1. Delayed Puberty – A Disorder in Timing????
Kristy Parker
PGY-2 Pediatrics
December 4th, 2009

2. CanMEDS Objectives Medical Expert
1. Outline the normal physiology, progression, and timing of pubertal development.
2. Delineate causes of delayed puberty in both the male and female.
3. Explain how to differentiate between constitutional delay and other causes of delayed puberty.
Manager
1. Outline appropriate investigations for male and female patients with delayed puberty.

3. Assessment of Puberty History Parents
Important to ask about onset of puberty in parents
Menarche (more reliable in mothers as they remember onset)
Male growth spurt (as most fathers recall their pubertal progression more vaguely)
Age of first shaving regularly
Parental heights (identify midparental height)
“late bloomer” vs. “early bloomer”
Body changes? (important to ask about EACH)
Thelarche (galactorrhea)
Adrenarche/pubarche (body odor, axillary & pubic hair, acne)
Menarche
Gonadarche

4. History cont’d… Important to include:
Past medical history (history of brain tumor, radiation, chemotherapy, known genetic disorder, chronic disease affecting growth)
Eating habits
Any evidence of disordered eating
Activity level
Is exercise excessive or is this an athlete with a high level of training
Growth history
Previous growth chart can be extremely helpful

5. History Review of Systems
CNS: visual changes/visual field abnormalities, headaches, anosmia
Cardiac: congenital anomaly
Respiratory: asthma
Renal:
GI: diarrhea, blood in stools

6. Physical Examination Examination of Growth
Height
Weight
Head circumference
Upper to lower segment ratios
Pubertal Assessment (Tanner staging)
Axillary hair
Pubic hair & staging
Breast development & staging
Genital development & staging
Neurological assessment
CPS position statement on growth measurment

8. Tanner Staging of Puberty in Males
Tanner I 
prepubertal (testicular volume less than 3.5 ml; small penis of 3 cm or less) [typically age 9 and younger]
Tanner II 
testicular volume between 1.6 and 6 ml; skin on scrotum thins, reddens and enlarges; penis length unchanged [9-11]
Tanner III 
testicular volume between 6 and 12 ml; scrotum enlarges further; penis begins to lengthen to about 6 cm [ ]
Tanner IV 
testicular volume between 12 and 20 ml; scrotum enlarges further and darkens; penis increases in length to 10 cm and circumference [ ]
Tanner V 
testicular volume greater than 20 ml; adult scrotum and penis of 15 cm in length [14+]

10. Tanner Pubic Staging Pubic hair (both male and female) Tanner I
no pubic hair at all (prepubertal Dominic state) [typically age 10 and younger]
Tanner II 
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females) [10–11.5]
Tanner III 
hair becomes more coarse and curly, and begins to extend laterally [11.5–13]
Tanner IV 
adult-like hair quality, extending across pubis but sparing medial thighs [13–15]
Tanner V 
hair extends to medial surface of the thighs [15+]

11. Tanner Breast Development
Breasts (female)
Tanner I 
no glandular tissue; areola follows the skin contours of the chest (prepubertal) [typically age 10 and younger]
Tanner II 
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen [ ]
Tanner III 
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with surrounding breast [ ]
Tanner IV 
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast [13-15]
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. [15+]

13. Normal Pubertal Physiology
HPG axis (hypothalamic-pituitary-gonadal) is essential in turning on puberty at appropriate times
Pulsatile secretion of GnRH is essential
GnRH is produced in hypothalamus (in arcuate nucleus)
GnRH travels to the anterior pituitary to stimulate the production of LH & FSH

15. Normal Pubertal Physiology
HPG axis is active in the first few weeks of life
LH & FSH rise as hCG from placenta is gone
This results because the fetoplacental unit acts to produce negative feedback on the HPG axis during late gestation
HPG axis usually quiescent during childhood
Result of negative feedback on the hypothalamus
Axis re-stimulated during adolesence
Stimulation results in a positive feedback loop (estrogen from maturing follicle stimulates LH surge for ovulation)
Pulsatile release of hormone increases overnight first. This eventually progresses to secretion during day and night. LH can be detected in pulsatile forms. FSH has longer half-life, so pulses not as evident
Menarche does not signal full maturation of HPG axis (may simply be withdrawl bleeding from progesterone -> cycle takes longer to become ovulatory

