Pediatrics notes about "Normal & Abnormal Puberty". These notes were published in 2018. You can download them also from - Telegram: https://t.me/pediatric_notes_2018 - Mediafire: http://www.mediafire.com/folder/u5u60m184t9z7/Pediatric_Notes_2018

1. Puberty
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Normal Puberty
- Adolescents experience several types of maturation: biological, cognitive, psychological.
- The complex series of biological transitions are known as puberty
 Puberty is
- the process of physical changes by which child’s body matures into an adult body capable
of sexual reproduction to enable fertilization.
- It is initiated by hormonal signals from the brain to the gonads.
- In response to the signals, the gonads produce hormones that stimulate growth, function, and
transformation of the brain, bones, muscle, blood, skin, hair, breast, and sexual organs.
• Growth spurt (growth in stature)
• Secondary sexual characters
• Body composition
• Bone size, mineralization
• Neuro-endocrine axis,
• Cardiovascular system
Adrenarche - Activation of the adrenal cortex for the production of adrenal androgens.
- becomes biochemically apparent at age of 6 years in both girls and boys
Gonadarche - Activation of the gonads by the pituitary hormones;
follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Pubarche - Appearance of pubic hair
- In girls, the median age is 9.5 to 10.9 years.
- In boys, it is around 12 to 12.5 years.
Thelarche - Appearance of breast tissue mean age at 9 and 11.
Menarche - The age of onset of the first menstrual period.
- The mean age of menarche is about 12.1-12.6 years.
Spermarche - The age at first ejaculation
- Heralded by: nocturnal sperm emissions & appearance of sperm in the urine.
- Typically occurs around the age of 13.5 years.
Definition of Puberty:
The most visible changes during puberty:
Definitions:

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- Adrenarche becomes biochemically apparent at about 6 years of age in both girls and boys.
- Adrenarche seems to be unrelated to the pubertal maturation of the hypothalamic-pituitary-
gonadal axis.
- Adrenarche generally precedes activation of the hypothalamic-pituitary-gonadal axis, or
gonadarche, by approximately 2–3 years.
Figure: Changes in the concentration of gonadotropins (LH and FSH), sex steroids (DHEA, androstenedione, and estradiol), and the number of oogonia
throughout fetal life and pubertal development. hCG, human chorionic gonadotropin; LH, luteinizing hormone; FSH, follicle-stimulating hormone; DHEA,
dehydroepiandrosterone.
Physiology:

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 The frequency and amplitude of pulsatile GnRH secretion are irregular and very low
as young as 5 years of age, primarily during sleep.
 FSH levels rise more than LH.
Puberty begins between 10 and 13 years of age.
 About 1 year before breast budding in prepubertal girls, nocturnal pulses of LH levels
exceeding those of FSH that increases in serum estradiol concentrations.
 Menarche occurs in late puberty, after a year-long rise in daily estrogen production.
 Feedback relationship between estradiol and gonadotropin secretion matures
and ovulation becomes established, often a year or more after menarche.
 As the amplitude of LH pulses increases, the theca cells of the ovaries begin to produce
testosterone and smaller amounts of progesterone.
 Early stages of male hypothalamic maturation seem to be very similar to the early stages of
female puberty, though occurring about 1–2 years later.
 LH stimulates Leydig cells of the testes to make testosterone blood levels begin to rise.
 Night time levels of testosterone are higher than daytime.
 Estradiol mediates:
• Growth spurt (↑ Height)
• Bone maturation,
• Epiphyseal closure.
• Induces at least modest development of breast tissue (gynecomastia)
in a large proportion of boys.
Childhood and Early Adolescence:
Puberty in female:
Puberty in male:
in both boys & girls

