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Early onset of Puberty

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Hector Granados

on 22 July 2016

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Transcript of Early onset of Puberty

Early onset of Puberty
(cc) photo by Metro Centric on Flickr
(cc) photo by Franco Folini on Flickr
(cc) photo by jimmyharris on Flickr
(cc) photo by Metro Centric on Flickr

Case Presentation
Risk Factors
Genetic Etiologies

Newer therapeutic options
Future directions
Everything starts
with a KISS!!
-Congenital CNS abnormality
Hypothalamic hamartoma

-Heterotopic mass of neurons and glial cells

-TGF-alpha may cause abnormalities in signaling pathways affecting GnRH secretion

-Ectopic pulse generator

-Associated with gelastic seizures

-Responds to GnRHa
Any insult that alters the HPG axis can present as CPP
-Established risk factor for CPP
Reported in domestic and international adoption
-Increased if adopted >2 years of age
-Possibly secondary to exposure to endocrine disruptors or psychosocial stress
-No increase risk following immigration
Molecular Genetic Causes of CPP
CPP in Hypothalamic Hamartoma
Trauma, Tumor, Infection, hydrocephalus, irradiation, etc..
CPP in Neurofibromatosis
The most common disorders of somatic development revealed in NF-1 patients are short stature and tall stature caused by CPP
Risk even with normal MRI
Mutations in KISS1R & KISS1 Gene
-Can be considered together and present with parallel features
-Heterozygous mutation

-Results in prolonged intracellular signaling due to a reduced rate of degradation of mutated proteins
Activating mutations in the KISS1 Receptor & Activating mutations in the KISS1 gene
Diagnostic Criteria Include
New Understanding of Pathophysiology & Management of Central Precocious Puberty
Hector Granados MD FAAP
Pediatric Endocrinology

Topic Overview

Childhood-irregular and low amplitude

Prepubertal-nocturnal increase in frequency and amplitude followed by similar pulses During the day

Adult-frequency of one pulse every 60 to 90 minutes

Gonadotropins Release:
Risk Factors for CPP
Pediatric Endocrinology, Mark A Sperling, Third Edition, Chapter 14, Page 531

Soriano-Guillen, Endocrine MEtab 2010
Bianco et al, Endocrine Press 2011
Mutations in MKRN3
-Encodes makorin RING-finger protein 3

-Imprinted gene from the paternal allele

-Critical region at 15q11-q13

-Four novel heterozygous mutations identified in 5 of 15 families with CPP
Abreu AP et al, NEJM 2013
Radiology? Controversial!
any acquired anomalies?
infection, trauma, irradiation?
MRI/CT? might not be necessary (>6 years)

Additional Tests?
Sex steroids not sufficient alone
-estradiol assays particularly poor
-newer versions use LC/MS
Random serum US LH (>0.3 U/L)-ICMA, IRMA-

Goals of Treatment
GnRH Analogs
CPP Treatment with Leuprolide Acetate
Currently approved for CPP
1-month formulation of 7.5 mg, 11.25 mg, and 15 mg
3-month formulation of 11.25 mg and 30 mg
The label does not provide weight based dosing for 3 month formulation
Height and CPP
There has never been a randomized controlled study of GnRH treatment vs no treatment in CPP
Developed in the 1980's
Down regulation of pituitary GnRH receptors
3 monthly Leuprolide 11.25 vs 30 mg in CPP Efficacy and Safety
Randomized 6 month trial
84 subjects (76 girsl) with CPP
21 naive, 42 previously treated
Outcome measures: peak stimulated LH, sex steroids, anthropometric parameters
30 mg group all suppressed, in the 11.25 group 3 subjects required alternative treatment
Psychological Aspects
Arrest early development
-Restore gonadotropins and sex steroids to prepubertal levels
Safety of 3 Monthly Depot Luprolide
Injection site pain ~23% of patients
Sterile abscess formation
No discontinuation due to drug related AE in the 6 month trial