16. Role of Gonadotropins FSH LH
Stimulates androstenedione by the ovary
Involved in spermatogenesis in the testes
Induces receptors for LH LH
Uses androstenedione for substrate to produce estradiol in theca cells
Stimulates testosterone synthesis by Leydig cells
FSH is usually higher than LH in prepubertal stages, and this reverses in pubertal stages

17. Age of Pubertal Progression
Females
Thelarche
Generally considered the onset of puberty
Occurs in most girls at
Menarche
Mean age of onset = 12 yrs
Adrenarche
Usual onset at approx age yrs
Linear Growth
Generally occurs before Tanner Stage 2 breast development
Generally adds 20-25cm of height in females
GH increases during puberty as well (provides 50% of growth spurt)
(NHANES III dates)

18. Are females entering puberty earlier?
Onset of puberty earlier, but completion has not changed
Differences between ethnic groups
? Related to environmental factors or food additives
? Related to better nutritional status, increased body mass/adiposity

19. Pubertal Progression Males Gonadarche Thelarche Pubarche Linear growth
Testicular enlargement generally heralds the onset of puberty (testes > 4ml). This usually starts around yrs.
Initial increases in testicular size are due to increase in Sertoli (supporting cells)
Average time to complete genital development = 3yrs
Thelarche
2/3 of males will have gynecomastia develop during puberty (midpubertal)
Gynecomastia results from direct testicular secretion of estrogen as well as peripheral conversion of prohormones to estrogen
Pubarche
Linear growth
Peak growth generally occurs after Tanner Stage 5
Generally adds 25-30cm in height for males

20. Pubertal Milestones Females Males Tanner stage 2 breasts
Testicular growth
Tanner stage 2 pubic hair
Tanner 2 genital development
Peak linear growth
Greatest weight gain
Tanner stage 3 genital
Tanner stage 3 breast
Tanner stage 3 pubic hair
Axillary hair growth
Acne
Onset of pubertal gynecomastia
Menarche
Axillary hair
Tanner stage 4 breast
Voice pitch changes
Tanner stage 4 pubic hair
Tanner stage 5 breast
Spermarche
Regular menstrual cycles
Tanner stage 4 genital
Tanner stage 5 pubic hair
Tanner stage 5 genital

21. http://psycnet. apa. org/journals/bul/110/1/images/bul_110_1_47_fig2a

22. Role of Bone Age
Comparing radiographs of hand & wrist to reference standards
Female skeletal maturity is generally 2 yrs advanced as compared to males
Pubertal events more correlated with bone age than chronological age

23. Psychological Effects
Puberty occurs during adolescence during time of identity formation
Period of increased physical changes
When teens are behind their peers in terms of development, can lead to substantial teasing/bullying & self-esteem issues

25. Jameson, J.L. Rites of passage through puberty: A complex genetic ensemble. PNAS.
October 30, Vol 104, No. 44.

26. NR0B1 gene is involved in development & function of the adrenal gland & HPG axis for gonadotropin secretion
GPR54 gene mutations affect GnRH release (these patients do respond to exogenous GnRH)
PROP1 mutations lead to problems in differentiation of gonadotropicc, somatotropic, lactotropic & thyrotropic cells.

