The document discusses definitions, causes, evaluation, and treatment of delayed puberty. It defines delayed puberty as a lack of development 2 standard deviations above the mean age. Causes include constitutional delay of puberty (most common in boys), hypogonadotropic hypogonadism resulting from hormone deficiencies, and hypergonadotropic hypogonadism from primary gonadal failure. Evaluation involves medical history, exam of secondary sex characteristics, labs of hormone levels, bone age, and imaging if needed. Treatment depends on the cause, ranging from observation for constitutional delay to hormone replacement for permanent deficiencies.

1. Dr. Md Razi Ahmad MD
Assit. Prof. GTCH Patna

2. INTRODUCTION
• Definitions:
• Delayed puberty is defined as the lack of pubertal
development by 2 SD above the mean age for the
general 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.

3. • In boys, a period of 3.2 +/–1.8 (mean +/–
SD) years is necessary to achieve adult
testicular volume after the onset of
puberty.
• In girls, the period from breast budding to
menarche is 2.4 +/–1.1 (mean +/–SD)
years.
• Therefore, evaluation is warranted if more
than 4–5yr has elapsed from the onset of
puberty to adult testicular size in boys or
menarche in girls.
Pubertal arrest

4. • 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

5. • 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.
• Delay of puberty leads to delay in the
acquisition of secondary sex characteristics,
psychological problems, defect in reproduction
function and the reduction of bone mass.
INTRODUCTION

6. • 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.

7. functional disorders
hypogonadotropic
hypogonadism
hypergonadotropic
hypogonadism

8. • The first group represents temporary
delays of puberty that are functional
disorders, most commonly,
constitutional delay of growth and
puberty.

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

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

13. CONSTITUTIONAL DELAY
OF PUBERTY AND GROWTH
• 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

14. • 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
CONSTITUTIONAL DELAY
OF PUBERTY AND GROWTH

15. Functional causes
Chronic renal disease, cardiac disease,
Chronic gastrointestinal disease/malnutrition
Sickle cell disease/iron overload
Chronic lung disease/cystic fibrosis/asthma
Anorexia nervosa
Bulimia nervosa
Psychogenic/stress
Extreme exercise
Drugs
Poorly controlled diabetes mellitus
Hypothyroidism
Cushing disease
Hyperprolactinemia
PCOS
AIDS, recurrent infections

16. HYPOGONADOTROPIC
Congenital
Isolated GnRH deficiency
Kallmann syndrome
KAL1, FGFR1, PROKR2
Idiopathic hypogonadotropic hypogonadism
GnRHR,FGFR1,GPR54,Leptin,FSHβ-subunit,LH β-subunit
Idiopathic hypogonadotropic hypogonadism associated with obesity
Leptin, Leptin receptor, PC1
DAX1 mutation ( Adrenal hypoplasia congenita
Pituitary transcription factor deficiency.
Panhypopitutirism (e.g. LHX3, PROP1)
Septooptic dysplasia (HESX1)
Syndromes
Prader-Willi syndrome
Noonan syndrome
CHARGE syndrome
Bardet-Biedl syndrome

18. HYPOGONADOTROPIC
Acquired
CNS tumors
Craniopharyngioma, germinoma, hypothalamic glioma,
optic nerve glioma, pituitary tumors
Trauma/surgery
Pituitary apoplexy
Infiltration
Hypophysitis
Lymphocytic
Granulomatous
Histiocytosis X
Sarcoidosis
Infectious—meningoencephalitis
radiotherapy

19. Hypergonadotropic (Congenital)
Tuner syndrome (45,X) (46XX/45X)
Swyer syndrome (46,XY)
Mixed gonadal dysgenesis (46,XX/46,XY)
Pure ovarian agenesis (46,XX)
Galactosemia
FSH or LH receptor gene mutations
steroidogenic defect (CAH)
Mixed gonadal dysgenesis (e.g. 46XY/45X)
Testicular dysgenesis (e.g. loss of functional SRY, Sox9, SF1,
WT1, DMRT)
Klinefelter syndrome
Noonan syndrome
LH receptor gene mutation
Androgen resistance
steroidogenic defect (CAH)

