Puberty

by
Dr. Hamdy Azab
Ass. Prof. Cairo University
 Puberty
Introduction
Puberty is defined as the period of time during
which
secondary sexual characteristics develop,
menstruation
begins and the psychological outlook of the girl
.changes
The end result of puberty is the establishment of
the fully
physically mature adult woman capable of
reproductive
performance and fully psychologically developed as
an
.adult
 Pubertal stages
Normal puberty is a progression of
events in both girls and boys that is
generally
complete in 3-4 years. In females,
thelarche (breast buds) is usually the
first sign of estrogen production and
occurs at an average age of 10.5
years, while
pubarche (pubic hair growth) generally
occurs about 6 months later. In 10-
20%
Pubertal stages
 Pubertal stages
Maximal growth velocity occurs in girls at age 12
and usually results in about a 9 cm increase in
.height
Menarche (initiation of menses) occurs on the
downward arm of the growth curve at a median
age of 12.5 years (white: 12.6 years; black: 12.15
/years; Mexican
American: 12.3 years). A variety of additional
factors affect pubertal onset, such as weight,
stress, and extreme physical activity. Some
authors have noted a younger
age of onset of breast development and possibly
menarche in African-American girls that may be
.attributable to a greater BMI
 Physiology of puberty
The onset of puberty is controlled by many
factors that remain incompletely
understood. The overall earlier onset of
puberty among the general population has
been attributed to the increasing
prevalence of obesity. It has been
proposed that a critical body weight or
body composition is the most salient issue
in the development and maintenance of
pubertal events. However, body weight
alone probably is not a sufficient
.explanation
 Physiology of puberty
It appears that the hypothalamic–pituitary–
gonadal axis in girls develops in two
.distinct stages during puberty
First, sensitivity to the negative or inhibitory
effects of the low levels of circulating sex
steroids present in childhood decreases
.early in puberty
Second, late in puberty, there is maturation
of the positive or stimulatory feedback
response to estrogen, which is responsible
.for the ovulatory midcycle surge of LH
 Physiology of puberty
Leptin has been proposed as the hormone responsible for the
initiation and progression of puberty. Leptin is produced
largely in adipocytes; and serum leptin concentrations are
highly correlated with body fat content. The potential
importance of leptin is illustrated by the observation that
mice and rats deficient in leptin fail to undergo pubertal
development, whereas the administration of leptin to such
.animals results in pubertal onset
Leptin appears to be one of several factors that influence the
maturation of the gonadotropin-releasing hormone (GnRH)
pulse generator, probably as a signal of the availability of
.metabolic fuel
GPR54 gene — The GPR54 gene on chromosome 19p13.3,
which encodes a G-protein coupled receptor, appears to
have an important role in the initiation of puberty via its
effect on hypothalamic GnRH .Mutations in GPR54 cause
autosomal recessive idiopathic hypogonadotropic
hypogonadism in humans and in a GPR54 knockout mouse
.model
 Precocious puberty

DEFINITION — Abnormal or precocious early

pubertal development is defined as children
entering puberty more than 2.5 standard
deviations (SD) earlier than the median or mean
.age
Based upon this definition and the assumption that
the average age of onset of puberty was 10 years
in girls and 12 years of age in boys,precocious
puberty had been defined as secondary
sexual development before the age of 8
years in girls and 9 years in boys
N.B. This disorder is five times more common in
.girls than boys
 Classification