27. Pubertal Delay
Based on statistical norms (>2 SD from the population mean)
Pubertal delay is most often seen in males
Present far more often than females as delay causes more significant psychosocial implications
Most commonly no pathology present

28. Timing of Puberty Consider pubertal delay if:
No breast development by age 13 in a female
No menses by age 15 in a female
Testicular size < 2.5cm or 4mL or pubic hair is not present by age 14 in a male
Consider precocious puberty if:
Breast development before age 8 or menarche before age 10 in females
Testes volume > 3ml before 9 years.
Pubic hair development before 8 years in females, and 9 years in males

29. Pubertal Delay Pubertal Delay Hypogonadotropic Hypogonadism
Hypergonadotropic
Hypogonadism
Eugonadotropic
Hypogonadism
Low FSH, LH
Low sex steroids
High FSH, LH
Low sex steroids
Normal FSH, LH

30. Pubertal Delay
Sedlmeyer et al. identified in their study that delayed puberty in men could be classified as
Constitutional delay of growth & puberty in 63%
Delay associated with underlying medical condition 20%
Hypogonadotropic hypogonadism 9%
Hypergonadotropic hypogonadism 7%

31. Hypogonadotropic Hypogonadism
Constitutional Delay of Puberty
Malnutrition
Excessive Exercise
Growth Hormone Deficiency
Isolated Gonadotropin Deficiency
Endocrine Causes
Miscellaneous syndrome complexes
Brain tumors
Craniopharyngioma, astrocytomas, gliomas, histiocytosis X, germinomas, prolactinomas
Iron overload (pituitary damage)
GnRH receptor abnormalities

32. Constitutional Delay of Puberty
Most common cause of pubertal delay
Delayed puberty often found in siblings or parents
Diagnosis of exclusion
Bone age is delayed & consistent with degree of pubertal maturation (usually delayed by 2yrs or more
Often associated with constitutional short stature

33. Constitutional Delay of Puberty cont’d…
Progressive height gain, but along lower limits of normal (contrast to isolated gonadotropin deficiency which has normal growth, but no pubertal growth spurt)
Early morning testosterone levels > 0.7nmol/L predict puberty within 15 months (Wu et al)

34. Constitutional Delay of Puberty cont’d…
Differentiated by pathological gonadotropin deficiency by observation over time (no definitive test available)
GnRH stimulation test occasionally used, but not conclusive
HPG axis responds to GnRH more strongly if it has already been exposed to this (reflects previous stimulation)
hCG stimulation test can also be undertaken (Degros et al)
Stimulated testosterone < 3 nmol/L suggestive of hypogonadotropic hypogonadism
Stimulated testosterone >9 nmol/L suggestive of CDGP

36. Kallman Syndrome A syndrome of isolated gonadotropin deficiency
1/10,000 males, 1/50,000 females
Present with ANOSMIA or HYPOSMIA
Can be difficult to differentiate from constitutional delay
KAL-1 gene encodes protein (anosmin) required for GnRH neurons to migrate from olfactory placode to cribiform plate
Can also be associated with harelip, cleft palate, and congenital deafness

37. Idiopathic Hypogonadotropic hypogonadism
Males often have eunochoid body proportions (upper-to-lower segment ratio of < 1)
Can be sporadic or familial
Can be related to problems in the receptor for GnRH
Can present as infant with micropenis & cryptorchidism. These infants will not show normal gonadotropin increase in the first few weeks of life

38. Excessive exercise
Questions as to whether lack of puberty related to low body weight or more as a direct effect of exercise
Interruption of training in ballet dancers, runners

39. Syndromes Associated with Pubertal Delay
Prader-Willi syndrome
Laurence Moon syndrome
Septo-optic dysplasia
Bardet-Biedl syndrome

40. Panhypopituitarism
Pubertal delay is usually not presentation (present with short stature earlier)

41. What controls the timing
of puberty? An update
on progress from genetic
investigations? Current
Opinion in Endocrinology. 2009

42. Hypergonadotropic hypogonadism
Gonadal damage secondary to chemotherapy/radiation
Enzyme defects in the gonads
Androgen insensitivity
Ovarian/testicular dysgenesis (causes of gonadal failure)

