Early Pubertal Changes What s Normal, What s Not

Early Pubertal Changes What s Normal, What s Not Mary Kreiter, MD Children s Memorial Hospital Northwestern University s Feinberg School of Medicine Division of Endocrinology Copyright 2005 Children s Memorial Hospital. All rights reserved. 1/25

Overview Pubertal norms Changing age of onset Pubertal variants Other causes of early secondary sexual characteristics Management of early pubertal variants Consequences of early pubertal variants Copyright 2005 Children s Memorial Hospital. All rights reserved. 2/25

Puberty normal range/tempo Girls Breast - 8-13 yrs (10.9) Pubic hair - 11.5 yrs Menarche - 12.9 yrs Growth spurt early Tanner V ~ 14 years Tempo 2 years (B M) (0.5-4 yrs.) Boys d testes (2.5 cm long dia.) 9-14 yrs (11.2) Pubic hair 12 yrs Growth spurt later Tanner V - ~ 16 yrs. Tempo - 1 genitalia stage q 1-1.5 yrs. Copyright 2005 Children s Memorial Hospital. All rights reserved. 3/25

Changing onset of puberty Speculation: Better health, nutrition Genetic factors Obesity Steroid use in animals for consumption Exposure to endocrine-disrupting chemicals In US: Cross-sectional studies show no change since 1970 s. Others Copyright 2005 Children s Memorial Hospital. All rights reserved. 4/25

Puberty changing onset in girls 20-25% ethnic minorities breast development between 7-8 years 48% AA s & 15% Caucasians have breast or pubic hair before age 8 No distinction: variants vs early puberty Overall age of menarche unchanged but 8.5 months earlier in African-American No updated data on boys Copyright 2005 Children s Memorial Hospital. All rights reserved. 5/25

Evaluation for early puberty LWPES recommendations (1999) Girls Under 7 (Caucasian), under 6 (African Am) After 7 (Caucasian), after 6 (African Am) Boys Advanced bone age New CNS finding Emotional state adversely affected Under 9, all ethnicities Copyright 2005 Children s Memorial Hospital. All rights reserved. 6/25

Evaluation for early puberty LWPES recommendations (1999) Controversies Midyettet al (Peds 111:47, 2003) ~12% had other endocrine pathology Acanthosis/Insulin resistance most common (7%) pathology limited to PH only or B & PH groups Kaplowitz(JCEM 89:3644, 2004) 78% with benign variants premature adrenarche, premature thelarche 9% true precocious puberty (13% acanthosis nigricans) Copyright 2005 Children s Memorial Hospital. All rights reserved. 7/25

Normal pubertal variants Premature thelarche Isolated breast development 6 mos-3 yrs Height velocity and bone age normal Can wax and wane, spontaneous remission Response to normal physiologic increases in estrogen May be difficult to distinguish from CPP 15% progress to precocious puberty E 2 low, no LH, FSH response to GnRH (a) Copyright 2005 Children s Memorial Hospital. All rights reserved. 8/25

Normal pubertal variants Adrenarche Puberty of adrenal glands; trigger unknown Little adrenal androgen activity before 6 DHEA-S levels 40-55 ng/dl Premature adrenarche Girls > boys; typical age 6-8 years More common in ethnic minorities, obese, CNS injury Copyright 2005 Children s Memorial Hospital. All rights reserved. 9/25

Normal pubertal variants Premature adrenarche Features- ABO, oiliness/acne, pubic or axillary hair Normal or mild accel. growth velocity, bone age Absence of excessive virilization, hyperpigmentation Distinguish from precocious puberty in boys Lack of testicular enlargement No earlier true pubertal development Height attainment within genetic potential Prepubertal precursor to PCO in some girls Copyright 2005 Children s Memorial Hospital. All rights reserved. 10/25

Normal pubertal variants Isolated menarche One or more episodes of vaginal bleeding No other evidence of puberty No accelerated growth Bone age not advanced E 2 low, no LH, FSH response to GnRH (a) Refer Copyright 2005 Children s Memorial Hospital. All rights reserved. 11/25

Central precocious puberty Disruption of inhibitory pathways Gonadotropin-dependent Early onset with progression <7 years (6 years, African American) in girls <9 years in boys Slowly progressive variants exist Incidence -1 in 5-10,000 2:1, 3:1 female:male Copyright 2005 Children s Memorial Hospital. All rights reserved. 12/25

Central precocious puberty Most idiopathic 95% girls, 40-80% boys Adopted girls Organic causes Tumors astrocytoma, optic glioma (NF), germ cell, pinealoma, hypothalamic hamartoma (<4 years) Other Injury (trauma, irradiation, ctx, infection) Congenital malformations (arachnoid cyst, hydrocephalus) Secondary Prolonged exposure to sex steroids (ex. poorly Rx d CAH) Copyright 2005 Children s Memorial Hospital. All rights reserved. 13/25

