Boys With Delayed puberty Professor of Pediatric Endocrinology Isfahan University of Medical Sciences M. Hashemipour

Delay in onset of secondary sexual development by age12-13 Delayed puberty Girls Delay in onset of secondary sexual development by age12-13 primary amenorhoe at 15.5-16y Boys Delay 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

Detained puberty 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)

Hypogonadotropin hypogonadism Hypergonadotropin hypogonadism Delayed Puberty Types Constitutional Hypogonadotropin hypogonadism Hypergonadotropin hypogonadism

Medical history 14yr old boy Shortest in his class No problem at school Always looks small

What do you ask him?

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

: Social and family history Student Non-smoker No siblings Mother has arthritis Father did not grow till he entered college

What's important in Physical examination?

No dysmorphic features CVS, Resp, Abd Exam are normal BP = 110/76 Physical Examination No dysmorphic features CVS, Resp, Abd Exam are normal BP = 110/76 Ht= 135cm Zcore = -3.9 Wt= 30kg

Arm span – height span= 2cm Growth Velocity =5cm/yr Physical Examination Arm span – height span= 2cm Growth Velocity =5cm/yr

Normal Testicular consistency No Pubic & Axillary Hair No gynecomastia . Testicular volume =2.5ml Testicular length = 1.5cm Penis length = 6cm Normal Testicular consistency No Pubic & Axillary Hair No gynecomastia

What's your differential diagnoses?

What's your investigation?

Hormonal and Biochemical study Normal BUN & ESR Normal T4 &TSH Low IGF1& IGFBP3 for age Normal IGF1& IGFBP3 for BA Normal GH stimulation test

Hormonal and Biochemical study Testosterone= 0.15ng / ml Celiac test= ok Cortisol levels = ok GnRH test shows no response Low Gonadotropin Normal prolactin

imaging BA=11.5yr MRI= Normal

What's your treatment ?

Vitamin A = 6000IU/week for 3 months 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

Testosteron level was 0.8ng/ml Testicular volume =5ml (Six month after stopping Testosteron) Testosteron level was 0.8ng/ml Testicular volume =5ml Testicular 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 normal Their “body clock” for puberty has just started later than their friends. .

CDGP is a common condition Boys > girls Boys look young Normal physical examination No evidence for systemic disease No evidence for hormonal dysfunction Usually normal nutrition.

CDGP Short stature HT at or below 3rd percentile

CDGP

HA < CA BA < CA GV= N . BA=HA p=BA p 8 8 8 8 8 8 8 8 8 8 8 8 8 8 TH HA < CA p p=BA 8 8 8 8 8 8 8 BA < CA 8 8 8 8 8 BA=HA 8 8 8 8 8 8 8 8 GV= N 8

CDGP Delayed puberty and pubertal growth spurt Family history of delayed puberty

CDGP Normal growth rate for bone age Delay bone age 1 -3 years Normal height for bone age

HT reach within the lower part of mid parental target HT Adult height HT reach within the lower part of mid parental target HT

HA < CA BA < CA GV= N BA=HA p=BA p 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 TH HA < CA p p=BA 8 8 8 8 8 8 8 BA < CA 8 8 8 8 8 BA=HA 8 8 8 8 8 8 8 8 GV= N 8

HT deficit at onset of puberty . HT deficit at onset of puberty

CDGP IGF-I is normal for BA Delayed Adrenarche

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

Diagnostic approach to delayed puberty

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

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

initial Approach Bone Age X-ray of the left hand and wrist to evaluate bone age

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

patients with CDP usually continue pubertal development . At Bone age : 11 to 13 years in girls 12 to 14 years in boys patients with CDP usually continue pubertal development

If elevated In patients who are apparently healthy Initial Approach In patients who are apparently healthy initial assessment of LH & FSH If elevated Hypergonadotropic Hypogonadism

Differential Diagnosis If low Hypogona Hypogo

If Gonadotropins low or lower limit of normal: DDx: Constitutional Delayed Puberty Brain tumor Hypopituitarism Hypothyroidism Hyperprolactinemia

