3. Thelarche Onset of breast development
Pubarche Onset of sexual hair growth
Menarche Onset of menstruation
Spermarche Appearance of sperms in seminal fluid
Gonadarche
Onset of pubertal function of gonads
producing sex hormones responsible for
pubertal changes
Adrenarche Onset of adrenal androgen production
4. HPG axis during childhood
• Matures by 12-14 wks GA
• Testosterone peak around 12 weeks
• Crucial phase for ANDROGEN
ACTION
• MALE GENITAL DEVELOPMENT
• LH & FSH peak around 24 weeks and
decrease to be low at birth
• LACK of FEEDBACK INHIBITION
• Rise in gonadotropin & PRL
• Boys- Increase in penile size
• Girls- Minimal breast
development
• Triggered by ↓ inhibitory & ↑ stimulatory signals with
permissive leptin levels
• Initially, nocturnal GnRH pulses f/b daytime surges too
• Initial nocturnal LH surge causes testosterone surges in the
morning
• LH > 25 times & FSH > 2.5 times
Hence, LH:FSH ratio > 1
• Testosterone > 20 ng/dl & estradiol > 10 pmol/L
5. GnRH regulation
• Secreted by arcuate nuclei
(Hypothalamus)
• Act on KIS1 receptors
• Role in pubertal onset
• Mediator role of peripheral
signals (leptin)
• Link between nutrition &
puberty
• CHECK POST or GATEKEEPER
of puberty
• Minimum threshold levels
required for initiating
puberty
• Leptin deficiency/resistance-
delayed puberty
• Maternally imprinted gene
• Loss of function mutation –
precocious puberty
Delayed puberty Precocious puberty
Act of commission Act of omission
Active process
Loss of active
inhibition
Signalling or
functional defect
Loss of function
mutations
6. GnRH stimulation
PULSATILE STIMULATION CONTINUOUS STIMULATION
Sensitizes pituitary
gonadotrophs
De-sensitizes gonadotrophs
Essential for subsequent
responsiveness to GnRH
No responsiveness
Use- Short acting GnRH analog
in CDGP for inducing puberty
Use- Long acting GnRH analog
in CPP to reverses pubertal
onset
10. Pubertal changes (GIRLS)
Ovaries
• 1st change of puberty
• Multicystic appearance due to FSH effect
• Should not be confused with PCOS (peripheral cysts)
Breast development (Thelarche)
• 1st external sign of puberty
• 5 tanner stages with Stage 4 suggesting impending menarche
• May be asymmetrical in initial stages
Pubic hair development (Pubarche)
• Usually follows thelarche but may precede in 15% cases
• Independent of GnRH, hence doesn’t respond to GnRH
suppression in precocious puberty
• Requires normal androgen receptors and adrenal function
• Pubarche without thelarche – premature adrenarche
Thelarche without pubarche – hyperestrogenic state
• Delayed puberty without pubarche – CDGP/ systemic illness
Delayed puberty with pubarche - hypogonadism
Vaginal mucosa
• Reflects estrogen status
• Red & glistening mucosa – lack of estrogen exposure
• Pink & pale mucosa – pubertal onset
11. Pubertal changes (GIRLS)
Uterine growth
• Lags behind ovaries
• Tubular to pear shaped structure due to ↑ corpo-cervical ratio
(>1)
• Endometrial thickness > 5 mm → impending menarche
• Menarche occurs 2.5 years after thelarche
• Menarche within 1 year of thelarche → discordant pubertal
development & hyperestrogenic state
• Menarche without thelarche – local causes
Growth spurt
• Occurs from B2 and lasts for 2 years
• Growth velocity of 9 cm/year
• Growth potential Tanner 2 – 25 cms
Tanner 4 – 8-10 cms
Skeletal maturation
• Estradiol – main regulator
• Thelarche – BA 10.5 years
• Menarche – BA 13 years
Status
Uterine
volume (ml)
Ovarian
volume (ml)
B1 1 0.8
B2 2.3 1.6
B3 10.3 3.2
B4-5 24.6 7.4
12. Pubertal changes (BOYS)
