DISORDERS OF PUBERTY

Puberty is the most important component of adolescent growth, characterized by appearance of secondary sexual characteristics as well as maturation of reproductive functions, e.g.

Important pubertal changes in girls include: (a) thelarche, i.e. breast enlargement, (b) adrenarche, i.e. appearance of pubic hair, and (c) menarche, i.e. onset of menstruation.

Corresponding changes in boys include: (a) increase in testicular size, (b) adrenarche, and (c) penile enlargement. Physiology of puberty: Onset and progression of puberty is regulated by many hormonal changes in HPG (hypothalamic-pituitary-gonadal) axis involving: (a) hypothalamic GnRH, (b) pituitary gonadotropins, e.g. LH and FSH, (c) gonadal steroids, e.g. estrogens and testosterone, along with adrenal androgens, e.g. DHEA/ DHEAS (Fig 22.6), in following general sequence:

• Pre-pubertal hyothalamic hypersensitivity: During pre-pubertal stage, gonadal steroid production is negligible but hypothalamus is extremely sensitive to them and even miniscule hormone levels are enough to exert negative feedback on hypothalamic GnRH and pituitary gonadotropin secretion.

• Earliest hormonal change to herald the onset of puberty is increase in adrenocortical androgen pro­duction (DHEA, DHEAS) at ~6-8 years, initiating adrenache, i.e. development of pubic and axillary hair.

• Rise in GnRH and gonadotropin levels: At ~7-8 years, hypothalamic sensitivity to gonadal steroids declines, leading to increased secretion of GnRH and consequently, pituitary gonadotropins. Initially, GnRH, LH and FSH are released in pulse-form during nights, but gradually raised levels are maintained throughout the day.

Fig.

adrenal androgens(DHEA#8725;DHEAS) at 6-8 years lead to development of secondary sexual hair.

• Increased gonadal steroid secretion: Rising pituitary gonadotropin levels lead to gonadal maturation and increased secretion of gonadal steroids. In males, LH stimulates Leydig cells for testosterone production while FSH promotes development of seminiferous tubules and spermatogenesis. In females, LH promotes luteinization in ovaries and estrogen/ progesterone secretion, while FSH is responsible for follicular development.

• Effects of gonadal steroids: Increased gonadal and adrenal steroid levels also leads to: (a) development of secondary sexual characteristics, (b) cyclic nature of menstruation, and (c) linear growth spurt as well as skeletal maturation.

Estrogen is prime determinant of breast growth, external genital changes and ovulation/menstruation in females; androgens, e.g. testosterone and its derivatives, are predominant hormones in males, leading to testicular and penile growth, typical body odor and voice changes. Adrenarche, i.e. development of sexual hair is mediated by androgens in both sexes.

Precocious puberty is defined as appearance of any of the secondary sexual characteristics before 8 years in girls and 9 years in boys; or onset of menarche before 10 years.

Etiology: Precocious puberty may be central or peri­pheral in origin, due to any cause of endogenous, exogenous or ectopic excess of puberty-determinant hormones (Table 22.14).

• Central precocious puberty (CPP) is true precocious puberty due to premature activation of HPG axis (gonadotropin dependent). It is essentially isosexual, associated with true development of gonadal, reproductive and physical functions along with secondary sexual characteristics.

• Peripheral precocious puberty (PPP) is caused by exogenous administration or endogenous excessive production of sex steroids from any source (gonadal, adrenal, ectopic) not dependent on HPG axis (gonadotropin independent).

Incomplete variants of PPP include—(a) premature thelarche in females, due to excess of ovarian estrogen, (b) premature adrenarche/pubarche, due to excess of adrenal androgens, and (c) premature menarche, due to transient rise in ovarian activity.

Diagnostic evaluation of these children includes:

• History with special reference to: (a) age of onset, (b) similar family history regarding pubertal events, and (c) preceding intracranial disease or hormone therapy.

• Physical examination with special reference to: (a) anthropometry for linear growth, which will reveal tall stature (except in cases with associated hypothyroidism),

TABLE 22.14: Causes of precocious puberty

Gonadotropin dependent or central PP:

• Idiopathic (sporadic or familial)

• Intracranial (hypothalamic/pituitary) causes

• Congenital/developmental malformations

• Post-infective: Meningitis, encephalitis

• Post-injury: Trauma, surgery, radiation

• Neoplastic: Craniopharyngioma, hypothalamic hamartoma

• Others: Empty Sella syndrome, hypothyroidism

Gonadotropin independent or peripheral PP: Isosexual peripheral precocious puberty (in girls)

• Ovarian: Benign cyst, gonadoblastoma*

• Adrenal: Adenoma, carcinoma

• Exogenous estrogen therapy

• Hypothyroidism, McCune-Albright syndrome

Isosexual peripheral precocious puberty (in boys)

