Delayed puberty

Etiology and diagnostic approach

Dr.Sulaiman Hajji MD FRCPI
Senior specialist Endocrinology and Diabetes
 AGENDA
• Definition
• Physiology
• Pathology
• Etiology
• Approach
• Treatment
 DEFINITION
• Puberty is a complex series of physical, psychosocial, and cognitive
transitions usually experienced by adolescents

• Puberty is the process of physical maturation where an adolescent

reaches sexual maturity and becomes capable of reproduction

• Phase of development between childhood and complete, functional

maturation of the reproductive glands and external genitalia
(adulthood)
 FACTS
• On average, puberty typically begins between 8 and 13 in females and 9 and 14 in males

• Genetics: 50-80% of variation in pubertal timing

• Puberty is associated with

• Emotional
• Hormonal changes
• Physical changes

• Puberty proceeds through five stages, termed Tanner stages, ranging from prepubertal, to full
maturity
 Terms
TERMS USED TO DESCRIBE PUBERTAL CHANGES
Term Definition
Adrenarche Pubic and axillary hair development
Gonadarche Gonadal maturation (may be 2 years after adrenarche)
Menarche Onset of menstrual bleeding
Thelarche Onset of breast development
Precocious puberty (male) Secondary sex characteristics before 9 years of age
Precocious puberty (female) Secondary sex characteristics before 8 years
Delayed puberty (male) No secondary sex characteristics by 14 years
Delayed puberty (female) No secondary sex characteristics by 13 years
PHYSIOLOGY
1. A critical event in puberty is an increase
in the pulsatile secretion of
gonadotropin-releasing hormone (GnRH)
from the arcuate nucleus in the
hypothalamus.

2. GnRH causes the release of luteinizing

hormone (LH) and follicle-stimulating
hormone (FSH) from the anterior
pituitary gland

3. Both LH and FSH affect the Leydig and

Sertoli cells in the testes and the theca
and granulosa cells of the ovary

4. Zona reticularis of the adrenal glands

secretes androgens such as DHEA,
resulting in the characteristics of
adrenarche. Zona reticularis functions
separately from the hypothalamic-
pituitary-gonadal axis.
 PHYSIOLOGY
• Hormonal changes in girls
• LH acts on the theca cells of the ovary to convert cholesterol into androgens.
• Granulosa cell converts the androgens to estradiol under the control of FSH
signaling.
• Estradiol acts on various organs until the completion of puberty

• Hormonal changes in boys:

• LH acts on Leydig cells to convert cholesterol into testosterone.
• Testosterone acts on various organs until the completion of puberty
 PHYSIOLOGY
Factors That Influence Puberty
• Genetics factors: 50-80% variation in pubertal timing.
• Environmental factors: Geographical differences, psychosocial stresses,
endocrine disruptors from pollutants, and exposure to chemical and industrial
compounds.
• Obesity: e.g. Leptin; hormone regulates appetite & metabolism through
hypothalamus. Permissive role in regulating the timing of puberty.
• Malnutrition and strenuous physical activity delay puberty.
Tanner scale and puberty
 TANNER STAGE
Tanner Staging, also known as Sexual Maturity Rating (SMR), is an objective classification system
that providers use to document and track the development and sequence of secondary sex
characteristics of children during puberty.

This scale was first quantified in 1969 by James

Tanner, a British pediatrician, after a two-decade-long
study following the physical changes in girls
undergoing puberty
 Tanner stage (male)
TANNER STAGE GENITALIA PUBIC HAIR GROWTH OTHER Age
1 Testes < 2.5 cm Villus hair only 2.0 – 2.4 inches Adrenarche Prepube
per year rtal
2 Testes 2.5 -3.2 cm Sparse hair at 2.0 – 2.4 inches Decrease in body 8–11.5
Thinning and penis base per year fat years
reddening of the
scrotum
3 Testes 3.3 -4.0 cm Thicker curly hair 2.8 – 3.2 inches Gynecomastia, 11.5–13
Increase in penis spreads to the per year voice break, years
length pubis increase muscle
mass
4 Testes 4.5 -4.5 cm Adult hair does 4 inches per year Axillary hair, 12–15
Penis growth not spread to the voice changes, years
Darkening of scrotum thighs acne

5 Testes >4.5 cm Adult hair spreads Deceleration, Facial hair, > 15

Adult genitalia to the medial cessation muscle mass years
thighs increase
Male tanner scale