Testicular enlargement
• Testicular volume > 4 ml → 1st sign of puberty
• Testicular volume > 10 ml → impending growth spurt
• Testicular volume > 20 ml → Voice change & final height
• Soft & small testis – hypogonadotropic hypogonadism
Firm testis – hypergonadotropic hypogonadism
• PP with adequate testicular enlargement – CPP
PP with limited testicular enlargement – adrenal defect
Penile growth
• Occurs 6 months after testicular enlargement
Pubic hair development
• Occurs 6 - 12 months after testicular enlargement
• Pubarche with delayed puberty – hypogonadotropic
hypogonadism
• No pubarche with delayed puberty – CDGP/ systemic
illness
Growth spurt
• Occurs from T 10 ml and lasts for 2.5 years
• Growth velocity of 10.2 cm/year
• Voice change & spermarche – advanced pubertal
development & limited growth
14. PRECOCIOUS PUBERTY
• Represents excess levels of sex steroids
• Onset of puberty early for the chronological age of the child
Definition:
GIRLS BOYS
• Thelarche < 8 years
• Pubarche < 8 years
• Menarche < 9.5 years
• Testicular enlargement (4 ml or more)
< 9 years
• Pubarche < 9 years
15. TYPES
PRESENTATIONS:
CENTRAL PP PERIPHERAL PP
Mediated by hypothalamus or pituitary gland Mediated by peripheral glands (Gonads/ adrenal glands)
ALWAYS isosexual (In congruence with sex of the child) Can be isosexual OR heterosexual
Extension of normal physiology Disruption of normal physiology
Natural order of pubertal events is followed Disordered sequence of pubertal events
GIRLS BOYS
Isosexual Heterosexual Isosexual Heterosexual
• Thelarche
• Pubarche
• Menarche
• Estrogenism of vaginal
mucosa
• Pubic hair
• Clitoromegaly
• Acne
• Male contour body
development
• Testicular enlargement
• Deepening of voice
• Moustache
• Increase in muscle bulk
• Gynaecomastia
17. INCOMPETE PRECOCIOUS PUBERTY
ISOLATED THELARCHE
Breast development with no progression
of puberty
2 peaks (1-3 years & 6-8 years)
Characteristics
• Low LH (< 0.2 mU/L)
• High FSH
• Microcystic ovaries on USG
• Red, glistening vaginal mucosa
• Low estradiol
• Normal bone age
Management
• No treatment required
• Regresses within 4-5 years
ISOLATED PUBARCHE
Only pubic hair development without
thelarche/ menarche
Usually after the age of 6 years
Common in SGA children with rapid
catch-up and IR with metabolic
syndrome
Virilizing disorders to be considered in
pubarche < 6 years
Characteristics
• High DHEAS with normal LH, FSH &
Estradiol
Management
• No treatment required
• Regresses within 4-5 years
ISOLATED MENARCHE
Only vaginal bleeding without
thelarche/ pubarche
Usually between the age of 4 to 8
years
Local causes
(tumor/trauma/infection/ abuse)
and bleeding diathesis to be ruled
out first
Characteristics
• Low LH, FSH & Estradiol
Management
• No treatment required
• Gynecology opinion
ISOLATED THELARCHE ISOLATED PUBARCHE ISOLATED MENARCHE
RED FLAG
SIGNS
• BA advanced > 2 years
• Accelerated growth
• Associated with pubic/axillary hair
• BA advanced > 2 years
• Accelerated growth
• Signs of virilization
• Marked elevation of DHEAS or
17OHP
• BA advanced > 2 years
• Accelerated growth
18. CENTRAL PRECOCIOUS PUBERTY
1. IDIOPATHIC
• More than 90% cases in girls with PP after the age of 6 years
• In boys, cause of CPP is usually organic. Hence, this is only a diagnosis of exclusion
[Supportive features: older age group, low basal and GnRH stimulated LH levels]
• No need for neuroimaging in girls with PP after 6 years of age
• No need for GnRH analogs
