Boys With Delayed pubertyM. Hashemipour

Professor of Pediatric EndocrinologyIsfahan University of Medical Sciences

Delayed pubertyGirlsDelay in onset of secondary sexual development by age12-13 primary amenorhoe at 15.5-16yBoysDelay in onset of secondary sexual development by age 14y

.mean duration from the onset of puberty to onset of menarche is 2.4 1.1 years

.Detained puberty Puberty has started but has not concluded after 5 years

A boy who has not completed his secondary sexual development, 4.5 years from the onset of puberty(T2) A girl who does not experience menses within 5 years from the onset of puberty(B2)

Delayed Puberty Types

Constitutional

Hypogonadotropin hypogonadism

Hypergonadotropin hypogonadism

Medical history14yr old boyShortest in his classNo problem at school Always looks small

What do you ask him?

No chronic disease Normal sense of smell Sexual function and patterns of body hairKnown testicular abnormalities

Student Non-smokerNo siblingsMother has arthritisFather did not grow till he entered college

What's important in Physical examination?

Physical ExaminationNo dysmorphic featuresCVS, Resp, Abd Exam are normalBP = 110/76Ht= 135cm Zcore = -3.9 Wt= 30kg

Physical ExaminationArm span height span= 2cm Growth Velocity =5cm/yr

.Testicular volume =2.5mlTesticular length = 1.5cmPenis length = 6cmNormal Testicular consistencyNo Pubic & Axillary Hair No gynecomastia

What's your differential diagnoses?

What's your investigation?

Hormonal and Biochemical studyNormal BUN & ESRNormal T4 &TSHLow IGF1& IGFBP3 for age Normal IGF1& IGFBP3 for BANormal GH stimulation test

Hormonal and Biochemical studyTestosterone= 0.15ng / mlCeliac test= okCortisol levels = okGnRH test shows no responseLow GonadotropinNormal prolactin

imaging

BA=11.5yrMRI= Normal

What's your treatment ?

We prescribed Oxandrolon for 6 months Zinc 12.5 mg/day Iron 12mg/day for 3 mo Vitamin A = 6000IU/week for 3 months

But Testicular volume &Testicular length did not change

, Diagnosis?

Any comments?

Because of not response to treatment We prescribe :Testosteron 50mg every month for three months Letrozol 2.5mg/day

(Six month after stopping Testosteron) Testosteron level was 0.8ng/mlTesticular volume =5mlTesticular length = 3cm

Diagnosis?

Constitutional Delayed puberty

. Discussion

.CDGP is not a medical disorder, but a temporary condition

If treatment is necessary for a child, it must be emphasized that they are normalTheir body clock for puberty has just started later than their friends.

CDGPis a common conditionBoys > girlsBoys look youngNormal physical examinationNo evidence for systemic disease No evidence for hormonal dysfunctionUsually normal nutrition.

CDGPShort statureHT at or below 3rd percentile

CDGP

.HA < CABA < CAGV= N888888888888888888888BA=HA

CDGP Delayed puberty and pubertal growth spurtFamily history of delayed puberty

CDGPNormal growth rate for bone ageDelay bone age 1 -3 years Normal height for bone age

Adult height

HT reach within the lower part of mid parental target HT

HA < CABA < CAGV= N888888888888888888888BA=HA

.HT deficit at onset of puberty

CDGP IGF-I is normal for BA Delayed Adrenarche

Nutrition CDGM Decreased vitamins A and D iron, and zinc deficiency

Diagnostic approach to delayed puberty

.Differentiation between HH and CDP is very difficult because:There is an overlap in physical and lab findings

Growth ChartPatients with HH have normal height in early or mid adolescence Patients with CDP are short

initial ApproachBone AgeX-ray of the left hand and wrist to evaluate bone age

.The onset of puberty correlates with BA BA=11-13y in girlsBA=12-14 in boys

.At Bone age :11 to 13 years in girls12 to 14 years in boyspatients with CDP usually continue pubertal development

Initial ApproachIn patients who are apparently healthy initial assessment of LH & FSH If elevatedHypergonadotropic Hypogonadism

Differential DiagnosisIf low Hypogona Hypogo

DDx: Constitutional Delayed Puberty Brain tumor Hypopituitarism HypothyroidismHyperprolactinemia

MalnutritionExercise intensityUse of medicationsChronic disease

.HA < CABA < CAGV= N888888888888888888888BA=HA

Differential Diagnosis:

Hypogonadotropin Hypogonadism Adrenarche is at the normal age Higher DHEAS than CDP

Isolated Gonadotropin DeficiencyAfter the age of 18:Absence of first signs of pubertyFailure of a rise in gonadotropinsFailure of a rise in gonadal steroids

