1

When puberty is early, what response is worthy?

Mark R. Palmert1

Jennifer Harrington1

Ian Comeau2

1Division of Endocrinology, Hospital for Sick Children2Division of Adolescent Medicine/Gynecology, Montreal Children’s

H it lHospital

Learning ObjectivesAt the end of this session you will be familiar with:

1. The age cut-offs for normal and abnormal pubertal timing

2. A diagnostic approach to the child with precocious puberty

3. Indications for and methods of treatment of precocious pubertyp y

4. The clinical indications of when a child warrants referral to a pediatric endocrinologist for further evaluation

2

Disclosures

We have no conflicts of interest or financialWe have no conflicts of interest or financial disclosures

We will be discussing off-label use of medications

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development She has not had any vaginal bleedingdevelopment. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hair.The MOST LIKELY diagnosis is:

1. Normal pubertal onset given racial background

2. Central precocious puberty

3

What are the age cut offs for normal and abnormal pubertal development?

Age Cut off Precocious Puberty

Delayed Puberty

Girls

Boys

4

Timing of the onset of puberty in U.S. girls

• African American girls in the U.S. have an gearlier age of onset of thelarche compared to girls of Caucasian descent.• Mean age of thelarche:

8.87 ± 1.93 years v.s. 9.96 ± 1.82 yearsHerman-Giddens ME et al. Pediatrics 1997

• In boys, there is only minor variation of timing in onset of puberty by ethnicity

Herman-Giddens ME et al. Pediatrics 2012

Decline in the age of breast development but not menarche

• Copenhagen Puberty studyp g y y2 population cohorts:

• 1991-1993: n = 1100 2006-2008: n = 995

• Mean age of B2

1991-1993: 10.9 yrs 2006-2008: 9.9 yrs

• Mean age of menarche

1991-1993: 13.4 yrs 2006-2008: 13.1 yrs

Aksglaede et al. Pediatrics 2009

5

What might affect the splay of ages within the “normal range”?

Effect of BMI on pubertal onset

• Obesity is associated with a younger age of pubertal onset

In a cohort of 1238 girls

BMI percentile Number of girls Mean age at thelarche(years)

Biro et al. Pediatrics 2013

< 50th 411 9.99 ± 0.07

50th to 84.9th 394 9.23 ± 0.07

85th to 94.9th 205 8.69 ± 0.11

> 95th 227 8.44 ± 0.10

6

What are the age cut offs for normal and abnormal pubertal development?

Age Cut off

Precocious Puberty

Delayed Puberty

Girls

Boys

7

What are the age cut offs for normal and abnormal pubertal development?

Age Cut off

Precocious Puberty

Delayed Puberty

Girls < 8 (7.5) years[evaluate <7 yrs

Case by case 7-8]y ]

Boys

What are the age cut offs for normal and abnormal pubertal development?

Age Cut off

Precocious Puberty

Delayed Puberty

Girls < 8 (7.5) years[evaluate <7 yrs

Case by case 7-8]y ]

Boys < 9 years

8

What are the age cut offs for normal and abnormal pubertal development?

Age Cut off

Precocious Puberty

Delayed Puberty

Girls < 8 (7.5) years[evaluate <7 yrs

Case by case 7-8]

≥ 13 years

y ]

Boys < 9 years

What are the age cut offs for normal and abnormal pubertal development?

Age Cut off

Precocious Puberty

Delayed Puberty

Girls < 8 (7.5) years[evaluate <7 yrs

Case by case 7-8]

≥ 13 years

y ]

Boys < 9 years ≥ 14 years

9

What “Counts?”

GnRH pulses

↑LH and FSH ↑LH ↑FSH

niz

ing

ho

rmo

ne

(LH

)

Breast development, uterine growth

Theca and granulosa cells

↑ Estrogen & ↑Androgen

Leydig cells

Sertoli cells

↑Testosterone

Penile growth

Testicular

↑Seminiferous tubules

Lu

tein

infancy childhood puberty adult

uterine growth, pubic hair

growth,Pubic Hair

growth

fetal

10

What clinical signs are indicative of hypothalamic-pituitary-gonadal activation?

BoysGirls y

Testes volume ≥4ml

( length ≥2.5 cm)

Girls

Breast buds

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development She has not had any vaginal bleedingdevelopment. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hair.The MOST LIKELY diagnosis is:

1. Normal pubertal onset given racial background

2. Central precocious puberty

11

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development She has not had any vaginal bleedingdevelopment. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hair.The MOST LIKELY diagnosis is:

1. Normal pubertal onset given racial background

2. Central precocious puberty

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.What investigation is MOST LIKELY to confirm your diagnosis of central precocious puberty?

