The Child with Precocious Puberty Stephen R. Marks, MD, and M. Joycelyn Elders, MD Little Rock, Arkansas

Precocious puberty can be very confusing and frightening to an affected child and his or her family. The following presentation includes the pertinent physiology, psychology, etiology, diagnosis, and treatment of precocious pubertal development. Radioimmunoassays for gonadotropins and several key hormones are now available which enable the clinician to evaluate and follow the patient's condition with confidence and expertise. Three drugs have been proven effective and the most recent one, typroterone acetate, has produced exciting clinical remissions with virtually no known side effects. Precocious puberty is a condition in which normal pituitary-gonadal function is activated at an abnormally early age. It is generally agreed that the diagnosis of precocious puberty is warranted when sexual maturation begins before the age of eight in girls and ten in boys. True precocious puberty arises in all cases from disturbed function of the brain which may or may not be associated with demonstrable structural abnormalities and is characterized by an adult pattern of sexual function in girls (menstrual cycles) and in boys (testicular development and spermatogenesis). In a large group of normal women studied in the United States in 1964 and 1965, the mean age at menarche was 12.6 years + 1.1 year. Testicular growth in males begins at a mean age of 11.8 years + 1.0 year.I

Pseudoprecocious puberty applies to those disorders in which secondary sexual characteristics develop without maturation of the gonads due to disease of the gonads or adrenal glands or, rarely, other hormone-producing tissues. In girls, several incomplete forms of "true" precocious puberty have been recognized: precocious thelarche, defined by Wilkins as the premature development of breast tissue in young girls without other sexual manifestations, and precocious adrenarche or pubarche, referring to the premature development of pubic or axillary hair or both. These two conditions are important to recognize because they are benign and must be differentiated from disorders of excessive androgen or estrogen secretion.1

Regulation of Sexual Development From the Departments of Pediatrics and Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Requests for reprints should be addressed to Dr. M. Joycelyn Elders, Department of Pediatrics, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72201.

The mechanisms regulating gonadotropin secretion are depicted in Figure 1. The gonads are controlled by the pituitary gonadotropins, follicle stimulating hormone (FSH), and luteinizing hormone (LH). In the female, FSH regulates oogenesis and estrogen sec-

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retion. Estrogens influence normal feminine habitus, growth of the uterus and endometrium, labia, and breasts. LH is required for ovulation, corpus luteum formation, and the initiation of progesterone secretion. Progesterone further stimulates estrogen-primed endometrium and breast growth. Adrenocortical androgens stimulate pubic, labial, and axillary hair in the pubertal female. In the male, FSH stimulates growth and maturation of the spermatic tubule and spermatogenesis; LH enhances growth of the interstitial (Leydig) cells and testosterone synthesis and secretion. Testosterone produces the pubertal growth spurt, phallic enlargement, scrotal virilization, facial, pubic, and axillary hair growth, and masculinization of the body contours. Pituitary gonadotropin secretion is influenced by several factors. Within the hypothalamus are catecholamineresponsive neurons which contain peptide-releasing factors (FSHrf and LHrf). After entering the pituitary portal vascular system, these peptides stimulate specific pituitary cells to release and possibly also to synthesize FSH and LH. In the female, estrogens usually inhibit FSH and LH secretion, acting in153

directly by suppressing hypothalamic FSHrf and LHrf (the "long" feedback loop). Under certain circumstances, such as the midcycle, a preovulatory increase in estradiol levels which im-

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Figure 2. Schematic diagram of the progressive change in gonadotropin secretion which results from a decrease in hypothalamic sensitivity to gonadal steroids. 154

ous tubular product (intermedin) is thought to regulate FSH release in the male but the chemistry and cell of origin of this material are unknown. FSH and LH may inhibit their own secretion by depressing hypothalamic FSHrf and LHrf (the "short" feedback loop) and FSHrf and LHrf may even inhibit their own elaboration within the hypothalamus (the "ultrashort" feedback

Extrahypothalamic areas of the central nervous system (CNS) may modify hypothalamic gonadotropin-releasingfactor activity. The role of the pineal gland in control of pubertal development has been obscure. The pineal gland is a light-sensitive structure which may inhibit hypothalamic gonadotropin-releasing-factor activity and gonadotropin synthesis in the rat.2 In humans, parenchymatous pinealomas are associated with depressed gonadal function, whereas nonparenchymatous lesions, such as gliomas and teratomas (which destroy the pineal gland), are associated with precocious sexual development. It has been suggested that pineal hyperfunction is associated with delayed puberty and hypofunction is associated with precocious puberty.3 The amygdala of the rat influences hypothalamic function through its hypothalamic radiationthe striae terminalis which when sectioned advances the onset of puberty in immature female rats. Higher CNS structures also modulate hypothalamic-pituitary-gonadal function; the influence of emotional state upon menstrual function is widely appreciated. To date, little is known about why the processes of maturation start when they do. Recent studies indicate that the prepubertal human child secretes gonadotropins and gonadal products, and that the secretion of these materials increases as the child ages. In experimental immature animals, the hypothalamic receptor sites of inhibitory (negative) feedback stimuli are extremely sensitive to both androgens and estrogens. The degree of sensitivity decreases as the animal ages until the sensitivity level approximates that of the sexually mature animal, and an adult reciprocal relationship between pituitary and gonadal secretory activity is established (Figure 2). The mechanism by which the sensitivity of the hypothalamic receptor sites ("gonadostat") declines is unknown. There may

