Disorder related to puberty

1. Disorders Of
Pubertal Development
Moderator:
Dr.Shilpa Khanna Arora
Presenters:
Dr.Monika Sharma, SR
Dr.Pronita Banerjee, PG

2. Period of transition from sexually immature child to
mature, potentially fertile adolescent and adult
Puberatum meaning age of maturity
HPG axis, crucial role in:
1. Promoting physical changes
2. Development of secondary sex characteristics
3. Maturation of gonads

3. Average age of onset of puberty:
8-13yrs (~10yrs) in GIRLS
10-15yrs (~12yrs) in BOYS

4. Physiology of Puberty
Hypothalamo-pituitary-gonadal axis

6. • LH and FSH levels- low before puberty, secreted in
pulsatile manner
• Prepubertal hypothalamic-pituitary-gonadal system
suppressed by negative-feedback control
• LH levels increase progressively with puberty
• Frequency of LH pulsation remain same, amplitude of
each pulse increase strikingly
• Percentage of peaks with high pulse amplitude increases
steadily

8. Main physiological events in puberty:
Gonadarche: activations of gonads by pituitary
hormones, LH and FSH
Adrenarche: increase in production of androgen by
adrenal cortex
Thelarche : onset of breast development (breast
bud)
Menarche : first menstrual period
Spermarche : appearance of sperms in seminal fluid

9. Girls
Thelarche
Height spurt
Pubarche
Menarche
Boys
Inc testicular vol
Pubarche
Height spurt
Adult testicular vol

10. Onset correlates with bone age
Thelarche: first sign of puberty in girls
Increase in testicular volume(>/=4mL) : first sign
of puberty in boys
Adrenarche and gonadarche are independent
processes
Estradiol responsible for epiphyseal fusion and
cessation of linear growth

11. Most common primary heralding sign of pubertal
development
Asymmetry in breast development common and best
left to observation until complete development
Unilateral onset of breast development may occur,
may take 6 months for opposite breast bud to become
palpable

12. Androgen producing fetal
zone of adrenal cortex
undergoes involution at
birth
Remains quiescent until
6yrs of age
Adrenarche characterised
by increase in serum levels
of DHEA-S in response to
ACTH

13. • 17-18% of final adult
height gained during
puberty
• Estradiol causes
acceleration of growth and
increase in GH and IGF-1
secretion
• Mean GH in mid- to late-
puberty: 13-15ng/ml.
(amplitude)

17. • Stage 1- no axillary hair
• Stage 2- scant axillary hair (usually coinciding with
onset of adrenarche)
• Stage 3- coarse axillary hair, less than adult
• Stage 4- full adult axillary hair

19. Definition: Appearance of secondary sexual
characteristics before age of 8yrs in girls and 9yrs in
boys (most accepted definition)
Or development of puberty 2.5-3SD earlier than the
median age

20. PRECOCIOUS
PUBERTY
Central precocious puberty
True
Gonadotropin-dependent
precocious puberty
Peripheral precocious
puberty
Pseudo
Gonadotropin independent
precocious puberty
Incomplete forms or
pubertal variants

22. Central precocious puberty (most common)
always isosexual
Premature activation of HPG axis -> sex hormone
secretion
Peripheral precocious puberty
Iso or hetero sexual
No activation of normal HPG axis
Some secondary sexual character appear
Mixed type
Peripheral precocious puberty induces HPG axis and
triggers central puberty
CAH, McCune-Albright synd,

23. • In all forms of sexual precocity, increased gonadal
steroid secretion increases height velocity, somatic
development, and the rate of skeletal maturation.
• Because of premature epiphyseal fusion, sexual
precocity can lead to the paradox of tall stature in
childhood but short adult height

24. Sporadic, transient isolated
breast development without any
other signs of pubertal
development
Usually occurs before 2 years,
rarely after 4 years
Generally regresses within 18
months ( may not in those
>2years/Tanner stage3)
Menarche at expected age

25. Areolar development absent
Inc sensitivity to estrogen
Growth and osseous maturation normal
Leuprolide or GnRH stimulation elicits robust FSH,
low LH and moderate estradiol increment
Occurrence in >3yrs age most often caused by
condition other than benign premature thelarche

26. Appearance of sexual hair before age of 8yrs in
girls or 9yrs in boys without other evidence of
maturation
More frequent in girls
Axillary hair appears later
Slightly advanced in height and osseous
maturation

