Key Points

• Lack of thelarche (breast development) by age 12 years in girls or lack of testicular enlargement by age 14 years in boys indicates delayed puberty.

• Constitutional delay is characterized by delayed but spontaneous onset of puberty, whereas organic delay is caused by gonadal, pituitary, or central dysfunction.

Delayed puberty in girls is defined as lack of thelarche by age 12 years or duration between thelarche and menarche longer than 5 years. In boys, delayed puberty is defined as no testicular enlargement by age 14 years with more than 5 years between initial and complete development of the genitalia. Delayed puberty in both males and females is classified as constitutional (idiopathic) or organic (gonadal, pituitary, or central cause). A retrospective study of 232 male and female patients with delayed puberty revealed that the majority (53%) had constitutional delay of growth and maturation, with much higher incidence in males (63%) than females (30%). The remaining 47% of the total 232 patients had mixed etiologies; 19% had functional hypogonadotropic hypogonadism, 12% permanent hypogonadotropic hypo-gonadism, 13% permanent hypergonadotropic hypogonad-ism, and no clear etiology for the remaining 3% (Sedlmeyer and Palmert, 2002).

Constitutional delay is characterized by physiologic delay but subsequent spontaneous onset of puberty and is a diagnosis of exclusion. The cause is a delay in GnRH pulse generation, with low levels of gonadotropins. Height and weight in these children tend to be below the fifth percentile, but most catch up during adolescence, reaching normal adult height and weight. Family history may reveal similar delays of puberty in one or both parents, which can be reassuring for the child and parent. Values for FSH, LH, DHEA-S, pro-lactin, testosterone, and estradiol levels will be consistent with prepubertal values until onset of puberty and normal sexual maturation.

The two common causes of delayed puberty from organic etiologies are pituitary dysfunction or hypogonadotropic hypogonadism. Panhypopituitarism in children may present as delayed puberty, but in conjunction with growth failure, secondary hypothyroidism, and adrenal insufficiency. Differentiation of organic forms of delay from constitutional delay may be difficult to establish in certain patients, requiring a series of observations and testing (no single study or imaging technique will differentiate these). Hypo-gonadotropic hypogonadism presents with low levels of FSH and LH as a result of defective GnRH pulsation. Causes include anorexia nervosa, excessive weight loss, extreme exercise (cross country runners), tumors, head trauma, infiltrative processes, infection, and radiation. Hypergonadotropic hypogonadism is usually caused by gonadal failure and presents with high levels of gonadotropins and low levels of sex steroids.

Evaluation of delayed puberty, as with all evaluations for abnormal sexual development, begins with a detailed history focusing on growth patterns, presence of any secondary sexual development, diet, exercise habits, congenital abnormalities, neurologic symptoms, and family history. Physical examination includes a thorough search for early signs of sexual maturation using Tanner staging. Measurement of arm span in relation to height is helpful in growth assessment. Arm span that exceeds height more than 5 cm is consistent with adult configuration. When present in children, this may mean delayed epiphyseal closure due to hypogonadism. Wrist radiography is useful to determine bone age. Initial laboratory screening should include complete blood cell count (CBC), erythrocyte sedimentation rate (ESR), and liver function tests (LFTs). Serum FSH, LH, estradiol, and testosterone levels can distinguish between primary and secondary hypogonadism. In primary hypogonadism (ovarian and testicular failure), serum gonadotropin levels will be elevated. In patients with constitutional delay of puberty and congenital GnRH deficiency, serum gonado-tropin levels will be low. Prolactin, TSH, adrenal andro-gens, and karyotype (to rule out Turner's, Klinefelter's, and Noonan's syndromes) should be evaluated if the clinical presentation warrants.

