demonstrated by Kelch,4 who administered very small amounts of estrogens to prepubertal children. Ethinyl estradiol, 2 to 3 mcg./m.2 per day suppressed urinary gonadotropin (follicle-stimulating hormone, FSH) excretion completely. Many other experiments in animals give strong support to this concept. If the ovaries are not able to synthesize even the small amounts of estrogens required during childhood (such as in Turner's syndrome), an increasing gonadotropin secretion is evident.

The alterations in sex steroid hormone levels that occur during adolescence are shown in Figure 3. Sensitivity of the gonadostat decreases, or rather the setting of the control is tuned in the direction of adult values. The first demonstrable effect of gonadotropin stimulation in boys is growth of the testis. There is strong correlation between the size of the testis and testosterone excretion in the urine.

Figure 6. Some forms of precocious puberty caused by cerebral lesions.

Figure 6. Some forms of precocious puberty caused by cerebral lesions.

RELEASING HORMONES AND CENTRAL NERVOUS FACTORS INFLUENCING ONSET OF PUBERTY

Sexual precocity means that the adjustment of the gonadostat (becoming less sensitive) happens much earlier than normal. Our knowledge of factors influencing the onset of puberty in the human is limited. Almost all of the experiments in this area have been done in animals (mostly rats or ferrets). It is known that there are centers that have a "childhood-preserving influence" (Figure 4). For example, the pineal gland contains soluble factors (e.g., melatonin) that inhibit sexual development. If the pineal gland is destroyed during childhood by a tumor, many of these male patients develop precocious puberty. In the ferret such puberty-inhibiting areas were demonstrated in the anterior part of the hypothalamus.5

Regarding sensitivity of the hypothalamus to circulating sex steroids, recent studies show that a steroid-5alpha-reductase converts testosterone into the physiologic effective metabolite 5 - alpha - dihydrotestosterone (=DHT). The activity of this enzyme is very high in the hypothalamus of baby rats. Hypothalamic 5-alphareductase activity decreases during childhood, and its activity is very low at the sixtieth day of life (puberty). Martini speculates that now less testosterone is converted so that higher testosterone plasma levels are necessary to effect equal inhibition. This hypothesis is the first approach to explain the assumed alteration of the gonadostat sensitivity.

AT WHAT AGE IS PRECOCIOUS SEXUAL DEVELOPMENT PATHOLOGIC?

If it is said that the average age at which the first menstrual bleeding occurs is, for example, 12.9 years, this statistical information is rather meaningless for the individual girl because there are great individual deviations from the arithmetic mean. In statistical terms, the single standard deviation (S.D.) for most pubertal events is one year. Thus, normal range equals mean ± 2 S.D. and menarche occurs between age 10.9 to 14.9 years in 95.5 per cent of all girls. Earlier menarcheal age occurs in 2.25 per cent of all girls but these girls are healthy and their sexual maturation is normal. Defining a date before which sexual maturation may be pathologic is arbitrary, and these data more or less depend on clinical experience. In our group a pubertal symptom occurring four years ( = 4 S.D.) before the mean is called "pathologic " and requires intensive diagnostic procedures to exclude cerebral disorders. This standard should not be taken as dogma but as a rule with many exceptions; e.g., any neurologic abnormality should be followed very carefully. Girls who mature later than these arbitrary limits of normal development also deserve investigation.

CLASSIFICATION AND NOMENCLATURE

Precocious puberty means precocious sexual maturation induced by pituitary gonadotropins. If sex steroid hormones are produced in a gonadal tumor, by disorders of the adrenal gland (e.g., adrenogenital syndrome or adrenal carcinoma), or by a gonadotropin-producing hamartoma of the liverorachorionepithelioma, the name of the disease should be used. Terms like "Pseudopubertas praecox" or "macrogenitosomia" are embarrassing and should be avoided.

A patient with precocious puberty normally passes through all stages of pubertal development. Growth spurt and pubarche indicate precocious androgen secretion and premature thelarche reflects estrogen production; the increasing cyclic activity of the hypothalamus causes menstrual bleedings.