Isolated Gonadotropin Deficiencyserial Ht and testicular measurements made over 1-2 years will help clarify the diagnosis

Isolated Gonadotropin DeficiencyAs no single test can distinguish between these two disorders, so we should rely on clinical clues and the natural evolution over time

Pituitary failure

Diagnostic EvaluationMorning serum testosterone >0.2ng/mlpredicted increase in testicular size to >4 mL within 12mo in 77% in boys 15 mo in 100% of boys

In boys with < 0.2ng/ml12.5% of boys will have puberty within 12mo

. Treatment

Treatmentwatchful waiting includes :periodic evaluation of testes & testosterone every 6 mo Reassurancepsychological counselingAssurance to family

Treatment TestosteroneOxandroloneGHTrace elements

TreatmentTreatment In BA

,Testosterone therapy may be started as early as A bone age of 1213 yr to decrease the psychological disturbance

Testosterone Therapy

At BA=12 CA=1414.5 yr50 mg once a month for three to six monthssix months later.It is Spontaneous pubertal development if Testicular enlargementincreasing testosterone >50 ng/dl

Management6-12 months after completing the first course of therapy IfTestosterone

Management Treatment should not continue more than 2 courses to differentiate CDP from permanent DP

Constitutional Delayed PubertyAfter 2 courses6-12 months after completing the second course of therapy 8am serum testosterone 50ng/dl: PPV 100% PNV59%LH peak> 14 IU 3 hours after triptorelin PPV 100% PNV72%

Dx= CDGP

Aromatase inhibitorAromatase inhibitors, alone or in combination with rh-GH

Growth Hormone Therapy: The value is controversial

Oxandrolone1.25-2.5mg/day0.05 mg/kg daily for 1 yearPediatrics. 1995 Dec;96(6):1095-100.

OxandroloneGrowth promoting effects is related to mild androgenic effects of it After oxandrolone withdrawal Increase in total serum testosteroneprogress in puberty.

GnRHa

Decapeptyl 01 mg/m2 s.c..(120 g/ kg, 500 g,100 g/m2

GnRHa

After 4 h LH and FSH should be measured LH>8 mIU/ml) in favor CDGPLH assay by commercial chemiluminescent kitAll of these patients entered spontaneous puberty within 1 year

Constitutional Delay PubertyFirst signs of secondary sexual development occur within 1 year after LH rises to pubertal levels after administration of 100 g GnRH subcutaneous GnRH agonistAfter GN and sex steroid begin to increase spontaneously above prepubertal values An 8 am serum testosterone> 20 ng/dL puberty develop within 12 to 15 month

Use of GnRH agonist and human chorionic gonadotrophin tests for differentiating constitutional delayed puberty from gonadotrophin deficiency in boys

The GnRH-agonist test and the repeated-injection hCG test are reliable diagnostic tools for differentiating CDP from GD in boys.

Clinical Endocrinology (2002) 56, 603607

synthetic LHRH01 mg/m2 iv bolus Blood samples for of LH, FSH and testosterone levels were drawn prior to injection and 30 and 60LH >7.5 IU/L usually precedes the first physical sign of sexual maturation by less than 1 year.

Buserelin test LH, FSH at 0 and 4 hours were measured. low LH response to buserelin, HH could be diagnosed with a sensitivity of 100% and a specificity of 96% Journal of Pediatrics 2006 Lh5 CDGP

,Kallmann

cdpuberty kallmankallmannPituitary failure

LHRH testHGH:0.625 ng/ml , TSH:3.35 uIU/ml Cortisol:19 ug/dlProlactine:3.66

Time(min)-1501530456090120FSHmIU/ml4.85.16.06.98.510.112.514.1LHmIU/ml1.31.32.65.08.610.710.811.9

Laboratory assessmentHCG stimulation test 3000 units/m2 per injection

One to three injections daily or on alternate daysTestosterone should be obtained within 24 hours of the last injection Testosterone levels greater than 170 ng/dl after a single injection 200 ng/dl on day 3 300 ng/dl on day 5 indicates normal testicular function

Pituitary failure

Prader-Willi syndrome

Diagnostic evaluationBA=HA

pubertal development

Testicular volume >3-4 mLLongitudinal measurement> 2.5 cmSerum testosterone > o.5 ng/mL

ManagementIf the LH level rises more than 2.5 SD above the mean value Testosterone level decreases below the normal range for ageWe think to HH

The upper segment to lower segment ratio

Birth : 1.7 3 years: 1.33 5 years : 1.17 10 years : 1.0

Upper to lower segmentpre-puberty ratio 1During puberty 1Adult men o.92Adult woman 0.95

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