Aberration of Puberty

Near East University

Department of Pediatrics

Asst. Prof. Dr. Nese Akcan

 Contents
• Variants of puberty
• Precocious puberty
– Definition
– Etiology
– Diagnosis
– Treatment
• Delayed puberty
– Definition
– Etiology
– Diagnosis
– Treatment
 Precocious puberty
Definition

• Appearance of
secondary sexual
characteristics at an
age more than 2.5 SD
below the mean
• Girls 8 years of age
• Boys 9 years of age
• Menstruation < 10
years
 Epidemiology

• Incidence 1/5000-1/10000 children

• Female / male 10/1

 True PP
Premature reactivation of the hypothalamic GnRH
pulse generator and HPG axis.

• More prevalent in girls (10-20 x )

• 95% of girls idiopathic
• 50-70% of boys organic
• PP due to organic lesions tend to be earlier
 True PP
Clinic
• Always sexual characteristics are appropriate
for gender
• Appearance of secondary sexual characteristics
is in appropriate order
• Early appearance of breast and pubic hair in
girls
• Early appearance of testicular enlargement and
pubic hair in boys
 True PP
Clinic
• Due to increased gonadotropins, E increase in girls:
– Breast tissue
– Growth spurt
– Bone maturation, increased bone age
– Uterus and ovaries enlarge
– Menstruation

• Due to increased gonadotropins, T increase in boys:

– Testes enlarge
– Pubic hair
– Growth spurt
– Bone maturation, increased bone age
– Penis enlarge
– Spermatogenesis
 True PP Etiology
• Idiopathic
• Tumors of central nervous system
– Astrocytoma, optic glioma, Hypothalamic hamartoma, Ependymoma,
craniyopharyngyoma
• Lesions of CNS
– Encephalitis, trauma, abscess
– Hydrocephalus, arachnoid cyst
– Cranial radiation
– Chemotherapy
• Neurocutaneous syndromes
-Tuberous sclerosis neurofibramatosis
• Hypothyroidism
• Dysmorphic syndromes
-Kabuki makeup syndrome, Russel silver syndrome, Williams syndrome
• Genetics
– Gain of function mutations in GPR54
• Long term exposure to sex steroids ( combined pp)
– Congenital adrenal hyperplasia
– McCune-Albright syndrome
• Nonketotic hyperglycaemia
 Normal

Craniopharyngioma

Hypothalamic hamartoma
2 yr old, boy 6 yr old, girl
Central precocious puberty Central precocious puberty
Hypothalamic hamartoma Idiopathic
Neurofibromatosis Tuberous sclerosis
 True PP

• Imitates normal puberty

• Absence of virilization in girls, absence of
feminizing findings in men ( always
ısosexual findings)
• First sign is the breast development in girls
and increase in testicle volumes in boys
• Somatic development accelerates in both
sexes
 Pseudoprecocious puberty
• Secretion of gonadal steroids independent
of pulsatile GnRH stimulation
– Gonadal
– Adrenal
– Exogenous

• Extrapituitary secretion of gonadotropins

• Gonadotropins are suppressed by negative
feedback of sex steroids ( T or E)
• Somatic development accelerates
• Significant progression at bone age
• According to the secreted hormone, it may
be isosexual or heterosexual
• If seconder sex characteristics are
appropriate to the genetic sex it is isosexual,
if seconder sex characteristics are
inappropriate to the genetic sex it is
heterosexual pp puberty
 Pseudoprecocious puberty
Clinic
Sex steroids increase
without an increase in gonadotropins

• Effects of E: • Effects of T:
– Breast tissue – Penile enlargement
– Growth spurt – Pubic hair
– Bone maturation, increased – Body hair
bone age – Growth spurt
– Uterus enlarge – No gonad enlargement
– No pubic hair
– No gonad enlargement
Girls with Girls with Boys with Boys with
isosexual PPP heterosexual PPP isosexual PPP heterosexual PPP
(E ) ( T or ( T or (E )
androgens ) androgens)

