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

3. 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

5. 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

6. 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

7. 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

8. Gonadotropin Secretion

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

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

11. 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

12. 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

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

14. 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)

15. 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)

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

17. 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

18. Problems with The Definition of Puberty (cont)
In boys
First sign of puberty is not noticed
Need to compare testicular volume with orchidometer

19. Tanner I
Tanner II
Tanner III
Tanner IV
Tanner V

22. Orchidometer

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

25. 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

26. MENARCHE
* J. Pediatrics 2005; 147:

27. 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 was evaluated

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

29. 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

30. 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

31. Results (cont.) The mean age for onset of pubic hair development was
8.78 years for AAF and years for CF
The mean age for menses was
12.16 years for AAF and years for CF
The mean age of onset of breast development was age
8.87 years for AAF and 9.96 years for CF

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

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

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

35. Conclusions
Lead to new guidelines that changed the definition of precocious puberty
Breast development and pubic hair are occurring significantly earlier than suggested

36. 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

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

38. 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

40. 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

41. 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.

42. 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

43. 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

44. 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

45. 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

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

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

51. 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

52. 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

53. 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

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

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

56. 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

57. Variations of Pubertal Puberty
Premature Adrenarche
Premature Thelarche
Premature menarche

58. 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

59. 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

60. 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

61. 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

62. 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

63. 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

64. Premature Thelarche (cont.)
Second period
After 6 years of age
May be symmetric or asymmetric
Maybe a consequence of temporarily increased ovarian steroid secretion

65. 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

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

67. 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

68. 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

69. Physical examination
Findings on exam can further direct your evaluation
effects of androgens (acne, hirsuitism, increased muscle mass and clitromegaly)

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

71. Treatment Options

72. 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

73. 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

74. 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

75. 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

76. 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

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

78. 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

79. 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

80. 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

82. 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

83. Side Effects of Histrelin Acetete
At the insertion site
Bruising
Pain
Swelling
Erythema
Soreness
 in clinical signs of puberty during the first month

84. Contraindications of Histrelin Acetate
Not recommended
for usage < age 2
Women who are pregnant or who become pregnant

85. Discontinuation of Therapy
Age to discontinue therapy must be individualized
Resumption of the hypothalamic-pituitary-gonadal axis begins promptly
Menses resumes within months, up to 4.5 yr
Spermatogenesis resumes
Documented pregnancy
Little or no growth spurt
Hyperandrogenism

86. 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

87. QUESTIONS