43. Gonadal Failure (bilateral)
In these cases, circulating levels of LH & FSH are high (hypergonadotropic hypogonadism)
Congenital
Turner Syndrome
Klinefelter’s Syndrome
Complete androgen insensitivity
Acquired
Chemotherapy/Radiation/Surgery
Postinfectious (ie. mumps orchitis, coxsackievirus infection, dengue, shigella, malaria, varicella)
Testicular torsion
Autoimmune/metabolic (autoimmune polyglandular syndromes)
“Vanishing Testes syndrome”
“Resistant Ovaries syndomre” (gonadatropin receptor problems)

44. Klinefelter’s Syndrome
45 XXY most common (2/3), remainder are mosaic or variant
Many affected boys will not be identified until adolescence when puberty is delayed
Some pubertal development, but testes eventually become fibrotic
Timing relates to degree of mosaicism in the patient
Small testicles & gynecomastia
Also often small phallus size
90-100% are infertile
More female type fat distribution
Tall in childhood, with euchanoid body habitus
Have fathered children (particularly those with mosaicism)

46. Turner Syndrome 45 XO genotype most common
Associated with short stature, variable degrees of puberty, primary amenorrhea & multiple congenital anomalies
Often presenting complaint is short stature, but in others, may present with delayed puberty
Most have primary ovarian failure
50% of patients have some breast develpoment, some axillary/pubic hair is typical for most patients
Associated with SHOX mutations which cause the short stature

47. Turner syndrome cont’d…
Residual ovarian function can cause breast development in 15-25%, menarche in 5-10% & pregnancy in 1-3%

49. Receptor Defects
LH gene defects and FSH gene defects can result in high levels of FSH & LH with low sex steroids
Secondary sex characteristics are driven by LH effects, can have FSH receptor defect & normal secondary sex characteristics

50. Eugonadotropic pubertal delay
Congenital Anatomic Anomalies
Imperforate hymen
Vaginal atresia
Vaginal aplasia
PCOS
Hyperprolactinemia

51. In this case, secondary sex characteristics are normal
May have cyclic lower abdominal pain

52. Chronic Illness Can affect underlying genetic potential
May limit adequate nutrition (ie. inflammatory bowel disease, cystic fibrosis)
May be associated with glucocorticoid use, chemotherapy or radiation

53. Other Endocrine Causes
Hypothyroidism
Interferes with gonadotropin secretion (affects pulsatile secretion of LH)
Hyperprolactinemia
Interfere with gonadotropin production
**prolactinomas may not always be visible on imaging**

54. Investigating Delayed Puberty
Investigations depend on clinical presentation, but may include
Bone age
Hormone levels (IGF-1, FSH, LH, estradiol, testosterone, DHEAS, prolactin, TSH)
Karyotype
Hormone stimulation tests
GnRH stimulation test
GH stimulation test
Imaging
MRI if gonadotropins high & no obvious cause of hypogonadotropic hypogonadism

55. Psychological Distress in Pubertal Delay
Much has been written about psychological distress in males with delayed puberty
Self-Esteem & Sexuality in girls with Turner Syndrome has been studied
Generally had low self-esteem scores (general & social)
Lifetime sexual experience associated with overall SEI score
Increasing sexual experience had no effect (all-or-none phenomenon)
Ross et al. -> initiation of estrogen therapy associated with increased self-esteem in girls with Turner syndrome
Psychosocial Adjustment in Turner Syndrome. Journal of Clinical
And Endocriological Metabolism

56. Stimulating Puberty in Males
Should be begun at 12yrs of age
Multiple indications
For CDGP
Indicated in those boys with psychological distress (who have poor body image, low self-esteem, are becoming socially withdrawn, or are subjected to teasing or bullying)
Time of therapy initiation may vary (if GH deficiency present, delay starting to optimize height achievement)
Testosterone supplementation may help with bone mineral density

57. Exogenous testosterone
Does not increase testicular size (normal puberty continues to progress)
Causes virilization (increased phallic size & scrotal rugae)
Accelerates development of secondary sex characteristics to avoid psychosocial complications
Should be used only if bone age is delayed, and introducted at approx. normal time of development
Also stimulates growth spurt
Side effects
Local discomfort at site of injection
priapism