•Breast •Cliteromegalia •Macrogenitalia •Gynecomastia

development •Acne •Pubic hair
•Vaginal •Sound thickening •Smell of sweat
Bleeding •Hairiness in •Musculer
androgen sensitive structure
areas •Frequent erection
•Virilization •Acne
•Prominent pubache •Testis
enlargement (if
testes tumor or
activated
mutation in FSH
receptor, or
combine early
puberty)
 Pseudo PP
Etiology-Isosexual
Females
Males
• Gonadal
• Gonadal
– Activation of LH receptor – Ovarian follicular cysts
(familial testotoxicosis) – E secreting ovarian tumors (
– Leydig cell tumors tumors ovarian tm, teca cell tm,
• Adrenal teratoma
– Congenital adrenal – Excessive aromatase enzyme
hyperplasia
– Adenoma, carcinoma
• HCG secreting tumors Both sexes
– Choriocarcinoma, – McCune Albright syndrome
dysgerminoma, teratoma,
hepatoma – Iatrogenic or exogenous sex steroids
 Pseudo PP
Etiology-Contrasexual

Feminization in males Virilization in females

• E secreting adrenal T • Congenital adrenal
• E secreting testicular T hyperplasia

• Aromatase excess syndrome • Virilizing adrenal T

• Exposure to E • Virilizing ovarian T
• Aromatase deficiency
• Exposure to androgens
 McCune Albright syndrome
• Activating mutation in  subunit of Gs protein
(GNAS1)
• Classical triad
– Polyosteotic fibrous dysplasia
– Cafe au lait spots
– Pseudo PP
 McCune Albright syndrome

• Other hormones whose functions needed G

protein can be involved :
• Cushing Syd
• Thyroid nodular hyperplasia
• Acromegaly
• Prolactinemia
• Hyperparathyroidism
Activating mutations associated with gonadal
gonadotropin receptors or postreceptor signal
transduction and PPP
 LH Receptor activating mutation
(familial testotoxicosis)

LH Receptor

G-protein activating mutation

( McCune Albright syndrome)
 Variants of puberty

• Premature thelarche
• Premature adrenarche
• Premature menarche
• Pubertal Gynecomastia
 Premature thelarche
• Sole breast development
• No other secondary sexual characteristics
• Only in girls
• Two peaks: first two yr and 6-8 yr
• Growth rate normal
• Bone age is not advanced
• Hormones prepubertal Up to 10-18% can
BUT progress to true pp
• Pelvic usg: prepubertal
• No treatment
 Premature adrenarche
• Early pubic or axillary hair
• Early maturation of zona reticularis
• Generally 6-8 years of age
• Girls > boys
• Acne, oily skin and adult type sweating
• Growth is not accelerated
• Bone age is not advanced
• Adrenal androgens (DHEAS) increased to
pubertal levels
• No treatment
 Premature menarche

• Periodical vaginal bleeding

• No secondary sexual characteristics
• Very rare
• Spontaneous resolution
• Etiology not known
• Pubertal development is normal
 Pubertal Gynecomastia

• Unilateral or bilateral
• Frequency: 30-60%
• No treatment
Diagnosis
 History
• Growth patern
• Family history
• Taking any sex steroids
• Losing or puting weight
• Headace , vomiting
• Poliuria, polidipsia
 Examination
• Height,Weight, Target Height
• Signs of Puberty
• Cafe’-au-lait marks
• Strabismus,ocular nerve palsies
• Unilateral larger testis
 Laboratory
• Left hand X-Ray for bone age
• E2 in girls, testosterone in boys, LH,
FSH, TSH, FT4,PRL
• GnRH stimulation test ( LH , FSH
concentrations at 0,30,60 minute)
• Pelvic ultrasound (in girls)
• MRI of Hypothalamic-pituitary area(If
considered Central PP,
• Whether or not neurological symptoms are
present in all cases diagnosed with TPP, we
should do cranial MRI !! (Especially for <6
year old girls and in all boys)
CASE 1.
5 year-old girl, breast development for 3-4 months
A1P1 Breast 2/2

To approach:
What do you want to know about the story of this
child?
What characteristics do you want to evaluate for
physical examination?
Which laboratory tests would be useful in
differential diagnosis?
Case 1:
There is no similar case in the family. She is first child of
family. The mother age of menarche is 11 years old. There is
no steroid intake.
Height: 75. Pers, parental height av. 10. Persantil
Initial examination: bone age 7 Premature telarche is excluded
years
Lab. E2 increase,LH increase,FSH increase;
pelvic US: enlargement ovary and uterus

PPP is excluded
Diagnosis: True PP

For differential diagnosis of True PP, Cranial MRI :normal

Definite diagnosis: idiopathic true early

puberty
Case 2.
3 years old boy, pubic hair for 6 months
A1P2 Testes bilateral 2 ml.

