Precocious puberty

Precocious puberty diagnosis management

1. Precocious puberty definition causes & management By Dr. ANIRUDH RAO Moderator Dr. V.R. ANAND

2. INTRODUCTION Onset of secondary sexual characteristics before the age of 8 yr in girls & 9 yr in boys CLASSIFICATION: central or gonadotropin dependent or true – always isosexual Peripheral or gonadotropin independent or precocious pseudopuberty – may be isosexual or heterosexual Combined peripheral and central : peripheral precocious puberty can induce maturatio n of the HPG axis & trigger the onset of central puberty

3. CAUSES CENTRAL PRECOCIOUS PUBERTY Idiopathic Organic brain lesions Hypothalamic hamartoma Brain tumours , hydrocephalus, head trauma, myelomeningocele COMBINED PERIPHERAL & CENTRAL Treated CAH McCune- Albright syndrome Familial male precocious puberty

4. PERIPHERAL PRECOCIOUS PUBERTY CAUSES GIRLS ISOSEXUAL CONDITIONS McCune Albright syndrome Ovarian cysts / tumours Granulosa theca cell tumour Teratoma , chorionepithelioma SCTAT associated with PJS Feminising adrenocortical tumour Exogenous estrogens HETEROSEXUAL CONDITIONS CAH Adrenal tumours Ovarian tumours Glucocorticiod receptor defect Exogenous androgens

5. PERIPHERAL PRECOCIOUS PUBERTY CAUSES BOYS ISOSEXUAL CONDITIONS CAH Adrenocortical tumour Leideg cell tumour Familial male precocious puberty Pseudohypoparathyroidism HCG secreting tumours Mediastinal tumor Teratoma GC receptor defect Exogenous androgens HETEROSEXUAL CONDITIONS Feminising adrenocortical tumour SCTAT associated with PJS Exogenous estrogens

6. INCOMPLETE/PARTIAL PRECOCIOUS PUBERTY Premature thelarche Premature adrenarche Premature menarche

7. CENTRAL PRECOCIOUS PUBERTY DEFINITION: Onset of breast development before the age of 8yr in girls & by the onset of testicular development before the age of 9 yrs in boys, as a result of early activation of HPG axis 5 to 10 times more common in girls than in boys In girls – 90% cases idiopathic In boys – 75% of cases structural CNS abnormality

8. CLINICAL MANIFESTATIONS Sexual development may begin at any age & follows the sequence observed in normal puberty In girls early menstrual cycles more irregular The initial cycles are usually anovulatory In boys testicular biopsies shown stimulation of all elements of the testes & spermatogenesis observed as early as 5-6 yrs of age

9. CLINICAL MANIFESTATIONS In affected girls & boys height, weight & osseous maturation are advanced Early closure of the epiphyses & ultimate stature is less Mental development is usually compatible with chronological age Emotional behaviour & mood swings common

10. CLINICAL FEATURES 3 patterns of pubertal progression Rapid – most common pattern. characterised by rapid physical & osseous maturation, leading to loss of height potential Slow - parallel advancement of osseous maturation & linear growth, with preserved height potential Spontaneously regressive/ unsustained - rare

11. CLINICAL MANIFESTATIONS 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 tumour can be detected radiologically Hypothalamic signs or symptoms include diabetis insipidus , adipsia , hyperthermia, unnatural crying or laughing, obesity & cachexia Visual signs may be the first manifestation of optic glioma

12. LAB INVESTIGATIONS Sex hormone levels usually appropriate for the stage of puberty in both sexes Measurement of LH in serial blood samples obtained during sleep is best & reveals pulsatile LH secretion GnRH stimulation test: predominant LH response over FSH after i.v administration of GnRH or GnRH 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 precocious puberty can be proved by detecting pubertal levels of estradiol (>50 pg/ml), 20-24 hr after stimulation with leuprolide

13. INVESTIGATIONS USG pelvis: in girls reveals progressive enlargement of ovaries f/b enlargement of uterus to pubertal size MRI: physiologic enlargement of the pituitary gland May also reveal CNS pathology

14. TREATMENT Virtually all boys and the large subgroup of girls with rapidly progressive precocious puberty are candidates for treatment. Girls with slowly progressive idiopathic central precocious puberty do not seem to benefit in terms of height prognosis from GnRH -agonist therapy. Former SGA infants may be at greater risk of short stature as adults & may require more aggressive treatment of precocious puberty, possibly in conjunction with human growth hormone therapy. Certain patients require treatment solely for psychologic or social reasons , including children with special needs and very young girls at risk of early menarche

15. TREATMENT The observation that the pituitary gonadotropic cells require pulsatile rather than continuous, stimulation by GnRH to maintain the ongoing release of gonadotropins provides the rationale for using GnRH agonists for treatment of central precocious puberty Long-acting formulations of GnRH agonists which maintain fairly constant serum concentrations of the drug for weeks or months , constitute the preparations of choice for treatment of central precocious puberty.

16. TREATMENT The available preparations include (1) leuprolide acetate ( Lupron Depot- Ped ) in a dose of 0.25-0.3 mg/kg (minimum 7.5 mg) intramuscularly once every 4 wk (2) longer-acting preparations of depot leuprolide allowing for injections 11. 35 - 30.0 mg IM every 90 days (3) histrelin ( Supprelin LA) , a subcutaneous 50 mg implant with effects lasting 12 months Other preparations Decapeptyl , goserelin acetate ( Zoladex ) are approved for treatment of precocious puberty in other countries

17. TREATMENT Other available treatment options include Subcutaneous injections of aqueous leuprolide , given once or twice daily (total dose 60 μg /kg/24 hr) Intranasal administration of GnRH agonist nafarelin ( Synarel ) 800 μg bid. The potential for irregular compliance with daily administration, as well as the variable absorption of the intranasal route for nafarelin may limit the long term benefit of these preparations on adult height.