Prader orchidometer
 Tanner stage (female)
STAGE Breasts PUBIC HAIR GROWTH OTHER Age
1 Elevation of papilla only Villus hair 2.0 – 2.4 inches Adrenarche and ovarian Prepubertal
only per year growth
2 Breast bud under the areola Sparse hair 2.8– 3.2 inches Clitoral enlargement, 8–11.5 years
Areola enlargement along the per year labia pigmentation,
labia growth of uterus
3 Breast tissue grows but has Coarser hair 3.2 inches per Axillary hair, acne 11.5–13 years
no contour or separation pigmented year
covers the
pubes
4 Projection of areola and Adult hair 2.8 inches per Menarche 12–15 years
papilla, secondary mound does not year
formation spread to the
thighs
5 Adult type contour, Adult hair Deceleration, Adult genitalia > 15 years
projection of papilla only spreads to cessation
the medial
thighs
female tanner scale
 FEMALES
• First sign is breast enlargement (Thelarche).
• Menarche usually occurs 2-3 yrs after breast
development (Thelarche).
• Growth spurt peaks before menarche.
• Pubic & axillary hair growth (dependent on
increased secretion of adrenal androgens).
• Growth spurt and closure of the epiphyses typically
begin and end earlier in girls than in boys
MALES
• First signs is testicular enlargement.
• There is a pronounced linear growth spurt.
• As plasma levels of testosterone increase, facial,
pubic, and axillary hair appears, lowering of the
voice, and initiation of spermatogenesis
(spermarche).
Question
A 16-year-old teenager presents to the A. The absence of penile enlargement by age
pediatrician with his mother. After the
12
mother leaves the room, the patient tells
the physician that he is worried about
puberty. He hasn't seen the doctor in 3 B. The absence of linear growth acceleration
years. His friends have had growth spurts by age 13
and started building muscle mass, and their
voices have changed. He still feels C. The absence of testicular enlargement by
underdeveloped. The physician takes a age 14
complete history and performs a thorough
physical examination. He reviews the D. The presence of gynecomastia at age 15
patient's past medical records and growth
charts and notes physical findings E. The absence of adult-type pubic hair
documented over the last few years,
distribution by age 16
concluding that the patient has delayed
puberty. Which of the following findings
supports his conclusion?
Question
A 16-year-old teenager presents to the A. The absence of penile enlargement by age
pediatrician with his mother. After the
12
mother leaves the room, the patient tells
the physician that he is worried about
puberty. He hasn't seen the doctor in 3 B. The absence of linear growth acceleration
years. His friends have had growth spurts by age 13
and started building muscle mass, and their
voices have changed. He still feels C. The absence of testicular enlargement by
underdeveloped. The physician takes a age 14
complete history and performs a thorough
physical examination. He reviews the D. The presence of gynecomastia at age 15
patient's past medical records and growth
charts and notes physical findings E. The absence of adult-type pubic hair
documented over the last few years,
distribution by age 16
concluding that the patient has delayed
puberty. Which of the following findings
supports his conclusion?
Question
A 14-year-old young woman is brought to the
physician by her mother. She is concerned that
A. peak height velocity, thelarche, menarche
her friends have developed breasts and had their
first periods, but she has not. Her mother B. thelarche, menarche, peak height velocity
mentions that she experienced menarche at 14.5
years. She informs the doctor that she is C. menarche, thelarche, peak height velocity
otherwise healthy, with no significant medical
problems or complaints. The physician performs a
complete physical examination, which is normal, D. thelarche, peak height velocity, menarche
and finds that she has attained sexual maturity
rating stage 3 by the sexual maturity ratings. He E. peak height velocity, menarche, thelarche
explains to the patient that the age of menarche
varies significantly between different individuals
and depends upon multiple factors, including
body fat percentage and genes. He tells her that
there is no present concern, given her sexual
development and reassuring physical exam. What
is the typical sequence of puberty in young
women?
Question
A 14-year-old young woman is brought to the
physician by her mother. She is concerned that
A. peak height velocity, thelarche, menarche
her friends have developed breasts and had their
first periods, but she has not. Her mother B. thelarche, menarche, peak height velocity
mentions that she experienced menarche at 14.5
years. She informs the doctor that she is C. menarche, thelarche, peak height velocity
otherwise healthy, with no significant medical
problems or complaints. The physician performs a
complete physical examination, which is normal, D. thelarche, peak height velocity, menarche
and finds that she has attained sexual maturity
rating stage 3 by the sexual maturity ratings. He E. peak height velocity, menarche, thelarche
explains to the patient that the age of menarche
varies significantly between different individuals
and depends upon multiple factors, including
body fat percentage and genes. He tells her that
there is no present concern, given her sexual
development and reassuring physical exam. What
is the typical sequence of puberty in young
women?
Question
An 11-year-old girl presents to the A. Adrenarche
pediatrician with her mother, who is
concerned about her daughter’ sexual
development. She mentions that she herself B. Pubarche
experienced the onset of menses at the age
of 10.5 years while her daughter has still not C. Coarse pubic hair
had a menstrual period. However, the
patient is otherwise a healthy girl with no D. Menarche
significant medical problems since birth. On
physical examination, her vital signs are E. Thelarche
stable. Breast development and pubic hair
are Tanner stage 2. The pediatrician
reassures the mother that her daughter’s
sexual development is within the normal
range for girls and there is nothing to worry
about at present. Which is a sign of Tanner
stage 2 of the breasts?
Question
An 11-year-old girl presents to the A. Adrenarche
pediatrician with her mother, who is
concerned about her daughter’ sexual
development. She mentions that she herself B. Pubarche
experienced the onset of menses at the age
of 10.5 years while her daughter has still not C. Coarse pubic hair
had a menstrual period. However, the
patient is otherwise a healthy girl with no D. Menarche
significant medical problems since birth. On
physical examination, her vital signs are E. Thelarche
stable. Breast development and pubic hair
are Tanner stage 2. The pediatrician
reassures the mother that her daughter’s
sexual development is within the normal
range for girls and there is nothing to worry
about at present. Which is a sign of Tanner
stage 2 of the breasts?
Delayed puberty
Delayed puberty
In boys In girls
• Absence of an increase • Absence of breast
testicular volume (less than 4 development at 13 year
ml) at 14 year
• Lack of pubic hair by 14
• Lack of pubic hair by 15