1. Bone age2. MRI brain3 Serum estradiol concentration3. Serum estradiol concentration4. Serum luteinizing hormone (LH) concentration5. Serum follicular stimulation hormone (FSH)

concentration

12

General Paradigm

Harrington et al. Arch Dis Child 2014

General Paradigm

Harrington et al. Arch Dis Child 2014

13

Premature Thelarche

De Vries et al. J of Pediatrics 2010

Premature Thelarche

CLINICAL FEATURES

• Typical onset birth 2 yrs

LABORATORY RESULTS

• If no evidence of• Typical onset birth- 2 yrs

• Breast development only

• No height acceleration

• Most will regress

• True puberty at normal age

• If no evidence of progression, investigations may not be indicated

• Bone age ≈ chronological age

• Reproductive function normal Greater than T3 breasts or

significant BA advancement → consider central precocious puberty

14

How can we identify patients with progressive central precocious

puberty?

1 Cli i l id f b t l i

How can we identify patients with progressive central precocious

puberty?

1. Clinical evidence of pubertal progression

2. In older children, basal LH concentrations (using a sensitive assay) ≥ 0.3 IU/L are indicative of central activation and predictindicative of central activation and predict subsequent pubertal progression

15

Utility of serum LH concentrations to identify children with activation of the HPG axis

Serum LH ≥ 0.3 IU/L had - 89% sensitivity

100% ifi it- 100% specificity to identify those children with subsequent pubertal progression

Interpretation of both basal and stimulated LH

Harrington et al. Arch Dis Child 2014

concentrations can be difficult in children <2 yrs

Harrington et al. Arch Dis Child 2014

16

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.What investigation is MOST LIKELY to confirm your diagnosis of central precocious puberty?

1. Bone age2. MRI brain3 Serum estradiol concentration3. Serum estradiol concentration4. Serum luteinizing hormone (LH) concentration5. Serum follicular stimulation hormone (FSH)

concentration

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.What investigation is MOST LIKELY to confirm your diagnosis of central precocious puberty?

1. Bone age2. MRI brain3 Serum estradiol concentration3. Serum estradiol concentration4. Serum luteinizing hormone (LH) concentration5. Serum follicular stimulation hormone (FSH)

concentration

17

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.Serum LH is 1.2 IU/L. Bone age is 11 years. Estimated final height is 148cm (<3rd percentile)Would you next consider organizing:

1. MRI brain

Central precocious puberty

• Can occur secondary to y• CNS lesions: hypothalamic hamartomas or

other tumors, cerebral malformations

• Idiopathic

• Presence of CNS lesions% f• 40-75% of boys

• 10-20% of girls• Uncommon in girls > 6 years of age

Pedicelli et al. JCEM 2014Mogensen et al. Plos One 2012

18

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.Serum LH is 1.2 IU/L. Bone age is 11 years. Estimated final height is 148cm (<3rd percentile)Would you next consider organizing:

1. MRI brainOur recommendations for imaging with

MRI in girls with CPP• All girls with onset of CPP < 6 yearsAll girls with onset of CPP < 6 years• In girls with onset of CPP 6-8 years:

imaging may not be needed in those girls with an increased BMI or positive family history of early puberty

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.Serum LH is 1.2 IU/L. Bone age is 11 years. Estimated final height is 148cm (<3rd percentile)Would you next consider organizing:

1. MRI brain2 Genetic testing2. Genetic testing

19

Genetics and central precocious puberty

• Genetic influences on the timing of puberty• Genetic influences on the timing of puberty• Similar age of menarche mothers & daughters

• Greater concordance between monozygotic than dizygotic twins

• Familial segregation analysis• 27.5% of CPP were familial27.5% of CPP were familial

Autosomal dominant with incomplete penetrance

De Vries et al. JCEM 2004

Abreu et al. NEJM 2013

• MKRN3 is a paternally expressed imprinted gene

• MKRN3 levels decline prior to pubertal onset

• Loss this “pubertal brake” may lead to CPPHagen et al JCEM 2015

20

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.Serum LH is 1.2 IU/L. Bone age is 11 years. Estimated final height is 148cm (<3rd percentile)Would you next consider organizing:

1. MRI brain2 Genetic testing2. Genetic testing

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.Serum LH is 1.2 IU/L. Bone age is 11 years. Estimated final height is 148cm (<3rd percentile)Would you next consider organizing:

