Delayed puberty , Etiology , Diagnostic approach

By – Dr . Aftab Ahmad

Mod – Dr. Jatin

Definition Delayed puberty is defined as failure to develop secondary sexual charecteristics by 2 SD beyond the mean age of onset for that population

An absence of an increase in testicular volume (less than 4 mL) at 14 yr in a boy

OR absence of any breast development at 13 yr in a girl. delay in the onset, progression or completion of puberty sufficient to cause concern to the adolescent, parents or physician

Pubertal arrest Those in whom puberty commences but does not progress

Therefore, evaluation is warranted if more than 4–5 yr has elapsed from the onset of puberty to adult testicular size in boys or menarche in girls.

in girls: lack of breast development by 13

more than five years between breast growth and menstrual period

lack of pubic hair by age 14 failure to menstruate by age 15-16

• in boys:• lack of testicular

enlargement by age 14

• lack of pubic hair by age 15

• more than five years to complete genital enlargement

Introduction Occurs in approximately 3% of children

In boys, delayed puberty is often constitutional and functional. (63 %)

In girls, delayed puberty is less common and often organic.

Normal puberty

Normal puberty

Normal puberty Normal puberty is initiated by the onset of pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus

These pulses cause release of luteinizing hormone (LH) and follicular stimulating hormone (FSH) from the pituitary gland

These pituitary gonadotropins then circulate to the gonads and stimulate production of sex steroids.

Classificationfunctional disorders

hypogonadotropic hypogonadism

hypergonadotropic hypogonadism

Functional disorder The first group represents temporary delays of puberty that are functional disorders, most commonly, constitutional delay of growth and puberty

Low LH/FSHLow T/E2

Hypogonadotropic hypogonadism

The second is hypogonadotropic hypogonadism, in which hypothalamic or pituitary failure results in deficiency of circulating gonadotropins.

Low LH/FSHLow T/E2

Hypergonadotropic hypogonadism

hypergonadotropic hypogonadism results from primary gonadal failure, resulting in elevated serum gonadotropin levels.

High LH/FSHLow T/E2

Constitutional delay in growth and puberty

The the single most common cause in both genders More often in boys than in girls.

It represent the extreme of the normal physiologic variations . CDGP is a diagnosis of exclusion.

Children with constitutional delay are more likely to be short for age. with a history of relatively normal growth rate.

Delays in bone maturation . Delay in adrenarche

Constitutional delay in growth and puberty

Frequently, there is a family history of late menarche in the mother or sisters or a delayed growth spurt in the father.

sporadic cases are also seen.

Puberty is not delayed beyond the chronological age of 16 yr in females and 18 yr in males

the onset of puberty corresponds better with bone age (BA) than chronological age

Evaluation of pubertal delay

History Totally absent or had started but then arrested. Family history of constitutional delay of puberty. Family history of infertility . Perinatal history prior medical illness. Medication. Psychosocial deprivation

History

Nutritional habits, exercise intensity. Neurologic symptoms such as headache, visual disturbances, seizures, and intellectual disability .

Sense of smell. Hypoglycemia. Cancer history :Radiation, Chemotherapy history compatible with testicular injury (bilateral cryptorchidism, surgery, irradiation, bilateral torsion)

Physical examination Growth parameter Ht, Wt, BMI .weight for height. The growth velocity ,Arm span. pubertal staging. Systemic exam. dysmorphisim Visual field exam. Fundoscopy. Evaluation of the sense of smell. Associated congenital abnormalities (eg, midline defects, cleft lip/palate, cryptorchidism, and microphallus )

Physical examination Mid Parental Height

Boys = Father ht ( cm ) + Mother ht (cm)/ 2 + 6.5 cm

Girls = Father ht ( cm ) + Mother ht (cm)/ 2 – 6.5 cm

Physical examination BOYS – Increase in testicular size is usually the first sign of puberty in boys testicular size greater than 4 mL in volume or a longitudinal measurement greater than 2.5 cm is consistent with the onset of pubertal development. Scrotal skin also changes in texture and reddens in early puberty

Physical examination

Physical examination GIRLS – Breast development in girls begins with formation of breast buds. This development is frequently unilateral for several months. Development of axillary and pubic hair may or may not accompany the onset of puberty. the vaginal mucosa changes from a reddish to pink.

Lab Initial screening should include: complete blood cell count. Serum prolactin Electrolytes , renal , liver panel. Celiac profile. erythrocyte sedimentation rate . Cortisol/ACTH LH,FSH. Bone age DHEAS Testosterone/estradiol. Thyroid function.

Lab Testosterone An 8AM total serum testosterone concentration level greater than 45 ng/dL indicates the initiation of puberty

Lab Estradiol

a plasma estradiol of more than 9 pg/mL is indicative of puberty. Elevations are reassuring for onset of early puberty. but levels below the limit may be seen in early puberty.

Lab Serum gonadotropin levels (LH and FSH).

Baseline serum gonadotropin values are typically low in both constitutional delay of puberty and congenital GnRH deficiency.

If elevated, the etiology for gonadal failure should be further investigated based on the differential diagnoses.