• However, there is a need to follow up 3-6 monthly
2. RADIATION
• Can cause both precocious as well as delayed puberty
• May have associated GH deficiency
• Treatment- GnRH analogs
LOW DOSE HIGH DOSE
18-24 Gy (e.g. ALL) > 50 Gy
Precocious puberty Delayed puberty
Impaired inhibitory pathway Pituitary damage
19. CENTRAL PRECOCIOUS PUBERTY
3. HYPOTHALAMIC HAMARTOMA
• Developmental malformation with disordered neuronal migration
• Abnormally located congenital tumor in tuber cinereum
• Composed of GnRH secreting neurons with glial cells and fibre bundles
• Independent of CNS inhibitory neurons
• Hence, not under the effect of hypothalamic pulse generator
IMAGING
• Sessile/ pedunculated mass attached to posterior hypothalamus between tuber cinereum and
mamillary body
POINTERS
• Generally before 4 years of age
• Rapid pubertal onset
• High LH & FSH levels
• Associated neurological features [ Neurosurgery, Gelastic epilepsy, developmental delay]
MANAGEMENT
• GnRH analog
• Surgery not required
20. CENTRAL PRECOCIOUS PUBERTY
4. BRAIN TUMORS
• Gliomas, Germinomas, Craniopharyngiomas
• NF1 with optic gliomas
5. CNS INSULT
• Trauma, infection, hydrocephalus, malformation
• Disruption of inhibitory signals
Management : GnRH analog to increase the final height (May be undesirable for caretakers)
Medroxyprogesterone acetate preferred (Controls puberty with no increase in height)
21. PERIPHERAL PRECOCIOUS PUBERTY [GIRLS]
1. FUNCTIONAL OVARIAN CYSTS
• Follicular ovarian cyst with estradiol production
MANIFESTATIONS:
• Some breast enlargement
• Disproportionate uterine development
• NO PUBARCHE
• Excessive estradiol – endometrial hyperplasia with withdrawal bleeding
• Fluctuant clinical course with resolution of pubertal changes without interventions on follow up
DIAGNOSIS
• USG – cystic enlarged masses seen in unilateral or bilateral ovaries
• Red flag signs – Solitary cyst ( R/O Hypothyroidism or MAS)
• AMH & Inhibin levels ( for granulosa cell tumors)
MANAGEMENT
• No treatment required ( self-limiting)
• If cyst > 5 cm (risk of ovarian torsion) or features of malignancy (solid areas, heterogenous, cysts
within cysts) – Surgery may be required
A. OVARIAN CAUSES
22. PERIPHERAL PRECOCIOUS PUBERTY [GIRLS]
2. PRIMARY HYPOTHYROIDISM
• VanWyk Grumbach syndrome
• TSH & FSH share same alpha subunit
• Hence, excess TSH acts on FSHr stimulating FSH action ( specificity spillover)
MANIFESTATIONS:
• Large ovarian cysts
• Thelarche, menarche, no pubarche
• Short stature and delayed bone age [ONLY cause of PP with delayed bone age]
DIAGNOSIS
• TFTs suggesting primary hypothyroidism
• USG – Solitary enlarged cyst
MANAGEMENT
• Levothyroxine – Regression of pubertal features & ovarian cyst
• Progesterone – in case of prolonged menorrhagia
A. OVARIAN CAUSES
23. PERIPHERAL PRECOCIOUS PUBERTY [GIRLS]
B. ADRENAL TUMOR
• Rare cause
• Tumor expresses aromatase, hence ↑ estrogen
Presentation:
• Peripheral precocious puberty with suppressed gonadotropin levels
Management:
• Surgical removal
C. EXOGENOUS ESTROGEN
• Topical or oral estrogen consumption
• Presents with rapid thelarche with risk of early withdrawal bleeding
• LH & FSH levels undetectable
Management : Discontinuation of the offending agent
24. PERIPHERAL PRECOCIOUS PUBERTY [BOYS]
1. CONGENITAL ADRENAL HYPERPLASIA (CAH)
• 21OHD & 11OHD are the most common causes
MANIFESTATIONS:
• Gradual onset
• Hyperpigmentation
• Pre-pubertal testicular volume
• Hypertension ( in 11OHD)
• Longstanding untreated CAH- triggers Central PP