To approach:
What do you want to know about the story of
this child?
What characteristics do you want to
evaluate for physical examination?
Which laboratory tests would be useful in
differential diagnosis?
Case 2:
First child of family. There are no similar cases in the
family. The mother also says that the growth of the child
accelerated. No steroids usage

Height: 97% , target height percentage 25%

Bone age :8 years
Premature adrenarche and TPP are excluded
Diagosis: Periferic PP
For the most common cause for PPP, 17OH prog was
checked and found as high
Definite diagnosis: Congenital adrenal hyperplasia
(21 OH deficiency)
 Consequences of PP

• Psychosocial disorders (low school performance,

depression)

• Short adult height

 Treatment
Aim
• Prevention of pulsatile gonadotropin release
in TPP
• Prevention of early Epiphyseal closure and
target adult height loss
• Prevention of early menarche (<10 years of
age) in girls
• Prevention of late complications of high
estrogen exposure, especially in girls (breast
canser etc.)
 Treatment

Aromatase
inhibitors

Testosterone receptor blockers

 GnRH analoges
• Leuprolide D-Leu6 subcut 20-50 µg/kg/g
IM 140-300 µg/kg/g

• Triptorelin D-Trp6 subcut 20-50 µg/kg/g

IM 60-120 µg/kg/g

In every 28 days, slowly soluble

storage preparations
 Side effects of GnRH analogs
• Local reactions (% 3-8)
• Sterile abscess (1.5%)
• Urticaria
• Polycystic over Synd (?)
• Increase in body mass index
• Decrease in bone density
• Asthma attacks
 Gonadal functions after GnRH
analog therapy
• After the end of Treatment
– 1.2 ± 0.8 year (0.1-4.3) after, menache
Jay N, 1992
Examples
•ÜA, 6 years 2 mo male
•Congenital hypothyroidism
until 6 mo
•Asphyxia and epilepsy
•In his follow-up, he has
acceleration in growth and his
mother says his hands and
feet are growing fast.
• Physical examination:
• A1 P1 Testis 5 ml on the right, 3-4 ml on
the left
• What is Preliminary diagnosis?
• What do you want for lab?
 Laboratuar

• LH: 0,912 LH pubertal,

In LHRH test
• FSH:0,694 LH Peak level >
• T. Testosteron<0.025 5

• KY: 7 Years
What do you want in the
next stage? Central PP
What kind of treatment
should we start?
Cranial and Pituitary MRI:
Suspected microadenoma in adenohypophysis
Treatment:
GNRH analoges
 Examples 2
• SS, 7 year 10 mo girl
• Vaginal Bleeding
• A1P1 Breast 2/2
• At the back of patient, 5x4cm Cafe au lait
spot with irregular edges which does not
pass midline of the body
• Lab:
LH<0.1
FSH<0.1
E2:457.2
KY: 8 year 10 mo
• Pelvic USG: uterus and left ovary
prepubertal, in right ovary 9x5.5 cm cycts
• Bone graphs: Polyosteotic fibrous
dysplasia

Diagnosis: ??
Mac Cune Albright
Synd
Delayed puberty
Delayed Puberty: Definition
The onset of sexual characteristics 2.5 SD above the mean
-in boys: No testicular enlargement by 14 years of age
-in girls: No breast development by 13 years of age or
No onset of menarche by 16 years of age
-in both sexes: More than 5 years elapse between the first sign of
puberty and the onset of menarche or completion of
genital growth

