Precocious Puberty Insights in Precocious Puberty Insights in ManagementManagement

Katrina L. Parker, MD

Pediatric Endocrinology

Morehouse School of Medicine

Precocious PubertyPrecocious Puberty

At the end of the presentation participants:Will be able to define pubertyWill be able to define precocious puberty

and its causesBe able to describe types of treatment for

precocious pubertyDescribe problems associated with

precocious puberty

Landmark Case of Precocious Landmark Case of Precocious PubertyPuberty

5 year old Lina Medina of Peru– Menses onset age 8 months– Breast development age 4– Advanced bone maturation age 5 – Was evaluated for abdominal tumor due to

increasing abdominal size at age 5– On 5/14/1939 gave birth to a 2.9 kg baby boy

PubertyPuberty

The process of physical maturation manifested by an increase in growth rate and the appearance of secondary sexual characteristics

Results in the individual having the capacity to reproduce

Changes are a result of ↑gonadotropin & sex steroid secretion

Mechanism of Puberty Mechanism of Puberty

GnRH stimulates pituitary gonadotropins (LH & FSH)

During childhood pubertal Gn secretion is initially low due to downregulation

Negative feedback of hypothalamic-pituitary-gonadal axis

As puberty progresses, episodic release of LH– Increased amplitude & frequency– Progressive secretion extends over the 24 hr period

Mechanism of why puberty occurs is unknown

Gonadotropin SecretionGonadotropin Secretion

LH / FSH

Testosterone

Sexual development & maintenance

Overview: Sex Hormones

LH / FSH

Estradiol

Sexual development & maintenance

Overview: Sex Hormones

Pubertal DevelopmentPubertal Development

Puberty is divided into five Tanner Stages – Each stage represents

the extent of testicular enlargement and pubic hair growth in males

The appearance of thelarche and pubic hair growth in girls

Normal PubertyNormal Puberty

Traditionally had been defined as the appearance of any secondary sexual maturation after the age of 8 in girls and 9 years in boys

Progression of PubertyProgression of Puberty

May progress very slowly In short burst with no visible change in

overall The earlier the onset, the slower the tempo

Normal pubertyNormal puberty

In males – First sign of puberty is enlargement of testicular

volume– Followed by the appearance of pubic hair and

accumulation of lean body mass– Growth spurt is noted toward the end of their

sexual maturation (late TS III or early TS IV)

PUBERTY

AVERAGE AGE of ONSET:

1. GIRLS 10 to 11 years (range 8 to 13

years)

2. BOYS 11 to 12 years (range 9 to 14

years)

PUBERTYINITIAL SIGNS OF PUBERTY:

1. GIRLS – Breast Development

2. BOYS – Testicular Enlargement

Volume > 3.0 cm³ Length > 2.5 cm

Problems with The Definition of Problems with The Definition of PubertyPuberty

In girls– Breast development maybe difficult to assess

using visual inspection– Discerning breast from fat tissue is a key

concern in overweight girls– Key- palpate under the aerolar

Problems with The Definition of Problems with The Definition of Puberty (cont)Puberty (cont)

In boys– First sign of puberty is not noticed– Need to compare testicular volume with

orchidometer

Tanner I

Tanner II

Tanner III

Tanner IV

Tanner V

OrchidometerOrchidometer

Factor That Affect PubertyFactor That Affect Puberty

GeneticsRace/EthnicityPrevious nutritionSubcutaneous fatBirth weight

Factors That Affect PubertyFactors That Affect Puberty

Exposure– PCB in utero

Girls started puberty earlier

– Elevated levels of phthalates Puerto Rico outbreak in the 1980s & 1990s

Obesity– Increased leptin and estrogen production– Insulin stimulation of ovaries & uterus

MENARCHE

12.34

12.53

12.75

1212.112.212.312.412.512.612.712.812.9

13

1963-1970 1988-1994 1999-2002

Age at Menarche

* J. Pediatrics 2005; 147:753-760

Are Children Entering Puberty Are Children Entering Puberty Earlier?Earlier?

Expert panel convened to settle a debate Are data sufficient to establish or suggest a

secular trend in the timing of puberty onset and/or progression?