1. MRI brain2 Genetic testing2. Genetic testing3. GnRH agonist treatment

21

Goals of treatment of CPP

1. Preservation of adult height2 All i t h i l i t d

• To intervene with treatment there needs to be evidence that these goals can be achieved

• In girls with “early puberty” (onset between 8 and 9

2. Alleviate psychosocial concerns associated with precocious pubertal onset

In girls with early puberty (onset between 8 and 9 years) there is insufficient data to support benefit of treatment

Treatment of central precocious puberty

Harrington J, Palmert MR. Treatment of precocious puberty ©2016 UpToDate®

22

Who to treat with GnRH agonist therapy?

1. Age of onset of central precocious puberty • Onset of CPP < 6 yrs: 9 10cm gain in adult height• Onset of CPP < 6 yrs: 9-10cm gain in adult height

• Onset of CPP 6-8 yrs: 4-7 cm gain in adult height

• Onset of CPP >8 yrs: no benefit to final height

2. Rate of progressionS• Slowly or intermittently progressive precocious puberty does not warrant treatment

3. Estimated final height

How long to treat?

In a study of 63 girls and 16 boys with CPP treated with GnRH agonistg

• Menarche occurred 17.5 ± 11.2 months after the last injection of GnRH agonist

• Girls who menstruated prior to being commenced on GnRHp gagonist treatment had an earlier onset of re-menarche compared to those who had not previously menstruated

• 9 months after last GnRH agonist injection compared to 19 months

Tanaka T et al. JCEM 2005

23

A previously well 6 ½ year old girl of African Canadian background presents with a 9 month history of progressive breast and pubic hair development. She has not had any vaginal bleeding. On examination she is at Tanner stage 3 for breast development and stage 2 for pubic hairpubic hair.Serum LH is 1.2 IU/L. Bone age is 11 years. Estimated final height is 148cm (<3rd percentile)Would you next consider organizing:

1. MRI brain2 Genetic testing2. Genetic testing3. GnRH agonist treatment

General Paradigm

Harrington et al. Arch Dis Child 2014

24

Peripheral Precocious Puberty

Excess Sex Steroid Production (e.g. Estradiol) with suppression of Hypothalamic-Pituitary-Gonadal Axis pp yp y(low LH, FSH)• Gonadal or non-gonadal source of sex steroid• Isosexual or contrasexual (rare)

Much less common than CPP• 32 of 460 PP pts in one series*

Goals of therapy:• Prevent progression• Maintain adult height potential• Monitor for secondary CPP

*Lee et al. J Pediatr Endocrinol Metab 2009

Peripheral Precocious Puberty

Wider differential diagnosis:• Primary Endocrine Causes:y

Adrenal Disorders / Adrenocortical CarcinomaSevere HypothyroidismAromatase Excess Syndrome

• Ovarian Causes:Ovarian Tumours Autonomous Functional Ovarian CystsMcCune Albright SyndromeMcCune Albright Syndrome

• Other Causes:Gonadotropin-Producing TumoursExogenous Sources of Sex Steroids

25

How about a case?14 month old girl presents with a history of vaginal spotting

for 3 days

On examination she has tanner stage 2 breast budsOn examination she has tanner stage 2 breast buds

Estrogenized hymen

Ultrasound demonstrates a unilocular, simple ovarian cyst

Mild enlargement of the uterus (4.2 cm length)

What is the most likely diagnosis?

Autonomous Functional Ovarian Cysts

2-5% of pre-pubertal girls have ovarian cysts• Of these 5% produce estradiol*p• The most common cause of peripheral precocious

puberty in girls

Typical Presentation:• Transient:

Breast Development, Vaginal discharge/bleedingVaginal discharge/bleeding Enlargement of the labia minoraOvarian cyst may be seen on ultrasound

• Bone age not advanced• LH (both stimulated and unstimulated) remains low

*Millar et al. Obstet Gynecol 1993

26

Autonomous Functional Ovarian Cysts

• Diameter > 1 2 cm strong indicator of function• Diameter > 1-2 cm strong indicator of function

• Spontaneous Regression

• Consider Surgery if > 3 cm or adnexal torsion

• If relapses, consider workup for McCune Albright Syndrome or 2º Central PP

Rodrihuez-Macias et al. Arch Dis Child 1999, Sinnecker et al. Eur J Pediatr 1999, De Sousa et al. Hormones 2008

Autonomous Functional Ovarian Cysts

Most cysts spontaneously regress and do not need t t tany treatment

Ongoing monitoring recommended to ensure resolution of signs of peripheral precocity and no recurrence

Recurrent episodes or development of other secondary sexual characteristics may suggest alternative diagnosis

27

How about our case?