Histrelin Subcutaneous Implant
Flexible non-biological hydrogel (Soft contact lens)
Delivers GnRHa histrelin for at least 1 year
-210 X more potent than naive GnRH
-Approved for CPP in 2007

Histrelin Characteristics
Contains 50 mg histrelin acetate
Provides constant release of drug (microporous walls)
-65 mcg per day
Rate of release determined by water content of the hydrogel
A single Histrelin Implant is Effective for two years for Treatment of CPP
33 children (26 girls) 7.2+-2.5 years tx with Histrelin implant for CPP (20 naive)
Peak stim LH at 12 and 24 months was equivalent
-0.89 IU/L +-0.51 vs 0.89 IU/L +-0.54, P:0.44
Safety of Histrelin Implant
Minor implant site reactions are common (50%)
Difficulty with implant removal (15-20%)
-Implant breakage
-~39% when left in place for 2 years
Low incidence of keloid scar (10%)
One case of implant extrusion and associated cellulitis
Distribution of age of puberty within normal and abnormal populations
GnRH Secretion (and its variants) from Fetal Development into Adulthood
Palmert R. et al, JCEM, 2001
Palmert R. et al, JCEM, 2001
Monitoring of Therapy
Resumption of Puberty in Girls and Boys Following Removal of the Histrelin Implant
Random US LH remains pubertal in Children with CPP
33 children (26 girls) with CPP treated with histrelin implant
Random US LH obtained at 6 months
GnRHa stim test performed at 12 months
71 patients (56 girls) treated with histrelin implant

43 (37 girls) explanted
-30 girls treated for CPP, 7 treated for other indications
Of 30 girls, 26 reached menarche 12.75 months (95% CI 5.6-15.9) after explantation (range 2-36 months)

Menarche occurred at 12.94 years (95% CI 10.5-15.3)
Potential New Approach to Diagnosis and Monitoring
Kisspeptin in 28 girls with CPP compared to 13 controls
-Measured at baseline and 6 months

Auxologic parameters
-Growth velocity
-Tanner Staging
-Skeletal maturation

Summary and Conclusions
Genetic etiologies of CPP beginning to be elucidated
-Familial Cases
Resumption of Puberty in Girls and Boys Following Removal of the Histrelin Implant
Thank You for Your Attention!!!
John S. Fuqua, JCEM 2013
Morgensen SS, Plos One 2012
Carel JC, JCEM 1999
Bouvattier C, JCEM 1999
Eugster E., PES Vancouver, CA 2014
Carel et al, Pediatrics 2009
Fuld K et al J Pediatr 2011
Lee PA et al, JCEM 2012
Lee PA et al, JCEM 2012
Nebesio et al, Curr Probl Pediatr Adolesc Health Care 2007
Nebesio et al, Curr Probl Pediatr Adolesc Health Care 2007
Lewis KA et al J Pediatrics 2013
Lewis KA et al J Pediatrics 2013
Lewis & Eugster J Pediatrics 2012
Demirbilek H, et al, JCEM 2013
Fisher MM, J Pediatr 2014
Fisher MM, J Pediatr 2014
Kids are Great!!! We just make 'em Better!!!
Ioannis Dedes, Systems Biology in Reproductive Medicine, 2012,

Modified from Pinilla L. Physiol Rev 2012
Premature Thelarche
Classical CPP
Slowly Progressive CPP
-Acquired CNS insult

-International adoption

-Family history of CPP

-Peripheral precocious puberty
Eugster E., Hormone Research 2009
Germ cell (hCG)
Li-Fraumeni Sx
Accidental exposure
Lavender oil
Hypothyroidism (Van Wik and Grumbach Syndrome)

Congenital Adrenal Hyperplasia
McCune-Albright Sx
-(G-protein systems)
Familial male-limited precocious puberty (LHCGR gene)