Data from 1940-1994 was evaluated

Conclusions from data analysis have not been consistent– Limited data comparability among studies– Different populations – Different time periods – Studies used different methods

Pediatric Research In Office Pediatric Research In Office SettingSetting

In 1997, a survey was conducted in 225 clinicians in pediatric practices

Pediatricians rated the amount of sexual maturation on girls undergoing complete physical examinations

ResultsResults

Data was analyzed on 17,077 girls– 9.6% were AAF– 90.4% were CF

Results:– 1% of CF & 3% of AAF are TS II pubic hair by age 3– 6.7% of CF & 27.2% of AAF are TS II by age 7– 14.7% of CF & 48.3% of AAF are TS II by age 8

Results (cont.)Results (cont.)

The mean age for onset of pubic hair development was – 8.78 years for AAF and 10.51 years for CF

The mean age for menses was– 12.16 years for AAF and 12.88 years for CF

The mean age of onset of breast development was age – 8.87 years for AAF and 9.96 years for CF

Copyright ©1997 American Academy of Pediatrics

Herman-Giddens, M. E. et al. Pediatrics 1997;99:505-512

Age of Menarche

Copyright ©1997 American Academy of Pediatrics

Herman-Giddens, M. E. et al. Pediatrics 1997;99:505-512

Prevalence of Breast Development

Copyright ©1997 American Academy of Pediatrics

Herman-Giddens, M. E. et al. Pediatrics 1997;99:505-512

Prevalence of Pubic Hair

ConclusionsConclusions

Lead to new guidelines that changed the definition of precocious puberty

Breast development and pubic hair are occurring significantly earlier than suggested

Lawson Wilkins Pediatric Lawson Wilkins Pediatric Endocrine SocietyEndocrine Society

Recommendations:– Breast development before 7 years in Caucasians and

age 6 in African-Americans is considered precocious– Warrants evaluation

There are no comparable data published in boys No change in the recommended age that boys be

evaluated

LWPES GuidelinesLWPES Guidelines

Use these guidelines ONLY in healthy girls with no signs of neurological or other disease that may pathologically advance puberty.

LWPES RecommendationsLWPES Recommendations

In boys– Fewer data are available on ages and patterns of

pubertal development– ? Lower interest in studying male puberty– ? May reflect less cultural awareness

Precocious PubertyPrecocious PubertyWhen puberty begins early & progresses

earlyOnset is occurring earlierTraditional definition

– Onset < age 8 in girls– Onset < age 9 in boys

Idiopathic type is the most common Height age, weight age and bone age all advanced Early closure of epiphyseal growth plates results in

adult short stature below genetic potential

Precocious PubertyPrecocious Puberty

Gonadotropin-dependent– Involves the premature activation of the hypothalamic-

pituitary-gonadal axis Gonadotropin-independent

– Secretion of sex steroids is independent of pituitary gonadotropin release

The prevalence – is estimated to be between one in 5,000 to 10,000

children annually in the United States.

Precocious PubertyPrecocious Puberty

Isosexual– Appropriate for sex

Contrasexual or heterosexual– Appropriate sex for the opposite sex

This terminology is cumbersomeUse of feminization in males &

masculinization in females should adequately designate these conditions

Differential Diagnosis of GnRH-Differential Diagnosis of GnRH-dependent precocious pubertydependent precocious puberty

Idiopathic Constitutional CNS lesions

– Hypothalamic hamartoma– Malignancies

Astrocytoma Ependymoma Glioma (maybe assoc with NF Type 1) Pineal tumors

Differential Diagnosis (cont) Differential Diagnosis (cont)

Miscellaneous– Significant head trauma– CNS infections (meningitis, encephalitis, abscess)– Empty sella syndrome– Ventricular cysts– Granulomas– Prior CNS irradiation– Congenital hydrocephalus– De Morsier syndrome

Secondary to GnRH-independent precocious puberty

Incomplete GnRH independent Incomplete GnRH independent precocious pubertyprecocious puberty

Males– Gonadotropin secreting tumors– Excessive androgen production– Testicular tumors (choriocarcinoma)– Virilizing congenital adrenal hyperplasia– Premature Leydig and germinal cell maturation– Extragonadal (i.e hepatoblastoma, germ cell tumors)

Activating mutation of LH receptor

Incomplete GnRH independent Incomplete GnRH independent precocious puberty (cont) precocious puberty (cont)