In some patients only a slightly elevated androgen production is evident, so precocious development of pubertal hairs and sometimes slight growth acceleration without breast development or transformation of the vaginal mucosa occurs (premature pubarche or adrenarche). Rather often, especially in girls one to two years of age, an isolated precocious breast development without other signs of puberty is found (premature thelarche). Precocious menstrual bleedings without other signs of puberty (premature menarche) are rare and might reflect early maturation of cycling activities. Thus, a complete precocious pubertal development can be differentiated from isolated forms (Figure 5).

Figura 7. Boy of 10 years. It is said that his penis was already enlarged at birth, and first pubertal hairs appeared at age three months.

Figura 7. Boy of 10 years. It is said that his penis was already enlarged at birth, and first pubertal hairs appeared at age three months.

FORMS OF EARLY SEXUAL MATURATION

Cerebral disorders causing early sexual development. In Figure 6 some forms of cerebral lesions causing premature sexual development are shown schematically.

Figure 8. Eight-year-old girl with congenital hydrocephalus. First signs of puberty at age five years.

Figure 8. Eight-year-old girl with congenital hydrocephalus. First signs of puberty at age five years.

As mentioned above, there is good evidence that the pineal gland has a negative influence on sexual maturation. If the pineal gland is destroyed by a tumor (e.g., pinealoblastoma), precocious development occurs in many of the male patients.

Cerebral tumors in the region between posterior hypothalamus and pineal gland often cause precocious sexual development. In the human it is not clear whether certain childhoodpreserving centers are destroyed or whether the connection between pineal gland and hypothalamus is interrupted. These cerebral tumors and those of the pineal gland usually produce significant neurologic symptoms and may be detected by usual neuroradiographic methods

A benign hyperplasia of cells from the hypophysiotropic area of the hypothalamus (hamartoma of the tuber einer eum) is a rare cause of early sexual development. These hamartoma were first described by Driggs and Spatz in 1939. 6 They often are combined with cerebral malformations, and the solid nodes (up to 3 cm. (1.2 in.) in diameter) do not always produce precocious sexual maturation. It is thought that when sexual precocity develops there is an autonomous proliferation of those cells which produce gonadotropin-releasing hormones. In two of our patients (see Figure 7) Professor Guillemin could detect a very high luteinizing hormone-releasing hormone (LH-RH) activity in the cerebrospinal fluid.7 For diagnosis in vivo, pneumoencephalography with tomography is necessary to evaluate the cysterna interpeduncularis.

Hydrocephalus, especially widening of the third ventricle, may be complicated by sexual precocity (Figure 8). In our experience, the process cannot be stopped by normalization of the intracerebral pressure after shunt operation. but the course of sexual development usually is rather slow. How cerebral centers are influenced is not clear.

The same uncertainty about localization of the disturbance exists when precocious puberty develops after inflammatory diseases of the central nervous system, such as encephalitis and meningitis. Sometimes children with these diseases have a transitory precocious development with complete remission after a certain time.

Genetic disorders with sexual precocious development. In McCune Albright syndrome polyostotic fibrous dysplasia, combined with typical nevi (Figure 9) and sexual precocity, occurs. Hypoostotic lesions of the bones filled with fibrous tissue usually are found, especially in the upper and lower limbs (femoral neck) and the skull. Spontaneous fractures are often the first sign of the syndrome. Normally, the course of sexual development is rather slow in this syndrome, although onset of thelarche may be very early. For some patients progressive deformations of the skeleton (femora, vertebral column) are dominating symptoms.

A number of children with neurofibromatosis develop precocious sexual development whose onset may be very early and course of development may be very rapid.

Isosexual familial precocious puberty has been described in 11 male members of a family by Beas.8 Male cases also are predominant in other reports.

Precocious sexual development in other diseases of endocrine glands. In untreated primary hypothyroidism and in Addison's disease precocious sexual development may occur as an extremely rare complication. It is speculated that as a consequence of high thyrotropic releasing hormone (TRH) production, for example, an "overlap mechanism" causes overproduction of hypothalamic gonadotropin releasing hormones.

In patients with the adrenogenital syndrome growth spurt and development of pubic hair are caused by excessive androgen production as a consequence of excessive ACTH stimulation to overcome the enzyme deficiency of Cortisol synthesis. If the Cortisol substitution is started late (e.g., bone age more than 8 to 10 years) an increasing endogenous gonadotropin production causes precocious sexual development. A similar mechanism may be responsible for true precocious puberty after stopping long-term androgen therapy during childhood.