• Uncontrolled 21OHD → ACTH driven increased size of adrenal rests → testicular adrenal rest tumors (TARTs)
→ Palpable as irregular masses
DIAGNOSIS
• Raised 17OHP (in 21OHD) & raised DOC levels (in 11OHD)
• Raised DHEAS but pre-pubertal gonadotropin levels
• USG scrotum in cases of suspected TARTs
MANAGEMENT
• Hydrocortisone – Suppresses puberty ( risk of triggering secondary CPP)
A. ADRENAL ANDROGEN PRODUCTION
50% cases of PP in boys
25. PERIPHERAL PRECOCIOUS PUBERTY [BOYS]
2. ADRENAL TUMORS
• Androgen producing tumors
• May also have increased cortisol production (Cushing syndrome)
MANIFESTATIONS:
• Aggressive, rapidly progressive
• Hyperpigmentation
• Pre-pubertal testicular volume
DIAGNOSIS
• Raised DHEAS, Testosterone
• CT Adrenals (USG adrenals may miss small tumors)
MANAGEMENT
• Surgical removal with chemotherapy (adrenolytic/static drugs)
A. ADRENAL ANDROGEN PRODUCTION
26. I. APPARENT LH EXCESS
• ↑ LH action → Leydig cell hyperplasia → Increased testosterone production
• Moderate testicular enlargement [ Leydig cells form only 20% of testicular volume]
B. TESTICULAR ANDROGEN PRODUCTION
1. hCG secreting tumors
• hCG and LH have same alpha subunit
• Hence, hCG stimulated LHCG receptors and cause LH excess
• Tumor develops from abnormally located germ cells in abdomen, mediastinum or CNS
• Choriocarcinoma, germinoma, hepatoblastoma, teratoma
MANIFESTATIONS:
• Moderate testicular enlargement (non-commensurate with pubertal development)
• Peripheral precocious puberty
DIAGNOSIS
• ↑ hCG, alpha-fetoprotein
• ↑ basal LH but poor GnRH response
• CT Chest, abdomen and head
MANAGEMENT
• Radiotherapy
27. I. APPARENT LH EXCESS
B. TESTICULAR ANDROGEN PRODUCTION
2. Testotoxicosis
• Familial male-limited precocious puberty [FMPP]
• Sex limited, autosomal dominant d/o affecting only boys
• Age of onset – 2-4 years
• Family history of affected males
• Genetics : Missense mutation (exon 11) of the transmembrane domain of LHr with single gene base change
• Gonadal steroidogenesis & spermatogenesis despite low LH,FSH levels
MANIFESTATIONS:
• Moderate testicular enlargement (non-commensurate with pubertal development)
• Peripheral precocious puberty
• If untreated, may progress to CPP
DIAGNOSIS
• Poor LH response to GnRH-ST
• Genetic analysis
MANAGEMENT
• Anti-androgens (Bicalutamide)
• Aromatase inhibitors (Letrozole/ anastrazole)
28. II. TESTICULAR TUMOR
B. TESTICULAR ANDROGEN PRODUCTION
• Composed of germ cells, Sertoli cells and Leydig cells
• Germ cell & Leydig cell tumors – androgen excess
• Sertoli cell tumors – estrogen excess ( gynaecomastia)
MANIFESTATIONS:
• Unilateral testicular enlargement (non-commensurate with pubertal development)
• Peripheral precocious puberty
DIAGNOSIS
• Undetectable LH, FSH
• CT scan
MANAGEMENT
• Surgery, chemotherapy and radiotherapy
29. McCUNE-ALBRIGHT SYNDROME
• Somatic activating mutation of GNAS1
• 2 of the triad : PPP, polyostotic fibrous dysplasia & Café au lait spots ( irregular borders) in one half of the
body
• Other endocrine manifestations – Hyperparathyroidism, hypophosphatemic rickets, pituitary adenomas &
thyrotoxicosis
MANIFESTATIONS:
• Peripheral precocious puberty (Both sexes)
• Girls- Recurrent ovarian cysts
• Intermediate testicular enlargement
DIAGNOSIS
• Clinical criteria with raised hormonal levels
MANAGEMENT
• Complicated treatment
• MPA (10 mg HS), ketoconazole (10-20 mkd Q6H), Spironolactone (2-4 mkd)
• Aromatase inhibitor (letrozole/ anastrazole 1-2 mg/day)
• SERM (Tamoxifen 10-20 mg/day)