Lab Sleep-associated gonadotropin secretion

In normal puberty during night there is episodic LH secretion coincident with the onset of sleep.

In compare to those with CDGP , Hypogonadotropic children typically do not experience an increase in serum LH during sleep

Lab Karyotyping : if physical examination suggest the presence of a genetic syndrome . Also in any short girl.

GnRH stimulation testing: limited benifit

Imaging Bone age : may be obtained at the initial visit to assess skeletal maturation and repeated over time if needed.

Skeletal age more closely correlates with sexual development than does chronological age.

Bone age more than 13 for girls and 14 for boys less likely to constitutonal

Imaging Pelvic /scrotal ultrasound:

Indicated when an dysgenesis is suspected to determine the presence or absence of internal organs.

Imaging MRI Brain

should be obtained in patients with hypogonadotropic hypogonadism.

Treatment The aim of treatment: Development of age-appropriate secondary sex characteristics . Induction of a growth spurt without inducing premature epiphyseal closure.

Achievement of normal muscle mass and bone mineral density for age.

Improvement in psychosocial wellbeing. In some patient reversal of GnRH defceincy.

Treatment constitutional delay: conservative management with observation over 6 mo to 1 yr may be warranted.

Constitutional delay of growth and puberty can cause significant psychosocial stress, particularly in males.

Cases must be evaluated on an individual basis for psychosocial distress, and subsequent need for intervention.

Treatment In cases of clearly permanent hypogonadism, therapy should be initiated at a normal pubertal age to avoid the delay of growth and psychological effect of pubertal delay.

Treatment of CDGP most physicians advocate a period of “watchful waiting”. including periodic evaluation, reassurance, and psychological counseling .

short course of testosterone therapy may be initiated .

A low dose of testosterone enanthate (50–100 mg given intramuscularly every 4 wk) for 4–6 mo will stimulate linear growth and secondary sexual characteristics without inappropriately accelerating bone age.

Treatment of permanent hypogonadal state in boys

Testosterone enanthate , administered by intramuscular injection, is the most common method of pubertal induction and maintenance .

Various schemes have been proposed, but most authors advocate a starting dose of 50 mg every 4 wk.

When the pubertal growth spurt is well established, the dose should be gradually increased to a full adult dose of 200 mg every 2 wk.

When hypogonadism is diagnosed at a prepubertal age, testosterone therapy may be started as early as a bone age of 11–12 yr .

Treatment ( Boys ) Transdermal Testosterone: a scrotal patch and a nongenital patch. When applied daily, result in similar testosterone concentrations to those seen in normal young men in magnitude and diurnal variation.

Treatment ( Boys ) Transdermal Testosterone: substantially more expensive than testosterone esters . can produce skin reaction . not yet approved in males younger than age 18 years their effectiveness in induction of puberty remains unclear

Treatment ( Boys ) Side effect: acne, and gynecomastia. fast skeletal maturation leading to impaired adult height. excessive aggressiveness. excessive stimulation of libido, priapism, polycythemia, obstructive sleep apnea mainly in obese subjects

Treatment ( Boys ) Beneficial effects: decline in total plasma cholesterol and LDL concentrations, increased lean body mass. decreased risk of osteoporosis

Treatment ( Boys )

Oxandrolone: Can be used for Induction of a pubertal growth spurt in CDGP . the mechanism of action is unclear. it is anabolic steroid that increases growth velocity without promoting excessive skeletal maturation

Doses of (0.1 mg/kg/day, 1.25 or 2.5 mg/d for 3–12 months).

Treatment ( Boys ) Human chorionic gonadotropin hCG can be used to induce puberty in CDGP. hCG 1500 U twice weekly, either SC or IM, for 6 months. The use of hCG appears to be more physiologic and potentially safer than Testesterone However, HCG is more expensive and requires multiple injections.

Treatment ( Boys )

aromatase inhibitor An aromatase inhibitor, e.g., letrozole (2.5 mg/PO) in addition to Testosterone. appears to increase the final Ht to approach mid-parental.

Treatment ( Boys ) Dihydrotestosterone (DHT) 50 mg IM every 2 weeks, for 4 months. is associated with appearance of secondary sex characteristics increased lean body mass and decreased body fat with no change in IGF-I. may increase the potential for final Ht.

Treatment ( Girls ) Estrogen : either long-term low doses, or gradual increases in dose providing adequate time for pubertal growth, and gradual breast development.

For constitutional : conjugated estrogen 0.3 mg po daily for 3-6 months

Treatment ( Girls ) A progesterone should be added after two years of estrogen , after full breast development or if spotting occurs. This is usually administered as: Provera (medroxyprogesterone) at a dose of 5–10 mg or micronized progesteroneat 200 mg/day (eg, Prometrium) for 10–14 d

Treatment ( Girls )

In girls without a uterus, such as in androgen insensitivity or XY gonadal dysgenesis, the same guidelines for estrogen replacement can be used, but there is no need for the addition of progesterone.

Follow up and monitoring Regular clinical follow-up assessing growth and pubertal progression every 3-6 months

Bone age assessment.

Follow up and monitoring Hematocrit level - the discontinuation of therapy is required if hematocrit is greater than 54% until it decreases to a safer level).

THANK YOU