Final yr mbbs Class on precocious puberty.pptx

Pp

1. PRECOCIOUS PUBERTY BY DR AJINKYA PATIL FELLOW PEDIATRIC ENDOCRINOLOGY

2. PUBERTAL PHYSIOLOGY SUMMARY

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

7. Gonadotropin effect BOYS GIRLS

8. PUBERTAL ONSET Reduced inhibitory & increased stimulatory signals in presence of permissive leptin effect Initially, nocturnal GnRH pulses f/b more daytime pulses Sex steroid pulses have a lag time of 12 hours (Hence, maximum in morning) Pubertal onset- Testosterone > 20 ng/dl & Estradiol > 10 pmol /L Inhibin levels increase before testosterone (Marker of pubertal onset) Genetic 60% variation in menarche Explains ethnic & gender differences Polygenic inheritance Maternal & Paternal pubertal timing Genes : KISS1, GPR54, MRKN3 4. Environmental 60% variation in menarche Explains ethnic & gender differences Polygenic inheritance Maternal & Paternal pubertal timing Genes : KISS1, GPR54, MRKN3 a. Nutrition BMI Leptin b. Stressors Psychological Physical (athletes) c. Endocrine disrupting chemicals (EDCs) exogenous chemicals 2. Neurochemical Excitatory – Glutamate Inhibitory – GABA, NPY, RFRP-3 3. Skeletal maturation Factors affecting pubertal onset & progression

9. HPG axis summary

10. Pubertal changes (GIRLS) Ovaries 1 st change of puberty Multicystic appearance due to FSH effect Should not be confused with PCOS (peripheral cysts) Breast development (Thelarche) 1 st 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 → 1 st 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

13. PRECOCIOUS PUBERTY

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

16. ETIOLOGY INCOMPLETE PRECOCIOUS PUBERTY COMPLETE CENTRAL PERIPHERAL Isolated thelarche Isolated pubarche Isolated menarche IDIOPATHIC ORGANIC NEUROGENIC - Hypothalamic hamartoma - CNS tumors (Glioma, astrocytoma, ependymoma) - Infections (TBM, meningitis) - Insults (Trauma, surgery, irradiation) - Malformations ( Arachnoid cyst, Hydrocephalus, septo -optic dysplasia, NF1, NTDs) MISCELLANEOUS - IUGR, Russel Silver syndrome - Mutations (KISS1, GPR54, MRKN3) - Endocrine disrupter syndrome GIRLS BOYS HYPOTHYROIDISM OVARIAN SOURCE - Functional ovarian cysts - Tumor (Granulosa cell tumor) ADRENAL SOURCE - Feminizing adrenal neoplasia EXOGENOUS ESTROGEN 5. HETEROSEXUAL PP - CAH - Virilizing adrenal/ ovarian tumor - PCOS ADRENAL SOURCE - CAH - Adrenal tumors TESTICULAR SOURCE - Tumors (Leydig cell tumor, adrenal rest tumor) - Apparent LH excess states ( FMPP/ Testotoxicosis , hCG secreting tumors) EXOGENOUS ANDROGEN HETEROSEXUAL PP - Feminizing adrenal tumors - Exogenous estrogen COMMON TO BOTH SEXES McCune-Albright syndrome

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 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 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) 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) 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

30. ASSESSMENT

31. 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 cm 3 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

33. CLINICAL POINTERS FINDINGS ETIOLOGY Bony deformity (Polyostotic fibrous dysplasia) Café au lait spots (Irregular margins) Heart (arrythmia) MAS Galactorrhoea Pituitary adenoma VanWyk Grumbach syndrome Hepatomegaly Hepatoma Hepatoblastoma Granulosa cell tumor Café au lait spots (regular margins) NF1 Oral melanosis Peutz-Jeghers syndrome Focal neurological deficit, abnormal fundus Neurogenic precocity Central PP Peripheral PP hCG dependent Testicular tumor

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 Isolated thelarche Atypical precocity 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

39. APPROACH

40. CASE SCENARIOS

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

44. MANAGEMENT

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

52. THANK YOU