1. Evaluating and Managing Precocious Puberty
and PCOS
Good Morning and thank you to Drs Kelly and Jacobson for inviting me to give this presentation today.
M. Jennifer Abuzzahab,MD
1 June 2012

2. Disclosures I have no relevant financial relationships to disclose.
I will be discussing off label use of medications.

3. Objectives
Recognize the normal timing and cadence of pubertal development
Describe the role of insulin in steroidogenesis
Identify when to refer to a specialist

4. Definitions Adrenarche (Pubarche) Gonadarche (Puberty) PCOS
Pubic or axillary hair
Premature adrenarche (<8yo girls, <9yo boys)
Gonadarche (Puberty)
LH/FSH activation of gonads
Gender specific sex-steroid production
PCOS
Ovarian Hyperandrogenism
Increased testosterone production (females)
Can not occur until after onset of puberty
For PCOS the higher androgens lead to Virilization, Hirsutism, Amenorrhea and often Infertility

5. Precocious Puberty
BMI major consideration in evaluation of puberty prior to age 8
Breast development can be seen in girls as young as 7 depending on ethnicity and BMI
Pubic hair prior to 8y in girls and 10y in boys is premature IF BMI is <85%
Rosenfield RL, Pediatrics 2009 ;123(1):84-88.

6. Steroidogenesis Role of Leptin Role of Insulin
Enhances 17,20 Lyase activity
Increases androstenedione
Increases DHEA-S
Role of Insulin
Increases ACTH-mediated steroidogenesis
Co-gonadotrophic effect on theca cell
Link between premature adrenarche and PCOS
Most obese people have high leptin levels, this then increases androgen production
In addition, insulin resistance, seen in many overweight children and a precursor to DM2 can increase androgen production from both adrenal glands and ovaries

7. Case 7 4/12 yo boy referred for early pubertal development
adult type body odor for two years, pubic hair development for 6-8 months
diet recall shows excessive portions at every meal and breakfast both at home and school
family history for type 2 Diabetes Mellitus in multiple family members
PE remarkable for height above mid parental target, obesity, Tanner 2 pubic hair, scrotal thinning, 2 cc testes, apocrine secretions but no axillary hair
lab tests: Bone age 9 years, adrenal precursors slightly elevated, testosterone & LH/FSH prepubertal
diet and exercise regimen started, attempt to get whole family involved

8. Xenobiotics Endocrine disruptors Mimic natural hormone binding
phthalates
BPA
phyto-estrogens
soy
lavender oil
tea tree oil
Phthalate (ooooh!) exposure in pregnant women may come from a variety of sources, most of which contain fragrances. A coalition of environmental and public health groups compiled a study of commonly used cosmetics and listed which of them had high levels of phthalates, “including nine of 14 deodorants, all 17 fragrances tested, six of seven hair gels, four of seven mousses, 14 of 18 hair sprays, and two of nine hand and body lotions, in concentrations ranging from trace amounts to nearly three percent of the product formulation.”
Phthalates are banned in cosmetics in the European Union, which may be why many of these companies also produce similar products that are phthalate free. Some examples from the full study (pdf) include:
“Unilever make hair sprays with (Salon Selectives and Aqua Net) and without phthalates (Thermasilk and Suave). L’Oreal markets Jet Set nail polish without DBP but puts the phthalate in its Maybelline brand. Procter & Gamble sells Secret Sheer Dry deodorant with phthalates and Secret Platinum Protection Ambition Scent without phthalates. Louis Vuitton has taken phthalates out of its Urban Decay nail polish but still has these dangerous chemicals in Christian Dior nail polish and the fragrance Poison.”
Not only are these ingredients legal to put in cosmetics in the United States, but not one of the products with them has anything in the ingredient list to let a consumer make an educated choice. You have to check a study such as this to know. Most phthlates are grouped in under the listing “fragrance”.

9. Xenobiotics Tea tree oil Linalool phthalates Lavendula acetate
                                                              
Tea tree oil
Linalool
It is easy to see how similar in structure tea tree oil and the two major components of lavender oil are to estrogen itself. Probably OK to use if you are making estrogen on your own…likely TOO much if prepubertal child. & can trigger pubertal changes.
phthalates
Lavendula acetate

10. Xenobiotics Bisphenol A Triclocarban
                                                              
Bisphenol A
TCC is similar in chemical structure to BPA and is (chemically speaking) a polychlorinated diphenyl urea
Triclocarban

11. Xenobiotics BPA Estrogen mimetic Mice fed high BPA become obese
Phthalates
Higher levels found in obese men/women
Linked to insulin resistance
Insecticides/herbicides/antifungals and many antibacterial soaps
Estrogenic
Potentiate steroid effects at receptor level