14 month girl, vaginal spotting, T2 Breasts, Ovarian cystsPast Medical History significant forPast Medical History significant for

• Hepatic Cholestasis • Failure to Thrive• Vitamin D Deficiency Rickets• Femur Facture• Bilateral Ovarian Cysts, diagnosed at 10 months

On re-examinationM lti l d d fé l it l• Multiple ragged edge café-au-lait macules

Diagnosis?

McCune-Albright Syndrome

Rare disorder - 1/100,000 to 1,000,000

Classic Triad• Precocious Puberty, Café-au-lait Macules,

Polyostotic fibrous dysplasia

28

McCune-Albright Syndrome

Pathophysiology• Post-zygotic activating somatic mutation of the yg g

alpha-subunit of G-protein coupled receptor encoded by GNAS1

• Mosaic distribution, resulting in varying phenotypes

• Due to tissue mosaicism genetic analysis on serum only 50% sensitive

Compared to affected tissue up to 90% sensitiveCompared to affected tissue, up to 90% sensitive• More frequent in girls than boys

McCune-Albright Syndrome

Endocrine Manifestations:

• Gonads – Peripheral Precocious PubertyGonads Peripheral Precocious Puberty

• Thyroid – Hyperfunction (40%)

• Kidney – Renal Phosphate wasting

• Pituitary – Growth Hormone Excess

• Adrenal – Rare, Cushing Syndrome

Most common: Peripheral Precocious Puberty, episodic, with intervening quiescence

29

McCune-Albright Syndrome

Historical Treatment:• MedroxyprogesteroneMedroxyprogesterone

Progesterone effect prevents episodes of ongoing vaginal bleeding

No effect on bone maturation, growth velocity or adult height

• KetoconazoleI t t t id d tiInterrupts steroid productionMay halt vaginal bleedingNo effect on bone maturation, growth velocity or

adult height

McCune-Albright Syndrome

Tamoxifen• Selective estrogen receptor modulatorg

Blocks end-organ estrogen response

• 28 patients for 1 year• Significant decrease in:

Vaginal bleeding episodesGrowth velocityBone maturation

• Progressive increase in uterine volume• No longer term trials

Eugster et al. Journal of Pediatrics 2003

30

McCune-Albright SyndromeLetrozole

• Aromatase InhibitorBlocks conversion of androgens to estrogensBlocks conversion of androgens to estrogens

• 9 girls followed for 3 years• Significant decreases in:

Bone age/Chronological Age ratioGrowth velocity SD scores

• 6 girls had no further vaginal bleeding, with the i d h i f i dremainder having fewer episodes

• Follow-up study of 22 girls treated for a mean of 3.8 years demonstrated further improvement in predicted adult height

Feuillan et al. J Clin Endocrinol Metab June 2007Estrada et al. Endocrine Reviews 2015

McCune-Albright Syndrome

Fulvrestrant• Pure estrogen antagonist also stimulatesPure estrogen antagonist, also stimulates

receptor degradation

• 29 girls followed for 12 months

• Significant:Decrease in days of vaginal bleeding

Decrease in bone age ad ancementDecrease in bone age advancement

• Longer-term follow-up yet to be studied.

Sims et al. International J of Ped Endo 2012

31

Work-up to keep in mind

With evidence of Peripheral PPO i fil T t t E t di l HCG• Ovarian profile: Testosterone, Estradiol, HCG

• Adrenal profile: DHEA-S, 17OH-Progesterone, Androstenedione

• Pelvic Ultrasound

Consider:• Assessment for cortisol excess

• Assessment of thyroid function

General Paradigm

Harrington et al. Arch Dis Child 2014

32

When to consider referring to apediatric endocrinologist?

Harrington et al. Arch Dis Child 2014

When to consider referring to apediatric endocrinologist?

Harrington et al. Arch Dis Child 2014

33

When to consider referring to apediatric endocrinologist?

Harrington et al. Arch Dis Child 2014

When to consider referring to apediatric endocrinologist?

Girls with virilization (progressive)

e.g. CAH, adrenal tumours

Girls with cyclical breast development or vaginal bleeding (suggestive of

McCune Albright Syndrome)

Harrington et al. Arch Dis Child 2014

Girls with ovarian tumours – at risk for secondary CPP

34

Any questions?