Females– Severe hypothyroidism– Ovarian cysts– Estrogen secreting neoplasm– Exposure to exogenous estrogen

Males and females– McCune Albright Syndrome

Incomplete Sexual PrecocityIncomplete Sexual Precocity

Females– Androgen secreting tumors– Virilizing congenital adrenal hyperplasia

Males– Estrogen secreting tumor

HistoryHistory

Age at onset of signs and symptoms Rate of progression Growth velocity

Family historyHormone exposurePrevious or current CNS abnormalitiesGelastic seizures

Diagnostic EvaluationDiagnostic Evaluation

History & physical exam– Height, weight, arm span, U/L ratio– Skin, hair, thyroid and neurological findings– Breast/pubic hair staging– Inspection of vaginal mucosa– Testicular/phallus size

Hormonal TestingHormonal Testing

Baseline elevation of FSH and FSH response to GnRH provocative testing

LH levels are consistent with early puberty– LH/FSH ratio > 1.0

Estradiol/testosterone levels may rise to the early pubertal range

Testing (cont.)Testing (cont.)

TSH Plasma 17-OH Progesterone, DHEASOther testing:

– Bone age, skeletal survey– Pelvic ultrasound– MRI of the brain

In malesIn males

Same evaluation in females, except also obtain:– Testosterone– Beta hcg– Specialized testing for LH receptor mutation

TherapyTherapy

Treat the underlying causeGnRH analogue

– Lupron depot ped, leuprolide acetate – Histrelin acetete

Monitor therapy– Plasma estradiol/testosterone levels– Growth velocity– Breast/testicular size regression

Variations of Pubertal PubertyVariations of Pubertal Puberty

Premature AdrenarchePremature ThelarchePremature menarche

Premature AdrenarchePremature Adrenarche

Development of pubic hair before age of 7 years in Caucasian girls and age 6 in African American girls

? Early maturation of the adrenal zona reticularis

Higher levels of basal and stimulated DHEA levels when compared to prepubertal children

Premature AdrenarchePremature Adrenarche

Linear growth velocity and skeletal maturation is slightly advanced

Maybe associated acne and axillary odorNo evidence of systemic virilizationExclude adrenal neoplasm and enzymatic

defects

Premature adrenarchePremature adrenarcheHistory

– Racial and ethnic background– History of IUGR, FH of NIDDM, HTN, PCOS higher

risk group20% of patients with precocious puberty present

with premature adrenarcheObtain baseline bone age, androgens (DHEAS,

androstenedione, 17OH-P, free testosterone, fasting lipid panel, SHBG)

Radiographic imaging R/O CNS or adrenal pathology should be reserved in minority of cases

Premature adrenarchePremature adrenarche

Independent of the hypothalamic pituitary gonadal axis

Biochemical evidence is found as early as 6 years in normal children – Increased basal dehydroepiandrosterone sulfate

(DHEAS)– Relative increase in ACTH

Mechanism is not known

AdrenarcheAdrenarche

Adrenal androgens– Begin to rise at about 6-8 years of age– Occurs approximately 2 years prior to an

increase in pubertal gonadotropin pulses and increased pituitary GnRH sensitivity

– Increase in DHEA and DHEAS production continues until age 14-16

Premature ThelarchePremature Thelarche

Has been diagnosed during two age periods– During the first two years of life

caused by the persistent increased infant gonadotropin secretion

Development almost always regress before 24 months of age

Premature Thelarche (cont.)Premature Thelarche (cont.)

Second period– After 6 years of age– May be symmetric or asymmetric

Maybe a consequence of temporarily increased ovarian steroid secretion

Premature ThelarchePremature Thelarche

May be symmetrical or unilateralIs not accompanied by other signs of

pubertyNormal estrogen levels, and heightBone age is normal or slightly advancedRare ovarian cystMay be first sign of precocious puberty

EvaluationEvaluation

Correct diagnosis– Idiopathic or pathologic

History– Any neurological diseases?