Idiopathic precocious puberty. Precocious puberty is idiopathic when other known reasons for the precocious sexual development have been excluded.9 In about 90 per cent of all children with complete precocious sexual development the reason for the regulatory disturbance is unknown. There is some speculation that very little hamartoma of the tuber cinereum, not demonstrable by radiography, may be present in some of these patients. It is remarkable that unspecific alterations of the EEG are found in most of the patients. Much more important is the fact that, in many cases, one of the parents had a rather early pubertal development but most were within the normal limits. From our present knowledge it is not clear by what mechanism the postulated gonadostat is adjusted to a higher level- that is, becomes less sensitive to circulating sex steroid hormones.

Figure 9. Typical nevus in a 10-year-old girl with McCune-Albrlght syndrome.

Figure 9. Typical nevus in a 10-year-old girl with McCune-Albrlght syndrome.

Figura 10. Nine-year-old dizygotic twins; first pubertal signs in the affected girl appeared one year before this photo was taken.

Figura 10. Nine-year-old dizygotic twins; first pubertal signs in the affected girl appeared one year before this photo was taken.

Precocious breast development usually is the first symptom inducing the parents to visit a physician, although excessive growth has been noted before in most of the patients. Figure 10 shows nine-year-old dizygotic twins. One of the sisters developed sexual precocity one year before the photo was taken.

In most cases of idiopathic precocious sexual development the sequence of the pubertal signs is normal but shortened in timing. Growth is accelerated in comparison to the normal length of children of the same chronologic age. Bone age is accelerated and, in most cases, is more advanced than height age, indicating a decreasing expectation for final height. Without treatment these children stop growing at a chronologic age of 9 to 11 years because of closure of the epiphyseal lines. The mean height is then 145 cm. (58.3 in.), although there is great variation. These children seem to be very tall in comparison with others of the same age until the normal children pass through normal pubertal growth. Thus, small adult stature is the most important remaining symptom after precocious sexual development.

As well as the visual signs of early maturation, all the other typical cytologic and endocrine symptoms of sexual maturation are present. Cytologic evaluation of the smear taken from vaginal mucosa shows estrogeninduced cornification of the superficial cells. Gonadotropins in blood and urine as well as testosterone, androstenedione, and estradiol levels in plasma correspond to normal puberty. Studies of the gonadotropin level in plasma or of gonadotropin excretion in the urine should be performed in each child with precocious puberty to exclude a gonadal or adrenal tumor. The necessity for a thorough neurologic investigation has been established above. Precocious puberty of the so-called idiopathic type is much more common in girls (7.5:1). In boys diagnostic procedures usually are necessary. For many parents the fear that their child may have an abnormal psychological development and possibly develop a premature sexual interest is of greatest significance. For the practicing physician the normal psychic and social development of the children is very often surprising. Social ostracism is extremely rare, especially if menstrual bleedings can be suppressed by treatment. In contrast, because of their physical superiority these children often occupy leading roles in their groups. Disturbing influences frequently come from the parents and grandparents, who must be instructed and directed carefully. Cooperation with a psychologist with special experience is desirable. The children's problems often arise later when their small stature causes a loss of their position of leadership in the peer group.

Isolated maturation of sex characteristics. Premature thelarche is a rather common variant of development. Figure 11 shows an 18-month-old girl with isolated breast development. Thelarche is observed during the first, sometimes second, year of life and normally vanishes until the third year. The girls are of normal stature, and their bone age is not accelerated. Height should be checked at regular intervals as commencing complete sexual maturation can be detected by increasing growth velocity. If the vaginal smear shows slight estrogenic stimulation (as in 50 percent of our patients), a gynecologic investigation to exclude an ovarian tumor is indicated. An intensive exploration is necessary to detect eventual estrogen intoxication.

Premature adrenarche occurs in some children of four to eight years of age as an isolated growth of pubic hair. It is not clear why this occurs. Testosterone and androstenedione levels are elevated, and a precocious maturation of adrenal enzymes is postulated. In some patients androgen secretion is so marked that an acceleration of growth and bone maturation is evident. Usually, sexual maturation is completed and other sex characteristics develop at the normal chronologic age. Great care should be taken to exclude adrenal adenoma oran adrenogenital syndrome with minor expression of the enzyme deficiency. In boys testicular androgenproducing tumors must be excluded by repeated investigation.