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Girls Boys
Puberty begins at age of 10–11 years 11–12 years
Puberty Completes by age of 15–16 years 16–17 years
The earliest sign The earliest 2ry
sexual
characteristic:
breast/areolar development
(thelarche)
The earliest stage of male
maturation:
increase in testicular volume
(≥3 mL)
Menarche occurs:
2.6 years after the onset of
puberty
Spermarche occurs:
shortly after the attainment
of peak height velocity
- It is sexual maturity rating of 2ry
sexual characteristics
- Tanner stage is assigned independently to genitalia, pubic hair, and breast
(e.g. a person can have Tanner stage 2 genitalia, Tanner stage 3 pubic hair).
Female Both Male
Stage Breast Pubic hair External genitalia
I Prepubertal, with no palpable
breast tissue.
Prepubertal with no pubic hair Prepubertal
II - Development of breast bud ,
- with elevation of the papilla and
- enlargement of areolar diameter
Sparse, Straight pubic hair
♂: along base of penis
♀: along lateral vulva
Enlargement of testes &scrotum;
scrotal skin reddens & changes in
texture
III Enlargement of the breast,
without separation of areolar
contour from the breast
Hair is darker, Coarser, & Curlier,
extending over the mid-pubis.
Enlargement of penis (length at
first); further growth of testes
IV The areola and papilla project
above the breast,
forming a secondary mound.
Hair is adult-like in appearance,
but does not extend to thighs
- Increased size of penis with
growth in breadth
- and development of glans;
- testes and scrotum larger,
- scrotal skin darker
V - Recession of the areola to
match the contour of breast;
the papilla projects beyond
the contour of areola & breast
Hair is adult in appearance,
extending from thigh to thigh
Adult genitalia
Pubertal changes:
Tanner staging of puberty:

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- Growth Velocity is the rate of growth over a fixed time interval.
- It helps in determining if child's growth pattern is following the expected normal growth curve.
- Velocity of growth is high during the first 2 years of life.
- Deceleration in child growth ends with onset of growth spurt of puberty.
The normal growth velocity of childhood:

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► In girls:
 Breast bud (thelarche)
 Pubic hair (pubarche)
 Growth spurt
 Body hair
 Breast matures
 Menarche
 Adult height
► In boys:
 Testicular growth
 Thinning & reddening of
Scrotal skin
 Pubic hair (pubarche)
 Penile & scrotal growth
 Axillary hair
 First ejaculation
(Spermarche)
 Growth spurt
 Facial hair
 Adult height
Sequence of puberty:

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Testicular volume is typically measured using the Prader orchidometer, a series of 3D
ellipsoids with a volume from 1 to 25 mL.
1. Central Control Mechanisms: hypothalamic pituitary gonadal axis
2. Peripheral Signaling e.g. leptin
1. Genetic factors:
- Black girls showing earlier onset of breast development compared to white girls.
2. Fat mass
- Underweight more likely to have delayed menarche
- Obese girls is associated with earlier onset of puberty.
- Obese boys is associated with later, rather than earlier, onset of puberty.
3. Environmental chemicals
- pesticide or fungicide residues, toxins e.g. lead
4. Chronic illness
Clinical application:
Triggering factors of puberty:
Factors affecting the timing of puberty:

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Precocious puberty
- It is the onset of puberty is < 8 years in girls and < 9 years in boys.
 Genetic factors: Race,
 Girls with early maternal menarche,
 Fat mass: Excessive weight gain or obesity in infancy and early childhood,
 Environmental chemicals: After exposure to estrogenic endocrine-disrupting chemicals
Complete Precocious puberty Incomplete Precocious puberty
1. Gonadotropin-dependent PP
(Central PP, True PP)
Premature thelarche
2. Gonadotropin-independent PP
(Peripheral PP, Pseudo PP)
Premature adrenarche
3. Combined PP Premature menarche
Definition:
Factors affecting:
Classification:

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Incomplete precocious puberty
1. Idiopathic isolated premature thelarche (girls)
- Most commonly, premature thelarche
 Begins around 2 years of age,
 Regresses within an average of 18 months from its development.
- Isolated breast development – may be asymmetrical, unilateral or bilateral.
- When it persists, degree of breast development typically does NOT exceed Tanner stage 3.
- Moderate  of Height velocity and bone age.
2. Idiopathic isolated precocious adrenarche (boys or girls)
- This is another common pubertal variant
 Characterized by:
 Early development of pubic hair at 6-7 in girls and 7-8 in boys
 With or without axillary hair and odour
 and/or a small amount of acne
 Slight  in Height and Bone age
 Etiology:
 Increased production of adrenal androgens in both sexes earlier than normal age
 OR hypersensitivity of pilosebaceous to androgen.
3. Idiopathic isolated precocious menarche (girls)
 Definition: Menstruation without any other manifestations of puberty in a young girl
prior to the age of 9 years.
 Etiology: The cause is unknown
 Diagnosis: of exclusion
(Exclude: foreign body, local masses, and McCune-Albright syndrome).
 Treatment: The situation is usually self-limited

