INTRODUCTION-• onset of secondary sexual characters before the age of 8 years in girls and 9 years in boys.• Two types-central-gonadotropin dependent or true. Is always isosexual and stems from hypothalamic-pituitary- gonadal activation with ensuing sex hormone secretion and progressive sexual maturation.• Peripheral- gonadotropin independent or pseudo. some of the secondary sex characters appear, but no activation of the normal hypothalamic-pituitary-gonadal interplay. May be isosexual or heterosexual (contrasexual)
Causes of central precocious puberty-• Idiopathic Organic brain lesions- Hypothalamic hamartoma Brain tumors, hydrocephalus, severe head trauma, myelomeningocele Hypothyroidism, prolonged and untreated
CENTRAL PRECOCIOUS PUBERTY-• Defined by the onset of breast development before the age of 8 years in girls and by the onset of testicular development (volume ≥ 4 mL) before the age of 9 years in boys, as a result of the early activation of the HPG axis.• 5- to 10-fold more often in girls than in boys and is usually sporadic.• A high prevalence of idiopathic central precocious puberty has been reported in girls adopted from developing countries, with the limitation that the exact date of birth may be uncertain.• 90% of girls have an idiopathic form,• 75% of boys have structural central nervous system (CNS) abnormality. Beyond its etiology, which thus needs to be specifically addressed, central precocious puberty can affect linear growth and the childs growth potential.
CLINICAL FEATURES-• Sexual development begins at any age and generally in normal sequence.• In girls- early menstrual cycles are more irregular and anovulatory. Pregnancy is reported as early as 5.5 years.• In boys, testicular biopsies have shown stimulation of all elements of the testes, and spermatogenesis as early as 5-6 years.• In affected girls and boys, height, weight, and osseous maturation are advanced. The increased rate of bone maturation results in early closure of the epiphyses, and the ultimate stature is < normal
• In hypothalamic hamartoma remain static in size or grow slowly, - no signs other than precocious puberty.• For symptomatic , manifestations may be present for 1-2 yr before the tumor can be detected radiologically.• Include diabetes insipidus, adipsia, hyperthermia, unnatural crying or laughing (gelastic seizures), obesity, and cachexia.• Visual signs (proptosis, decreased visual acuity, visual field defects) may be the first manifestation of an optic glioma.
• Mental development is usually compatible with chronological age. Emotional behavior and mood swings are common, but serious psychological problems are rare.• Natural course- rapid- most common pattern. characterized by rapid physical and osseous maturation, leading to a loss of height potential.• Slow-this pattern characterized by parallel advancement of osseous maturation and linear growth, with preserved height potential.• spontaneously regressive or unsustained central precocious puberty – marks the need for longitudinal observation
LAB. INVESTIGATIONS-• With sensitive assays, serum LH concentrations are undetectable in prepubertal children but become detectable in 50-75% of girls and a higher percentage of boys with central sexual precocity.• Measurement during sleep increases diagnostic power and reveals the pulsatile LH secretion.• GnRH stimulation test. Predominant LH response over FSH after iv administration of GnRH or agonist like Leuprolide. However in girls, LH:FSH ratio can remain low until mid- puberty. In such girls with “low” LH response, the central nature of sexual precocity can be proved by detecting pubertal levels of estradiol (>50 pg/mL), 20-24 hr after stimulation with leuprolide.
• Pelvic ultrasound reveals progressive enlargement of ovaries followed by uterus to pubertal size.• Osseous maturation advances.• An MRI scan usually shows normal enlargement of the pituitary gland, during puberty; it may also reveal CNS pathology.
TREATMENT-• Long term GnRH agonists In the USA, the most commonly used preparation is leuprolide acetate (Lupron Depot Ped), in a dose of 0.25-0.3 mg/kg (minimum, 7.5 mg) i.m. once every 4 wk. Other preparations (D-Trp6-GnRH [Decapeptyl], goserelin acetate [Zoladex]) are approved for treatment of precocious puberty in other countries.• Alternatively, histrelin (Supprelin LA), a subcutaneous 50 mg implant with effects lasting 12 mo, is approved by the FDA .• Intranasal and subcutaneous injection formulae are also available.• IUGR at greater risk of short stature as adults and require more-aggressive treatment of precocious puberty, possibly in conjunction with human growth hormone (hGH) therapy.
ETIOLOGY IN BOYS-• Boys Isosexual (masculinizing) conditions -Congenital adrenal hyperplasia Adrenocortical tumor Leydig cell tumor Familial male precocious puberty Isolated Associated with pseudohypoparathyroidism hCG-secreting tumors Central nervous system Hepatoblastoma Mediastinal tumor associated with Klinefelter syndrome Teratoma Glucocorticoid receptor defect Exogenous androgen Heterosexual (feminizing) conditions- Feminizing adrenocortical tumor SCTAT associated with Peutz-Jeghers syndrome Exogenous estrogens
MAC CUNE ALBRIGHT SYNDROME-• A rare disorder prevalence 1 in 100000 to 1000000. Is associated with patchy cutaneous pigmentation and fibrous dysplasia of the skeletal system.• a missense mutation in the gene encoding the α-subunit of GS, the G protein that stimulates cAMP formation, resulting in the formation of the putative gsp oncoprotein. Activation of receptors (corticotropin [ACTH], TSH, FSH, and LH receptors) that operate via a cAMP-dependent mechanism, as well as cell proliferation, ensue.• expressed differently in different tissues, accounts for variability of clinical expression.
