Normal Physiology of Puberty and Adrenarche

Puberty is the transitional period between the juvenile state and adulthood, characterized by attainment of secondary sex characteristics and reproductive capability. The control center of puberty is comprised of hypothalamic GnRH neurosecretory neurons (pulse generator) located in the medial basal hypothalamus [King et al., 1985]. Kisspeptin (product of the KISS 1 gene) and the kisspeptin receptor (KISS1R), also known as GPR54 (a member of the rhodopsin family of G protein coupled receptors), have emerged as key regulators of the hypothalamic-pituitary-gonadal (HPG) axis [de Roux et al., 2003; Seminara et al., 2003]. Kisspeptin neurons found in the hypothalamus directly innervate and stimulate GnRH neurons. Kisspeptin neurons also express the estrogen receptor and the androgen receptor, which enable negative feedback action of sex steroids. Kisspeptin signaling in the brain is critical for triggering and guiding the tempo of sexual maturation at puberty [Oakley et al., 2009]. In addition, the tachykinin neurokinin B (encoded by TAC3) and its receptor NK3R (encoded by TACR3) also serve as central regulators for normal gonadatropin secretion and pubertal development [Topaloglu et al., 2009].

Puberty is not a sudden event, but rather reflects a milestone on a continuum that begins before birth. The GnRH pulse generator becomes pulsatile by midgestation, and remains active in early infancy until about 6 months of age in boys and 12–24 months in girls [Grumbach, 2002]. Between late infancy and the onset of puberty, the GnRH pulse generator becomes relatively quiescent as a consequence of an as yet poorly defined central nervous system (CNS) inhibitory mechanism. After a quiescent period of approximately 10 years, the GnRH pulse generator is disinhibited, leading to increased amplitude and frequency of LH and FSH secretion, and resulting in increased sex steroid production (principally, estradiol and testosterone) and attainment of physical puberty [Grumbach, 2002].

Adrenarche refers to the prepubertal rise of adrenal androgen precursors – in particular, dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) – as a consequence of maturation of the zona reticularis of the adrenal cortex. DHEA can be converted peripherally to testosterone; thus, adrenarche is typified clinically by mild androgenic effects, such as a change in body odor and the appearance of axillary and pubic hair and acne. The mechanisms that regulate adrenarche are not well understood. Adrenache is independent of the maturation of the hypothalamic-pituitary-gonadal axis, preceding the onset of puberty by about 2 years [Miller, 1999].

The normal age of onset of secondary sexual characteristics (defined as 2.5 SD on either side of the mean, or where approximately 99 percent of the population falls) is 6–13 years in girls and 9–14 years in boys. The appearance of secondary sexual characteristics, acceleration of growth, and the capacity of reproduction are hallmarks of puberty. The development of puberty is characterized by sequential events that are specific for each gender. In females, secondary sexual characteristics include breast development, the appearance of pubic and axillary hair, maturation of the labia, and estrogenization of the vaginal mucosa. The development of pubic and axillary hair is influenced by androgens produced in both the adrenal cortex (adrenarche) and the ovary. Menarche usually occurs 2–3 years after initiation of breast development. The pubertal growth spurt, which normally occurs in the early stages of puberty for girls, can result in a gain in height of 25 cm or more. In males, puberty begins with testicular enlargement (≥ 2.5 cm in the longest dimension) followed by the appearance of sexual hair and phallic enlargement. The growth spurt occurs during midpuberty, which results in an average 28 cm gain in height [Grumbach and Styne, 2003]. Abnormalities of puberty include sexual precocity and delayed or arrested puberty, each with a broad differential diagnosis. While pubertal disorders can arise from defects at the level of the hypothalamus, pituitary, or gonads, the focus of this discussion is on hypothalamic and pituitary causes of sexual precocity and delayed puberty.

Sexual Precocity

Sexual precocity is usually defined as the development of secondary sexual characteristics before 6–7 years of age in girls [Herman-Giddens et al., 1997], and before 9 years of age in boys. In all cases thus far described, sexual precocity results from an increase in circulating sex steroids. An endocrine approach to the differential diagnosis of sexual precocity would include consideration of exogenous and endogenous sources of these steroids. Endogenous sources include the gonads and adrenal cortex, either of which may secrete sex steroids inappropriately as the result of a primary process intrinsic to these tissues, or secondary to a circulating stimulatory factor. As previously noted, this chapter will focus only on hypothalamic/pituitary causes of sexual precocity.