• Testicular: Leydig cell tumor

• Adrenal: Congenital adrenal hyperplasia**

• HCG secreting tumors: Choriocarcinoma

• Exogenous androgen therapy

• Hypothyroidism, McCune-Albright syndrome

Heterosexual precocious puberty (in girls)

• Congenital adrenal hyperplasia

• Virilizing ovarian or adrenal neoplasms

• Exogenous androgen therapy

Heterosexual precocious puberty (in boys)

• Estrogen producing adrenal tumors

• Exogenous estrogen therapy

*/**Commonest cause in females and males respectively, excluding exogenous hormonal therapy

(b) Marshal and Tanner staging for pubertal changes (Table 13.2), (c) testicular size for tumors, (d) other endocrinal disturbances, e.g. hypothyroidism, CAH, etc.

Baseline investigations in all cases must include: (a) skeletal survey for bone age, and (b) serum gonadal steroid (estradiol and testosterone) levels. Bone age is advanced in complete precocious puberty, normal in incomplete variants of PPP and reduced in cases associated with hypothyroidism.

Detailed investigations in cases with multiple signs of precocious puberty, advanced bone age and abnormal basal hormonal levels, including:

- Hormonal assays for adrenal steroids (DHEAS, 17-OHP, androstenedione), HPG axis (GnRH stimulation test), LH/FSH levels, HCG levels (ecto­pic source) and thyroid function tests. LH/FSH levels are elevated in CPP and suppressed in PPP. GnRH stimulation test shows positive (pubertal) response CPP but not in PPP.

- Radiological investigation with USG for uterus pelvis and adrenal masses, along with neuroimaging in suspected cases of CPP.

Management aims to suppress pubertal changes and achieve target height potential and includes:

• Treatment of primary cause or withdrawal of exogenous hormonal medications,

• Specific hormonal inhibitors in idiopathic/untreatable cases, as follows:

- CPP: GnRH analogues, e.g. triptorelin/leuprolide as monthly IM preparations till desired age for puberty. Discontinuation of these analogues leads to resumption of puberty.

- PPP: Treatment of the associated hormone defi­ciencies, e.g. eltroxin for hypothyroidism, hydro­cortisone and fludrocortisone for CAH, along with surgical excision of tumors, if required. Aromatase inhibitors like letrozole, estrogen inhibitors, e.g. testolactone and anti-androgens like ketoconazole, spironolactone or cyproterone acetate may be used in selected cases.

• Periodic monitoring and psychological support.

Delayed puberty denotes maturational lag in HPG axis, clinically indicated by:

• Absence of the onset of breast development by 13 years in girls and testicular enlargement (gt; 3 ml) in boys by 14 years of age.

• A gap of gt;5 years between first sign of puberty and completion of genital growth/menarche, or

• Absence of menarche by 15 years in females.

Etiology: Delayed puberty is often constitutional, with similar family history and simultaneous lag in height and bone age. Pathological delay may be classified according to gonadotropin levels as hypogonadotropic hypogonadism due to central hypophyseal or pituitary causes and hypergondotropic hypogonadism due to peripheral causes (Table 22.15).

Clinical evaluation is on same lines as for precocious puberty. History of orchitis should be additional enquired in males. Gonads should be carefully examined for stretched penile length and testicular volume. As many cases are chromosomal in origin, dysmorphic features may provide important clues for diagnosis. Afemale child with delayed puberty and short stature should be assessed for Turner syndrome.

Laboratory investigations should be more conservative as most cases are merely constitutional, though baseline investigations for bone age determination and exclusion of chronic illness, e.g. tuberculosis, renal function tests, are essential to exclude common causes.

Detailed investigations include:

• USG abdomen (gonadal/internal genitals) and CT/

MRI brain (intracranial lesion).

• Karyotyping and cytogenetic studies for chromosomal defects.

• Relevant hormonal assays, as per clinical suspicion, e.g. thyroid function tests, sex-steroid levels (testosterone, estradiol, prolactin), basal and GnRH stimulated gonadotropin levels and HCG stimulation test in cases with non-palpable testis. A rise in testosterone levels after HCG indicates functioning testis.

• Gonadal biopsy in cases of suspected dysgenesis or DSD.

Management is conservative in most cases, including better nutrition, treatment of primary cause, e.g. infec­tions, undernutrition, systemic illnesses and identifiable endocrinal causes, along with periodic follow-up.

Hormonal therapy should be deferred except in severe pubertal delay, as it may accelerate skeletal maturation and reduce ultimate adult height. Low-dose testo­sterone may be used in boys with severe delay to accelerate development of secondary sexual features and restore self-esteem; while low-dose daily estrogen therapy is used in girls till menstruation followed by cyclic therapy.