Delayed puberty Mehdi salek MD Delayed puberty Initial

Delayed puberty Mehdi salek MD

Delayed puberty Initial physical changes of puberty are not present by age Ø 13 years in girls Ø 14 years in boys

Delayed puberty lack of appropriate progression of puberty more than 4. 5 -5 years A boy who has’nt completed secondary sexual development within 4. 5 years Ø A girl who does’nt menstruate within 5 years Ø

Classification of Delayed Puberty Gonadotropin deficiency v CNS tumors v Functional HH v Infiltrative v Trauma v Isolated Gonadotropin v Genetic forms v CDP Hypergonadotropic Hypogonadism

Classification of Delayed Puberty n n Non-pathologic

Classification of Delayed Puberty n n Transient Permanent

Evaluation

Evaluation History n Infertility n Anosmia → HH n Cryptorchidism → HH n Small penis in neonate → HH n low Gn in neonatal period → HH

Evaluation n n Family pattern attainment of menarche Family history of delay pubertal Constitutional delay often have a positive family Birth trauma Familial marriage

Evaluation Ø Ø Ø Chemotherapy Glucocorticoid therapy Surgery History of intense exercise Exposures to irradiation

Growth chart Ø Growth pattern Late onset growth failure CNS mass lesion Organic disease Occasionally MRI IS necessary

Growth chart Ø Normal growth velocity for BA → CDGP Normal growth pattern without growth spurt Ø With anosmia Kallmann syndrom Ø Without anosmia ↓isolated gonadotropin

Physical Examination Ø Ø Ø Ø Neurologic examination Gynecomastia midline facial malformations Size of glandular breast tissue , areolarsize Testing of sense of smell Galactorrhea Turner stigma Retractile testes

Physical Examinatin n Height especially HT velocity at least 6 12 months upper to lower segment ratio n ↑↑U/L → CDG n ↓↓U/L → Hypogonadism n

Physical Examinatin n n Signs of puberty Testicular location , size, and consistency Prepubertal: n Normal size testis <2. 0 cc or longer<1. 5 cm Early puberty: q Normal size testis >3. 0 cc or longer >2. 5 cm pubertal-aged n A testis ≤ 1. 0 cm particularly if unusually firm or soft suggestive of a hypogonadal state.

initial Approach n n Skeletal age Gonadotropin status

initial Approach BA = 11 -13 years Gonadotropin measurement High Primary gonadal failure Girl Boy Turner Klinefelter

initial Approach Mild Elevated→ Gn. RH Test Exaggerated response Primary gonadal failure

initial Approach Low or lower limit of normal level Ø Constitutional Delay Ø Chronic disease Ø permanent Gonadotropin

initial Approach n Low gonadotropin levels and pubertal delay may result from a physiologic delay or a permanent defect

General Approach Diagnosis of HH versus CDP is more difficult because of Overlap in physical and laboratory finding

General Approach Hypogona Hypogo Ø FSH and LH are low n They haven't a pulsatile LH with↑ bone age

General Approach Overlap between HH and an immature hypothalamus if BA<10– 11 years for girls BA<12– 13 for boys

General Approach In older adolescent Ø Minimal response to Gn. RH Test suggests Gonadotropin Deficiency Ø Pubertal rise in the child with delayed puberty suggests CDP

General Approach n n Patients with HH have normal height in early or mid adolescent Patients with CDP have a normal growth rate for BA but are short for CA.

Laboratory assessment Ø CBC Electrolytes LFT ESR Prolactin Cortisol IGF-1 TSH, Free T 4 Sex steroids , DHEAS FSH, LH Ø MIH, INSL 3, PSA Ø Ø Ø Ø Ø

Laboratory assessment Karyotype Ø Bone age Ø Brain imaging for HH or hyperprolactinemia Ø pelvic ultrasound n urinary p. H, SG n urea nitrogen, creatinine Ø

Treatment

Management Ø Girls low dose estrogen therapy started at 13 years or bone age >11 years Ø Continue 3 - to 4 -month in CDP Ø

Management Ø Ø Ø 0. 3 mg of conjugated estrogens every other day 5 ug of ethinyl estradiol daily 0. 025 mg transdermal estrogen twice weekly

Management If permanent HH Estrogen can be increased every 6 to 12 months in order to reach full replacement doses after two to three years of therapy

Management During 2 -3 years n Daily doses of 0. 6 - 1. 25 mg of conjugated estrogen or 10 -20 ug ethinylestradiol are accepted as full replacement doses Cyclical progesterone 5 to 10 mg of daily for 12 days can be added every month to induce monthly menstrual bleeding n

Management Ø Ø Ø Boys The initial dosage should be low to avoid priapism and rapid pubertal development Dose should be adjusted based on intellectual maturation, and psychological needs Response, age, social

Treatment If skeletal age is immature v Risk of accelerating BA, short adult height If it is started at pubertal bone age 12 -13 v No detrimental effect on adult height v leads to somatic and genital growth

Treatment In boys of age 14 n n Testosterone Dose 50 to 100 mg IM every four weeks Three to six months Oxandrolone 2. 5 mg/day

Management After a few months Treatment should be stopped for Differentiation temporary from permanent Then Testosterone level to determine for endogenous androgen production.

