Delayed Puberty – A

Disorder in Timing
Physical Examination

• Examination of Growth
• Height
• Weight
• Head circumference
• Upper to lower segment ratios
• Pubertal Assessment (Tanner staging)
• Axillary hair
• Pubic hair & staging
• Breast development & staging
• Genital development & staging
• Neurological assessment

CPS position statement on growth measurment

Tanner Staging of Puberty in Males
• Tanner I 
• prepubertal (testicular volume less than 3.5 ml; small penis of 3 cm or less)
[typically age 9 and younger]
• Tanner II 
• testicular volume between 1.6 and 6 ml; skin on scrotum thins, reddens and
enlarges; penis length unchanged [9-11]
• Tanner III 
• testicular volume between 6 and 12 ml; scrotum enlarges further; penis
begins to lengthen to about 6 cm [11-12.5]
• Tanner IV 
• testicular volume between 12 and 20 ml; scrotum enlarges further and
darkens; penis increases in length to 10 cm and circumference [12.5-14]
• Tanner V 
• testicular volume greater than 20 ml; adult scrotum and penis of 15 cm in
length [14+]
Tanner Pubic Staging

Pubic hair (both male and female)

• Tanner I 
• no pubic hair at all (prepubertal Dominic state) [typically age 10 and
younger]
• Tanner II 
• small amount of long, downy hair with slight pigmentation at the base of the
penis and scrotum (males) or on the labia majora (females) [10–11.5]
• Tanner III 
• hair becomes more coarse and curly, and begins to extend laterally [11.5–13]
• Tanner IV 
• adult-like hair quality, extending across pubis but sparing medial thighs [13–
15]
• Tanner V 
• hair extends to medial surface of the thighs [15+]
Tanner Breast Development

Breasts (female)
• Tanner I 
• no glandular tissue; areola follows the skin contours of the chest (prepubertal)
[typically age 10 and younger]
• Tanner II 
• breast bud forms, with small area of surrounding glandular tissue; areola begins to
widen [10-11.5]
• Tanner III 
• breast begins to become more elevated, and extends beyond the borders of the
areola, which continues to widen but remains in contour with surrounding breast
[11.5-13]
• Tanner IV 
• increased breast size and elevation; areola and papilla form a secondary mound
projecting from the contour of the surrounding breast [13-15]
• Tanner V 
• breast reaches final adult size; areola returns to contour of the surrounding breast,
with a projecting central papilla. [15+]
Normal Pubertal Physiology
- HPG axis (hypothalamic-
pituitary-gonadal) is
essential in turning on
puberty at appropriate
times
- Pulsatile secretion of
GnRH is essential
- GnRH is produced in
hypothalamus (in arcuate
nucleus)
- GnRH travels to the
anterior pituitary to
stimulate the production
of LH & FSH
Role of Gonadotropins

• FSH
• Stimulates androstenedione by the ovary
• Involved in spermatogenesis in the testes
• Induces receptors for LH
• LH
• Uses androstenedione for substrate to produce
estradiol in theca cells
• Stimulates testosterone synthesis by Leydig cells
• FSH is usually higher than LH in prepubertal stages,
and this reverses in pubertal stages
Age of Pubertal Progression

• Females
• The larche
• Generally considered the onset of puberty
• Occurs in most girls at 9.5-10.4
• Menarche
• Mean age of onset = 12 yrs
• Adrenarche
• Usual onset at approx age 9.4-10.6 yrs
• Linear Growth
• Generally occurs before Tanner Stage 2 breast development
• Generally adds 20-25cm of height in females
• GH increases during puberty as well (provides 50% of growth spurt)

(NHANES III dates)

Pubertal Progression

• Males
• Gonadarche
• Testicular enlargement generally heralds the onset of puberty (testes >
4ml). This usually starts around 10.8-11.1 yrs.
• Initial increases in testicular size are due to increase in Sertoli (supporting
cells)
• Average time to complete genital development = 3yrs
• Thelarche
• 2/3 of males will have gynecomastia develop during puberty
(midpubertal)
• Gynecomastia results from direct testicular secretion of estrogen as well
as peripheral conversion of prohormones to estrogen
• Pubarche
• Linear growth
• Peak growth generally occurs after Tanner Stage 5
• Generally adds 25-30cm in height for males
Pubertal Milestones
Females Males
Tanner stage 2 breasts Testicular growth
Tanner stage 2 pubic hair Tanner 2 genital development
Peak linear growth Tanner stage 2 pubic hair
Greatest weight gain Tanner stage 3 genital
Tanner stage 3 breast Tanner stage 3 pubic hair
Axillary hair growth Peak linear growth
Acne Onset of pubertal gynecomastia
Menarche Axillary hair
Tanner stage 4 breast Voice pitch changes
Tanner stage 4 pubic hair Acne

Tanner stage 5 breast Spermarche

Regular menstrual cycles Tanner stage 4 genital
Tanner stage 5 pubic hair Tanner stage 4 pubic hair
Tanner stage 5 pubic hair
Tanner stage 5 genital
 Role of Bone Age
• Comparing radiographs of
hand & wrist to reference
standards

• Female skeletal maturity is

generally 2 yrs advanced
as compared to males

• Pubertal events more

correlated with bone age
than chronological age
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 < 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
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
Hyper gonadotropic Hypogonadism
Patients with hypergonadotropic hypogonadism may
have some or all of the following characteristic findings:
• Increased FSH level
• Increased LH level
• Low testosterone level
• Impaired production of sperm
Hypogonadotropic Hypogonadism
The condition of hypogonadotropic hypogonadism is
generally associated with the following findings:
• Low or low-normal FSH level
• Low or low-normal LH level
• Low testosterone level
• Impaired production of sperm
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
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)
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
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
Hypergonadotropic hypogonadism
• Gonadal damage secondary to chemotherapy/radiation
• Enzyme defects in the gonads
• Androgen insensitivity
• Ovarian/testicular dysgenesis (causes of gonadal failure)
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)
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)
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
statureResidual ovarian function can cause breast
development in 15-25%, menarche in 5-10% &
pregnancy in 1-3%
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
Eugonadotropic pubertal delay

• Congenital Anatomic Anomalies

• Imperforate hymen
• Vaginal atresia
• Vaginal aplasia
• PCOS
• Hyperprolactinemia

• In this case, secondary sex characteristics are normal

• May have cyclic lower abdominal pain
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