Normalize growth rate
Preserve genetic height potential
Ameliorate psychosocial distress?
Puberty: Stage of development during which secondary sexual characters appear

Prenatal Gonads Release Hormones
GnRH Pulse Generator
GnRH Inhibited
GnRH Brake
Secondary Sex Characters
Biochemical parameters
-GnRH/GnRHa stimulation test
-Sex Steroids
-Random US LH
-Pubertal value indicates lack of
GnRHa have established track record for safety and efficacy
-Refinements in the delivery systems
Optimal strategies for monitoring therapy and discontinuation yet to be identified
Kisspeptin system affords opportunities for the development of novel approaches to diagnosis, monitoring and treatment of CPP
In 59% of patients, random US LH exceeded the prepubertal range of <=0.3 IU/L
GnRH Stim test revealed complete HPG axis suppression (<4) in all subjects
Leuprolide stimulation test: (LH >5 U/L)
-Prolonged test with serial values
-Single 30-60 minute post-GnRHa LH
-Single 2 hour post-GnRHa LH
-24 hr sex steroids
Pelvic ultrasound-helpful if other results are equivocal
-Uterine lenght 3.4-4.0 cm, ovarian volume 1-3 cc
Most of the evidence is based on relationship between height outcome and the age at which treatment is begun
Outcome is usually the difference between predicted and actual height

Height prediction methods are imperfect
Consideration include risk for emotional distress and problem behavior
-early menarche associated with higher risk
Conclusions from existing studies inconsistent
No firm recommendations for or against therapy
Excellent track record of safety and efficacy
Treatment of choice for CPP worldwide
Multiple drugs and routes of administration available
Histrelin implant and 3 monthly leuprolide newer options
Randomized study of all doses-Mean peak stimulated LH and FSH values were higher in the 11.25 mg 3 montly group
No difference in estradiol, growth velocity or BA advancement were observed.
Inserted using a trocar usually by a surgeon
-Local anesthesia, conscious sedation, or general anesthesia
PAH z-score increased from baseline to 24 months (-1.5+-1.23 vs -1.03+-1.33, p:0.02)
BMI z-score remained stable
Kisspeptin levels were higher in girls with CPP than in controls (10.2+2.6 pg/mL vs 8.6+-1.5 pg/mL, p=0.019)

Kisspeptin significantly declined in girls with CPP after HPG axis suppression (7.3+-1.3 pg/mL, p=0.0001)
Time to menarche in girls, testicular volume increase in boys
Of boys, all had increase in testicular volume within 1 years of explantation
No Disclosures
Or Conflict of Interest

Incidence and Prevalence of Central Precocious Puberty
Affects 1/5,000–1/10,000 children

Prevalence is approximately 10 times higher in girls compared with boys

Racial differences are significant: African-American girls enter puberty earliest, followed by Hispanic and then Caucasian girls
1. Mericq V, et al. Clin Endocrinol. 2009;71:686-690.
2. Berberoglu M. J Clin Res Pediatr Endocrinol. 2009;1:164-174.
3. Carel JC, Léger J. N Engl J Med. 2008;358:2366-2377.
4. Tiejian W, et al. Pediatrics. 2002;110:752-757.

Precocious puberty is Defined as the appearance of secondary sexual characters in;
-Boys younger than age 9
-Girls younger than age 6-8
Lee PA. Pediatr Endocrinol. 1999
Early pubertal changes

Accelerated growth rate

Advanced bone age

Originally described by Marshall and Tanner, 1969, 1970
International Adoption
-Girls; breast development and growth rate acceleration
Central- Gonadotropin dependant
Peripheral-Gonadotropin independant
Normal Variants:
-Premature benign thelarche
-Premature bening Adrenarche
GnRH: Gonadotropin Releasing Hormone
Precocious Puberty
-Boys; testicular growth, followed by penile growth and onset of pubic hair
Peripheral Precocious
Lecture Available at .com
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