Management Testosterone <50 ng/dl Ø Give another course After a few months Treatment should be stopped for Differentiation temporary from permanent n Given 1 -2 course Ø

Management Ø Ø If testosterone remain low→ Gona Continue treatment with androgen Dosages gradually increase to full replacement after three to four years 100 mg/wk, 200 mg/ two wk or 300 mg three week intervals

Management n The skin gel preparation 50, 75, or 100 mg Absorption over a 24 -hours Recommended sites are the shoulders, upper arms and abdomen n

Management n Testosterone >50 ng/dl →CDP Treatment should be stop n To assess progression of puberty Hypothalamic-pituitary-testicular function can be assumed if n Testosterone > 275 ng/dl n Testicular examination is normal n

Management Bone age n 12 to 13 years in girls n 13 or 14 years in boys n patients with CDP usually continue pubertal development n patients with gonadotropin deficiency do not progress and may regress.

Management when fertility is desired n Biosynthetic LH and FSH administration is utilized n Episodic administration of LHRH n Portable pumps to administer LHRH in episodic fashion over prolonged periods

Case History Ø Ø Ø 15 yr old boy Shortest in his class No problem at school Always a small boy No chronic disease Father didn’t grow till he entered college

Case physical Ø Ø Ø Ø No dysmorphic features CVS, Resp, Abd Exam normal Normal development Ht= 135 cm Wt= 30 kg U/l = near one Testicular volume =2. 5 ml

Case physical Ø Ø Ø Ø Testicular length = 1. 5 cm Penis = 4 cm Normal Testicular consistency No gynecomastia Arm span – height span= 2 cm GV =5 cm/yr PH=1

Hormonal and biochemical studies Ø Ø Ø Normal BUN /ESR Normal T 4 &TSH Low IGF 1& IGFBP 3 for age Normal IGF 1& IGFBP 3 for BA Decreased FSH& LH

Hormonal and biochemical studies Ø Ø Ø Testosterone= 0/15 ng / ml Celiac test= ok Cortisol levels = ok LHRH shows not yet in puberty Normal prolactin

Case treatment Ø Ø Ø Oxandrolon for 6 month Zinc 12. 5 mg/day Iron 12 mg/day for 3 mo Vitamin A = 6000 IU/week for 3 mo But Testicular volume &Testicular length Didn’t change

Case imaging Ø BA=12 yr

Diagnosis? Any treatment ?

Case treatment n n Testosteron 1 mg/kg for 4 month Letrozol 2. 5 mg

Case treatment Six month after stopping of Testosteron Ø Testosteron level was 0/8 ng/ml Ø Testicular volume =5 ml Ø Testicular length = 3 cm

Discussion

Constitutional Delay Puberty Ø Ø Multifactorial Fathers has similar pattern often in boys Normal size at birth. . -

Constitutional Delay Puberty By three years of age n Decrease height , BA, growth velocity By usual age of puberty n immaturity become more noticeable as the approaches with somatic and sexual pubertal At older age than typical n Puberty occurring spontaneously

Constitutional Delay Puberty n n 61 No history of systemic illness. Normal nutrition. Normal P/E. Normal hormones

Constitutional Delay Puberty n n 62 Delayed puberty. Delayed bone age. a short adolescent with bone age delay greater than three years is more likely to have a pathologic problem.

Constitutional Delay Puberty n n n Growth velocity and height are usually appropriate for bone age Delay in the reactivation of the Gn. RH pulse generator Adrenarche and gonadarche occur later

Constitutional Delay Puberty Outcome is benign Ø Normal physical development, sexual and reproductive function Ø

Constitutional Delay Puberty n Not one test yet distinguishes between CDP and HH, so watchful waiting is usually in order

Constitutional Delay Puberty Hypogonadotropin hypogonadism n Adrenarche at a normal age n Higher DHEAS than CDG n Failure of a rise in Gonadotropin or sex steroid by age 18

Treatment n n n Assurance to family GH treatment Treatment for BA>12 y Don’t Treatment for BA<10 y or CA<12 Oxandrolon Transdermal patch and gel preparations of testosterone