THERAPY

In 1962 Kuppermann and Epstein10 introduced medroxyprogesterone for the treatment of precocious puberty. The theoretical basis for this therapy is schematically outlined in Figure 12. There is evidence that gestagens like estrogens and androgens have an effect on those hypothalamic centers that control plasma levels of sex hormones. High gestagen plasma diminish gonadotropin secretion. cause gestagens have no influence growth and bone acceleration, a sion of precocious sexual development theoretically can be expected. Longterm observations by Kaplan11 show that the practical experience does not meet theoretical expectations. After long-term treatment there is no significant improvement of growth prognosis. Breast development diminished only in some girls but menstrual bleeding stopped in all cases. So the value of treatment with medroxyprogesterone is in question now, and many pediatric endocrinologists have rejected this regimen.

Figure 11. Eighteen-month-old girl with isolated premature thelarche and normal height.

Figure 11. Eighteen-month-old girl with isolated premature thelarche and normal height.

Figure 12. Mechanism by which gestagens inhibit gonadotropin release in treatment of precocious sexual development.

Figure 12. Mechanism by which gestagens inhibit gonadotropin release in treatment of precocious sexual development.

Synthetic steroids like cyproterone acetate do possess gestagen activity. They also are anti-androgens. Antiandrogenic activity means that the effect of circulating endogenous androgens is blocked at the target-organ level. Treatment with this drug seems to be more effective but a final evaluation cannot be given now. Recent evidence indicates that cyproterone acetate does not improve the prognosis for ultimate height."

BIBLIOGRAPHY

1. Tanner, J. M. Growth and Endocrinology of the Adolescent. L.I. Gardner, ed. In Endocrine and Genetic Disorders of Childhood. Philadelphia and London: W. B. Saunders Co., 1969, 19.

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

3. Tanner, J. M., Whltehouse, R. H., and Healy, M. J. R. A New System for Estimating Skeletal Maturity from the Hand and Wrist with Standards Derived from a Study of 2600 Healthy British Children. Paris: Centre International de l'enfance, 1962.

4. Kelch, R. P., Kaplan, S. L.. and Grumbach, M. M. Suppression of plasma and urinary gonadotropins by exogenous estrogens in prepubertal and pubertal children. American Pediatric Society, Washington. May 1972. Abstract In Ped. Res. 6 (1972), 354.

5. Werff ten Bosch, J.J. van der. Control of Puberty by Endocrine and Other Factors. Proceedings Second International Congress Endocrinology (London) Part 2. 833. Internat. Congr. Ser. N. 83. Amsterdam and New York: Excerpta Medica Foundation, 1965.

6. Driggs, M. and Spatz. H. Virchows Arch. Path. Anat. 305 (1939), 567.

7. Bierich, J. R., Blunck, W., and Schönberg, D. Über Frühreife II. Frühreife bei cerebralorganischen Erkrankungen. Mschr. Klnderheilk. 115 (1967), 509.

8. Beas, F., ZurbrUgg, R. P., Leibow, S. G., Patton, G. R., and Gardner, L. I. Familial male precocity: report of the eleventh child found, with observations on blood group linkage and urinary Cig-steroid excretion. J. Clin. Endocrin. 22(1962), 1095.

9. Blunck, W., Bierich, J. R., and Bettendorf, G. Über Frühreife III. Idiopathische Pubertas praecox, temporäre Frühreife und praemature Thelarche. Mschr. Kinderheilk. Î5(1967), 555.

10. Kuppermann, H. S. and Epstein, J. A. Medroxyprogesterone acetate in the treatment of constitutional sexual precocity. J. Clin. Endocrin. 22 (1962). 456.

11. Kaplan, S.A.. Ling, Sh. M., and Irani, N. G. Idiopathic isosexual precocity-therapy with medroxyprogesterone. Amer. J. Dis. Childh. 116 (1968). 591.

12. Werder, E. A., MUrset, G., Zachmann, M., Brook, C. G. D., and Prader, A. Treatment of precocious puberty with cyproterone acetate. Pediat. Res. 8 (1974), 248.

10.3928/0090-4481-19740701-05

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