Puberty

YOHANES IDDO ADVENTA

 Adolescents  maturation, including cognitive, psychosocial,
and physical

 most visible changes during puberty are growth in stature and

development of secondary sexual characteristics
specific components

 ●Thelarche is the appearance of breast tissue, which is primarily

due to the action of estradiol from the ovaries.

 ●Menarche is the time of first menstrual bleed. The first menstrual

bleed is often not associated with ovulation

 ●Spermarche is the time of the first sperm production (heralded by

nocturnal sperm emissions and appearance of sperm in the urine)

 ●Pubarche is the appearance of pubic hair, which is primarily due to

the effects of androgens from the adrenal gland
 Precocious puberty (precocious
gonadarche)  pubertal onset at
an age 2 to 3 standard deviations
(SD) below the mean age of onset
of puberty.

 US  appearance of breast
development before the age of
eight years in girls, and testicular
enlargement before the age of
nine years in boys
 develop signs of puberty between
six and eight years of age? the need
for clinical evaluation depends
 Delayed puberty is defined as the absence of signs of puberty
by an age 2 to 3 SD above the mean age of onset of puberty

 US  corresponds to an upper limit of 12 to 13 years for girls (for

breast development) and of 13 to 14 years for boys (for testicular
enlargement) 
PHYSIOLOGY AND
ENDOCRINOLOGY OF
PUBERTY
 Gonadarche is driven by an increase in
the pulsatile secretion of
gonadotropin-releasing hormone
(GnRH) from the hypothalamus,
resulting in increases in both frequency
and amplitude of pulses of luteinizing
hormone (LH) secretion

 GnRH stimulates the gonadotroph cells of

the anterior pituitary gland to secrete
follicle-stimulating hormone (FSH) and
LH, which in turn stimulate sex-
steroidogenesis and eventually
gametogenesis in the gonads.
 In girls, FSH stimulates the growth of ovarian follicles and, in
conjunction with LH, stimulates production of estradiol by the
ovaries.

 Early in puberty  estradiol stimulates breast development

and growth of the skeleton, leading to pubertal growth
acceleration.

 Later in puberty, the interplay between pituitary secretion

of FSH and LH, and secretion of estradiol by ovarian follicles
leads to ovulation and menstrual cycles.
 Though temporally correlated, gonadarche and adrenarche are
physiologically distinct events.

 Adrenarche begins when the zona reticularis of the adrenal

gland begins to synthesize the adrenal androgens
 dehydroepiandrosterone (DHEA) and androstenedione 
androgenic changes including
 growth of pubic and axillary hair, maturation of the apocrine sweat glands
(leading to adult-type body odor), and development of acne.
PUBERTAL CHANGES

 Sexual maturity rating (Tanner stages) — Puberty consists of a series of

events that usually proceed in a predictable pattern with some variation in
timing of onset, sequence, and tempo

 Growth spurt — Approximately 17 to 18 percent of adult height accrues

during puberty

 Bone growth — Bone growth accelerates during puberty, in concert with

heigh

 Weight and body composition  especially in lean body mass and the
proportion of body fat (adiposity), with different patterns in girls as
compared with boys.
Stages in breast
development in girls
Stage 1: Prepubertal, with no palpable breast
tissue.

Stage 2: Development of a breast bud, with

elevation of the papilla and enlargement of the
areolar diameter.

Stage 3: Enlargement of the breast, without

separation of areolar contour from the breast.

Stage 4: The areola and papilla project above the

breast, forming a secondary mound.

Stage 5: Recession of the areola to match the

contour of the breast; the papilla projects beyond
the contour of the areola and breast.
Stages of
development in
pubic hair in girls.
Stage 1: Prepubertal with no pubic hair.

Stage 2: Sparse, straight hair along the

lateral vulva.

Stage 3: Hair is darker, coarser, and

curlier, extending over the mid-pubis.

Stage 4: Hair is adult-like in appearance,

but does not extend to the thighs.

Stage 5: Hair is adult in appearance,

extending from thigh to thigh.
TIMING OF PUBERTAL EVENTS

 Trends in pubertal timing — Pubertal onset in girls has been

trending earlier in the United States and in most other developed
countries

 The mean ages for the onset of breast development were 8.87
years in African-American girls and 9.96 years in white girls, and
the mean age for pubic hair growth was 8.78 years in African
American girls and 10.51 years in white
Physiology of pubertal onset

 increase in the pulsatile secretion of GnRH from the

hypothalamus.
 The question, "What triggers puberty?" can therefore be
reframed as, "What triggers the increase in GnRH
secretion at puberty?"