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Complete precocious puberty
1. Gonadotropin-dependent Precocious Puberty (Central PP, True PP)
 Definition: activation of the hypothalamic-pituitary gonadal axis at an earlier-than-normal age.
Isosexual development Contrasexual development
pubertal changes appropriate for the sex of
the child e.g.
• breast-budding in girls
• testicular enlargement in boys
- pubertal features inappropriate for the sex
of the child e.g.
• In females are male-hormone-directed e.g.
clitoromegaly
• In males are female-hormone-directed, e.g.
breast development
 Causes:
• Idiopathic
• Organic brain lesions:
- Hypothalamic hamartoma; produces pulsatile GnRH
- Other CNS tumors
- CNS irradiation
- Other CNS lesions: hydrocephalus, severe head
trauma, myelomeningocele
• Familial or Constitutional
• Prolonged Untreated primary hypothyroidism
In boys In girls
• Organic brain lesions • Idiopathic
• Familial or Constitutional • Organic brain lesions
• Prolonged Untreated hypothyroidism • Familial or Constitutional
• Idiopathic • Prolonged Untreated hypothyroidism
Figure: Activation of the hypothalamic-
pituitary gonadal axis in Central PP

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2. Gonadotropin-Independent Precocious Puberty (Peripheral PP, Pseudo PP)
 Definition:
- Refers to gonadal or adrenal sex steroid secretion NOT resulting from activation of
hypothalamic-pituitary-gonadal axis (i.e. pituitary-independent or peripheral in origin).
- Can involve isolated androgen, isolated estrogen, or combined androgen and estrogen production
 Causes:
In boys In girls
• Leydig cell tumor of testis
• hCG-secreting tumors
• Familial male-limited precocious puberty
(Familial testotoxicosis)
• Estrogenic Ovarian tumors
• Estrogenic Ovarian cysts
• Untreated Congenital adrenal hyperplasia (CAH)
• Virilizing Adrenocortical tumor
• Glucocorticoid receptor defect
• Estrogenic adrenal tumor
• Exogenous sex steroids (androgen)
• McCune-Albright syndrome
• Exogenous sex steroids (estrogens)
• McCune-Albright syndrome (girls>boys)
3. Combined peripheral and central
 Causes:
• Treated congenital adrenal hyperplasia
• McCune-Albright syndrome, late
• Familial male precocious puberty, late
Figure: Inactivation of the hypothalamic-
pituitary gonadal axis in peripheral PP

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McCune–Albright syndrome (MAS)
- As an example of Gonadotropin-Independent Precocious Puberty
- It is characterized by the classical triad of; mnemonic: APC
1. Café au lait spots (unilateral): Irregularly edged hyperpigmented macules
2. Polyostotic fibrous dysplasia Slowly progressive bone disorder
3. Autonomous hyperfunction:
 Ovary “most commonly involved”  Gonadotropin-Independent PP.
but other endocrine involvement includes:
 the thyroid (Hyperthyroidism)
 the parathyroid (hyperparathyroidism).
 the adrenals (Cushing syndrome)
 the pituitary (gigantism),
- At least two of these features should be present for the diagnosis to be made.
 Medical history:
- Onset & duration of Precocious Puberty.
(as well as the timing of pubertal onset in the parents and siblings)
- CNS manifestations: headaches, seizures, changes in mood or vision.
- Family history of CNS disease
- Exogenous Estrogen intake
 Physical examination:
- Height
- BMI
- Skin pigmentation
- Blood pressure
- Vaginal discharge
- Skin, hair changes
 Pubertal staging: Tanner stage (Pubic hair, breast, penis), Growth velocity
 Bone age: by radiographic assessment
Evaluation:

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Central Precocious puberty Peripheral Precocious puberty
a If organic cause: Treat the cause
b If non-organic cause:
Long acting LHRH analogue
 No role of Long acting LHRH analogue for PPP
a Aromatase inhibitors e.g. testolactone.
Prevent testosterone conversion to E2.
b Anti-androgen e.g. spironolactone or ketoconazole
c Anti-estrogen: prevents epiphyseal closure
Delayed puberty
i.e. absence of an increase in testicular volume (less than 4 mL) at 14 years in a boy
Or absence of any breast development at 13 years in a girl.
OR abnormal progression through puberty once initial pubertal changes have begun
1. Temporary delays of puberty (constitutional delay of growth and puberty)
2. Hypergonadotropic hypogonadism (1ry
hypogonadism); disease of gonads
3. Hypogonadotropic hypogonadism (2ry
hypogonadism); disease of hypothalamic-pituitary
Treatment:
Definition:
Classification:

