Normal & abnormal puberty

Abdulmoein Eid Al-Agha, MBBS, FRCPCH

Professor of Pediatric Endocrinology,
King Abdulaziz University Hospital
http://aagha.kau.edu.sa
 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 13 yrs in girls

– Occurs between 9 and 14yrs in boys
 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
• 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
 Influencing Factors
• Genetics: 50-80% of variation in pubertal
timing

• Environmental factors e.g. nutritional status,

environmental hormonal disruptors

• Leptin → regulates appetite and metabolism

through hypothalamus. Permissive role in
regulation of timing of puberty
 Adrenal Steroids
• Adrenarche: development of pubic and
axillary hair, body odor and acne
• DHEA, DHEA-S, Androstenedione
– Begins before rise in gonadotropin secretion
– Responsible for appearance of axillary hair
ad in part for appearance of pubic hair
(adrenarche)
• •
 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 – 11 yrs in girls
– Mean age 12 – 14yrs in boys
 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
Tanner Stages Females
 Puberty
Somatic changes
pubic & axillary hair
acne
perspiration and characteristic body odour
(release of volatile acids= glutaric acid)
oily skin and hair
All these changes happen due to increased
adrenal androgens which are formed equally in
both males and females
- Adrenal androgens
androstenedione, DHEA, DHEAS
 Skeletal changes in girls

Widening of pelvis and carrying angle

Major increase in BMD
Increased adipose tissue with typical
female distribution
95% of growth happened < menarche
Menarche usually by age 12.5-14.5 yr
Increased in muscle bulk but not to same
extent as males
 Menarche
• During puberty estradiol levels fluctuate widely
(reflecting successive waves of follicular
development that fail to reach ovulatory stage)
• Endometrium affected by estradiol.
• Undergoes cycles of proliferation and
regression until point where withdrawal of
oestrogen results in the first menstrual bleed
(menarche)
• Increase of only 5% of final height after
menarche
 3 5

11 l 15 l '.
 Puberty: Boys
• First signs often go unnoticed
• Testicular enlargement (12-13 yrs)
• Prepubertal testis – 1-3 mls volume
• Puberty begins when volume reaches 4mls
• Penile and scrotal enlargement occur approx 1
yr after testicular enlargement. Pubic hair
appears at same time
Tanner Stages Males
 Secondary sexual development
• First signs of puberty
– Testicular volume of
4mls
– Slight progressive
increase in scrotal folds
– Slight increase in scrotal
pigmentation
 Pubertal Growth Spurt: Boys
• Occurs later than in females by average 2
years
• Testosterone less of a stimulus to GH
responsiveness than estradiol
• Testosterone required in larger concentrations
to produce same anabolic effect
• Greater and later growth spurt in boys
 - 5

2 3- 5

1 11 12 13 15 l
 Final adult 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 1-2 yrs
after menarche
 Final height in males

• Males
– By 16 to 18 years most males have completed
puberty, their growth rate begins to slow, their
shoulders have broadened, limbs and trunk are
muscular and they have adult body and facial hair
– Produce sperm and are physically able to produce
offspring
 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 ~ 70% in boys

 Types
Central, True, GnRH dependent
- 89-98% of cases (major type)
Periphral, Pseudo, GnRH Independent
- 10 - 15 % of cases (not major type)
Mixed type
- Started with peripheral with 2ry. activation of central
Isolated Forms
- Thelarche
- Adrenarche
 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
 Central type Peripheral type

H-P-G axis Activateadxis suppressed

LH & FSH Adult values Pre-pubertal

Sex steroids High High

Gonads Pubertal size Small in size (unles

tumor)
 Central, True, GnRH dependent

Etiology
„
Idiopathic
- most girls ( 90 %)
„
Secondary
- most boys ( 70-80%)
 Etiology of central precocious puberty
CNS disorders
Hypothalamic Hamartoma
Glioma (NF-1)
Astrocytoma
Craniopharyngioma
Ependymoma, germinoma
CNS radiation therapy
Post trauma (surgery)
Etiology of Central precocious puberty
Inflammation (Brain abscesses)
Neurological & mental retardation
Hydrocephalus
 Etiology of peripheral type
Gonadial: McCune-Albright, tumour, cyst
Adrenal: Virilising CAH, tumours Ectopic:
hCG secreting tumours
- Germinoma, Hepatoblastoma
Exogenous source of hormone
Familial male dependent (Testotoxicosis)
McCun A lbright Syndrome
 Laboratory Studies
Sex steroid levels
-Basal LH, FSH
GnRH stimulation test
-A definitive CPP diagnosis is confirmed by a brisk rise
in LH 20-40 minutes after infusion of GnRH (100 mcg),
which is more than the rise in FSH.
- No increase in LH and FSH after infusing GnRH
suggests precocious pseudo-puberty.
- Pre-pubertal girls with premature Thelarche
sometimes show an exaggerated rise in FSH after
GnRH.
hCG
- hepatoblastoma, germinoma
17 OHP &11DOC
- CAH
 Bone Age