 Theoretically, puberty can start as the result of the emergence

of activators of GnRH secretion or the suppression of
inhibitors of GnRH secretion.
Activators of GnRH secretion

 Glutamate has long been known to stimulate GnRH neuronal

activity in animal models, but whether glutamate is directly involved
in determining pubertal timing remains unclear. Similarly, while the
hormone leptin is required for normal pubertal onset in humans, it
seems unlikely to play a role in determining pubertal timing, as
discussed above.

 Another stimulatory factor, kisspeptin, appears to have an

important role in the initiation of puberty in humans
 Signaling by neurokinin B also appears to be an important stimulus
for pubertal onset 
Inhibitors of GnRH secretion

 Patients with precocious puberty provide insight into potential

inhibitors of GnRH secretion. It has long been recognized that
lesions of the central nervous system (CNS) can cause
precocious puberty.
 The neurotransmitter gamma-aminobutyric acid (GABA)
appears to play an important role in these inhibitory pathways. 

 Loss-of-function mutations in the gene MKRN3 have been found

to be a genetic cause of precocious puberty 
 Mutations in DLK1 have also been suggested to be a cause of
delayed puberty.
Precocious
puberty
 Precocious puberty is the onset of pubertal development at an
age that is 2 to 2.5 standard deviations (SD) earlier than
population norms.

 The cause :
 a variant of normal development (eg, isolated premature
adrenarche or isolated premature thelarche) to
 pathologic conditions with significant risk of morbidity and even
death (eg, malignant germ-cell tumor and astrocytoma).
 ●Is the child too young to have reached the pubertal
milestone in question?

 ●What is causing the early development?

 attributable to androgen and/or estrogen effects?
 source of sex hormone?

 ●Is therapy indicated, and, if so, what therapy?

DEFINITION
 Precocious puberty is
traditionally defined as the onset
of secondary sexual
characteristics before the age of
eight years in girls and nine
years in boys

 These limits are chosen to be 2

to 2.5 standard deviations
(SD) below the mean age of
onset of puberty.

 mean age of onset of puberty of

approximately 10.5 years in girls
and 11.5 years in boys
 The hypothalamic-pituitary-gonadal axis
 biologically active in utero and briefly during the first week of
life  more active again during infancy, with peak activity between
one and three months of age

 In girls, luteinizing hormone (LH) levels decrease at approximately

the same time as in boys, but the follicle-stimulating hormone
(FSH) concentrations can remain elevated into the second
year of life.
 "mini puberty of infancy"; its biologic relevance is unknown
 The neonatal stage is followed by active suppression of the
hypothalamic-pituitary-gonadal axis until puberty occurs
EPIDEMIOLOGY

 expect that the

prevalence rate should
be around 2 percent, ie,
2 in every 100 children.
THRESHOLD FOR EVALUATION

 We suggest careful evaluation of children presenting with signs of

secondary sexual development younger than the age of eight
years in girls or nine years in boys.

 The level of concern and extent of evaluation should

increase with younger age at presentation but decrease
in the presence of factors associated with earlier pubertal
timing
 Given the trend towards earlier pubertal development :
 a comprehensive history, physical examination, and clinical follow-up
may be sufficient if the clinical evaluation does not raise any
additional concerns
CLASSIFICATION

 Precocious puberty can be classified based upon the underlying

pathologic process
 ●Central precocious puberty (CPP) –

 CPP (also known as gonadotropin-dependent precocious

puberty or true precocious puberty) is caused by early
maturation of the hypothalamic-pituitary-gonadal axis.

 isosexual
 CPP is pathologic in up to 40 to 75 percent of cases in boys,
compared with 10 to 20 percent in girls 
 ●Peripheral precocity – also known as peripheral precocious
puberty, gonadotropin-independent precocious puberty
 excess secretion of sex hormones
 may be appropriate for the child's gender (isosexual) or inappropriate,
with virilization of girls and feminization of boys (contrasexual).

