1. Puberty – Normal and Abnormal
For UG-2014

2. Puberty
Disorders of puberty constitute one of most common referrals to paediatric endocrine clinics
Careful history and examination paramount
Ensure sensitivity at all times
Chaperone during pubertal examination

3. Puberty
Physiological transition from childhood to reproductive maturity
Associated with:
Growth spurt
Appearance of both primary and secondary sexual characteristics in children
Occurs between 8 and 14yrs in girls
Occurs between 9 and 14yrs in boys

4. Puberty
Important to understand
Range of normal
Population differences

5. Normal Puberty: Endocrine control
Onset of puberty signalled by the secretion of pulses of Gonadotrophin Releasing Hormone (GnRH)
Prior to puberty: hormonal feedback / central neural suppression of GnRH release suppress onset of puberty
Hypothalamo-pituitary-gonadal axis starts working in foetus. After birth, sex hormones and gonadotrophins (FSH, LH) found in adult levels
Levels reduce in months after birth; pulsatile GnRH reduces in childhood and increases in frequency and amplitude before puberty
For 2 yrs before puberty, rise in adrenal androgens early pubic hair and spots

7. Physiology of Puberty
Activation of the hypothalamic – pituitary – gonadal axis
Induces and enhances progressive ovarian and testicular sex hormone secretion
Responsible for the profound biological, morphological and psychological changes which adolescents experience

8. Influencing Factors Genetics: 50-80% of variation in pubertal timing
Environmental factors e.g. nutritional status
Leptin → regulates appetite and metabolism through hypothalmus. Permissive role in regulation of timing of puberty
Adrenarche: development of pubic and axillary hair, body odour and acne

9. Adrenal Steroids DHEA, DHEA-S, Androstenedione
Begins before rise in gonadotrophin secretion
Responsible for appearance of axillary hair ad in part for appearance of pubic hair (adrenarche)

11. Physical Changes 5 stages from childhood to full maturity
Marshall and Tanner (P1 – P5)
Reflect progression in changes of the external genitalia and of sexual hair
Secondary sexual characteristics
Mean age 10.5yrs in girls
Mean age 11.5 – 12yrs in boys

12. Puberty: Girls Breast enlargement usually first sign. Thelarche
Often unilateral
Menarche usually 2-3 yrs after breast development
Growth spurt peaks before menarche
Pubic and axillary hair growth: sign of adrenal androgen secretion
Starts at similar stage of apocrine gland sweat production and associated with adult body odour

13. Examination: Girls
Examine in supine position. Helps differentiate between true breast enlargement vs adiposity
Genital exam: pubic hair, changes in vaginal mucosa.
Cliteromegaly suggests androgen excess and virilisation
Mild acne normal in early puberty but rapid onset and progression may suggest androgen excess
Vaginal exam only if sexually active
NEVER rectal exam

14. Pubertal Stages (Tanner) Female
P1 Prepubertal
P2 Early development of subareolar breast bud +/- small amounts of pubic and axillary hair
P3 Increase in size of palpable breast tissue and areolae, increased dark curled pubic/axillary hair
P4 Breast tissue and areolae protrude above breast level. Adult pubic hair but no spread to medial thighs.
P5 Mature adult breast. Pubic hair extends to upper thigh

16. Menarche
During puberty oestradiol levels fluctuate widely (reflecting successive waves of follicular development that fail to reach ovulatory stage)
Endometrium affected by oestradiol. Undergoes cycles of proliferation and regression until point where withdrawal of oestrogen results in the first menstrual bleed (menarche)
Increase of only 4% of final height after menarche

17. Ovarian development Rising levels of plasma gonadotrophins
Stimulate ovary to produce increasing amounts of oestradiol
Oestradiol ► secondary sex characteristics
Breast growth and development
Reproductive organ growth and development
Fat redistribution (hips,breasts)
Bone Maturation

18. Ovarian development Prepuberty volume – 0.3 – 0.9cm3
> 1.0cm3 indicates puberty has begun
During puberty – rapid increase in size
Mean post pubertal volume 4cm3

19. Ovulation First ovulation occurs 6 – 9 mths after menarche
Plasma progesterone remains at low levels even if secondary sexual characteristics have appeared
Rising progesterone after usually ► ovulation
Plasma testosterone rise during puberty (not as much as in male)

20. Development of Uterus Prepubertal uterus is tear-drop shaped
Neck and isthmus account for up to 66% of uterine volume
Following production of oestrogens – uterus becomes pear shaped
Uterine body increases in length (max 5 – 8cm) and thickness (proportionately more than cervix)

22. Puberty: Boys First signs often go unnoticed
Testicular enlargement (12-13 yrs)
Prepubertal testis – 2mls diameter
Puberty begins when volume reaches 4mls
Penile and scrotal enlargement occur approx 1 yr after testicular enlargement. Pubic hair appears at same time