PRESENTATION-• GIRLS- The average age at onset girls is about 3 yr, vaginal bleeding as early as 4 mo of age and secondary sexual charecters at 6 mo of age.• Estradiol levels vary from normal to markedly elevated (>900 pg/mL), are often cyclic, and can correlate with the size of the cysts.• BOYS- Precocious puberty is less common but has been reported in several instances.• At Pubertal age, Central precocious puberty overrides the antecedent precocious pseudopuberty.
LAB. INVESTIGATIONS-• . Estradiol levels vary from normal to markedly elevated (>900 pg/mL), are often cyclic, and can correlate with the size of the cysts.• Testicular histology has demonstrated large seminiferous tubules and no or minimal Leydig cell hyperplasia; these findings might simply reflect the fact that biopsy specimens were obtained at an early stage of pubertal development.
TREATMENT-• Pubertal progression is variable in these patients. In girls- Functioning ovarian cysts often disappear spontaneously; aspiration or surgical excision of cysts is rarely indicated.• Aromatase inhibitors such as letrozole (1.25-2.5 mg/d orally) or antiestrogens (such as tamoxifen; fulvestrant is currently being investigated).• in boys, in combination with antiandrogens (such as spironolactone 50-100 mg bid, or flutamide 125-250 mg bid). Long-acting analogs of GnRH is indicated only for patients whose puberty has shifted from a gonadotropin-independent to a predominantly gonadotropin-dependent mechanism.
INCOMPLETE(PARTIAL) VARIANTS-• Isolated manifestations of precocity without development of other signs of puberty.• Premature thelarche- isolated breast development that most often appears < 2 yr of life. Sporadic and asymmetric. ; activating mutations of the GNAS1 gene encoding the α- subunit of the GS protein have been described in some patients without other signs of McCune-Albright syndrome.• Menarche occurs at the expected age, and reproduction is normal. Basal serum levels of FSH and the FSH response to GnRH stimulation >normal girls Plasma LH and estradiol are consistently < limits of detection. Ultrasound examination of ovaries show a few small (<9 mm) cysts.
• However, In some girls, breast development is associated with definite evidence of systemic estrogen effects, such as growth acceleration or bone age advancement. Pelvic sonography shows enlarged ovaries or uterus. This condition, referred to as exaggerated or atypical thelarche, differs from central precocious puberty because it spontaneously regresses.• PREMATURE PUBARCHE(ADRENARCHE)-appearance of sexual hair before the age of 8 yr in girls or 9 yr in boys without other evidence of maturation.• Girls >boys. Associated with reduced 3β-hydroxysteroid dehydrogenase activity, and an increase in C-17,20-lyase activity. Leads to increased DHEA, androstenedione and 17HOP
Exaggerated form is atypical premature adrenarche. May developone or more features of systemic androgen effect, such as marked growth acceleration, clitoral (girls) or phallic (boys)enlargement, cystic acne, or advanced bone age (>2 SD above the mean for age).
• Although it has been considered a benign condition, longitudinal observations suggest that approximately 50% of girls with premature adrenarche are at high risk for hyperandrogenism and polycystic ovary syndrome, alone or more often in combination with other components of the metabolic syndrome (insulin resistance possibly progressing to type 2 diabetes mellitus, dyslipidemia, hypertension, increased abdominal fat) as adults.• Premature Menarche-is a diagnosis of exclusion. In girls with isolated vaginal bleeding in the absence of other secondary sexual characters, more common causes such as vulvovaginitis, a foreign body, or sexual abuse, and uncommon causes such as urethral prolapse and sarcoma botryoides must be carefully excluded.
• The majority of idiopathic premature menarche have only 1-3 episodes of bleeding; puberty occurs at the usual time, and menstrual cycles are normal. Plasma levels of gonadotropins are normal, but estradiol levels may be elevated, probably owing to episodic ovarian estrogen secretion. Occasional patients are found to have ovarian follicular cysts on ultrasound.
Approach to a girl with precocious puberty Early breast development Increased height velocity and advanced yes bone age Associated sec.sexual characters , axillary and pubic hair no yes age <2years >2 year Infantile Pelvic ultrasound evaluation of mamoplasia gonads and uterus Prepubertal Pubertal GnRH stimulation testPremature thelarche
Approach to a boy with penile enlargement<9years Penile enlargement < 9 years Increased height velocity and advanced bone age Increased testicular size yes no Adrenal etiology symmetrica l asymmetrical Raised Raised 17-OHP levels• yes no cortisol, cortic Glucocorticoid otropin resistance DHEAS high CAH Adrenal tumour