Precocious puberty M. Šnajderová Pediatrická klinika, 2. LF UK a FN Motol, Praha Photos of patients and other documents which are subject to copyright were removed

Precocious puberty Acceleration of any sign of puberty >2.5 SD above mean range of normal population (Goldfarb, 1985): Girls < 8 yr Boys < 9 yr Incidence: 0.6% children

Early puberty (constitutional acceleration) 2 – 2.5 SD from the mean of population range (Rallison, 1986) Girls : 8 – 9 yr (B2) Boys : 9 – 9.5 yr (testes length >2.5 cm, volume > 4 cm3) Early puberty: ??? Pathology x variation of normal development ???

Variants of normal development Incomplete forms of sexual precocity Premature pubarche Premature thelarche

Pubarche (adrenarche precox) Age (frequently ≤ 7 years in both girls and boys) BA Growth velocity DHEAS, A-dion …cortisol level in normal range Exclude blocks adrenal steroidogenesis (US, gynecology, ACTH test?) Follow up

Precocious puberty Gonadotropin - dependent Gonadotropin- independent central peripheral

Precocious puberty: classification

DIAGNOSTICS  THERAPY

GnRH test: diagnostics and monitoring in CPP GnRHa HYPOTHALAMUS GnRH PITUITARY  LH,  FSH    LH,   FSH GONADS  E2  T

          p<0,01  p<0,001 ICPP: idiopathic CPP OCPP: organic CPP  p<0,01  p<0,001

Menstrual cycle after therapy USG: ovaries – no pathological findings 11.5% some girls after short interval after menarche 10% 1 OCPP (NF 1) menarche after induction 3.5 yrs after therapy, at present induction of menarche in another 2 OCPP girls

Not to treat premature telarche, pubarche familial early onset of puberty (slow progressive)

Therapy to stop the progression of puberty to preclude or attempt to reclaim compromised growth potential

CPP - treatment GnRH agonists : depot i.m. , s.c. 11.25 mg trp GnRH antagonists : ? Monitoring : hormonal levels, growth, development

Effect of therapy: CPP Start of therapy: BA ≤ 11 r End of therapy: BA 12 – 13 r Recovery of hormonal secretion after discontinuation Adult height is close to target height Bone age

Idiopathic slow progressive CPP non treated

Therapy organic CPP : if there is an underlying treatable cause – therapy should be given BA acceleration, younger age, growth prognosis Gonadotropin-independent: adrenal suppression in CAH …

Peripheral precocious puberty PPP Sex steroids: not after activation of reproductive axis hypothalamus – pituitary - gonads. Isosexual or heterosexual. Congenital Secondary CPP Postnatal Exogenous endogenous MAS FMPP CAH Anabolic steroids Tumors COC Adrenal gland Gel (T) granulosa cells Cosmetics Leydig cells tumor producing hCG ovarian cysts

PPP heterosexual CAH 21-OHD,11beta-OHD,3beta-OHSD Ovarian tumors Adrenal tumors

PPP isosexual Exogenous sex steroids or gonadotropins McCune-Albright syndrome Ovarian tumors Adrenal tumors Limited or reversible forms (chronic primary hypothyroidism, exogenous sex steroid or gonadotropins, ovarian cysts)

MAS (girls and boys) Somatic activating mutation GNAS (gene encoding stimulation of Gsα in intracelular cascade_ endocrine and other tissues). Mutation in mosaic form, heterogenous clinical spectrum. Clinical signs: fractures, Cushing syndrome, sublinical hypothyroidism. Frequently precocious puberty at the age 2-6 yrs. Vaginal bleeding, breasts enlargement (not in any case). Bleeding migt be present repeatedly, fluctuation in breasts enlargemen. Ovarian cysts – production of estrogen. Triad PPP café au lait Fibrous bone dysplasia

FMPP Familial male-limited precocious puberty Heterozygous activating mutation LHR+ Not so frequent comparred with MAS, positive family history Mutation AD or de novo Female: asymptomatic (LH and FSH is necessary for ovarian steroidogenesis) Male: early virilisation at 2 yrs (penis, PH, acné, body odour), small testicles

MAS: therapy Girls Aromatase inhibitors (dBA, growths): Letrozol Tamoxifen No surgery!!! Boys Prespective study: missing Good results: antiandrogens

FMPP therapy Antiandrogen and/or aromatase inhibitor Testolacton and spironolacton Prospect in combination: Antiandrogen: bicalutamid Aromatase inhibitor: anastrozol

Secondary CPP Primary PPP – after elimination of negative feedback when on therapy Start of CPP in children with BA acceleration Frequent in girls with breast enlargement treated for PPP In boys with progresssion of testicular volume LH levels GnRHa therapy