58. Androgen Supplementation
Testosterone
IM Injections (once puberty has begun)
Doses of mg IM using testosterone esters have been used for periods of 6-12 months
Depot testosterone like this results in high testosterone peaks & a duration of action of 2-3 weeks
Theoretic advantage for negative feedback on HPG axis to be alleviated with “wearing off” of exogenous testosterone
Oral
Associated with more gradual effects
Testosterone undecanoate 40mg po qdaily
Oxandrolone 2.5mg po qdaily
Gels, transdermal patches, etc. have not been studied as well in boys & dosing is less predictable

59. hCG
Can also use to stimulate development of secondary sexual characteristics
Increases testicular size
Can be used to stimulate fertility
units qalt days

60. Stimulating Puberty in Females
Estrogen Replacement
Increased gradually to adult replacement levels (as puberty is normally a slow process)
Aims:
Attainment of secondary sexual characteristics
Attainment of menses
Stimulation of pubertal growth spurt
Acquisition of bone mineral mass
Uterine development

61. Estrogen Replacement in Females
Initiate replacement at age yrs & should continue over course of normal puberty (approx. 3 yrs)
Effect of estrogen on growth plate is dose dependent
Higher doses stimulate epiphyseal growth plate closure
Once dose of 10-15mcg of ethinyloestradiol has been reached, breakthrough bleeding becomes apparent – once this occurs, progesterone should be added on a cyclic basis to prevent endometrial hyperplasia
Dosing
0.3mg conjugated estrogen daily
5mcg of ethinyl estradiol daily
Transdermal estrogen 25mcg twice weekly
Increase q6-12 months until maximum (20 mcg)

62. Suggested dosing increments
Ethinyloestradiol
2mcg/day X 6 months
4 mcg/day X 6 months
6 mcg/day X 6 months
10 mcg/day X 6 months
15 mcg/day X 6 months
17-estradiol
5mcg/day po
10 mcg/day po
15 mcg/day po
20 mcg/day po
Introduce progesterone once breakthrough bleeding has occurred, after this point can switch to an oral contraceptive pill

63. Estrogen Side Effects Thromboembolism Endothelial dysfunction
Hyperlipidemia
Increased risk of breast & gynecological malignancy
Increased risk of gallstones

64. Achieving Fertility May require pulses of GnRH in females
hCG in males 1-2 times/week helps to maintain spermatogenesis
IU hCG IM 3 times weekly
hMG IM 3 times weekly

65. References
Ambler, G.R. Androgen Therapy for Delayed Male Puberty. Current Opinion in Endocrinology :
Carel, J., Elie, C., Ecosse, E., Tauber, M., Leger, J., Cabrol, S., Nicolino, M., Brauner, R., Chaussain, J, and J. Coste. Self-Esteem and Social Adjustment in Young Women with Turner Syndrome – Influence of Pubertal Management and Sexuality: Population-Based Cohort Study. The Journal of Clinical Endocrinology & Metabolism (8):
Delemarre, E.M., Felius, B., and H.A. Delemarre-van de Waal. Inducing Puberty. European Journal of Endocrinology : S9-S15.
Gajdos, Z.K.Z., Hirschhorn, J.N. and M.R. Palmert. What controls the timing of puberty? An update on progress from genetic investigation. Current Opinion in Endocrinology, Diabetes & Obesity :
Hindmarsh, P.C. How do Initiate Oestrogen Therapy in a Girl who has not Undergone Puberty? Current Endocrinology : 7-10.
Normal Pubertal Development. Lee, P.A. and Kulin, H.E. Pediatric Endocrinology: The Requisites pg
Rosen, D.S. and C. Foster. Delayed Puberty. Pediatrics in Review Vol 22 (9): pg
Kulin, H.E. and J. Muller. The Biological Aspects of Puberty. Pediatrics in Review Vol 17 (3)
Mirsa, M. and M. M. Lee. Delayed Puberty. Pediatric Endocrinology. The Requisites pg
Sperling, M. Pediatric Endocrinology Puberty and Its Disorders in the Female. Pg