23. Pubertal Growth Spurt: Boys
Occurs later than in females
Testosterone less of a stimulus to GH responsiveness than oestradiol
Testosterone required in larger concentrations to produce same anabolic effect
Greater and later growth spurt in boys

24. Examination: Boys
Testicular growth: associated with enlargement of seminiferous tubules, epididymis, seminal vesicles and prostate
Testicular enlargement: FSH dependant
Prader orchidometer: assessment of testicular volume
Signs of androgen excess without commensurate increase in testicular volume: worrisome e.g CAH, testicular tumour
Penile growth, scrotal changes, pubic hair occur 1-2 yrs after testicular enlargement
50% of males varying degrees of breast hypertrophy
Later signs: growth spurt, acne, voice deepening, facial hair

25. Pubertal Stages (Tanner) Male
P1 Prepubertal, testicular volume < 2mls
P2 Enlargement of scrotum and penis. Scrotum slightly pigmented. Few long dark pubic hairs
P3 Lenghtening of penis. Further growth of testes and scrotum. Pubic hair darker, coarser and more curled
P4 Penis increases in length and thickness. Increased pigmentation of scrotum. Adult pubic but no spread to medial thighs
P5 Genitalia adult in size and shape. Pubic hair spread to thighs

27. Secondary sexual development
First signs of puberty
Testicular volume of 4mls
Slight progressive increase in scrotal folds
Slight increase in scrotal pigmentation

28. Testicular Volume

30. Final height Puberty usually completed within 3 - 4 yrs of onset
Left wrist x-ray to assess bone age
Final adult height results from complete fusion of epiphyses
Occurs approx 2yrs after menarche

31. Assessment of abnormal puberty
Many causes
Aim of assessment: determine whether underlying pathological abnormality vs constitutional and benign pubertal changes
NB: recognise abnormal timing and progression of puberty

32. What is abnormal? Delayed Puberty Early or Precocious Puberty
More common in females
Uncommon in males (usually pathological)
< 8yrs in females
< 9yrs in males
May be associated with a growth spurt

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

34. 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.

35. 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

36. 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

37. 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

38. 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%

39. 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

40. 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

41. 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)

42. 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

44. 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

45. 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

46. 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

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

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

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

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

51. 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)

52. 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)

54. 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

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

57. 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

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

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

60. 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

61. 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**

62. 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

63. 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

64. 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

65. 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

66. 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

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

68. 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

69. 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)

70. 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

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

72. 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

73. Assessment 1 Full history of previous growth and development
Record timing and sequence of physical milestones and behavioural changes of puberty
Full medical and surgical history
If underweight: take full nutritional history
Family hx of early or delayed puberty
Family hx of any genetic disease

74. Assessment 2 Plot height, weight, BMI and growth velocity
Compare with old measurements if available
Examine all systems: endocrine / neurology NB
Optic fundi, visual fields, sense of smell
Genitalia, body habitus, stage of puberty

75. Delayed Puberty: Hypogonadotrophic
Constitutional (familial, sporadic)
Chronic illness (CF, Crohns Disease, Renal failure)
Malnutrition (Anorexia, CF, coeliac disease)
Exercise
PCOS
Tumours of pituitary/hypothalamus (craniopharyngioma)
Hypothalamic syndromes (PWS, Laurence-Moon-Biedl)
Hypothyroidism
Suppression 20 to hyperthyroidism, hyperprolactinemia, Cushing Syndrome, CAH
Panhypopituitarism

76. Delayed Puberty: Hypergonadotrophic
Congenital
Turner Syndrome
Klinefelters Syndrome
Acquired
Irradiation / Chemotherapy
Surgery
Testicular torsion, trauma
Infection
Autoimmunity

77. Precocious Puberty
Onset of secondary sexual characteristics < 8yrs in girls and < 9yrs in boys
5 times more common in girls
Usually benign central process – girls
Pathological in ~ 50% in boys

78. Precocious puberty
Defined as the onset of secondary sexual characteristics before 8 yr age in girls and 9 yr in boys.

79. Classification of precocious puberty
True precocious puberty ( central or gonadotropin- dependent = CPP)
Precocious pseudopuberty ( peripheral, gonadoptropin independent (PPP)
Mixed type

80. Conditions causing central precocious puberty
Idiopathic
organic brain lesions
(inflamation, malformation, trauma, chemotherapy, radiotherapy, brain tumor)
Hypothyroidism

81. Conditions causing precocious pseudopuberty in females
Iso sexual ( feminizing ) conditions
Mc cune – Albrightsyndrome
Autonomous ovarian cyst
Ovarian tumors
Feminizing adrenocortical tumor
Exogenous estrogens
cont

82. Hetrosexual (masculinizing)
Congenital adrenal hyperplasia
Adrenal tumor
Ovarian tumor
Glucocorticoid receptor defect
Exogenous androgens.