Personality changes Headaches or visual symptoms

– Drug exposure

Problems in Girls With Problems in Girls With Precocious PubertyPrecocious Puberty

Are taller than peers initially Compared to their peers:

– Maybe more likely to have psychological problems– Unintended pregnancies– Higher rates of substance abuse

Increased incidence of PCOS ? Increased breast cancer risk Unsure of the long term effects on bone mineral

density

In GnRH dependent precocious puberty – Characterized by an acceleration of growth and

bone maturationEarly growth manifests as tall stature for

age As bones continue to be exposed to sex

steroids, growth plates mature and fuse – Result in overall decreased adult height

Physical examinationPhysical examination

Findings on exam can further direct your evaluation – effects of androgens (acne, hirsuitism,

increased muscle mass and clitromegaly)

Minimum bone age determination– If advanced, pursue further evaluation

GnRH stimulation test

Treatment Options Treatment Options

TreatmentTreatment

GnRH agonist– Desensitizes the pituitary– Blocks LH and FSH secretion– Prevents continued sexual development for the

duration of the treatmentGrowth may almost stop while on therapy± addition of growth hormone remains

controversy

GnRH AgonistGnRH Agonist

Nona- or deca peptides that are structurally similar to endogenous GnRH

Are available as subcutaneous and intranasal preparations– Are given as daily or monthly depot injections– Lupron depot Ped, leuprolide acetate, or

histrelin

Side effects of GnRH AgonistSide effects of GnRH Agonist

Usually mild Therapy has been available for greater than 20

years– Not possible to say there will be no long term

complications in some patients

During therapy– Hot flashes, skin rashes– Pain at the injection site– Sterile abscess at the injection site in 10% of patients

Histrelin Implant Therapy for Histrelin Implant Therapy for Precocious PubertyPrecocious Puberty

11 girls with CPPAge at diagnosis: 6.5 years (range 2-9

years)GnRH Stimulation Test

– Peak LH 23 ± 28 miu/ml– Peak FSH 20 ± 25 miu/ml

All girls underwent implant placement

Histrelin Implant StudyHistrelin Implant Study

Girls were divided into 2 Groups:– Group A: 6 girls were followed for 15 months

after implant insertion– Group B: 5 girls had their implant removed

after 9 months

GnRH Stimulation test were performed– Group A 6, 9, 12 & 15 months– Group B 6 & 9 months

ResultsResults

In all girls – Breast development regressed– Growth velocity decreased– Bone age advancement slowed – Basal Gn and stimulated response and estradiol

levels were suppressed

Copyright ©2005 American Academy of Pediatrics

Hirsch, H. J. et al. Pediatrics 2005;116:e798-e802

Fig 2. Peak LH levels (in response to GnRH-STs) in the individual patients immediately before initiating depot GnRHa (pretreatment), immediately before implant insertion while patients were on depot GnRHa treatment (preinsertion), and 6, 9, 12, and 15

months after histrelin implant insertion

Copyright ©2005 American Academy of Pediatrics

Hirsch, H. J. et al. Pediatrics 2005;116:e798-e802

Fig 1. Mean {+/-} SEM levels of LH and FSH (shown on a logarithmic scale) 0, 20, 40, and 60 minutes after a bolus intravenous injection of GnRH (indicated by arrows)

SupprelinSupprelin®® LA LA

SUPPRELIN® LA – Is 12-month implant for treating central

precocious puberty (CPP) – Was approved by the FDA in May, 2007 – Is inserted on the inner aspect of the upper arm

Copyright ©2005 American Academy of Pediatrics

Hirsch, H. J. et al. Pediatrics 2005;116:e798-e802

Fig 3. Implant site in 1 patient 6 months after implant insertion

Side Effects of Histrelin Acetete Side Effects of Histrelin Acetete

At the insertion site– Bruising– Pain– Swelling– Erythema– Soreness– in clinical signs of puberty during the first

month

Contraindications of Histrelin Contraindications of Histrelin AcetateAcetate

Not recommended – for usage < age 2– Women who are pregnant or who become

pregnant

Discontinuation of TherapyDiscontinuation of Therapy

Age to discontinue therapy must be individualized Resumption of the hypothalamic-pituitary-gonadal

axis begins promptly Menses resumes within 12-18 months, up to 4.5 yr Spermatogenesis resumes Documented pregnancy Little or no growth spurt Hyperandrogenism

SummarySummary

Pubertal development is occurring earlier in children

Precocious puberty occurs more commonly in girls

The exact incidence of precocious puberty in males is unknown

Various treatment modalities are available to arrest pubertal development

QUESTIONSQUESTIONS