A radiograph of the
hand and wrist to
determine bone age
is a quick and useful
means to estimate
the likelihood of
precocious puberty
and its speed of
progression
 Imaging Studies
MRI Brain
- Perform an MRI after hormonal studies
(GnRH test) to confirm a CPP diagnosis.
- Ask the radiologist to do a high-resolution study
focusing on the hypothalamic-pituitary area.
- The younger girls with CPP, the greater the
chance of finding CNS pathology
girls younger than 6 y.
For boys younger than 9 years, the incidence of
CNS findings is much higher than in girls, and MRI
should be part of the evaluation.
Pelvic ultrasound
- Ultrasound is unnecessary for girls with a definite
diagnosis of CPP.
- If performed, however, ultrasound usually shows
bilaterally enlarged ovaries, often with multiple small
follicular cysts, and an enlarged uterus with an
endometrial stripe.
- Pelvic ultrasound is essential when precocious pseudo-
puberty is suspected (based on examination or hormone
levels) because an ovarian tumor or cyst may be
detected.
U/S Testes
Adrenal U/S
 Goals of treatment

Decrease the progression of pubertal

changes
Decrease bone maturation
Increase the predicted final adult height
Psychosocial and behavioural therapy
 Modalities of treatment CPP
Surgical Care
- When CPP is caused by a CNS tumor other than a
Hamartoma, perform a resection to the extent possible
without impinging on vital structures such as the optic
nerves.
Radiation therapy
- often is indicated if surgical resection is incomplete.
Unfortunately, removal of the tumor rarely causes
regression of precocious puberty.
Medical Care
Gonadotropin-releasing hormone (GnRH) agonists
 GnRH agonists
• Acts as an agonist at pituitary GnRH receptors
• By interrupting the normal pulsatile
stimulation and the desensitization of the
GnRH receptors
• It indirectly down regulates the secretion of
gonadotropin (LH) and (FSH) leading to
hypogonadism and thus a dramatic reduction
in estradiol and testosterone levels in both
sexes
Pituitary downregulation
 GnRH agonist

Daily S/C preparation Depot-preparations

• Desoriline • Leuprorelin
4-8 ug/kg/d acetate (Lupron)
• Busereline
0.3 mg / kg (7.5 mg)
20-40ug/kg/d
• Tryptorelin
• leuprolide
(Decapeptyl)
20-50 ug/kg/day
50-100ug/kg
• Nafarelin(intranasal)
800-1600ug/kg/day • Goserelin (Zoladex)
 Combined use of GH& GnRHa
It appears that patients with CPP who grow poorly during
GnRHa therapy may have alterations in their GH-IGF-I
axis.
This may be attributable to an exaggerated and sustained
decrease in the secretion of GH with the withdrawal of sex
steroids after the GnRHa therapy has been initiated.
Treatment to slow skeletal maturation in the face of
suppressed GH secretion will still result in compromised
adult height.
This has led some investigators to speculate that at least a
subset of patients with CPP would benefit from the addition
of GH therapy to the GnRHa treatment.
 Treatment of peripheral type

Medical therapy
Medroxyprogestrone acetate (Provera)
Ketoconazole
Aromatase enzyme inhibitors (testolctone)
Androgen antagonists

Surgical treatment of underlying pathology if present

 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
 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 < 4mL or pubic
hair is not present by age 14 in
a male
 Pubertal Delay

Pubertal Delay

Hypogonadotropic Hypergonadotropic Eugonadotropic

Hypogonadism Hypogonadism Hypogonadism

Low FSH, LH High FSH, LH Normal FSH, LH

Low sex steroids Low sex steroids
 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
 Hypogonadotropic Hypogonadism
• Constitutional Delay of Puberty
• Malnutrition
• Excessive Exercise
• Isolated Gonadotropin Deficiency
• Brain tumors
– Craniopharyngioma, astrocytomas,
gliomas, histiocytosis X, germinomas,
prolactinomas
• Iron overload (hemosiderosis)
• GnRH receptor abnormalities
 Kallman Syndrome
• yndrome 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
 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
 Syndromes Associated with Pubertal
Delay
• Prader-Willi syndrome
• Laurence Moon syndrome
• Septo-optic dysplasia
• Bardet-Biedl syndrome
 Hypergonadotropic hypogonadism

• Gonadal damage secondary to

chemotherapy/radiation
• Enzyme defects in the gonads
• Androgen insensitivity
• Ovarian/testicular dysgenesis (causes
of gonadal failure)
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)
 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 t
– Timing relates to degree of mosaicism in the patien
• Small testicles & gynecomastia
• Also often small phallus size
• 90-100% are infertile
• More female type fat distribution
• Tall in childhood, with euchanoid body habitus
 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 development,
some axillary/pubic hair is typical for most patients
• Associated with SHOX mutations which cause the
short stature
 Eugonadotropic pubertal delay
• Congenital Anatomic Anomalies
–Imperforate hymen
–Vaginal atresia
–Vaginal aplasia
• PCOS
• Hyperprolactinemia
 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
 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**
 Investigations of 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
Wishing you
Best Success