Precocious puberty (sometimes referred to as “true” or “central” precocious puberty) is defined as early puberty specifically resulting from premature reactivation of the GnRH pulse generator. Precocious puberty most commonly is idiopathic, but can result from a broad range of abnormalities, including CNS tumors, hamartoma of the tuber cinereum, congenital malformations, subarachnoid cysts, CNS infection, irradiation, and trauma. The incidence of precocious puberty is significantly higher in females. In studies of girls with precocious puberty, idiopathic precocious puberty ranges from 63 to 74 percent [Pescovitz et al., 1986; Cisternino et al., 2000]. In contrast, only 6 percent of boys with precocious puberty are idiopathic [Pescovitz et al., 1986]. Idiopathic precocious puberty is a diagnosis of exclusion and it is, thus, essential to search for underlying neurological causes. Tumors involving in the posterior hypothalamus, such as glioma, germinoma, and teratoma, can cause precocious puberty. Most of these tumors are thought to trigger early puberty by interfering with mechanisms that normally inhibit the GnRH pulse generator. Few LH/FSH-secreting adenomas have been reported [Demura et al., 1977]. Hamartoma of the tuber cinereum, a congenital malformation, can cause central precocious puberty. Hamartomas are small lesions (4–25 mm), may be sessile or pedunculated, and usually do not enlarge with time (Figure 97-2). Histologically, they appear to be composed of normal brain tissue and contain GnRH secretory neurons, which may serve as an “ectopic pulse generator” [Mahachoklertwattana et al., 1993]. In some hypothalamic harmatomas, the production of transforming growth factor (TGF)-α can initiate early puberty by activating the normal GnRH pulse generator [Jung et al., 1999]. Hamartomas of the tuber cinereum are often associated with gelastic (laughing) seizures. Recently, an autosomal-dominant activating mutation in GPR54 was found in a girl with central precocious puberty [Teles et al., 2008].

Fig. 97-2 Hamartoma of the tuber cinereum in a 3-year-old girl by magnetic resonance imaging.

Note a small (6-mm × 6-mm), pedunculated and isointense hypothalamic mass in the sagittal view. The patient had midpubertal breast development, and an advanced bone age of 6 years at a chronologic age of 3 years.

Ectopic human chorionic gonadotropin (hCG)-secreting tumors in the CNS (and elsewhere), e.g., hypothalamic germinomas, can cause sexual precocity in boys [Sklar et al., 1981]. Such patients do not have central precocious puberty, in that they do not have premature reactivation of the hypothalamic GnRH pulse generator. Rather, the ectopic hCG interacts with the LH/hCG receptor on testicular Leydig cells, resulting in increased testosterone secretion and virilization. In girls, ovarian estrogen secretion requires both LH and FSH. Thus, ectopic secretion of hCG alone causes sexual precocity only in boys [Grumbach and Styne, 2003]. The accurate diagnosis of precocious puberty and its cause requires a detailed history, physical examination, hormonal testing, and imaging studies of the CNS. Idiopathic precocious puberty is often familial, exhibiting autosomal-dominant inheritance [de Vries et al., 2004]. The occurrence of early breast and pubic hair development is often seen in girls with precocious puberty, while testicular enlargement and other signs of virilization are seen in boys with precocious puberty. Hormonal analysis demonstrates increased amplitude and frequency of LH and FSH pulsatile secretion, resulting from increased pulsatile secretion of GnRH. This finding can be demonstrated either by serial sampling of LH and FSH or by single LH/FSH measurements using highly sensitive immunochemiluminescent assays. Dynamic testing using GnRH or a GnRH agonist is also used routinely to diagnose precocious puberty. Magnetic resonance imaging (MRI), with particular attention to the hypothalamic-pituitary area, should be carried out in any child diagnosed with precocious puberty.