27. Coincides with precocious maturation of zona
reticularis adrenarche)
Idiopathic premature adrenarche is slowly progressive,
requires no therapy
Atypical premature adrenarche:
Precocious puberty plus
1 or more features of systemic androgen effect-
marked growth acceleration, clitoral/phallic
enlargement, cystic acne, advanced BA (>2SD)

28. Rare entity
R/o more common causes, such as vulvovaginitis,
FB, sexual abuse
Uncommon causes- urethral prolapse,
saccharomces botryoides

30. • Complete precocious puberty, or true (complete)
isosexual precocity (ISP)
• Results from premature reactivation of the
hypothalamic GnRH pulse generator/pituitary
gonadotropin-gonadal axis
• So it is also called gonadotropin dependent precocious
puberty (GDPP)

31. 1 Idiopathic true precocious puberty
2 CNS tumors
• Optic glioma associated with neurofibromatosis type 1
• Hypothalamic astrocytoma, ependymoma, glioma,
craniopharyngioma
3 Other CNS disorders
• Developmental abnormalities including hypothalamic hamartoma of
the tuber cinereum
• Encephalitis
• Static encephalopathy
• Brain abscess
• Sarcoid or tubercular granuloma
• Head trauma
• Hydrocephalus
• Arachnoid cyst
• Myelomeningocele
• Vascular lesion

32. 4 Cranial irradiation
5 True precocious puberty after late treatment of
congenital virilizing adrenal hyperplasia or other
previous chronic exposure to sex steroids
6 True precocious puberty due to gain of function
mutations:
• in KISS1R/GRP54 gene
• in KISS1 gene

33. • Girls > 5(boys)
• Always isosexual
• 75-90% of girls ->idiopathic, while two thirds of boys
have CNS pathology
• Younger the age, greater likelihood of pathology
• IDIOPATHIC: merely a normal event occurring early
and puberty progresses normally

34. 3 main patterns of pubertal progression:
Rapidly progressive: most girls <6yrs of age at
onset, majority of boys
Slowly progressive: girls >6yrs of age at onset;
parallel advancement of osseous maturation and
linear growth with preserved height potential
Spontaneously regressive/unsustained: rare

35. • Hypothalamic hamartomas m/c brain lesion causing
central precocious puberty
• Heterotopic CNS tissue acting as ectopic GnRH pulse
generators
• Puberty may occur very early with rapid progression
• Often a/w gelastic or other types of seizures with
developmental delay
• Serum LH levels and response to GnRH stimulation are
very high

36. • Hypothalamic s/s - DI, hyperthermia, gelastic seizure,
obesity, cachexia in intracranial lesions
• Usually manifest before 3 years
• may be sessile or pedunculated,usually attached to the
posterior hypothalamus between the tuber cinereum
and the mamillary bodies
• Patients present with CPP can be associated with
laughing (gelastic), petit mal, or generalized tonic-
clonic seizures; mental retardation; behavioral
disturbances; and dysmorphic syndromes beginning as
early as the neonatal period.

37. • Common in male
• Surgery is not recommend in
the absence of strong
evidence of growth of the
mass or of an associated
complication such as
intractable seizures or
hydrocephalus.
MRI appears as a small
pedunculated mass attached to
tuber cinereum or floor of 3rd
ventricle

38. If extrapituitary secretion of gonadotropins or secretion
of gonadal steroids independent of pulsatile GnRH
stimulation leads to virilization in boys or feminization
in girls, the condition is termed incomplete ISP,
pseudoprecocious puberty, or GnRH-independent
sexual precocity (GIPP).

39. Child with suspected precocious puberty
- Assess for SMR staging
- Measure height & compare with previous height
measurement
Early development of two or more signs of puberty
Precocious
Puberty
NoYes
Normal variant
Further workup
required

40. History:
• Age of onset
• Pattern of growth
• Rapidity of progression
• Past CNS infection
• Exogenous hormonal exposure
• Birth history
• Family h/o early puberty
Examination:
• Anthropometry
• Serial height
measurement
• Staging of puberty
• Androgen/estrogen
effects
(acne,hirsutism,inc
muscle
mass,clitoromegaly)
• Thyroid / P/A exam
• Fundoscopy
• Skin lesions

