Precocious Puberty Insights in Management Katrina L. Parker, MD Pediatric Endocrinology Morehouse School of Medicine

Precocious Puberty At the end of the presentation participants: Will be able to define puberty Will be able to define precocious puberty and its causes Be able to describe types of treatment for precocious puberty Describe problems associated with precocious puberty

Landmark Case of Precocious Puberty 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

Puberty 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 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 Secretion

Overview: Sex Hormones LH / FSH Testosterone Sexual development & maintenance

Overview: Sex Hormones LH / FSH Estradiol Sexual development & maintenance

Pubertal 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 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 Puberty May progress very slowly In short burst with no visible change in overall The earlier the onset, the slower the tempo

Normal 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: GIRLS 10 to 11 years (range 8 to 13 years) BOYS 11 to 12 years (range 9 to 14 years)

PUBERTY INITIAL SIGNS OF PUBERTY: GIRLS – Breast Development BOYS – Testicular Enlargement Volume > 3.0 cm³ Length > 2.5 cm

Problems with The Definition of Puberty 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 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

Orchidometer

Factor That Affect Puberty Genetics Race/Ethnicity Previous nutrition Subcutaneous fat Birth weight

Factors 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 * J. Pediatrics 2005; 147:753-760

Are Children Entering Puberty 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 Setting 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

Results Data was analyzed on 17,077 girls Results: 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.) 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

Herman-Giddens, M. E. et al. Pediatrics 1997;99:505-512 Age of Menarche Herman-Giddens, M. E. et al. Pediatrics 1997;99:505-512 Copyright ©1997 American Academy of Pediatrics

Prevalence of Breast Development Herman-Giddens, M. E. et al. Pediatrics 1997;99:505-512 Copyright ©1997 American Academy of Pediatrics

Prevalence of Pubic Hair Herman-Giddens, M. E. et al. Pediatrics 1997;99:505-512 Copyright ©1997 American Academy of Pediatrics

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

LWPES 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 Puberty When puberty begins early & progresses early Onset is occurring earlier Traditional 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 Puberty Gonadotropin-dependent Gonadotropin-independent 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 Puberty Isosexual Contrasexual or heterosexual Appropriate for sex Contrasexual or heterosexual Appropriate sex for the opposite sex This terminology is cumbersome Use of feminization in males & masculinization in females should adequately designate these conditions

Differential Diagnosis of GnRH-dependent precocious puberty Idiopathic Constitutional CNS lesions Hypothalamic hamartoma Malignancies Astrocytoma Ependymoma Glioma (maybe assoc with NF Type 1) Pineal tumors

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 precocious 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 precocious puberty (cont) Females Severe hypothyroidism Ovarian cysts Estrogen secreting neoplasm Exposure to exogenous estrogen Males and females McCune Albright Syndrome

Incomplete Sexual Precocity Females Androgen secreting tumors Virilizing congenital adrenal hyperplasia Males Estrogen secreting tumor

History Age at onset of signs and symptoms Family history Rate of progression Growth velocity Family history Hormone exposure Previous or current CNS abnormalities Gelastic seizures

Diagnostic 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 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.) TSH Plasma 17-OH Progesterone, DHEAS Other testing: Bone age, skeletal survey Pelvic ultrasound MRI of the brain

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

Therapy Treat the underlying cause GnRH analogue Monitor therapy Lupron depot ped, leuprolide acetate Histrelin acetete Monitor therapy Plasma estradiol/testosterone levels Growth velocity Breast/testicular size regression

Variations of Pubertal Puberty Premature Adrenarche Premature Thelarche Premature menarche

Premature 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 Adrenarche Linear growth velocity and skeletal maturation is slightly advanced Maybe associated acne and axillary odor No evidence of systemic virilization Exclude adrenal neoplasm and enzymatic defects

Premature adrenarche History Racial and ethnic background History of IUGR, FH of NIDDM, HTN, PCOS higher risk group 20% of patients with precocious puberty present with premature adrenarche Obtain 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 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

Adrenarche 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 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.) Second period After 6 years of age May be symmetric or asymmetric Maybe a consequence of temporarily increased ovarian steroid secretion

Premature Thelarche May be symmetrical or unilateral Is not accompanied by other signs of puberty Normal estrogen levels, and height Bone age is normal or slightly advanced Rare ovarian cyst May be first sign of precocious puberty

Evaluation Correct diagnosis History Idiopathic or pathologic Any neurological diseases? Personality changes Headaches or visual symptoms Drug exposure

Problems in Girls With Precocious 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 maturation Early 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 examination Findings on exam can further direct your evaluation effects of androgens (acne, hirsuitism, increased muscle mass and clitromegaly)

Minimum bone age determination GnRH stimulation test If advanced, pursue further evaluation GnRH stimulation test

Treatment Options

Treatment GnRH agonist Growth may almost stop while on therapy Desensitizes the pituitary Blocks LH and FSH secretion Prevents continued sexual development for the duration of the treatment Growth may almost stop while on therapy ± addition of growth hormone remains controversy

GnRH 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 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 Precocious Puberty 11 girls with CPP Age 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 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

Results In all girls Breast development regressed Growth velocity decreased Bone age advancement slowed Basal Gn and stimulated response and estradiol levels were suppressed

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 Hirsch, H. J. et al. Pediatrics 2005;116:e798-e802 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) Hirsch, H. J. et al. Pediatrics 2005;116:e798-e802 Copyright ©2005 American Academy of Pediatrics

Supprelin® 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

Fig 3. Implant site in 1 patient 6 months after implant insertion Hirsch, H. J. et al. Pediatrics 2005;116:e798-e802 Copyright ©2005 American Academy of Pediatrics

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

Discontinuation 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

Summary 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

QUESTIONS