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Table 1. Etiology of Precocious Puberty Female 1. True, complete Idiopathic Weil-Albright syndrome CNS insult neoplasm congenital cyst hamartoma meningitis encephalitis brain abscess congenital anomaly

Male 1. True, complete Idiopathic

Familial CNS insult same as for female Hypothyroidism 2. Gonadotropin-secreting neoplasm Hepatoblastoma Teratoma

Chorionepithelioma

injury tuberous sclerosis Hypothyroidism 2. Gonadotropin-secreting neoplasm

Chorionepithelioma Teratoma 3. Pseudoprecocity

Ovarian feminizing mesenchymoma luteal cyst Adrenal feminizing adenoma carcinoma Exogenous estrogen ingestion or application 4. Incomplete Premature thelarche Premature pubarche (adrenarche) 5. Miscellaneous Vaginitis Vaginal or cervical neoplasm Foreign body

be intrinsic age-related alterations in receptor cell physiology, or the influence of the extra-hypothalamic inhibitor sites may wane with age, permitting the hypothalamic receptors to express their intrinsic sensitivity level.2

Etiology of Isosexual Precocious Puberty Idiopathic precocious puberty encompasses the largest proportion of cases of premature but otherwise normal development. This disorder is diagnosed by exclusion of organic disease of the CNS and other known causes of the syndrome (Table 1). The two earmarks of this disorder are isosexual (same sex) premature sexual development and accelerated physical development. In general,

3. Pseudoprecocity Testicular Leydig cell adrenal rest neoplasm Adrenal congenital adrenal hyperplasia virilizing adenoma carcinoma Exogenous androgen administration Chorionic gonadotropin administration 4. Incomplete Premature pubarche (adrenarche)

Gynecomastia Neurofibromastosis Klinefelter syndrome

though not in every case, sexual development follows the usual pattern of normal puberty. The commencement and rate of sexual development may vary considerably. A very sudden appearance of sex characteristics leads to a suspicion of a rapidly growing tumor of the brain or gonads, or of an ectopic gonadotropin-forming growth. Early in the development of the disease, an accelerated, somatic development becomes evident-the increased growth in height, combined with progressively accelerating skeletal growth. Growth in height remains behind skeletal maturation. The considerably iicreased bone development leads to premature closure of the epiphyses and thus to a cessation of growth at the age of 11 to 13 years, with a top age of 13 to 14 years. Without treatment, girls with idiopathic precocious puberty reach on an average a height of 145 to 149 cm.

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In contrast to the accelerated sexual and somatic development, the intellectual, psychic, and psychosexual maturation of the children remain appropriate for their chronological age; a strong discrepancy between the physical appearance and psychological status is always apparent. The patients are regularly thought to be older than they really are and so are treated as older children, which often leads to undue strain. Reactive behavior disorders often result. The patients are infantile in attitude towards their own sexuality. This leads to the danger of easy seduction of the girl and the number of pregnancies before the age of 15 years in these children is high. An understanding of pregnancy and birth is usually completely lacking in infantile mothers. A particularly extreme case was a Peruvian girl, who at the age of five years eight months gave birth to a 6'/2 lb child and, after the delivery, continued playing with her dolls.1 Some authors have given accounts of slightly abnormal EEG findings with many of their patients, but a statistical comparison with a healthy control group is absent from these works. Bierich4 has also reported nonspecific, abnormal EEG findings, but no significantly higher frequency was recognizable. Consequently, only a qualitative assessment is possible, namely that the "gonadostat" of these patients reaches the transition to normal adolescence prematurely. The strong preponderance of idiopathic precocious puberty in the girl indicates that perhaps the regulatory centers of the diencephalon, which require a more complicated enzymatic system for cyclic gonadotropin secretion than in the male, are particularly susceptible to disturbances.4