• GnRH analog may be required if CPP develops
31. A. IS IT PRECOCITY?
GIRLS BOYS
CLINICAL
• Breast development (B2 or more)
(Exclude lipomastia in obese girls)
• Pink & pale vaginal mucosa
• Advanced growth and bone age
• Pubertal testicular volume (>3 ml)
• Streched penile length > 2.5 cm
( Not reliable & convenient)
• Advanced growth and bone age
HORMONAL
• Estradiol > 10 pg/ml
( Assays not sensitive enough for such low
levels)
• Testosterone levels ( > 20 ng/dl)
PELVIC
IMAGING
UTERUS
• Tubular to pear shaped
• Corpocervical ratio > 1
• Endometrial thickness > 3 mm
• Uterine length > 4 cm
OVARIES
• Volume > 2 cm3
• Cysts > 6 with atleast 1 cyst > 4 mm
32. HISTORY
HISTORY INTERPRETATION
Age at presentation • < 6 years – organic pathology
Gender • Girls (> 6 years) – idiopathic ; Boys – organic pathology
Progression Minimal – Slowly progressive variant
Gradual – Idiopathic PP
Rapid progression - tumor / other underlying disorder
Growth acceleration – sex hormone excess
CNS history Symptoms of Raised ICP
Seizures ( Gelastic epilepsy- Hypothalamic hamartoma ; NF1)
Head trauma, developmental delay
Hypothyroidism Weight gain, constipation, poor school performance & goiter
Macro-orchidism in boys
Drug usage Topical androgen usage, estrogen usage
Past history CNS infection, trauma, radiotherapy, hydrocephalus, developmental delay
Family history • Family history of early puberty – Idiopathic PP
• Similar disease (males) – FMPP
• Any liver disease – Hepatoma, hepatoblastoma
• Similar disease – CAH
Risk factors • SGA, Adopted children – risk for early puberty
34. BONE AGE
• Most valuable tool for assessment of precocious puberty
• TW3 method preferred as it is reproducible & based on Asian population
• Reflection of a growth potential of the child
• In PP, it reflects the tempo of pubertal progression
DIAGNOSIS
• Advanced > 2 years – True precocious puberty
• Advanced 1-2 SD – Incomplete PP
• Delayed bone age - hypothyroidism
PROGRESSION
• Rapid progression of puberty
• Height for bone age < -2SD
• ∆ BA/ ∆ CA > 1.2
RESPONSE TO THERAPY
• Rate of increment of BA < progression of chronological age
Stoppage of therapy
12-12.5 years of bone age
35. COMPLETE vs INCOMPLETE PUBERTY
ISOLATED THELARCHE ISOLATED PUBARCHE ISOLATED MENARCHE
Mimics • True precocious puberty • CAH
• Adrenal tumor
• True precocious puberty
• Virilizing ovarian tumors
• Exogenous estrogen administration
• Vulvovaginitis
• Foreign body
• Sexual abuse
• Coagulation abnormality
EVALUATION • LH, FSH • DHEAS, 17OHP, USG abdomen • Local examination
Feature Isolated
thelarche
Atypical
precocity
Growth Normal Accelerated
Course Non-progressive Progressive
Gonadotropin High FSH,
Normal LH
High LH & FSH
Bone age Normal Advanced
USG Pre-pubertal Pubertal
ISOLATED PUBARCHE
DHEAS TESTOSTERONE DIAGNOSIS
Mild elevation Low Premature
pubarche
Elevated Mild elevation CAH
Very high Elevated Adrenal tumor
Normal High Ovarian tumor
36. CENTRAL vs PERIPHERAL PRECOCIOUS PUBERTY
CLINICAL ASSESSMENT
GIRLS
• Rapid progression with menarche within 1 year of thelarche – hyperestrogenic state (PPP)
• Orderly development of thelarche, pubarche & menarche – CPP
• Early pubarche without thelarche – premature pubarche or adrenal disorders (PPP)
• Thelarche without pubarche – Premature thelarche or hyperestrogenic state (PPP)
BOYS