P.S.delayed puberty is more common in boys, because the testes are less sensitive to
gonadotropins than ovaries.
Primary amenorrhea : No onset of menses by 16 yr of age or within 3 yr
or onset of breast development or 1 yr of Tanner V
Secondary amenorrhea: No menses for 3 months after previous
established regular menses.
Delayed Puberty: Classificiation and Etiology

I.With normal or Low serum gonadotrophin values

(Central hypogonadism: Hypogonadotropic Hypogonadism)
A.Transitory (Physiologic)
1-Constitutional delay
B.Reversible
1-Chronic systemic diseases
2-Malnutrition
3-Excessive physical activity
C.Permanent
1-Hypogonadotropic hypogonadism
II.With increased serum gonadotrophin values
(Primary gonadal failure: Hypergonadotropic hypogonadism)
A-Congenital
B-Acquired
 Delayed puberty
Etiology

Inadequate gonadal steroid secretion

Constitutional delay Hypogonadism

in growth and puberty 25%
75%

The most common

cause is :
Hypogonadotropic Hypergonadotropic
Constitutional
12% 13%
delay
Delayed Puberty:Etiology
With Normal or low gonadotropins (Central hypogonadism)
A-Transitory :(Physiologic); Constitutional delay of puberty
B-Reversible:
1-Chronic systemic diseases
a)Endocrine:IDDM, Hypothyroidism, adrenal failure, hyperprolactinemia
b)Nonendocrine: CRF, Chron’s disease, thalassemia, psychiatric, drugs
2-Malnutrition, Anorexia nervosa
3-Excessive physical activity (Athletes, ballet dancers etc)
C-Permanent:Hypogonadotropic hypogonadism
a)Congenital:
Hypothalamic Diseases: Septo-optic dysplasia and other midline defects
Kallmans syndrome
Laurance-Moon-Biedle syndrome
Prader-Willi syndrome, Alstrom syndrome
GnRH defect with X-linked adrenal hypoplasia
Icthyosis and hypogonadism
Pituitary disorders:Congenital deficiency of gonadothropins, hypoplasia
b)Acquired:Hypothalamo-pituitary area tumors, cysts, infiltrations, infections,
r adiotherapy, post
s urgery, autoimmune hypophysitis
 Constitutional delay in puberty

• Delay in timing mechanisms that regulate the onset of

puberty
• %0.6 of children
• Boys > Girls
• Family history (+), genetic role
• Normal physical examination
• Healthy individuals
 Constitutional delay
in puberty

• Delay in puberty
• Delay in growth spurt
• Delay in bone maturation
• Bone age retarded
• Adult height reaches target
height
• Psychosocial problems
 Treatment
• Psychological support
• Testosterone treatment for 6-12 months (?)
 Hypogonadotropic hypogonadism

• Pubertal delay
• No effects of gonadotropins and sex steroids
• Problem in hypothalamus or pituitary gland
• Low FSH, LH
• Low sex steroids
 Hypogonadotropic hypogonadism
etiology
• CNS disorders (tumors, infiltrative dis, infections, radiotherapy,
trauma)
• Isolated gonadotropin deficiency
– Kallmann syndrome (KAL1, FGF8,
FGFR1, PROK2, PROKR2, TAC3,
TACR3, Kiss1, Kiss1R mutations)
– GnRHR deficiency
– Others (Lep, LepR mutations)
• Multiple pituitary hormone deficiency
– Syndromes (Prader-Willi, Laurence-Moon)
– Genetic (PROP1, HESX1, LHX3 mutations)
• Functional causes (chronic systemic dis, malnutrition, anorexia
nervosa, psychologic stress, heavy exercise)
 Kallmann syndrome

• HH with anosmia/without anosmia

• X linked- KAL1 gene, anosmin-1 protein
• Anosmin-1 is responsible for the migration of
GnRH ve olfactory neurons