Peripheral precocious puberty Gonadotropin-independent Sex steroid production Gonadal Adrenal HCG-producing neoplasms CNS (dysgerminoma, teratoma, chorioepithelioma) Hepatoma, choriocarcinoma Copyright 2005 Children s Memorial Hospital. All rights reserved. 14/25

Peripheral precocious puberty Gonadal steroid production M c Cune Albright syndrome (MAS) Familial male precocious puberty (FMPP) Tumors Ovarian benign cyst, granulosa cell, theca cell, gonadoblastoma, carcinoma, sex cord Testicular Leydig cell, sex cord Copyright 2005 Children s Memorial Hospital. All rights reserved. 15/25

M c Cune Albright syndrome and familial male precocious puberty M c Cune Albright (MAS) Activating mutation of G s -alpha subunit Café au lait lesions, polyostotic fibrous dysplasia, autonomous endocrine hyperfunction No LH response to GnRH (a) Familial male precocious puberty (FMPP) Activating mutation of the LH receptor Onset usually prior to age 3-4 Enlarged testicles, no LH response to GnRH (a) Copyright 2005 Children s Memorial Hospital. All rights reserved. 16/25

Peripheral precocious puberty Adrenal steroid production Congenital adrenal hyperplasia (CAH) Adenoma Carcinoma Other Hypothyroidism External steroids Copyright 2005 Children s Memorial Hospital. All rights reserved. 17/25

Distinguishing forms of puberty clinical considerations Girls Feminizing Only Premature thelarche CPP Exogenous Ovarian cysts, tumors M c Cune Albright Virilizing Only Premature adrenarche CAH Adrenal tumors (Exogenous) Both CPP Tumor (E 2 & androgens) Copyright 2005 Children s Memorial Hospital. All rights reserved. 18/25

Distinguishing forms of puberty clinical considerations Boys +Testicular Enlargement CPP Familial male PP Test. tumors (asymetric) HCG-producing tumors -Testicular Enlargement Premature adrenarche CAH Adrenal tumors Exogenous Copyright 2005 Children s Memorial Hospital. All rights reserved. 19/25

Distinguishing forms of puberty Ht velocity Bone Age Sex Steroids LH Response Central + MAS, FMPP - Tumors (peripheral) - Other Peripheral N- N- N- - Premature Thelarche N- N- N- - Premature Adrenarche N- N- N- - Copyright 2005 Children s Memorial Hospital. All rights reserved. 20/25

Early pubertal changes laboratory evaluation Girls (feminizing only) Without evidence of accelerated growth Reassess in 3-4 months With evidence of accelerated growth Early AM LH, FSH, pediatric estradiol (E 2 ), Bone Age (BA) Refer Bone age >2 SD for CA, E 2 over 10 pg/ml Girls (virilizing only) Without evidence of accelerated growth Reassess in 3-4 months, (glucose, insulin) With evidence of accelerated growth Early AM 17-OHP, DHEA-S, androstenedione (AD), T, BA (glucose, insulin) Refer BA >2 SD for CA; d 17-OHP, AD or T; DHEA-S d over PH stage Copyright 2005 Children s Memorial Hospital. All rights reserved. 21/25

Early pubertal changes laboratory evaluation Boys- d testicular size Early AM LH, FSH, Testosterone (T). Bone Age (BA) Refer Bone age >2 SD for CA, T over 10 pg/ml Boys-w/o d testicular size Without evidence of accelerated growth Reassess in 3-4 months, (glucose, insulin) With evidence of accelerated growth Early AM 17-OHP, DHEA-S, androstenedione (AD), T, BA (glucose, insulin) Refer Bone age >2 SD for CA; d 17-OHP, AD or T; DHEA-S d over PH stage Copyright 2005 Children s Memorial Hospital. All rights reserved. 22/25

Therapy early pubertal variants Premature thelarche Education and reassurance Follow-up Premature adrenarche Education and reassurance Hygiene Nutrition and lifestyle intervention Follow-up monitor for signs of PCO after menarche Copyright 2005 Children s Memorial Hospital. All rights reserved. 23/25

Therapy central precocious puberty No intervention Slowly progressive Uncompromised height potential No psychosocial issues GnRHa therapy Rapidly progressive Early menarche likely Compromised height potential Psychosocial burden Copyright 2005 Children s Memorial Hospital. All rights reserved. 24/25

Central precocious puberty outcome Slowly progressive, no intervention Boys and girls Final height close to target height Bone age advances in step with chronologic age Girls Menarche 11-12 years Rapidly progressive, GnRHa therapy Final height Close to target height Improved over predicted Copyright 2005 Children s Memorial Hospital. All rights reserved. 25/25