Early, normal, delayed puberty, treatment

Physiology of puberty
Reproductive function in man starts with sex differentiation in fetal life and is followed by maturation at puberty and then heterosexual intercourse in adulthood. The same basic phenomenon governs all these aspects of reproductive function. Its starting point is the "gonadotropin releasing hormone (GnRH) pulse regulator'', described by Knobil, located in the arcuate nucleus of the medial basal hypothalamus. The pulsatile secretion of GnRH activates the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) which in turn activate the secretion of testosterone by the Leydig cells in the testes. A restraining system modulates the function of the GnRH pulse regulator. During fetal life and in the neonatal period there is very little restraint. By 4 to 6 months of age, greater (but not complete) control is imposed over the pulse regulator, and this degree of repression is maintained until the early stages of puberty at which time there is a progressive lessening of restraint. An important question remaining to be answered about the physiology of puberty is where the restraining system originates, and how it modulates the pulse regulator.

Although testicular maturation or "gonadarche'' is the main hormonal event in puberty, it is preceded by 6 to 12 months of adrenal androgen secretion or "adrenarche." The trigger of adrenarche is probably a pituitary peptide related to, but different from, adrenocorticotropic hormone (ACTH). This putative hormone has been termed adrenal androgen stimulation hormone (AASH). The modulator of AASH secretion is as elusive as that of the GnRH pulse regulator.

Puberty begins in boys at 9 to 14 years and is completed within 3 to 4.5 years. Table 1 lists the developmental stages of external genitalia and pubic hair as described by Tanner.

Precocious Puberty
When the first signs of puberty occur prior to 9 years of age in boys, puberty is considered precocious. The precocity is called central if its etiology is related to an early activation of the hypothalamus and pituitary with episodic production of gonadotropins. Treatment with a long acting GnRH analogue will be effective in arresting the sexual maturation because constant levels of GnRH eventually turn off the endogenous secretion of LH. A magnetic resonance imaging scan (MRI) may show abnormalities of the central nervous system (CNS). Often precocious puberty is related to a benign hamartoma. Rarely, a malignant tumor is discovered in which case surgery is indicated. When the MRI reveals no CNS abnormality the precocity is referred to as idiopathic.

Precocious puberty is called peripheral when it occurs in the absence of secretion of pituitary LH/FSH. In rare cases, a tumor (such as a hepatoma) can secrete human chorionic gonadotropin (hCG) which in turn activates the secretion of testosterone by the Leydig cells. Also rare are the tumors of Leydig cells which produce testosterone. Adrenal tumors can be virilizing. One can also encounter a mild form of congenital adrenal hyperplasia which produces signs of virilism. Finally, patients with McCune-Albright Syndrome show the triad of precocious puberty, bone fibrous dysplasia, and cafe au lait spots of the skin. The etiology of this syndrome is thought to be a mutation of the G-proteins which are coupled to various membrane receptors.

Delayed Puberty
Puberty is considered delayed in boys when there is no noticeable enlargement of the testes by 14 years of age. As with precocious puberty, delayed puberty can be due to central causes (hypogonadotropic hypogonadism) or peripheral causes (hypergonadotropic hypogonadism).

The lack of gonadotrophic secretion may be secondary to various CNS tumors or destructive disorders (histiocytosis, sarcoidosis, Lupus). It can also be related to congenital malformations of the brain such as pituitary aplasia, Kallmann syndrome, septo-optic dysplasia, or to head trauma with hemorrhage. In some of these patients, it might be possible to re-establish episodic LH secretion by episodic administration of GnRH. Such therapy is rather cumbersome and usually patients choose testosterone replacement treatment using an intramuscular injection of testosterone enanthate every 3-4 weeks.

Primary gonadal failure is associated with hypersecretion of LH/FSH, hence the term hypergonadotropic hypogonadism. This situation can result from several abnormalities of sex chromosomes such as Klinefelter syndrome (47,XXY) and its variants including the so-called "46-XX males'' in whom the Y-chromosome gene responsible for testicular determination (SRY) has been translocated to the pseudoautosomal region of an X-chromosome. Testicular failure can be due to bilateral trauma or tumor, radiation or an auto-immune disorder. Poorly explained cases of partial gonadal dysgenesis, Noonan Syndrome (46,XY,male Turner) and anarchia (``Vanishing Testes'') will also result in hypergonadotropic hypogonadism. In most of these situations, the only possible therapy is testosterone replacement.

Suggested Readings

Germak JA, Knobil E. Control of puberty in the rhesus monkey. In: Grumback MM, Sizonenko PC, Aubert ML, eds. Control of the Onset of Puberty. Baltimore, MD: Williams and Wilkins Pub.; 1990:69.

Grumbach MM, Sizonenko PC, Aubert ML, eds. Control of the Onset of Puberty. Baltimore, MD: Williams and Wilkins Pub.; 1990.

Migeon CJ, Berkovitz GD, Fechner PY. Diagnosis of Pediatric Disorders in Biochemical Basis of Pediatric Disease. Soldin SJ, Rifai N, Hicks JMB, eds. Washington, D.C.: AACC Press Pub.; 1992:165.

Kappy, M, Blizzard RM, Migeon CJ. Wilkins -The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. 4th ed., Springfield, IL.: Charles C. Thomas Pub., 1994.