If Gonadotropins low or lower limit of normal: Malnutrition Exercise intensity Use of medications Chronic disease

HA < CA BA < CA GV= N . BA=HA p=BA p 8 8 8 8 8 8 8 8 8 8 8 8 8 8 TH HA < CA p p=BA 8 8 8 8 8 8 8 BA < CA 8 8 8 8 8 BA=HA 8 8 8 8 8 8 8 8 GV= N 8

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

Isolated Gonadotropin Deficiency After the age of 18: Absence of first signs of puberty Failure of a rise in gonadotropins Failure of a rise in gonadal steroids

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

Isolated Gonadotropin Deficiency As 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 Evaluation Morning serum testosterone >0.2ng/ml predicted increase in testicular size to >4 mL within 12mo in 77% in boys 15 mo in 100% of boys In boys with < 0.2ng/ml 12.5% of boys will have puberty within 12mo

Treatment .

Treatment “watchful waiting” includes : periodic evaluation of testes & testosterone every 6 mo Reassurance psychological counseling Assurance to family

Treatment Testosterone Oxandrolone GH Trace elements

Treatment Treatment In BA<10 y Has the risk of accelerated BA& short adult height

, Testosterone therapy may be started as early as A bone age of 12–13 yr to decrease the psychological disturbance

Testosterone Therapy Testicular enlargement At BA=12 CA=14–14.5 yr 50 mg once a month for three to six months six months later. It is Spontaneous pubertal development if Testicular enlargement increasing testosterone >50 ng/dl

Management 6-12 months after completing the first course of therapy If Testosterone <50 ng/dl Not Testicular enlargement Give another course for 3-6 months

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

Constitutional Delayed Puberty After 2 courses 6-12 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 inhibitors, alone or in combination with rh-GH

Growth Hormone Therapy: The value is controversial

Oxandrolone 1.25-2.5mg/day 0.05 mg/kg daily for 1 year Pediatrics. 1995 Dec;96(6):1095-100.

Oxandrolone After oxandrolone withdrawal Growth promoting effects is related to mild androgenic effects of it After oxandrolone withdrawal Increase in total serum testosterone progress in puberty.

Any Question?

GnRHa Decapeptyl 0·1 mg/m2 s.c.. (1–20 μg/ kg, 500 μg, 100 μg/m2

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

Constitutional Delay Puberty First signs of secondary sexual development occur within 1 year after LH rises to pubertal levels after administration of 100 μg GnRH subcutaneous GnRH agonist After 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, 603–607

synthetic LHRH 0·1 mg/m2 iv bolus Blood samples for of LH, FSH and testosterone levels were drawn prior to injection and 30 and 60 LH >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 Lh<5 HH LH>5 CDGP

, Kallmann

cdpuberty kallman kallmann Pituitary failure

LHRH test Time (min) -15 15 30 45 60 90 120 FSH mIU/ml 4.8 5.1 6.0 6.9 15 30 45 60 90 120 FSH mIU/ml 4.8 5.1 6.0 6.9 8.5 10.1 12.5 14.1 LH 1.3 2.6 5.0 8.6 10.7 10.8 11.9 HGH:0.625 ng/ml , TSH:3.35 uIU/ml Cortisol:19 ug/dl Prolactine:3.66

Laboratory assessment HCG stimulation test 3000 units/m2 per injection One to three injections daily or on alternate days Testosterone 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 evaluation BA=HA <CA  Constitutional delay puberty Late onset growth failure specially with DI  CNS tumor

Testicular volume >3-4 mL Longitudinal measurement> 2.5 cm pubertal development Testicular volume >3-4 mL Longitudinal measurement> 2.5 cm  Serum testosterone > o.5 ng/mL

Management If the LH level rises more than 2.5 SD above the mean value Testosterone level decreases below the normal range for age We think to HH

Birth : 1.7 3 years: 1.33 5 years : 1.17 10 years : 1.0 Upper to lower segment 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 segment pre-puberty ratio ≥ 1 During puberty ≤1 Adult men o.92 Adult woman 0.95