Incidence Wilkins' compiled 770 cases of precocious puberty of all types and concluded that this disorder has a female to male ratio of 2 to 1 and in girls is far less indicative of serious disease. Eighty percent of prematurely developed girls have no demonstrable structural abnormality of brain, pituitary gland, or ovary (idiopathic) whereas more than 60 percent of sexually precocious boys have serious organic diseases of some type. In boys, 20 percent of the cases are due to intracranial disease, 25 percent to adrenal disease, and less than 10 155

percent to lesions of the testicle. In girls, ovarian tumors account for 15 percent of the cases and intracranial lesions for only four percent. Certain peculiar and inexplicable sex differences have been observed in the incidence of true precocious puberty. Idiopathic precocious puberty is four to ten times as common in girls than boys; Albright's dysplasia as a cause of precocious puberty rarely occurs in boys; hypothyroidism as an etiology has been recognized almost exclusively in girls; and precocious puberty due to pineal tumors had occurred but with the rarest exception in boys.1 Of the genetically dependent forms of precocious puberty, the autosomally recessive variant is rare in both sexes. The autosomally dominant form, however, occurs only in boys, and is somewhat more common; in these cases, transmission occurs through the afflicted fathers or through phenotypically healthy mothers.4

Differential Diagnosis of Precocious Puberty

History As in all diagnostic evaluations made in clinical medicine, a major goal must be to differentiate benign entities from harmful disease. A careful history may offer clues. Exogenic, hormonal activities are by no means rare; the question whether or not the girl has come into contact with drugs containing estrogen (contraceptive pills, some skin creams, ointments, vitamins) must always be asked. With boys, too, one must determine whether or not drugs with sex hormone activity (anabolic steroids, HCG) have been administered. Questions related to possible neurologic disease are of utmost importance and should be examined in detail. Such findings as personality changes, increased appetite, headaches, visual disturbances, and epileptic seizures are of note (Table 2). Cyclic menstruation usually occurs in girls with true precocious puberty but can occur in patients with ovarian tumors. Irregular menses can occur in patients with true precocious puberty, however, and frequently occur in patients with ovarian tumors. Vaginal bleeding or discharge of blood as the only symptom is nearly always due to foreign bodies, polypi, or injuries. 156

Table 2. Evaluation of the Child with Isosexual Precocious Puberty History Recent growth acceleration Behavior Changes CNS trauma or infections Precocious development in parents Use of facial creams or other medications Physical Examination Precise measurements of height, weight, head circumference, arm span, sitting height, breast diameter, phallic length and width, and longest diameter of testes Thorough neurologic evaluation Funduscopic and gross visual fields Skin Hyperpigmentation-Congenital adrenal hyperplasia (CAH) Cafe-au-lait spots Coast of Maine (McCune-Albright) Coast of California (neurofibromatosis) Carotenemia, dryness, coolness (hypothyroidism) Sebaceous gland activity (androgen effect) Sexual development Bimanual pelvic examinations Galactorrhea-hypothyroidism, pituitary or hypothalamic tumor Testicular size-Bilateral enlargement-precocious puberty Unilateral enlargement-tumor Normal-adrenal androgen excess (CAH) carcinoma Radiologic Findings Advanced-Precocious puberty Adrenal neoplasm Gonadal neoplasm Congenital adrenal hyperplasia Bone Age Precocious adrenarche

(moderately advanced)

Normal-Precocious thelarche

Retarded-Hypothyroidism Skull Films-T Sella Size-Primary hypothyroidsm CNS tumor Foramina-Visual field defects Optic

(neurofibromatosis)

The family history should be thoroughly investigated for other members who have had the same condition or for siblings with a history of congenital adrenal hyperplasia.4'5

Physical Examination The physical examination includes a general evaluation including recording of body measurements and vital signs, inspection of the skin foi cafe-au-lait spots (Albright syndrome), a thorough neurological evaluation (fundus, visual fields, head circumference, motor, sensory and mental status), the degree and stage of sexual maturation, and meticulous palpation of the testes in males. Tanner's system of staging sexual de-

velopment is very useful for noting the patient's degree of development. In males, uneven tumorous enlargement of the testes suggests Leydig-cell adenomas or adrenal rest tumors as in congenital adrenal hyperplasia2 (Table 2). Androgen excess will lead to acne, hirsutism, increased muscle mass, voice changes, clitoromegaly (female), and increased size of the penis (male). Estrogenic changes in females include breast growth with deepening of areolar pigmentation, development of the labia minora, and progression of the vaginal mucosa from a shiny bright red appearance with sparse thick secretions to a dull gray-pink rugated surface with copious thick secretions.5

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Table 3. Hormonal Findings

Luteinizing and follicle stimulating hormone

T1T

Gonadotropin secreting tumor

>10 Precocious puberty Premature adrenarche Gonadotropin secreting tumor 250 pg/ml Ovarian tumor >20 pg/ml Precocious puberty 150 ng/dl Testicular tumor >40 ng/dl Precocious puberty