Delayed or Arrested Puberty

Delayed puberty may be defined, in boys, by the absence of testicular enlargement by 14 years of age, and in girls, by the absence of breast development by 13 years of age. The differential diagnosis of delayed puberty can be divided into three major categories: constitutional delay in growth, hypogonadotropic hypogonadism, and hypergonadotropic hypogonadism. Constitutional delay in growth, the most common cause of delayed puberty, is a normal variant, and is thought to result from a prolonged quiescent period of the GnRH pulse generator. Such patients often have a family history of delayed puberty and have delayed skeletal maturation without evidence of endocrinopathy or other organic diseases. Hypergonadotropic hypogonadism, which indicates a defect at the level of the gonads, will not be reviewed in this section. Hypogonadotropic hypogonadism indicates a defect at the level of the hypothalamus or pituitary, and may result from a variety of CNS disorders that can lead to delayed or absent puberty. Hypogonadotropic hypogonadism can be congenital or acquired, can occur alone or in association with multiple hypothalamic and pituitary hormone deficiencies, and may be organic or functional in etiology.

Hypogonadotropic Hypogonadism Associated with Multiple Hypothalamic/Pituitary Hormone Deficiencies

Hypogonadotropic hypogonadism can also present in combination with other hypothalamic/pituitary hormone deficiencies. Human mutations of pituitary transcription factors known to cause delayed puberty include Prop-1 and Lhx3. Prop-1 (prophet of Pit-1) is a paired-like homeodomain transcription factor expressed only in the anterior pituitary. Combined pituitary hormone deficiencies caused by mutations in Prop-1 occur with an incidence of about 1 in 8000 births. Patients with mutations in Prop-1 have combined pituitary hormone deficiencies, which may include deficiencies of GH, PRL, TSH, and gonadotropins. Such patients have hypogonadotropic hypogonadism in association with short stature and hypothyroidism [Wu et al., 1998]. Lhx3 is a LIM-type homeodomain protein. Mutations in Lhx3 have been associated with anterior pituitary hypoplasia and complete deficits of GH, PRL, TSH, and gonadotropins. Lhx3 mutations are also associated with decreased range of motion in the cervical spine [Netchine et al., 2000].

Other genetic factors that lead to delayed puberty include mutations of prohormone convertase (PC)1, leptin, and leptin receptor genes. A defect in PC1 has been shown to disrupt GnRH processing, and results in hypogonadotropic hypogonadism and obesity associated with impaired processing of insulin and POMC. Mutations in leptin and the leptin receptor are associated with a similar clinical picture of hypogonadotropic hypogonadism, hyperinsulinemia, and obesity [Kalantaridou and Chrousos, 2002; Beier and Dluhy, 2003]. Congenital midline defects of the CNS, such as septo-optic dysplasia (SOD), empty sella syndrome, and Rathke’s cyst, are often associated with hypothalamic/pituitary dysfunction, which may include hypogonadotropic hypogonadism. The genetics of SOD and its related pituitary hormone deficiencies will be reviewed in detail in the section on hypothalamic/pituitary disorders of statural growth.

Numerous CNS lesions can lead to hypogonadotropic hypogonadism, including CNS tumors (primarily, third ventricular), CNS infection, invasive diseases, cranial irradiation, and trauma. These CNS disorders often present with combined anterior and posterior pituitary hormone deficiencies. CNS tumors of the sella and parasellar region associated with multiple hypothalamic/pituitary hormone deficiencies include craniopharyngioma, pituitary adenomas, optic and hypothalamic gliomas, and germ-cell tumors. Delayed or arrested puberty is the second most common presenting symptom of CNS tumors following headache. Craniopharyngiomas, the most common tumor of the sella and parasellar region in children, are slow-growing, space-occupying tumors (Figure 97-3). Most patients present before their teenage years with headache, visual loss, and multiple hypothalamic/pituitary hormone deficits. Pituitary adenomas in children usually present as microadenomas with pituitary hormone hypersecretion. Nonsecreting adenomas in children are rare, and are usually macroadenomas. Prolactinoma is the most common pituitary adenoma in the pediatric population and frequently is associated with delayed or arrested puberty. Nonsecreting macroadenomas can also cause delayed puberty, at least in part, through elevation of prolactin as a consequence of stalk compression [Kunwar and Wilson, 2001]. Cranial irradiation to the third ventricular area also may be associated with hypogonadotropic hypogonadism.

Fig. 97-3 Craniopharyngioma in a child by magnetic resonance imaging.

Note a large suprasellar mass elevating the floor of the third ventricle.