41. Pubertal development before 8 years in girls or 9 years n boys
Perform history and physical examination (if clinically indicated, perform LH,FSH,
estradiol, testosterone, DHES, GnRH stimulation)
Isolated examination findings HPG axis activation
Atypical
pubertal
progression
Early but typical
pubertal
progression
Prepubertal LH or
gonad size
Pubertal LH
CPPPPP
-exogenous
steroid
-hypothyroidism
McCune AS
High DHES or
17-OH
progesterone
CAH
Adrenal
tumour
Premature
Thelarche
(glandular breast
tissue)
Prepubertal
vaginal bleeding

42. Baseline samples for LH, FSH & Estradiol/testosterone taken
Single dose GnRH @ 100 mcg or leuprolide acetate @ 20
mcg/kg
- LH measured at 30 to 40 minus post GnRH or 60 minutes
post leuporlide acetate
- Estradiol/testosterone measured after 24 hrs

43. Baseline LH LEVELS: <0.1=> PREPUBERTAL,
>0.3=> PUBERTAL
For most LH assays, value of 3.3 to 5 IU/Ldefines
upper limit of normal. For stimulated LH, levels
above this suggest CPP
Peak stimulated LH/FSH ratio -
CPP - higher peak (~ > 0.66)
Non progressive precocious puberty < 0.66
CPP - higher stimulated estradiol/testosterone

44. USG (uterine length of >3.5cm and volume
>1.8mL are two most specific indicators of true
CPP)
Thyroid function tests
Bone age
GnRH stimulation tests
Neuroimaging, always indicated in males with
CPP

45. GnRH agonists d/t long duration of action, desensitise
gonadotropin cells of pituitary to endogenous GnRH
and halt progression of CPP
Indications of treatment:
Rapidly progressive puberty-All boys and most girls are treated
Adult height going to be significantly compromised
Former SGA at greater risk of short stature as adults, require
aggressive treatment
Menarche occurs before 6 years of age
Pubertal development is psychologically distressing to the child

46. Available preparations:
Leuprolide acetate depot preparation @ 0.25-
0.3mg/kg IM once every 4weeks or 3 monthly
formulation of 11.5mg
s/c aqueous leuprolide OD or two divided
dosage @60mcg/kg/d
Histrelin s/c implants 50mg lasting 12months
Intranasal nafarelin 800mcg bid

48. • F:M is 2:1
• activating mutations in the gene encoding the α-subunit
of the GTP-binding protein (Gsα) that stimulates adenyl
cyclase
• The sexual precocity often begins during the first 2 years
of life and is frequently heralded by menstrual bleeding

49. • It is characterized by the triad of
A.irregularly edged hyperpigmented macules (café au
lait spots of the coast of Maine type)
B. Polyostotic fibrous dysplasia
C. more commonly in girls GnRH-independent sexual
precocity
• Symmetric testicular enlargement f/b phallic
enlargement and pubic hair, as in normal puberty

50. Extra gonadal manifestations :
Hyperthyroidism-multilocularis goiter (mildly inc
T3, dec TSH)
Cushing syndrome- b/l nodular adrenocortical
hyperplasia in early infancy; b/l adrenalectomy
required
Gigantism or acromegaly d/t inc GH
Phosphaturia l/t rickets or osteomalacia

52. Biochemical findings:
Suppressed levels of LH and FSH, no response to GnRH or
leuprolide stimulation
Estradiol level vary, Normal to markedly elevated, often
cyclic
Management:
Girls: aromatase inhibitor (letrozole 1.25-2.5mg/d PO);
antiestrogens (tamoxifen 5-20mg/d PO)
Boys: combined with antiandrogens (spironolactone 50-
100mg bid; flutamide 125-250mg bid; bicalutamide 25-50 mg
daily)

53. o Untreated/undertreated hypothyroidism
o Massively elevated concentration of TSH interacts
with FSH receptors, inducing FSH like effects in
absence of LH effect on gonads
o No pubarche/skeletal maturity
o Plasma TSH levels markedly elevated, >500microl/ml
o Mildly elevated prolactin and estradiol
o Treatment of hypothyroidism results in rapid
normalisation of biochemical and clinical
manifestations

54. • most common childhood estrogen-secreting ovarian
mass and ovarian cause of sexual precocity
• Antral follicles up to about 8 mm common in normal
prepubertal girls.
• Occasionally, the antral follicles secrete estrogen and
may form large masses, or the follicular cysts may
recur and cause recurrent signs of sexual precocity and
acyclic vaginal bleeding