• Pre-pubertal testis with features of precocity – Peripheral PP
• Pubertal testis corresponding to extent of precocity – CPP
• Pubertal testis but not corresponding to penile length – PPP ( hCG tumor/ testotoxicosis)
• Unilateral testicular tumor – androgen producing testicular tumor
LABORATORY ASSESSMENT
PARAMETER PRE-PUBERTAL PUBERTAL
Basal LH < 0.1 mU/L > 0.3 mU/L
GnRH-ST LH < 5 mU/L > 5 mU/L
GnRH-ST LH:FSH < 0.66 > 0.66
GnRH stimulation test
Preparation Dose Max. dose Route Sampling
Gonadorelin 1-2
mcg/kg
100 mcg IV 0,30,60
min
Lupride 10-20
mcg/kg
1 mg SC 0,2 hours
Triptorelin 100 mcg 100 mcg SC 0, 2 hours
37. CENTRAL vs PERIPHERAL PRECOCIOUS PUBERTY
LABORATORY ASSESSMENT
LABORATORY ASSESSMENT
PARAMETER PRE-PUBERTAL PUBERTAL
Basal LH < 0.1 mU/L > 0.3 mU/L
GnRH-ST LH < 5 mU/L > 5 mU/L
GnRH-ST LH:FSH < 0.66 > 0.66
GnRH stimulation test
Preparation Dose Max. dose Route Sampling
Gonadorelin 1-2
mcg/kg
100 mcg IV 0,30,60
min
Lupride 10-20
mcg/kg
1 mg SC 0,2 hours
Triptorelin 100 mcg 100 mcg SC 0, 2 hours
38. CAUSE OF PRECOCIOUS PUBERTY
MRI BRAIN
Indications
In a case of central precocious puberty with
• All boys with CPP
• All girls with CPP below 6 years of age
• Girls with CPP 6-8 years with rapid progression or associated with neurological or visual deficit
EVALUATION FOR SPECIFIC CAUSES
• Testicular tumors – AFP, hCG, LDH & USG scrotum
• MAS- Bone scan, TFT, S/E
• Testotoxicosis – genetic studies
• Girls with PPP – AMH, Inhibin, hCG & AFP
• Girls with ovarian cysts – USG
• CAH- 17OHP
• Adrenal tumor- DHEAS, Testosterone, adrenal imaging
41. 2 year old girl with thelarche
Differentials?
Isolated thelarche
Precocious puberty
PLAN?
Growth, Bone age
Gonadotropin levels
USG abdomen
FINDINGS
Normal height
SMR – A1P1B2B2M0
LH 0.1 mU/L , FSH 3.2 mIU/L
Estradiol < 10 pmol/L
DIAGNOSIS
Isolated thelarche
5 year old girl with vaginal bleeding & no thelarche
Differentials?
Local causes
PLAN?
Vaginal mucosal examination
Gynaecological examination
Coagulation work up
FINDINGS
Red glistening vaginal mucosa
SMR – A1P1B1B1M1
LH < 0.01 mU/L , FSH 3.2 mIU/L
Estradiol undetectable
Coagulation work up normal
DIAGNOSIS
Local causes
42. 7 year old girl with pubarche without thelarche
Differentials?
premature adrenarche
Adrenal androgen excess (CAH/ adrenal
tumor)
PLAN?
Growth, Bone age
Signs of virilization
DHEAS, LH, FSH, estradiol
FINDINGS
Normal height, bone age 7.5 years
SMR – A1P2B1B1M0 , no virilization
LH 0.01 mU/L , FSH 2.4 mIU/L
Estradiol < 10 pmol/L
DHEAS 400 nmol/L (mild elevation)
DIAGNOSIS
Premature adrenarche
7 year with thelarche & growth failure
Differentials?
Isolated thelarche
Hypothyroidism (VanWyk Grumbach
syndrome)
PLAN?
Gonadotropin levels
Bone age
USG abdomen
fT4, TSH
FINDINGS
Bone age 5.2 years
LH < 0.01 mU/L , FSH 0.8 mIU/L
Estradiol 100 pmol/L
USG – large ovarian cyst
TSH > 100 mIU/L
DIAGNOSIS
Hypothyroidism
43. 4 year old boy with enlarged penis and testis
Differentials?
precocious puberty
PLAN?
Growth, Bone age
SMR
Gonadotropin levels
MRI brain
FINDINGS
bone age 6.5 years
SMR – A1P1T4T4
LH 2.2 mU/L , FSH 4.6 mIU/L
Central or peripheral PP?
DIAGNOSIS
Central precocious puberty
MRI Brain – hypothalamic hamartoma
5 year old boy with penile enlargement (9 cm) &
small testis (1 ml)
Differentials?
Peripheral precocious puberty
TESTICULAR OR ADRENAL SOURCE ?
ADRENAL SOURCE
Differentials?