• Failure to menstruate by age

• More than 5 years to of 15
complete genital enlargement
Delayed puberty
Stalled puberty
Puberty can be considered "stalled" if it was not completed within
approximately four years of its onset. Approximately 95 % of healthy
children complete their full pubertal development within four years

In the clinical setting, an evaluation may be initiated before this

threshold is reached if there is no evidence of pubertal progression for a
sustained period of time (eg, for two or more years).
Delayed puberty
Occurs in approximately 3% of children Classification

In boys, delayed puberty is often 1- functional

constitutional and functional (63%)

2- hypogonadotropic hypogonadism
In girls, delayed puberty is less common
and often organic
3- hypergonadotropic hypogonadism
Delayed puberty
Classification Definition Hormonal profile
Functional Temporary delays of puberty that LOW LH/FSH
are functional disorders, most LOW T/E2
commonly, constitutional delay of
growth and puberty
Hypogonadotropic hypogonadism Hypothalamic of pituitary failure LOW LH/FSH
result in deficiency of circulation LOW T/E2
gonadotrophins
Hypergonadotropic hypogonadism Result from primary gonadal failure HIGH LH/FSH
resulting in elevated serum LOW T/E2
gonadotrophins level
 Functional
Classification Causes
Functional • Constitutional delay of growth and puberty
• Chronic systemic disease
• Acute illness
• Malnutrition
• Celiac disease
• Cystic fibrosis
• Thalassemia and sickle cell disease
• Hypothyroidism, hyperprolactinemia, diabetes mellitus, Cushing's disease
• Anorexia nervosa, bulimia
 Hypogonadotropic hypogonadism
Classification Causes
Hypogonadotropic Acquired
hypogonadism • Tumors
• Benign tumors and cysts, Craniopharyngiomas
• Germinomas, meningiomas, gliomas, astrocytomas
• Infiltrative diseases
• Hemochromatosis, Granulomatous diseases, Histiocytosis
• Head trauma
• Pituitary apoplexy
• Drugs – Marijuana
Congenital
• Isolated GnRH deficiency (also known as idiopathic hypogonadotropic hypogonadism)
• Without anosmia
• With anosmia (Kallmann syndrome)
Associated with adrenal hypoplasia congenita
• GnRH deficiency associated with intellectual disability/obesity
• Laurence-Moon-Biedl syndrome
• Prader-Willi syndrome
• Idiopathic forms of multiple anterior pituitary hormone deficiencies
• Congenital brain malformations
 Hypergonadotropic hypogonadism
Classification Causes
Hypergonadotropic Congenital
hypogonadism • Turner syndrome – 45,XO
• Klinefelter syndrome – 47,XXY)
Acquired
• Autoimmune or postinfectious
• Following trauma or surgery
• Chemotherapy, radiation therapy
 Constitutional delay of growth and puberty (CDGP)

• Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty

• More often in boys than girls

• CDGP is the diagnosis of exclusion

• Due to a transient functional defect in production of GnRH from the hypothalamus, caused by individual
genetic variations

• CDGP tends to have familial patterns of inheritance

• Children with CDGP are more commonly shorter for age, delay in bone maturation and adrenarche

• Not delayed beyond 16 year in girls and 18 year in boys

 Approach – History
• Many causes

• Aim of assessment: determine whether underlying pathological

abnormality vs constitutional and benign pubertal changes

• NB: recognize abnormal timing and progression of puberty

 Approach – History
• Questions about the initiation and evolution of body odor, acne, testicular
growth, and pubic and axillary hair should be asked of patients and their
parents

• Also, it is important to inquire about the psychosocial impact and

emotional stress affecting the patient.

• A family history should be retrieved, including childhood growth patterns

and the parents' age at pubertal onset. It has been estimated that 80% of
patients with CDGP have first-degree family members with delayed puberty
 Approach – History
• Underlying secondary disorders can cause temporary delay of puberty (functional) if they are of
sufficient intensity and duration
• Poorly controlled type 1 diabetes
• Celiac disease
• Severe asthma
• Thyroid disease
• Thalassemia
• Sickle cell disease

• As well as
• Medication use
• Nutritional status
• Bilateral cryptorchidism
• Hyposmia or anosmia may suggest Kallmann syndrome
• History of chemotherapy or radiotherapy
 Approach – physical exam
• Tanner scale, growth chart, and orchidometer are the tools needed to document
and track the development of secondary sexual characteristics and puberty

• Generally looking for any dysmorphic features, midline defects, along with
obtaining height and weight and plotting the measurements for comparing it
with previous ones to assess longitudinal growth is the main part of the
examination.

• The Prader orchidometer is widely used in clinical settings to estimate the

testicular volume and is inexpensive, usually correlates well with
ultrasonography for testicular size and volume
 Approach – physical exam
• 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
 Approach – investigations
• Serum LH, FSH, E2 and testosterone.
• TFT, prolactin, and insulin-like growth factor (IGF-1)
• CBC, ESR, RFT, TTG Ab and LFT
• Karyotype
• A radiograph of the left hand and wrist to evaluate bone age should be obtained at the initial visit
to assess skeletal maturation and then repeated over time if needed.
• Testicular ultrasonography can be used to determine testicular volume
• Additional tests : Inhibin B, AMH, GnRH stimulation, or GnRH-agonist stimulation tests, and HCG
stimulation tests
• Depending upon the clinical presentations MRI brain to rule out intracranial tumors or genetic
testing may be indicated.
 THERAPY
• Patients with specific cause of delayed puberty

• Patients with presumed constitutional delay of growth and puberty

• Constitutional delay of growth and puberty (CDGP) vs isolated gonadotropin-
releasing hormone (GnRH) deficiency
• "watchful waiting," with reassurance and psychological support for the
patient and family, or short-term hormonal therapy, with testosterone in boys
and estradiol in girl

• Hormonal therapy
Question
• A 15-year-old girl was referred to the endocrine Estradiol 32 pmol/L (77–1145)
clinic by her primary care physician with features FSH 46 U/L (1.4–18.1)
of primary amenorrhea. She had normal growth LH 44.5 U/L (3.0–8.0)
and no delay in attaining developmental Prolactin 350 mU/L (45–375)
milestones. Apart from a bicuspid aortic valve for
Testosterone 1.2 nmol/L (0.6–1.9)
which she was under cardiology follow-up, she had
no history of any significant medical disorder. On Free T4 8.5 pmol/L (11.5–22.7)
examination, she was 151 cm tall, with a lack of TSH 7.4 mU/L (0.35–5.5)
development of secondary sexual characteristics.
Which one of the following is the most likely
diagnosis, based on her
clinical profile?
A. Autoimmune hypothyroidism
B. Kallmann syndrome
C. Klinefelter’s syndrome
D. Noonan syndrome
E. Turner’s syndrome
Turner’s syndrome
 Summary
• Delayed puberty
• In boys: Absence of an increase testicular volume (less than 4 ml) at 14 year
• In girls: Absence of breast development at 13 year

• Primary vs 2ndry
• Establish the cause
• Full evaluation
• Treat
THANK YOU