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I. Temporary delays of puberty
a Constitutional delay of growth and/or puberty
b Chronic illness:
GI disease e.g. inflammatory bowel disease, pulmonary disease, Renal failure, hepatic disease
c Nutritional Disorders:
• Malnutrition, Anorexia nervosa, Excessive energy expenditure.
d Endocrinopathies:
• Diabetes mellitus, Growth hormone deficiency, Hypothyroidism
• Hyperprolactinemia, Glucocorticoid excess syndrome
II. Hypergonadotropic Hypogonadism (1ry
hypogonadism)
low serum testosterone or estrogen  High FSH and LH + lack of pubertal development
Congenital Acquired
 Males
• Klinefelter’s syndrome (XYY)
• Noonan’s syndrome
• Gonadal dysgenesis (XO/XY)
• Defects in testosterone synthesis/action
• Inborn errors of testosterone synthesis
(5a-Reductase deficiency)
• Partial androgen insensitivity
• Leydig cell agenesis or hypoplasia Anorchia
(Vanishing Testis)
 Males
• Bilateral Orchitis
• Surgical or traumatic castration
• Chemotherapy, radiotherapy
 Females
• Turner’s Syndrome (XO)
• gonadal dysgenesis (XO/XY, or XX)
 Females
• Premature idiopathic ovarian failure
• Autoimmune
• Surgical or traumatic castration
III. Hypogonadotropic Hypogonadism (2ry
hypogonadism)
Low FSH and LH  low serum testosterone or estrogen
Congenital Acquired
• Idiopathic hypogonadotropic hypogonadism
• Kallmann syndrome
• Adrenal hypoplasia congenita
• GnRH receptor defects
• Septo-optic dysplasia
• Panhypopituitarism
• Prader-Willi syndrome
• Laurence-Moon-Biedl syndrome
• Head trauma
• Tumors e.g. craniopharyngiomas
• Infiltrative diseases e.g. Histiocytosis X
• Effects of infection
• Effects of radiotherapy
• Effects of surgery

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 Constitutional delay of puberty
- Represent the extreme of normal physiologic variations in timing of puberty onset.
- +ve family history - CA > (BA = HA)
 Idiopathic Hypogonadotropic Hypogonadism
- Defects in the production or regulation of gonadotropin-releasing hormone (GnRH) in
the hypothalamus → lack of LH and FSH production by the pituitary.
 Kallmann syndrome
- Gonadotropin deficiency accompanied by anosmia.
 Klinefelter’s syndrome
- The most frequent form of hypogonadism in males
- Caused by seminiferous tubule dysgenesis.
- Karyotype: (47, XXY)
- phenotypic characteristics:
• Tall stature with long legs and arms,
• Micropenis, small, firm testes,
• Poor muscular development,
• Borderline IQ, and poor social adaptation.
 TURNER’S SYNDROME
- The most common cause of 1ry
hypogonadism in females.
- Karyotype: XO or its mosaics
- phenotypic characteristics:
Short stature, webbed neck, low posterior hairline, hypertelorism, left-sided cardiac defects.
- Ovarian function:
varies in girls with Turner’s syndrome, giving variable progression through puberty, but
patients seldom reach menarche.

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(for both precocious & delayed puberty)
1) Radiology:
- A skeletal age of 10 in girls & 12.5 in boys usually correlates with onset of pubertal development.
• Cranial MRI → Central cause • Pelvic ultrasound → Peripheral cause
2) Hormonal profile:
- Initial assessment of serum or urine gonadotropin levels (LH and FSH).
- Assessment of serum estradiol, testosterone levels
FSH and LH estradiol, testosterone
Central precocious puberty ↑ ↑
Peripheral precocious puberty  ↑
Hypogonadotropic hypogonadism  
Hypergonadotropic hypogonadism ↑ 
3) Karyotype.
(of delayed puberty)
Boys Girls
• Testosterone therapy • Estrogen therapy induces breast
development in girls with hypogonadism,
• in boys with probable constitutional delay
of growth and puberty, a period of
“watchful waiting”, including:
periodic evaluation, reassurance, and
psychological counseling
• A progestagen should be added after
starting estrogen within few months
• In girls without a uterus, there is NO need
for the addition of progestagen.
 GnRH and gonadotropin therapy:
- In some cases of hypogonadotropic hypogonadism, pulsatile administration of GnRH →
induction of puberty.
- Gonadotropin therapy has not been commonly used in adolescents
but reserved for therapy for adult infertility.
Initial diagnostic evaluation:
Treatment: