Constitutional Delay of Growth and Puberty

Constitutional delay of growth and puberty (CDGP) is a frequent variant of normal pubertal maturation. It is characterized by a slowing of the growth rate as well as by a delay in the timing and tempo (rate of progression of the various stages) of puberty. Typically, these boys seek medical evaluation in the early teens as they become aware of the discrepancy in sexual development and height between themselves and their peers.

Clinically, these patients have a height age (the age corresponding to the height at which the patient’s height is at the 50% percentile) that is delayed with respect to their chronological age but is concordant with their bone age. Sexual development is prepubertal or early pubertal, and is again appropriate for the bone age, but delayed for chronological age. There is often a family history of one parent or a sibling of either sex having also been a “late bloomer.”

Height velocity continues at a prepubertal rate or slows slightly as a prepubertal dip, in contrast to peers of the same chronological age, whose height velocities begin to accelerate at the age of 13 to 14 years. When the height is plotted on the standard growth curve, the height gain of these boys appears to be decelerating since the standard growth curve incorporates the pubertal growth spurt at an “average” age. This further accentuates the difference between the delayed boys and their normally developing counterparts. The apparent deceleration in growth compared with chronologically matched peers is usually a compelling concern of the patient and / or his family and brings the adolescent to medical attention.

Biochemically, boys with CDGP resemble normal boys with comparable bone ages. Serum levels of GH, IGF-1, insulin-like growth factor binding protein 3 (IGF-BP, luteinizing hormone, follicle-stimulating hormone and testosterone may be low for chronological age, but are normal when compared with levels in boys of the same stage of sexual development.

The suppressed hypothalamic-piruitary-gonadal axis found in CDGP represents an extension of the physiological hypogonadotropic hypogonadism present since infancy.

Hypogonadotropic Hypogonadism

Insufficient pulsatile secretion of gonadotropin-releasing hormone and the resulting luteinizing hormone and follicle-stimulating hormone deficiency lead to lack of sexual maturation, or sexual “infantilism.” The degree of this deficit varies, and hence the phenotype can vary from complete sexual infantilism to conditions that are difficult to differentiate from CDGP (Table Hypogonadotropic Hypogonadism).

The gonadotropin-releasing hormone deficiency may be secondary to a genetic or developmental defect that is not detected until the age of the expected puberty, or it may be due to a tumor, an inflammatory process, a vascular lesion, or trauma.

Table Hypogonadotropic Hypogonadism

  • CNS disorders
  • Tumors
  • Other CNS disorders
  • Isolated gonadotropin deficiency
  • Kallmann’s syndrome
  • X-linked congenital adrenal hypoplasia
  • Isolated luteinizing hormone deficiency
  • Miscellaneous disorders
  • Prader-Willi syndrome
  • Laurence-Moon syndrome
  • Bardet-Biedl syndrome
  • Cystic fibrosis
  • Other chronic diseases
  • CNS Disorders

Tumors. CNS tumors that delay puberty are usually extrasellar masses that interfere with gonadotropin-releasing hormone synthesis, secretion, or stimulation of pituitary gonadorropes. In this particular condition, virtually all patients have a deficiency of one or more additional pituitary hormones. GH deficiency due to neoplasms is often associated with a relatively late onset of growth failure, in contrast to idiopathic and familial hypopituitary children, who usually have growth failure early in life.

Craniopharyngioma is the most common brain tumor of nonglial origin and the most common brain tumor associated with hypothalamic-pituitary dysfunction and sexual infantilism. These tumors account for 80% to 90% of neoplasms arising in the pituitary region. They originate from squamous rest cells in the remnant of Rathke’s pouch between the adenohypophysis and the neurohypophysis. The tumors may be completely inrrasellar (25%), solely extrasellar, or a combination of both.

Although histologically benign, craniopharyngiomas can be aggressive, sending papillae that invade surrounding tissues. In addition, they commonly have cystic components that may be multiple and may enlarge, causing compression of adjacent neurological structures. Craniopharyngiomas commonly present with nonendocrine symptoms such as headache and visual disturbance and, less commonly, with manifestations of endocrine deficiency such as delayed growth. Up to 80% of patients have evidence of endocrine dysfunction at diagnosis. GH deficiency is the most frequent finding, present in up to 75% of patients, followed by gonadotropin deficiency in 40%, adrenocorticorropic hormone (ACTH) and thyroid-stimulating hormone (TSH) deficiency in 25%, and diabetes insipidus in 9% to 17%.

Surgery is the treatment of choice for craniopharyngioma and, ideally, total resection of the tumor. In all but small, totally intrasellar or circumscribed tumors, for which total resection is possible, it is clear that surgical management alone carries an unacceptably high rate of recurrence and adjuncrive radiotherapy should be given.

The treatment-associated morbidity is dependent on the size and invasiveness of tumor at diagnosis, the experience of the surgeon, and the route of surgical approach. Regardless of the approach, the incidence of endocrine dysfunction is high following surgical treatment, although it may be less when a transphenoidal approach is used.

Sexual infantilism can be caused by other extrasellar tumors that arise or involve the hypothalamus. Germinomas or other germ cell tumors of the CNS are the extrasellar tumors that most commonly cause sexual infantilism, although, when all primary CNS tumors are considered, germinomas are rare. The diagnosis is usually made during the second decade of life. Polydipsia and polyuria are among the most common symptoms, followed by visual difficulties, growth failure, and delayed or precocious puberty. The most common hormonal abnormalities are diabetes insipidus and GH deficiency. Pure germinomas are radiosensitive, and thus, radiation is the preferred treatment. When a mixed germ cell tumor is found, both radiation and chemotherapy may be required.

Hypothalamic and optic gliomas or astrocytomas as well as prolactinomas can also cause sexual infantilism.

Other CNS Disorders. Radiation of the head for treatment of CNS tumors, leukemia, or neoplasm may cause hypothalamic-pituitary damage. GH deficiency is the most common endocrine abnormality, followed by gonadotropin deficiency; consequently, delayed puberty and growth failure should always be suspected in children who have received CNS radiation therapy.

Midline malformations of the head and the CNS are associated with a variety of endocrine deficiencies. In septooptic or optic dysplasia, the optic nerve is usually affected, leading to small, dysplasric, pale optic discs and nystagmus; severely affected patients may be blind. The midline hypothalamic defect may cause GH, TSH, ACTH, and gonadotropin deficiency; short stature and delayed puberty are common.

Other rare CNS disorders that can lead to delayed puberty include tuberculous or sarcoid granulomas of the CNS, hydrocephalus, vascular abnormalities, and head trauma.

Isolated Gonadotropin Deficiency In contrast to patients with brain tumors and secondary GH deficiency or CDGP, patients with isolated gonadotropin deficiency are usually of appropriate height for age. Because levels of gonadal steroids are too low to fuse the epiphyses, these children develop eunuchoid body proportions, defined as having an arm span that is 2 cm greater than the total body height, with the lower body being 2 cm longer than the upper body. If not treated, these children will become tall adults, although only rarely is more than 2.5 to 7.5 cm added to the adult height.

Kallmann’s syndrome is the most common form of isolated hypogonadotropic hypogonadism with delayed puberty; anosmia or hyposmia due to agenesis or hypoplasia of the olfactory lobes and / or sulci is associated with gonadotropin-releasing hormone deficiency. Undescended testes, micropenis, and gynecomasria are frequent findings; other less common defects include cleft lip, cleft palate, seizure disorder, short metacarpals, pes cavus, hearing loss, cerebellar ataxia, ocular motor abnormalities, and renal dysplasia or aplasia.

Hypogonadotropic hypogonadism can be transmitted by autosomal recessive inheritance with none of the other features of Kallmann’s syndrome in patients with X-linked congenital adrenal hypoplasia, which is due to a deletion or mutation of the DAX1 gene. Affected boys with X-linked congenital adrenal hypoplasia frequently have severe primary adrenal insufficiency, which can be lethal if untreated. The testes are undescended in many of the patients, but micropenis is rare. At the age of expected puberty, signs of sexual maturation do not develop, including the lack of development of pubic and axillary hair and testicular enlargement and persistent low levels of serum follicle-stimulating hormone, luteinizing hormone, and testosterone.

Isolated luteinizing hormone deficiency (the fertile eunuch syndrome) is associated with deficient testosterone production and spermatogenesis; in most cases, the isolated gonadotropin deficiency is incomplete. Treatment with human chorionic gonadotropin (human chorionic gonadorropin) has been shown to increase testosterone secretion and spermatogenesis.

Miscellaneous Disorders

Prader-Willi syndrome is a complex, multisystem disorder that includes neonatal hypotonia and failure to thrive, developmental delay and mild cognitive impairment, characteristic facial appearance, early childhood-onset obesity, hypogonadism with genital hypoplasia and incomplete pubertal development, and mildly short stature.

This genetic disorder is caused by the lack of expression of normally active paternally inherited genes at chromosome 15qll-ql3. Approximately 70% of the patients have a paternal deletion of the 15qll-ql3, and 25% have uniparental disomy in which both chromosomes 15 are derived from the mother, possibly by nondisjuncrion during maternal meiosis.

The Laurence-Moon and Bardet-Biedl syndromes are two different entities, although both are autosomal recessive traits, and both feature reriniris pigmentosa and hypogonadism. Many Bardet-Biedl syndrome patients have developmental delay, as do all Laurence-Moon syndrome patients.

Chronic systemic disorders and malnutrition are associated with delayed puberty or failure to progress through the stages of puberty. It is necessary to distinguish the effects of malnutrition, which can lead to functional hypogonadotropic hypogonadism, from the primary effects of the disease. In general, any cause of weight loss to less than 80% of ideal weight for height can lead to gonadotropin deficiency; weight gain usually restores hypothalamic-piruitary-gonadal function.

Cystic fibrosis also delays puberty — in large part, through malnutrition. Even with normal pubertal progression, however, boys usually have oligospermia caused by obstruction of the spermatic ducts with viscid material unrelated to their nutritional status. Further, boys with cystic fibrosis have an autoimmune reaction against sperm that could be detected at the time of appearance of spermatogenesis.

Boys with sickle cell anemia often have mild delayed puberty and impaired Leydig cell function, due to ischemia of the testes or gonadotropin deficiency, or both. Other chronic conditions, including thalas-semia major, hemophilia, Crohn’s disease, celiac disease, chronic renal disease, poorly controlled diabetes mellirus, and hypothyroidism are also associated with delayed pubertal development.

Chemotherapy for malignant diseases may also influence the age of puberty and, if administered during puberty, can impair gonadal function and cause primary hypogonadism. Radiation to the head may cause hypogonadotropic hypogonadism and / or GH deficiency, and radiation to the abdomen and pelvis and certain types of chemotherapy.

Hypergonadotropic Hypogonadism

Klinefelter’s Syndrome and Its Variants

Klinefelter’s syndrome, the most frequent cause of hypergonadotropic hypogonadism in phenotypic males (approximately 1 in 600 to 1 in 800 males), does not delay the onset of sexual development. Common features include small, firm testes, impaired spermatogenesis, gynecomastia, and eunuchoid body proportions. Puberty starts at the usual age, but with small testes, the secondary sex characteristics do not attain normal development. The diagnosis is confirmed by the presence of one or more extra X chromosomes in the karyotype. School performance is usually poor, with an average verbal intelligence quotient that is 10 to 20 points below normal controls. Hormonal measurements at adolescence usually show high follicle-stimulating hormone levels, moderately elevated luteinizing hormone levels, and plasma testosterone in the low normal range.

Klinefelter variants with more than one extra chromosome include 46, XY / 47, XXY; 48, XXYY, and 48, XXXY karyotypes — all associated with more severe genital and mental impairment. The rare 46, XX male also has some features of Klinefelter’s syndrome.

Other Forms of Primary Testicular Failure Other types of primary congenital testicular failure in otherwise normal males include anorchia and “vanishing testes syndrome.” The latter condition features an empty scrotum at birth, with evidence of the temporary presence and function of testes in utero. Anorchia (total absence of testes) can be differentiated from abdominal cryptorchidism (undescended testes) by the high levels of luteinizing hormone and / or follicle-stimulating hormone, their elevated responses to a gonadotropin-releasing hormone challenge, and, most importantly, the lack of testosterone response to stimulation with exogenous human chorionic gonadotropin.

Luteinizing hormone resistance caused by an luteinizing hormone receptor abnormality has been reported as a cause of infantilism in a phenotypic male.

Acquired bilateral lesions of the testes that occur during childhood and may lead to hypogonadism at adolescence include bilateral testicular torsion, severe scrotal trauma, and orchiris (e.g., mumps).


Treatment of delayed puberty depends on the diagnosis. Most boys with constitutional delay of growth and adolescence, without intervention, will undergo normal pubertal development spontaneously, and will reach their target height as predicted by parental stature. Development may, however, occur several years after that of their peers, and many adolescents will suffer significant emotional distress because they differ in their appearance from their peers during these years. Androgen therapy was initially proposed to alleviate this psychological stress. Recent data have emerged that support androgen therapy in these boys for its beneficial effects on bone-mineral density and body composition, in addition to its psychological benefits.

In the authors’ practice, testosterone enanthate or cypionate 50 to 100 mg is administered intramuscularly every four weeks for three months. Almost all boys respond to this therapeutic trial by showing some increase in appetite, body weight, and height, and many show early testicular enlargement. An early-morning testosterone level measured at least three weeks after the last injection will reflect the boy’s own endogenous testosterone production. If no physiologic changes are apparent after three months, the dose may be increased by 25 to 50 mg every four weeks. Treatment is continued for another three months, and the boys are then reevaluated: an increase in testicular size indicates gonadotropin release despite exogenous testosterone. It should be noted that boys with permanent hypogonadotropic hypogonadism will not have testicular growth. If growth and development cannot be sustained without therapy after one year of testosterone treatment, the presence of permanent hypogonadotropic hypogonadism is more likely, and further investigation is warranted.

The use of pulsatile gonadotropin-releasing hormone administration is not practical for the routine induction of puberty in adolescent boys, due to high cost, the frequency of administration (every 90-120 minutes), and the route of administration (subcutaneously or intravenously); therefore, long-term testosterone replacement is the treatment of choice for hypothalamic or pituitary gonadotropin deficiency.

Congenital or acquired gonadotropin deficiency due to CNS lesions requires testosterone replacement therapy at the normal age of onset of puberty. An exception may occur when GH deficiency coexists; in this condition, it is generally advisable to initiate testosterone replacement by the age of 14 years to maximize linear growth.

Plasma testosterone and luteinizing hormone levels should be monitored every six months during puberty, and yearly thereafter in patients with Klinefelter’s syndrome. If the luteinizing hormone level rises by more than 2.5 SD above the mean value or if the testosterone level decreases below the normal range for age, testosterone replacement therapy is indicated.

Gonadal steroid treatment regimens are the same in both hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. Boys are given testosterone enanthate, 50 to 100 mg every four weeks intramuscularly at the start, and this is increased gradually every two to three weeks to adult replacement doses of 200 mg. Skin patches of testosterone (2.5 and 5 mg) may be useful in motivated teenagers.

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