12. Case Presentation 3-11/12 yo girl with 6 months of breast development
Term infant, 7# 10oz
No known exposures
Rapid height gain over past year, without significant change in weight
PE: Tanner 3 breast, Tanner 1 pubic hair

13. Case Presentation

14. Case Presentation Bone Age advanced at 5y9m Estradiol <15ng/dL
GnRH stimulation testing revealed no rise in LH/FSH or estrogen
pelvic ultrasound revealed prepubertal ovaries, no cysts, uterine enlargement
Endocrine RN noted glitter “all over” patient at time of stim test

15. Case Presentation

16. Xenobiotics Choose plastics 1,2,4 or 5
Use stainless steel or glass bottles
Consider alternatives to canned foods
Fresh
Frozen
Glass
Avoid microwaving in plastic

17. Xenobiotics Avoid phthalates Diethyl phthalates are “scent enhancers”
Vinyl toys
Vinyl shower curtains
Glitter body products
Diethyl phthalates are “scent enhancers”
Certain air-fresheners
Look for fragrance free personal care products, detergents, cleansers

18. Premature Adrenarche Fetal programming
girls with low birth weight (-1.5SD)
predisposed to insulin resistance
rapid pubertal progression
early-normal menarche
The typical growth pattern of IUGR/LBW girls especially those with good catch-up growth is to have an exaggerated adrenarche, develop hyperinsulinemia prepubertally and then have a rapid progression through puberty with early-normal onset of menarche and high-risk of PCOS/syndrome X
Ibanez, L. JCEM 1993;76:1599

19. Premature Adrenarche History and Physical Exam Laboratory Evaluations
Birth history
Tanner staging
Laboratory Evaluations
17-OHP, Androstenedione, DHEA-S, consider Testosterone
LH/FSH
Consider Estradiol
Radiologic Evaluation
Bone Age
1-2 year advance expected

20. Case Presentation
nearly 5 yo girl with BO for 2 years, breasts for 1-2 months
attends preschool, keeps up with her peers.
Mood swings and some flirtatious behavior over the past 6 months.
Term infant 7#,4 oz (AGA), adopted at 11 days of age.
no hormone or body building supplement exposures
Ht cm (+2.2 SD), Wt 25.4 kg (+2 SD), BMI 18.1 (95%), T2 breasts (flat disks of acinar tissue) with T3 contour, T1 pubic hair (fine, dark hairs across mons pubis), prepubertal labia. no axillary hair, very light apocrine secretions.

21. Case Presentation

22. Case Presentation
AGA infant, not at higher risk for precocious puberty, type 2 DM or PCOS.
BA only 1.5 years advanced
Adrenal precursors normal
Breast tissue from peripheral conversion to Estrone
Following clinically as slightly higher risk for true central precocious puberty.

23. Premature Adrenarche Metformin treatment for girls with LBW and PA
Less insulin resistance
Less androgen excess
Less atherogenic lipid profile
Altered body composition
BMI 19.5 vs 20.3
Fat 13.1kg vs 16.1kg
Lean 25.8kg vs 24.8kg
Menarche one year later in treated group
Dr Ibanez has studied growth and early pubertal development in girls with h/o lower birth weight (not always SGA)…find same fetal programming with higher rates of PA. 38 girls studied randomized to metofromin or NO metformin therapy (due to effects of insulin on steroidogenesis)
In the third year of the study, the girls received double the metformin dose 0/19 had menarche yet 5/19 untreated group had menarche
Ibanez, L. JCEM 91: , 2006.

24. Premature Adrenarche
Metformin therapy may be indicated for girls with LBW and premature adrenarche
Prevents earlier steps in the cascade from LBW infant to early puberty and menarche, obese BMI and IR/PCOS
Normalizes pubertal progression and growth in this population
May attenuate the activity of the GnRH pulse generator and enhance gonadal feedback on LH secretion
Insulin has effects far beyond glucose metabolism

25. Insulin Resistance Pseudoacromegaly Blunted pubertal growth spurt
Premature Adrenarche
Pubertal delay in males
PCOS
M De Simone. Int J Obes Relat Metab Disord Dec;19(12):851-7
M Vignolo. Eur J Pediatr Apr; 147(3):242-4.

26. Insulin Resistance
Mantazoros CS, Flier JS, Adv Endo Metab 1995;6:193

27. Case 13-9/12yo girl menarche at age 10
Irregular menses and increased acne for one year
Significant weight gain over past two years
Strong family history for type 2 diabetes
Many female family members with “thyroid condition”
What’s unusual about her history?