WORK UP
Adrenal imaging (CT scan)
17OHP (SOS DOC)
BP monitoring
Findings
High 17OHP (120 ng/ml)
Adrenal hyperplasia on CT
DIAGNOSIS
Hypothyroidism
Adrenal tumor
CAH
45. CENTRAL PRECOCIOUS PUBERTY
LONG ACTING GnRH ANALOG
• Used to arrest the progression of puberty and for auxological benefits
• Modification of natural GnRH molecule with AA substitution
• GnRH analog 15-200 times more potent than natural GnRH analog
• Prolonged receptor occupancy & action, with no toxicity
Mechanism of action:
• Long acting analogs mimic continuous GnRH supply
• Desensitize pituitary gonadotropin secretion
• Reverse pubertal changes
• Causes initial flare up with occasional withdrawal bleeding
• Temporary and not a cause for concern
• Poor compliance may therefore cause frequent flare ups and nullify the
desensitizing effects of long acting GnRH analog.
46. LONG ACTING GnRH ANALOG…
INDICATIONS:
• Main considerations : growth and psychosocial maturity.
• For maximum auxological outcome,
CPP in girls < 6 years of age
CPP in girls 6-8 years of age with advanced bone age (> 2 years) or compromised final adult height
CPP in boys
Girls with developmental delays or who are not mature enough to cope with pubertal development
47. LONG ACTING GnRH ANALOG…
PREPERATIONS:
DRUG DOSE FREQUENCY REMARKS
Leuprolide acetate
(D-leu)
3.75 , 7.5 mg
11.25 & 22.5 mg
4 weekly
3 monthly
• Most commonly used GnRH analog
• No difference between monthly vs 3 monthly
injections and no added benefit of increasing
dose
• If inadequate response, increase the frequency
Triptorelin
(D-Trp)
3.75 mg
11.25 mg [60 mcg/kg]
4 weekly
3 monthly
• IM injection
• More potent
• No need to increase dose with increase in
weight
Goserelin
3.6 mg
10.8 mg
4 weekly
3 monthly
• SC injection
Buserelin
(D-SertBu)
6.3 mg 2 monthly
Histrelin
(D-His)
Implant Annually • Not available in India (Available in USA)
• Implanted in arm region
48. EVIDENCE BASED PRACTICE GUIDELINES
• Histrelin implant provides most effective response with decreased number and cost of procedures
• Monthly depot leuprolide doses
USA – 7.5 mg to 15 mg
Europe and Asia – 3.75 mg IM every 28 days
Weight based dosing no longer recommended for Leuprolide depot preparations [ Tanaka et al. JCEM 2005]
• Expected duration of dose response based on various prospective extension studies
Histrelin – within days
Depot higher doses- within weeks
Depot lower dose range – within 3 months
• Unstimulated LH levels above pre-pubertal levels do not indicate inadequate suppression
• Monthly vs 3-monthly Leuprolide depot – No differences in clinical responses
49. LONG ACTING GnRH ANALOG…
MONITORING :
CLINICAL BIOCHEMICAL RADIOLOGICAL
Height, Height SD,
Growth velocity,
Tanner stage
LH,FSH, Estradiol/Testosterone 2
hours post-injection
Bone age (annually)
USG pelvis ( 6 monthly)
PARAMETER ADEQUATE INADEQUATE
Growth velocity 4-6 cm > 6 cm
Breast stage Stable Increase
Pubic hair stage Increase Increase
Bone age Stable Advancement
Post GnRHa LH < 4 mU/L > 4 mU/L
Action Same dose Increase frequency
GUIDE FOR
TREATMENT?
CLINICAL
MONITORING OVER
BIOCHEMICAL
SUPPRESSION
50. LONG ACTING GnRH ANALOG…
DISCONTINUATION OF TREATMENT :
• No single clinical variable to determine the best age for discontinuation.
• No significant auxological benefit beyond BA 12.5 years (girls) & 14 years (boys)
• It may be continued to halt pubertal progression and in girls with severely compromised height.
• Menarche is usually attained within 12-18 months of discontinuation of treatment
GnRH ADVERSE EFFECTS:
• Remarkable safety profile
• May increase adiposity ; Hence, need for lifestyle measures
• Injection site reactions
• Long term studies do not suggest any adverse outcomes post GnRH therapy on
- future fertility
- PCOS
- Child psychological adjustment & anxiety, depression, ADHD or academic performance
- Bone mineral density
51. SCOPE FOR FUTURE RESEARCH IN CPP
• Prospective studies to verify dosing, monitoring and long term outcomes
• Kisspeptin & Neurokinin B antagonists
• Outcome studies on SC vs IM administrations