• AD Kallmann – mutation in FGFR-1 gene

no anosmia
 Hypergonadotropic hypogonadism

• Pubertal delay
• No effects of gonadotropins on gonads
• Problems in
– gonads or
– receptors of gonadotropins or
– sex steroid synthesis
• High FSH, LH
• Low sex steroids
 Hypergonadotropic hypogonadism
etiology
• Girls • Boys
– Gonadal disease – Gonadal disease
• Turner’s syndrome • Klinefelter syndrome
• Gonadal dysgenesis • Gonadal dysgenesis
• Autoimmune gonadal failure • Autoimmune gonadal failure
• Metabolic diseases • Infections
• Radiotherapy • Radiotherapy
• Chemotherapy • Chemotherapy

– Gonadotropin resistance – Gonadotropin resistance

• LH resistance • LH resistance
• FSH resistance • FSH resistance
– Disorders of sex steroid – Disorders of sex steroid
synthesis synthesis
• SF1, StAR, • SF1, StAR,
• 17 OH’lase, 17,20 liyase aromatase • 17 OH’lase, 17,20 liyase,
def, • 3 OHsteroid De’Hase,
• 3 OHsteroid De’Hase,
 Turner’s syndrome

• Incidence 1/2000 girls

• 45 XO, 45 XO/46 XX
• Abnormalities of X chromosome
• Complete ovarian failure
• Growth retardation, nuchal skin thickness, cubitus valgus
• Cardiac and renal abnormalities
 Klinefelter syndrome
• Incidence 1/500, 1/1000
• 47 XXY and mosaic type (47XXY/46XY)
• Small testes
• Azospermia
• Decreased testosterone level
• Decreased sexual functions
• Tall and long extremities
• Learning difficulties
• Obesity
• Increased risk of breast ca
Delayed Puberty: Diagnosis: a) History
-Age on onset of any pubertal sign, pubic hair erection, cyclic
abdominal pain etc
-Family history of delayed puberty/hypogonadism:
Congenital etiologies
-Delayed but spontaneous puberty in parents or relatives:
Constitutional delay
-History of chronic illness, physical activity, diet
Reversible etiologies: Systemic disease, athletes, anorexia N.
-History of prior chemotherapy, radiotherapy, surgeries, trauma,
infections: Acquired etiologies
-History of headache, visual disturbances:
İntracranial tumor, cyst, infiltrations
-Careful questioninig of galactorrhea:
Hyperprolactinomia
Delayed Puberty:Diagnosis
b)Physical examination
-Short stature:
Constitutional delay, Turner syndrome, Prader Willi S, hypogonadism with GH deficiency

-Tall stature and enuchoid body habitus (U/L ratio decreased):

hypogonadotropic hypogonadism, klinefelter syndrome, Kallman synd

-Underweight:Anorexia nervosa, malnutrition

-Associated abnormalities:
-Anosmia:Kallmann syndrome
-Blindness, hypoplastic optic disc:Septo-optic dysplasia
-Papilledema, visual field defect:intracranial lesions
-Obesite:Laurance-Moon-Biedl, Alstrom, Prader Willi sydromes
-Midline defects:Hypopituitarism

-Spesific findings in systemic diseases and endocrinopathies

 Delayed Puberty

Short stature Pause in growth Tall Stature

Chronic disease Cerebral Tm Klinifelter
Turner Kallman
GH Deficiency Gn Deficiency
Constitutional
Hypothyroidism
Gn+GH Deficiency
Constitutional
Delayed Puberty: Diagnosis:Laboratory evaluation
1-Basal gonadotropin levels
*Diagnostic in hypergonadotropic hypogonadism (primary gonadal failure)
Basal FSH and LH are >15 mIU/ml

*Not diagnostic in hypogonadotropic situations

Due to pulsatile secretion of gonadotropins basal gonadotropin levels are
normally found low and are not very helpful in differential diagnosis of HH
Basal LH and FSH are usually < 2.0 mIU/ml

2-Stimulated gonadotropin levels:

*GnRH (LHRH) test:
-Prepubertal response (no significant increase in LH) is obtained in all types of
hypogonadotropic hypogonadism: (transitory, reversible or permanen, not helpful in differing
one another)

-Post-GnRH LH < 2.5 suggests permanent hypogonadotropic hypogonadism,

however not pathognomonic
Delayed Puberty: Diagnosis:Laboratory evaluation:
*GnRH test (Cont’d)
-Exagerated response in hypergonadotropic hypogonadism
*GnRH analogue tests:(i.e. Leuprolide test):
-better in differentation of low gonadotropins situations