18. TREATMENT Treatment results in decrease of the growth rate, generally to age appropriate values Treatment results in enhancement of the predicted height In girls, breast development may regress in those with Tanner stages II-III development Most commonly the size of the breasts remains unchanged in girls with stages III-V development or may even increase slightly because of progressive adipose tissue deposition

19. TREATMENT Pubic hair usually remains stable in girls, or may progress slowly during treatment, reflecting the gradual increase in adrenal androgens. Menses, if present, cease. Pelvic sonography demonstrates a decrease of the ovarian and uterine size. In boys, there is decrease of testicular size, variable regression of pubic hair , and decrease in the frequency of erections.

20. TREATMENT If treatment is effective, the serum sex hormone concentrations decrease to pre pubertal levels (testosterone <10-20 ng / dL in boys ; estradiol <5-10 pg/ml in girls). The serum LH and FSH concentrations decrease to less than 1 IU/L in most Patients The incremental FSH and LH responses to GnRH stimulation decrease to less than 2-3 IU/L. Serum LH and sex hormone levels remain suppressed for as long as therapy is continued but puberty resumes promptly when therapy is discontinued, typically at a “pubertal” chronological age

21. TREATMENT In patients with hypothalamic hamartoma and associated intractable gelastic or psychomotor seizures stereotactic radiation therapy (gamma knife surgery) is effective and less risky than neurosurgical intervention. Combined growth hormone therapy should be considered for patients with associated GH deficiency

22. McCune – albright syndrome A rare disorder pevalence 1 in 1 lakh to 1 in 10 lakh . Is associated with patchy cutaneous pigmentation & fibrous dysplasia of the skeletal system A classical cause of peripheral precocious puberty, it can also induce pituitary, thyroid, and adrenal aberrations characterized by autonomous hyper function of many glands and caused by a missense mutation in the gene encoding the α-subunit of GS, the G protein that stimulates c AMP formation, resulting in the formation of the putative gsp oncoprotein . Activation of receptors ( corticotropin ,ACTH, TSH, FSH, and LH receptors) that operate via a cyclic AMP dependent mechanism as well as cell proliferation ensue.

23. PRESENTATION GIRLS- average age at onset is about 3 yrs Young girls have suppressed levels of LH and FSH, and there is no response to GnRH or leuprolide stimulation. Estradiol levels vary from normal to markedly elevated (>900 pg/ml ) & often cyclic may correlate with the size of the recurrent ovarian cysts. BOYS- precocious puberty is less common but has been reported in several instances. At pubertal age, central precocious puberty over rides the antecedent precocious pseudopuberty

24. LAB INVESTIGATIONS Estradiol levels vary from normal to markedly elevated (>900 pg/ml), are often cyclic may correlate with the size of the recurrent ovarian cysts. Testicular histology has demonstrated large seminiferous tubules and no or minimal Leydig cell hyperplasia; these findings may simply reflect the fact that biopsy specimens were obtained at an early stage of pubertal development

25. TREATMENT : Pubertal progression is variable in these patients. Functioning ovarian cysts often disappear spontaneously; aspiration or surgical excision of cysts is rarely indicated For girls with persistent estradiol secretion aromatase inhibitors such as letrozole (1.25-2.5 mg/day orally) or anti estrogens such as tamoxifen (5-20 mg/day orally) The same compounds have also been used in boys, in combination with anti androgens such as spironolactone 50-100 mg bid , flutamide 125-250 mg bid or bicalutamide 25-50 mg daily

26. INCOMPLETE (PARTIAL) VARIANTS Isolated manifestations of precocity without development of other signs of puberty Premature thelarche - sporadic, transient condition of isolated breast development that most often appears in the 1st 2 yr of life. In some girls, breast development is present at birth and persists. Growth and osseous maturation are normal or slightly advanced. The genitalia show no evidence of estrogenic stimulation. Breast development may regress after 2 yr, often persists for 3-5 yr, and is rarely progressive. Menarche occurs at the expected age , and reproduction is normal.

27. PREMATURE THELARCHE Basal serum levels of FSH and the FSH response to GnRH stimulation may be greater than that seen in normal controls Plasma levels of LH and estradiol consistently less than the limits of detection. Ultrasound examination of the ovaries reveals normal size, but a few small cysts may seen In some girls, breast development may be associated with definite evidence of systemic estrogen effects, such as growth acceleration or bone age advancement. Pelvic sonography may reveal enlarged ovaries or uterus. This condition, referred to as exaggerated or atypical thelarche differs from central precocious puberty because it spontaneously regresses.

28. PREMATURE PUBARCHE The 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 3 beta HSD activity& increase in C- 17,20-lyase activity. Leads to increased DHEA, androstenidione & 17 HOP

29. Idiopathic premature adrenarche is a slowly progressive condition that requires no therapy. ATYPICAL PREMATURE ADRENARCHE : some patients with precocious pubarche has 1 or more features of systemic androgen effect, such as marked growth acceleration, clitoral or phallic enlargement, cystic acne, or advanced bone age About 50% of girls with premature adrenarche are at high risk for hyperandrogenism and polycystic ovary syndrome, alone or in combination with other components of the metabolic syndrome

30. PREMATURE MENARCHE It is a diagnosis of exclusion. In girls with isolated vaginal bleeding in the absence of other secondary sexual characteristics, 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 girls with 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 low, but estradiol levels may be occasionally elevated, probably owing to episodic ovarian estrogen secretion associated with ovarian follicular cysts that can be detected on ultrasound

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