 ●Benign or nonprogressive pubertal variants – Benign

clinical pubertal variants
 isolated breast development in girls (premature thelarche) or
 isolated androgen-mediated sexual characteristics (such as
pubic and/or axillary hair, acne, and apocrine odor) in boys or girls
CAUSES OF CENTRAL
PRECOCIOUS PUBERTY
 Central precocious puberty  caused by early maturation of
the hypothalamic-pituitary-gonadal axis  the pattern and
timing of pubertal events is usually normal.

 CPP can be treated  a gonadotropin-releasing hormone (GnRH)

agonist, which leads to downregulation
 Idiopathic  80 to 90 percent of cases of girls
 Central nervous system lesions
 Genetics
 KISS1
 MKRN3
 DLK1 (delta-like 1 homolog)
 Previous excess sex steroid exposure
 high serum levels of sex steroid (eg, those with McCune-Albright
syndrome and poorly controlled congenital adrenal hyperplasia)
 Pituitary gonadotropin-secreting tumors
CAUSES OF PERIPHERAL
PRECOCITY
 derived either from the gonads or adrenal glands or from
exogenous sources
 Further characterization
 appropriate for the child's gender (isosexual) or
 inappropriate, with virilization of girls and feminization of boys
(contrasexual)

 The approach to treatment for peripheral precocity depends on

the cause. GnRH agonist therapy is ineffective, in contrast
to patients with central precocious puberty (CPP)
 Ovarian cysts — A functioning follicular cyst of the ovaries is
the most common cause of peripheral precocity in girls

 Ovarian tumors  rare  Granulosa cell tumors, the most

common type
 Both girls and boys  excess estrogen will cause feminization, while excess androgen
will result in virilization.
 Primary hypothyroidism 
 Exogenous sex steroids — Feminization, including gynecomastia in boys, has been attributed
to excess estrogen exposure from creams, ointments, and sprays
 Adrenal pathology 
 McCune-Albright syndrome — McCune-Albright syndrome is a
rare disorder
 defined as the triad of peripheral precocious puberty, irregular café-
au-lait ("coast of Maine") skin pigmentation, and fibrous dysplasia of
bone

 MAS should be considered in girls with recurrent formation of

follicular cysts and cyclic menses
TYPES OF BENIGN OR
NONPROGRESSIVE PUBERTAL
VARIANTS
 Early pubertal development fits into this category when the
early development of secondary sexual characteristics
does not herald underlying pathology and is not followed
by progressive development

 Premature thelarche 
 Premature adrenarche
 Pubic hair of infancy
 Benign prepubertal vaginal bleeding 
 Nonprogressive or intermittently progressive precocious
puberty
EVALUATION

 Guiding principles — The evaluation for precocious puberty

focuses on answering the following questions:

 ●Who should be evaluated? 

 ●How quickly is the puberty progressing? 
 ●Is the precocity because of excess androgen or
estrogen? 
 Initial evaluation — The evaluation of a patient suspected to
have precocious puberty begins with a history and physical
examination

 ●Medical history – The history focuses on when the initial

pubertal changes were first noted, as well as the timing of
pubertal onset in the parents and siblings
 ●Physical examination – This includes height, weight, and
height velocity (cm/year).

 ●Pubertal staging – Secondary sexual development should be

assessed to determine the sexual maturity rating (Tanner stage)
of pubertal development.

 ●Bone age 
 Initial laboratory evaluation — If there is evidence of progressive
development of secondary sexual characteristics, further evaluation
is needed to determine its cause, whether therapy is needed,
and, if so, which treatment is appropriate

 The first step is to measure basal luteinizing hormone (LH),

follicle-stimulating hormone (FSH), and either estradiol
and/or testosterone concentrations. The results are used to
differentiate between CPP and peripheral precocity, which then
guides additional testing

 Basal serum luteinizing hormone 

 Basal serum follicle-stimulating hormone 

 Serum estradiol 

 Serum testosterone 
Imaging

 ●Central precocious puberty (CPP)

 •Brain magnetic resonance imaging (MRI) 
 •Pelvic ultrasound 

 ●Peripheral precocity
 •In girls with progressive peripheral precocity, a pelvic ultrasound
can be performed to help identify the presence of an ovarian cyst or
tumor.
Delayed puberty
definitions

 Delayed

 Stalled

 Hypogonadism
etiology

 Primary hypogonadism
 Secondary hypogonadism
 Constitutional delay
 Isolated GnRH def
 Other forms of functional hypogonadotropic hypogonadism
 Hypothalamic of pituitary disease