23. Hypergonadotropic
Acquired
Girls
Radiation
Chemotherapy
Trauma/surgery
Infections
Autoimmunity
Idiopathic failure
Boys
Radiation
Chemotherapy
Trauma/surgery
Infections
Vanishing
toxin

24. systems
pubertal
auxological
imaging
lab
Evaluation of Pubertal Delay

25. Evaluation of Pubertal Delay
• HISTORY:
• totally absent or had started but then arrested.
• family history of constitutional delay of puberty.
• Family history of infertility .
• The review of symptoms.
• Perinatal history
• prior medical illness.
• Medication.
• psychosocial deprivation

26. • 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)
Evaluation of Pubertal Delay

27. • 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

29. • 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

30. PHYSICAL EXAMINATION

32. • 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.
PHYSICAL EXAMINATION

34. • Initial screening should include:
• complete blood cell count.
• Electrolytes , renal , liver panel.
• erythrocyte sedimentation rate .
• LH,FSH.
• Testosterone/estradiol.
• thyroid function.
• serum prolactin.
• Celiac profile.
• Cortisol/ACTH.
LAB

35. • Testosterone
• an 8AM total serum testosterone
concentration level greater than 45
ng/dL (1.6 nmol/L ) indicates the
inception of puberty
LAB

36. • estradiol
• a plasma estradiol of more than 9
pg/mL (32 pmol/l) is indicative of
puberty.
• Elevations are reassuring for onset of
early puberty.
• but levels below the limit may be
seen in early puberty.
LAB

37. • 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

38. • Sleep-associated gonadotropin
secretion
• Normal puberty begins at night with
the onset of 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

39. • Karyotyping :
• if physical examination suggest the
presence of a genetic syndrome .
• Also in any short girl.
• GnRH stimulation testing:
• limited benifit
LAB

40. • 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

41. • Pelvic /scrotal ultrasound:
• Indicated when an dysgenesis is
suspected to determine the presence or
absence of internal organs.
imaging

42. • MRI:
• should be obtained in patients with
hypogonadotropic hypogonadism.
imaging

43. treatment
functional
Chronic disease
Underling
cause
Testosterone
estrogen
observation
constitutional
Testosterone
permanent
hypogonadortopic
Testosterone
Estrogen/
progestrone
Underling
cause
Testosterone
hypergonadotropic
Estrogen/
progestrone
Psychological
and
reassurance

44. • 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

45. • 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

46. • 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

47. CDGP VS HH
• Determining the etiology of delayed
puberty during initial evaluation can be
challenging.
• clinicians often cannot distinguish
constitutional delay of growth and puberty
(CDGP) from isolated hypogonadotropic
hypogonadism (IHH).

48. • A family history of delayed puberty is
strongly suggestive of CDGP (seen in
50–75%).
• Adolescents with CDGP may have
delayed adrenarche and pubarche along
with delayed gonadal development.
• The presence of progressive pubertal
development by age 18 yr in boys or 16
yr in girls is the “gold standard” for
differentiating CDGP from HH.
CDGP VS HH

49. Constitutional
Delay of
Growth and
Puberty VS
Permanent
Hypogonadot
ropic
Hypogonadis
m

50. • 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 4–6mo will
stimulate linear growth and secondary sexual
characteristics without inappropriately accelerating
bone age.
TREATMENT of constitutional delay of
growth and puberty in boys

51. • 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 of permanent
hypogonadal state in boys

52. • Testosterone:
• Testosterone therapy is utilized for induction
of puberty in boys with constitutional delay of
puberty, hypogonadotropic hypogonadism,
and hypergonadotropic hypogonadism.
• testosterone esters Intramuscularly are the
most commonly used.
• Testosterone enanthate and cypionate are
preferred over testosterone propionate
TREATMENT (MALE)