3-Determination of sex steroids

-Basal:In all types of delayed puberty basal estrogen and testosteron
levels are lower than normal pubertal levels
-Stimulated: In boys testosterone response to IM adminisration of HCG
is helpful in diagnosing testosterone biosynthesis defects
-Tests for systemic diseases
-Endocrine: TFT, Prolactine, Cortisol, GH, sex steroids precursors
-Nonendocrine: CBC, biochemistry, ESR
Delayed Puberty:Diagnosis:Laboratory evaluation:

5-Radiologic investigation:
Bone age: delayed in most conditions except Turner S.
X-ray of cella:Craniopharengeoma and other tumors
Pelvic USG: (in girls) shows ovarian activity (follicle cysts) or change in
shape and size of the uterus
MRI of the head: in hypogonadotropic hypogonadism

6-Cytogenetic studies: in hypergonadotropic hypogonadism

Bucceal smear
Karyotype
Delayed Puberty:Management
I-Treatment of underlying causes
Surgical: Tumors, cysts
Medical: Treatment of systematic and endocrine disorders
Improvoment of nutritional status
Treatment of emotional disturbances
Discontinuation of heavy physical activity, drugs
in constitutional delay:
Reassurance and watchful waiting
A short course of sex hormone therapy if there is poor self image and
psychological distress.
II-Treatment of hypogonadism:
Goals of treatment:
1-to promote secondary sexual characteristics
2-to start menstrual periods in girls
3-to prevent detrimental effecets of hypogonadism on bone
Delayed Puberty:Management
Treatment hypogonadism: (replacement therapy with sex steroids)

In males:Testosterone
-Depot testosterone (enanthate or cypionate)
6-12 months 50 mg/month IM
6-12 months 100 mg/month IM
After that 220-300 mg every 3-4 weeks IM
*Sustanon ampul 250mg includes short and long acting T esters

- Transdermal testosterone patches:

Provide more physiologic delivery but less practical
10-15 mg of testosterone placed daily on scrotal skin
Oral testosterone
Testosterone undecaonate (Virigen) 20-40mg/day
Halotestin 5-10mg/day
Oral testosterone may cause hepatotoxicity
Delayed Puberty:Management
in Females:Estradiol
-İnitially continious estrogen therapy (Ethynil estradiol or conjugated estrogen) alone for 2 years (to
promote feminization)
-A progestational agent (medroxprogesterone acetate) is added when breakthrough bleeding starts
(cyclic therapy)
*Estrogen for 1-21. days each month

*Progesterone for 14-21. days of each month

Ethynil Estradiol Conjugated Estrogen MPA

(Progynon-C) (Premarin) (Farlutal)
12 months 5 g 0.325 mg -
12 months 10 g 0.625 mg -
12 months 10 g 0.625 mg 5 mg
12 months 20 g 1.2 mg 10 mg

*Once the optimal height is achieved patients can be switched to birth control pills which are more
convenient to use (i.e. Myralon tablet)
Delayed Puberty:Management
Induction of fertility:
In hypogonadotropic hypogonadism:
-In both sexes this is best achieved by pulsatile adminisration of
GnRH by a programmable pump in patients with hypogonadism of
hypothalamic origin.

Also combination of LH (hCG) and FSH (Human menopausal

gonadotropin) is used to induce ovulation and spermatogenesis in
patients with hypogonadism of either hypothalamic or pituitary
etiology.

In primary ovarian failure:

-Pregnancy is possible by oocyte donation and in vitro fertilization.
 Case
DM, 17 years 8 mo boy
No beard and mustache
Enuchoid body habitus
A2P2 Testes bilateral 3-3 ml
What do you want to learn more ??
No additional illness, no history of trauma,
no problem with smell, no similar case,
angry boy, Bad school success, no
verbal or language problems
Total testosteron :0.36 (low)
LH:0.393 (low)
FSH: 0.259 (low)
Other pituitary hormones, cranial and
pituitary MRI normal
Karyotype: 46,XY
Genetic analysis ??
Thank you…