83. Conditions causing precocious pseudopuberty in males
Isosexual
congenital adrenal hyperplasia
Adrenocortical tumor
Leydig cell tumor
Familial male precocious puberty
HCG secreting tumor
Teratoma
cont

84. Hertrosexual Glucocorticoid receptor defect Exogenous androgen
Feminizing adrenocortical tumor
Exogenous estrogens

85. Approach to patient with precocious puberty
History
(Medication )
(family history of precocious puberty)
Physical examination
(Wt, Ht, Eye, Thyroid, abdomen, tests)
paraclinical findings
bone age
cont

86. (ovaries, Uterus, adrenal glands, testes) MRI of brain
Estradial
Testosterone LH
FSH
GnRH stimulation test
(LH/FSH> 1)
(LH>5- 10 IU/L)
Sonography
(ovaries, Uterus, adrenal glands, testes)
MRI of brain
(MRI of hypothalamus and hypophysis)
cont

87. The goals of treatment for CPP
Improvement of adult height
Prevention of social and psychological problems.

88. Treatment of CPP
GnRH analogues
GnRH antagonist
Aromatize inhibitors

89. Indications for therapy with GnRH agonist
True precocious puberty in males
Rapid progressive CPP in girls
To stop puberty because of social and psychological reasons

90. The effect of GnRH agonist therapy on:
Growth
Skeletal age
Pubertal development
Hormones

91. Treatment is effective if:
Serum sex hormone concentration decrease to prepubertal levels
( testosterone < 20ng/ dL in boys estradial
< 10pg/mL in girls)
Serum FSH and LH < 1 IU/L
LH/FSH < 1

92. Physiological status after completion of therapy
Growth rate
Bone density
Pubertal development
Hormones
Fertility

93. Premature thelarche / pubarche
Thelarche – beginning of breast development
Pubarche – first appearance of pubic hair
(more common in certain populations e.g asian / afro-caribbean )
More common than true precocious puberty
Benign variants
breast development in girls < 3yrs with spontaneous regression
Pubic hair in boys and girls < 7yrs due to adrenal androgen secretion in middle childhood
NB Examination normal or may be slight advance in growth curve

94. Precocious Puberty Gonadotrophin dependant
Idiopathic (sporadic / familial)
Congenital (Hydrocephalus)
Acquired (irradiation/surgery/infection)
Tumours (hamartomas/gliomas)
Hypothyroidism
Russell Silver Syndrome
Mc Cune Albright Syndrome

95. Precocious Puberty Gonadotrophin Independant
Normal pattern of puberty absent
Virilisation of female (CAH)
Feminisation of a boy (oestrogen producing leydig tumour)
Adrenal Tumour
Ovarian Tumour

96. Investigations Blood Tests (first line) Second line FBC U&E LFT’s
TFT’s
FSH/LH
Oest/Testosterone
17 OHP / 11 DOC
Adrenal androgens
Prolactin
Second line
GnRH assay
Beta –HCG
Karyotype if indicated

97. Diagnostic Imaging Pelvic USS (ovarian tumours / cysts)
Testicular USS (tumour)
Adrenal USS (MRI / CT better if tumour considered)
Bone Age (if within 1yr of CA, puberty not started or only just started; if > 2yrs, puberty already started)
Brain MRI in all males and patients with neurological signs or symptoms)

98. Management Treat systemic disease Psychological support
Promote puberty / growth if necessary
Low dose testosterone
Ethinyloestradiol

99. Issues Treatment of the cause e.g. cranial neoplasm
Behavioural difficulties – psychology
Reduce rate of skeletal maturation (early growth spurt may result in early epiphyseal closure and reduced final adult height)
Halt or slow puberty (GnRH analogue)
Inhibit action of excess sex steroids

100. Growth and Puberty GH plays role in pubertal development
Amplifies ovarian response to gonadotrophins
IGF-1 enhances gonadotrophin effect on granulosa cells
Isolated GH deficiency associated with pubertal delay, diminished Leydig cell function and decreased response to chorionic gonadotrophins
GH administration can restore testicular responsiveness to LH and Leydig Cell steroidogenesis

101. Growth and Puberty
Growth hormone-releasing factor (GRF) levels and GH secretion increase considerably during puberty, mainly at night
Amplitude of GH peaks increases in early puberty – growth spurt
IGF-1 ►important modulator of growth during childhood and adolescence
Adrenal androgens have little physiological role in normal growth

102. Thelarche
Absence of a growth spurt and axillary or pubic hair differentiates thelarche from precocious puberty

103. Ambiguous genitalia Range of presentations
Inadequately developed male to virilised female
Most common cause is Congenital Adrenal Hyperplasia → virilised female
Urgent identification as can cause adrenal failure in neonatal period
Do not ascribe sex immediately
Identify cause of intersex
Karyotype does not indicate the sex of rearing
Family counselling imperative
Early surgery now less popular

104. Thank You