28. Case
PE: obesity, acanthosis nigricans, T5 breast, T5 pubic hair in male estucheon, moderate acne face/chest, prominent sideburns
Adrenal precursors normal
freeTestosterone elevated at 7.6
total testosterone 65
Estradiol 72
LH/FSH normal
What’s unusual about her history?

29. Case

30. Polycystic Ovarian Syndrome
Virilization
Hirsutism
Amenorrhea/Oligomenorrhea
Infertility

31. Polycystic Ovarian Syndrome
Adolescent females
Need not have cysts
Need not have LH > FSH
Must be differentiated from Adrenal Disease
Exaggerated Adrenarche is a harbinger of PCOS after menarche

32. Polycystic Ovarian Syndrome
Diet and Activity History
Laboratory Evaluations
Free Testosterone
Sex Hormone Binding Globulin
Adrenal Precursors
Androstenedione
17 OH Progesterone
DHEAS
Two hour post-prandial glucose and insulin

33. Polycystic Ovarian Syndrome
Treatment
Diet and Exercise
Oral Contraceptives
low androgenic progesterone (desogestrel)
low-estrogen pills not sufficient to supress Testosterone production
Spironolactone
Metformin

34. Polycystic Ovarian Syndrome
Oral contraceptives
Chose low bio-available progesterone
Desogen
Ortho-cyclen
Increases estrogen and SHBG
Decreases FSH and LH by negative feedback
Decreases all steroid production by the ovary
Idiosyncratic elevation of cholesterol in 5% of women on OCP
New “low” estrogen products not sufficient for teens or PCOS

35. Ovarian steroidogenesisLH +
Cholesterol +
Pregnenolone
Progesterone + -
17OH-Progesterone
Androstenedione
Thecal Cell
Testosterone
FSH + - -
Estrone
Estradiol
Granulosa Cell
Inhibin
Insulin
IGF-1

36. Ovarian steroidogenesisLH +
Cholesterol +
Pregnenolone
Progesterone + -
17OH-Progesterone
Androstenedione
Thecal Cell
Testosterone
FSH + - -
Estrone
Estradiol
Granulosa Cell
Inhibin
Insulin
IGF-1

37. Ovarian steroidogenesisLH +
Cholesterol +
Pregnenolone
Progesterone + -
17OH-Progesterone
Androstenedione
Thecal Cell
Testosterone
FSH + - -
Estrone
Estradiol
Granulosa Cell
Inhibin
Insulin
IGF-1

38. Polycystic Ovarian Syndrome
Biguanides (Metformin)
Reduces free testosterone levels
Induces normal ovulatory cycles in 91% of women with PCOS
Must consider need for contraception in adolescent population
Gluek, et al. Metabolism, 48(4),

39. Polycystic Ovarian Syndrome
Biguanides (Metformin)
Decreases hepatic glucose output
Increases hepatic and muscle sensitivity to insulin
Start low, 250mg with dinner
slow increase to goal mg
may change to XR
Side effects: anorexia, weight loss, abdominal pain, diarrhea
Risk of lactic acidosis, Vit B12 deficiency
Check renal panel, start MVI

40. Growth Case 14 4/12 yo girl referred for irregular periods
Breast development at 11, menarche at 13
Irregular periods: cycles d, 3-9d menses
rapid weight gain over past year (20#)
skips breakfast, otherwise reasonable diet
Birth history: term infant 5# 8 ounces
FHX: type 2 DM mgm, pgm, HTN pgf
BMI 26.2 (90%), light mustache, mild acanthosis nigricans
Laboratory evaluations
adrenal precursors normal
free testosterone 3.7% ( )
SHBG 0.1 (1 - 3)
fasting insulin 12, glucose 64
cholesterol 160

41. Growth Case

42. Case 15 1/2 yo Hmong girl concerned about excessive acne
skips breakfast, very light lunch, concentrates calories at the end of the day
sedentary lifestyle: “lots of homework”, babysitting
breast development at 10 y, no menarche
BMI 33
Acanthosis Nigricans, acne, skin tags, hirsute, mild clitoromegaly (2.2 cm x 0.8 cm)
testosterone elevated, adrenal normal, glucose 211, insulin 296

43. Case

44. Conclusions Normal timing and cadence of pubertal development
Adrenarche
Puberty
Menarche 2-21/2 years after breast development
Steroidogenesis altered by obesity
Leptin
Insulin
Aromatase in adipocytes
Identify when to refer to a specialist
Puberty before 8yo (girls), 9yo (boys)
BA more than 2 years advanced