Therapy for delayed puberty is targeted at the underlying disorder, if identified. If the cause is unknown, observation with reassurance and psychosocial support and reevaluation after 4 to 6 months is an option. Hormonal therapy with estrogen (girls older than 12 years) or testosterone (boys older than 14 years) is another option. Short-term use of exogenous hormones does not appear to have long-term sequelae, except for the potential effect on skeletal maturation, which might result in failure to achieve potential adult

Table 35-4 Precocious Puberty: Types, Causes, and Treatment

Etiology

Symptoms

Tests/Treatment

Central Precocity*

Idiopathic

Secondary sexual characters development

GnRH analogues Discontinue at 11 years.

CNS lesions (including congenital defects): hamartomas, tumors, infection, trauma, radiation, after androgen exposure, craniopharyngioma, others

History of trauma Medical history

Headache, visual changes possible

FSH, LH, prolactin, sex steroids, TSH MRI of brain

Treatment per pathology

Primary hypothyroidism

Signs of hypothyroidism without increase in growth velocity

Thyroid profile Treatment with thyroxine

Incomplete Isosexual Precocity

Females: Isolated precocious thelarche

Breast enlargement without other secondary sexual changes

Most cases are benign.

Females: Isolated precocious adrenarche

Pubic hair development, adult odor, acne

DHEA may be increased.

Adrenal steroid hormones and sex hormones: normal ACTH stimulation test to exclude CAH Usually benign; no treatment needed

Females: Isolated precocious menarche

Menarche precedes breast development or appearance of pubic hair.

Normal bone age

Ultrasound: normal pelvis with prepubertal uterus Usually benign; check for abuse and ovarian and genital pathology.

Females: Estrogen-secreting tumors of ovary or adrenals Ovarian cysts

Abdominal symptoms Signs of precocious puberty

CT or MRI in addition to hormonal tests Treat as per pathology

Females/males: McCune-Albright syndrome

Autonomous hyperfunction of gonads; rapid development of precocity Café au lait spots, fibrous dysplasia

Ultrasound/CT of abdomen: large ovarian masses LFTs, DHEA sulfate, TSH, phosphate, cortisol

Males: Gonadotropin-secreting tumors; excessive androgen production Testicular or adrenal tumors Virilizing CAH

Premature Leydig's and germinal cell maturation

Excessive virilization Enlargement of testis (unilateral)

CT/MRI of abdomen Ultrasound Hormonal tests Treat per pathology. Surgery may be indicated.

Males/females: Iatrogenic

History of using sex steroids and related products

Stop causative agent.

Contrasexual Precocity (Isolated Virilization)

Isolated precocious adrenarche.

Females: Virilizing CAH; androgen-secreting ovarian or adrenal neoplasm; Cushing's syndrome; glucocorticoid resistance; arrhenoblastoma

Prepubertal masculinization

Tests for CAH

Cortisol

Testosterone

MRI of abdomen and pelvis Treat per pathology.

Males: Estrogen-secreting tumor, chorionepithelioma; increased extraglandular aromatization of adrenal steroids causing increased extraglandular estrogen production and unusual CAH variations

Prepubertal feminization in boys is rare.

Tests for CAH

Cortisol and estrogen levels Testosterone

MRI of abdomen and pelvis Treat per pathology.

Iatrogenic

History of using sex steroids and related products

Stop causative agent.

Nonprogressive precocious puberty

Stabilization of precocity Normal bone age

Normal bone age

Ultrasound: normal pelvis with prepubertal uterus

Modified from Carel JC, Léger J. Precocious puberty. N Engl J Med 2008;358(22):2366-2377. *True precocious puberty: gonadotropin dependent.

CNS, Central nervous system; GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; MRI, magnetic resonance imaging; DHEA, dehydroepiandrosterone; ACTH, adrenocorticotropic hormone; LFTs, liver function tests; CT, computed tomography; CAH, congenital adrenal hyperplasia.

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height. In females taking estrogen replacement therapy, progestins should be added to the regimen after breakthrough bleeding occurs or after 1 year of therapy.

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