55. • concentration of estradiol fluctuates, usually
correlating with changes in the size of the follicular
cyst or cysts in pelvic sonography
• They do not have increased plasma granulosa cell
tumor markers such as AMH or inhibin.
• concentration of LH is suppressed, a pubertal pattern
of pulsatile LH secretion is absent, and the LH rise
induced by GnRH is prepubertal and pubertal or high
estradiol

56. • Treatment is medroxy progesterone acetate and potent
aromatase inhibitor such as letrozole
• Laproscopic puncture of cyst for large or persistent
cyst

57. Defined as the lack of pubertal development (Tanner
stage 2 breast development in girls or testicular
enlargement to >= 4mL in boys) by the age that is 2-
2.5 SDs beyond the population mean.
Beyond age of 14 yrs in boys, 13yrs in girls
2%of adolescents
PUBERTAL ARREST: no progress in puberty over
2yrs/ failure to complete after 5 yrs of onset

63. Constitutional delay in growth and puberty
• CDGP is a normal variant of growth and puberty which is characterized by a
decline in growth velocity between 2 and 3 years of age, followed by normal
height velocity during prepubertal period (along the third percentile) and delayed
but spontaneous pubertal growth and development before the age of 18 years.
• It is accompanied by delay in skeletal maturation (BA < CA); however, the bone
age correlates with height age.
• CDGP is the most common cause of delayed puberty and is more common in
boys.

64. • A family history is present in 50–80 %. family history
of “late bloomers,” manifested by an older age at
menarche in women or significant linear growth
occurring in the late teenage years in men.
• Pathogenesis: genetic (AD).
• typical clinical findings:short stature, delayed bone
age, and low-normal growth velocity, combined with
the absence of any other identifiable cause of short
stature and pubertal delay.

65. May result from:
Genetic/developmental:
• isolated hypogonadotropic hypogonadism:
Kallaman syndrome m/c
Tumor/trauma/vascular/irradiation
Endocrinopathies

66. m/c form of IHH
Characterised by: anosmia/hyposmia d/t
agenesis/hypoplasia of olfactory lobe
1 in 10,000 male; 1 in 50,000 females
m/c inherited as XLR
A/w : cleft lip/palate, pes cavus, seizure d/s,
short metacarpal, u/l or b/l renal aplasia,
cerebellar ataxia

67. m/c form of male hypergonadotropic hypogonadism
1 in 1000 male
Characteristic karyotype 47XXY
Enter puberty normally but have pubertal arrest
Disproportionate length of extremities, long legs
Neurobehavioural abnormalities common
a/w aortic valvular d/s, ruptured aortic aneurysm; SLE, osteoporosis
Malignancies: midline germ tumors

69. m/c form of female hypergonadotropic
hypogonadism
1 in 2500 female
Characteristic karyotype 45XO
Can be recognized in newborn period

71. History:
• Pattern of growth since birth
• Pubertal failure
• Pubertal arrest
• Micropenis
• Cryptorchidism
• h/s/o chronic illnesses
• Nutritional history
• Psychosocial history
• Family h/o delayed puberty f/b
spontaneous onset
Examination:
• Anthropometry
• Eunuchoid proportion
• Serial height
measurement
• Staging of puberty
• Obesity
• dysmorphism
• Anosmia test with graded
solution

73. • 8am testosterones, LH, FSH
• TFT
• IGF1
• Karyotype(raised FSH,LH)
Serum total testosterone >50ng/dl
GnRH agonist stimulated peak LH >14U/L
hCG stimulated increase in total testosterone
>260ng/dL
Serum inhibin-B >35pg/mL

74. In boys:
Exclusion of serious organic disease/ chromosomal
variation (PRIMARY GOAL)
If just late puberty-> REASSURANCE
Oral testosterone undecanoate capsules 40mg daily
Depot testosterone esters 50-125mg I/m monthly
Transdermal patch - 10mg release daily

75. Very low dose ethinyl estradiol 0.1 mcg/kg/day
Physiological low dose transdermal estradiol 6.25mic-
>12.5->25 estradiol patch changed twice weekly
Started as low dose as per induction
Ovarian USG performed 6 monthly to look for
follicular activity
Dose increased gradually over next 2 to 3 yrs
Cyclic therapy started after 12 to 18 months
IN GIRLS:

76. CASES

80. THANK YOU!