Normal Biochemistry and Physiology of Prolactin

PRL was identified in humans in the early 1970s after the lactogenic acitivity of GH was blocked by GH antiserum. PRL is a 199-amino-acid peptide synthesized in lactotroph cells, which constitute 15–25 percent of functioning anterior pituitary cells. PRL has homology to GH and placental lactogen in its structure and function. Regulation of prolactin secretion is distinct from that of other anterior pituitary hormones. PRL is the only pituitary hormone that is regulated predominantly by the hypothalamus through an inhibitory mechanism mediated by dopamine via the hypothalamic-pituitary-portal circulation. Other inhibitory factors include TGF-β and endothelin-1, thought to act via paracrine mechanisms. Stimulatory factors include TRH, oxytocin, and vasoactive intestinal polypeptide (VIP). The principal physiologic functions of PRL are enhanced mammary gland development during pregnancy and lactation. PRL may be increased through physiologic and pathologic mechanisms. Physiologic stimuli include pregnancy, lactation, stress, sleep, and exercise. Pathologic causes of hyperprolactinemia include prolactinomas, injury to the hypothalamic-pituitary stalk secondary to tumors or other CNS disease (infiltration, granuloma, irradiation, trauma), a variety of systemic disorders, including chronic renal failure and cirrhosis, and a variety of drugs ranging from dopamine receptor blockers and dopamine synthesis inhibitors to oral contraceptives.

Clinical Features and Management of Hyperprolactinemia

The principal clinical feature of hyperprolactinemia, regardless of the cause, is galactorrhea, which may be unilateral or bilateral. Other clinical features may include delayed or arrested puberty, amenorrhea in females, and gynecomastia in males. Prolactinoma is the most common tumor of the pituitary, comprising about 50 percent of anterior pituitary adenomas. Most prolactinomas are less than 1 cm in diameter, i.e., microprolactinomas, and normally do not cause significant mass effects. However, with macroprolactinoma, headache and visual disturbance can be the first presenting symptoms. Rarely, patients with macroprolactinoma present with hydrocephalus, cranial nerve palsies, and seizures [Colao et al., 1998].

If a prolactinoma is diagnosed, therapeutic options include medical management with dopamine agonists, surgery, and adjunctive radiotherapy. While medical management is often considered the principal intervention, numerous reports indicate that microprolactinomas can be removed surgically, though with variable recurrence rates. Macroprolactinomas are less likely to be cured surgically and often require chronic dopamine agonist treatment. Dopamine agonists are effective and safe pharmacologic interventions for both micro- and macroprolactinoma [Pivonello et al., 2004; Verhelst et al., 1999]. Cabergoline is better tolerated and more effective than bromocriptine [Di Sarno et al., 2001]. Withdrawal of cabergoline after long-term therapy has been safe, although careful monitoring of tumor progression is necessary [Colao et al., 2003]. Nearly all prolactinomas have been reported to respond to cabergoline treatment, irrespective of tumor size and preceding treatment with higher doses (>3 mg/week) [Ono et al., 2008]. Adjunctive radiotherapy has been considered beneficial in some patients with macroprolactinoma. The skill and experience of the surgeon clearly play a role in determining the optimal treatment and outcome.

Adrenocorticotropic Excess

Excessive production of ACTH from the pituitary arises either from CRH overproduction or from a primary ACTH-producing adenoma (Cushing’s disease). The first sign of Cushing’s disease in a growing child is often impaired linear growth [Mindermann and Wilson, 1995]. Other classic signs and symptoms of Cushing’s disease include excessive weight gain (central obesity), buffalo hump, plethora, “moon facies,” acne, striae, hypertension, hirsutism, fatigue, pubertal delay or arrest, bruising, and headache [Magiakou et al., 1994; Devoe et al., 1997; Magiakou and Chrousos, 2002]. Usually, at the time of diagnosis, ACTH-producing adenomas are significantly smaller than other pituitary adenomas (Figure 97-4). These tumors are usually not well demarcated, and are often less than 10 mm in diameter (microadenoma).

Fig. 97-4 Adrenocorticotropic hormone-secreting pituitary adenoma in a 15-year-old girl by magnetic resonance imaging.

A, A crescent-shaped, hypodense area is indicated by the arrow in the coronal view. B, A 3-mm × 2-mm hypodense nodule in the inferior aspect of the pituitary is indicated by the arrow in the sagittal view.