53. • testosterone esters, such as enanthate 50
mg monthly given IM for 4–12 months.
• Thereafter, the doses are gradually
increased with 50 mg every 6 to 12 months.
• After reaching 100-150 mg monthly
,decrease interval to every 2 weeks.
• Then adult dose 200 mg every 2 weeks.
TREATMENT (MALE)

54. • The following schedule also may be
proposed :
• first year: 25 mg every 2 weeks;
• second year: 50 mg every 2 weeks;
• third year: 100 mg every 2 weeks;
• fourth year onward: 200 mg every 2
weeks .
TREATMENT (MALE)

55. • 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 (MALE)

56. • 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 (MALE)

57. • 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 (MALE)

58. • Beneficial effects:
• decline in total plasma cholesterol and
LDL concentrations,
• increased lean body mass.
• decreased risk of osteoporosis .
TREATMENT (MALE)

59. Testosterone
Testoserone
enathate, cypionate
and propionate. IM
Initiate after age 12 years of
age at 50 mg every 4 weeks.
Increase with 50 mg every 6
to 12 months. After reaching
100-150 mg monthly
,decrease interval to every 2
weeks. adult dose 200 mg
every 2 weeks
Not for use in boys with
bone age <10 years.
Erythrocytosis, weight
gain, prostate
hyperplasia.
Premature epiphyseal
closure .
Local side effects (pain,
erythema)
Testosterone
undecanoate.IM
Adult dose 1000 mg every
10-14 weeks.
Can cause POME
Testosterone gel Can be started when 50%
adult dose with
intramuscular testosterone
achieved.
Local irritation. Avoid
contact with other
TREATMENT (MALE)

60. Testosterone
Oral testosterone
undecanoate
at the starting dose of 40
mg/daily in the morning.
the levels of testosterone
seem to be slightly more
erratic.
hepatotoxic
trans-buccal
testosterone
30 mg per buccal system.
30 mg twice a day
Gum irritation
TREATMENT (MALE)

61. TREATMENT (MALE)

64. TREATMENT (male)
• 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).

65. • 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 (male)

66. • 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 (male)

67. • 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 (male)

68. • 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)

69. • For other indications:
• Premarin (conjugated estrogen) may be
used at a dose of:
• 0.3 mg every other day for 6 months
followed by an increase to every day for 6
months
• then 0.625 mg daily for 6 months,
• followed by 1.2 mg.
TREATMENT (GIRLS)

71. • 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 5–10mg or
• micronized progesteroneat 200 mg/day
(eg, Prometrium) for 10–14 d
TREATMENT (GIRLS)

72. • After adult doses of estradiol and
medroxyprogesterone are reached, oral
contraceptive pill may be substituted for
separate preparations of these
compounds.
TREATMENT (GIRLS)

73. • 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.
TREATMENT (GIRLS)

74. GNRH THERAPY
• In some cases of hypogonadotropic
hypogonadism, pulsatile administration of
gonadotropin releasing hormone has
resulted in induction of puberty .
• frequently used for stimulation of
spermatogenesis or induction of ovulation
in infertile adult patients.

75. • Patients of either sex with hypogonadotropic
hypogonadism are potentially fertile
• to initiate gametogenesis, the typical
approach to fertility induction is pump-
administered GnRH therapy (assuming an
intact pituitary gland)
• or parenteral combination gonadotropin
treatment (synthetic LH/hCG and
recombinant FSH) .
further TREATMENT

76. follow-up and monitoring
• regular clinical follow-up assessing
growth and pubertal progression
every 3-6 months
• bone age assessment.

77. • Testesterone:
• 1. therapy should restore serum testosterone levels into the mid-
normal range for pubertal stage.
• 2. measurement of testosterone should be:
• - testosterone enanthate or cypionate: midway between
injections.
• - i.m. long-acting testosterone undecanoate: before the new
injection.
• - transdermal testosterone patch: 3-12 hours after application.
• - transdermal testosterone gel application: after 1-2 weeks
independently from application.
• - buccal testosterone tablet: immediately before the application
of new tablet.
follow-up and monitoring

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

79. • LH and FSH :
• the assessment of LH and FSH has
poor clinical value
follow-up and monitoring