Central precocious puberty is characterized in

girls by both breast and pubic hair sexual
maturation. It is caused by earlier activation of
the normal pubertal developmental process
mediated by the HPG axis. In these patients, the
sexual characteristics are appropriate for the
.(child's gender (isosexual
Peripheral precocious puberty, is caused by an
autonomous peripheral excess sex hormones (eg,
estradiol and testosterone), which is independent
of the HPG axis. In these patients, it is further
.classified to isosexual or contrasexual
 Central (True) precocious
puberty
Idiopathic; 80-90% of cases
CNS tumors, most commonly hamartomas
CNS radiation
Other CNS lesions, such as hydrocephalus, cysts, trauma or
infection, empty sella syndrome
Genetics — GPR54 is a G protein-coupled receptor which acts
as a ligand for kisspeptin. The action of the kisspeptin-
GPR54 signaling complex is essential for gonadotropin-
releasing hormone physiology and for initiation of puberty.
Gain-of-function mutations in GPR54 can cause central
precocious puberty. Conversely, loss-of function mutations
.in GPR54 can cause hypogonadotropic hypogonadism
Primary hypothyroidism; rarely in longstanding cases due
.to stimulation of FSH receptors by high TSH
 Peripheral Precocious Puberty
((Gonadotropin-Independent
Ovarian cysts — Follicular cysts of the ovaries is the most
common cause of independent precocity in girls. Affected
.patients often present after an episode of vaginal bleeding
Ovarian tumors — Granulosa-cell tumors, Leydig cell tumors
.and gonadoblastoma are rare causes of precocious puberty
Gonadotropins/HCG producing tumors- choriocarcionoma, 
dysgerminoma, teratoma
Adrenal pathology- CAH- There are a variety of types. These
are autosomal recessive disorders of adrenal
steroidogenesis leading to excess (ACTH), hence excess
cortisol precursors which get pushed into the androgen
.pathway leading to androgen excess
Exogenous estrogen — Feminization has been attributed to
excess estrogen exposure from creams and ointment, and
.food contamination
 Peripheral Precocious Puberty
((Gonadotropin-Independent
McCune-Albright syndrome — (MAS) is a rare
disorder defined as the triad of peripheral
precocious puberty, café-au-lait skin
pigmentation, and fibrous dysplasia of
.bone
Patients with MAS have a somatic mutation
of the alpha subunit of the G3 protein that
activities adenylate cyclase. This mutation
leads to continued stimulation of
endocrine function (eg, precocious
puberty, gigantism, Cushing syndrome,
adrenal hyperplasia, and thyrotoxicosis),
.in various combintations
 Evaluation

Basal LH levels and GnRH

stimulation — Children with central
precocious puberty can be distinguished
from those with peripheral precocious
puberty on the basis of measurements of
LH levels, at baseline and after
administration of GnRH. In peripheral PP,
LH and FSH levels are low at baseline and
will not increase with GnRH stimulation. In
a central process, basal levels of LH and
FSH are often at pubertal levels and will
.increase with GnRH stimulation
 Treatment of central
precocious puberty
Decision to treat — The decision to treat central precocious puberty
depends on the etiology and the pace of the sexual maturation.
When there is an identifiable CNS lesions, therapy is directed, if
possible, toward the underlying pathology. If there is not an
identifiable cause, the decision whether to treat is dependent on
.the rate of sexual maturation and the estimated adult height
Children who present very young and have a rapid progress of
maturation will have epiphyseal fusion at an early age. They will
attain the smallest adult height and therefore, benefit most from
.therapy
Children with central precocious puberty who are already close to the
age of normal puberty or who have a very slowly progressive
.variant of precocious puberty may not require treatment at all
GnRH agonist therapy has become the standard for children with
central
precocious puberty. The depot form of leuprolide acetate is given at a
.dose of 300 μg/kg every four weeks
 peripheral precocious
 puberty
Children with tumors of the testis, adrenal gland,
and ovary are treated by surgery. Those with
hCG-secreting tumors may require some
combination of surgery, radiation therapy, and
chemotherapy depending upon the site and
.histologic type
Children with obvious defects in adrenal
steroidogenesis should be treated with
.glucocorticoid therapy

McCune-Albright syndrome — In girls with MAS,

testolactone, which inhibits aromatization of
androgen to estrogen, has been at least partially
successful in decreasing the recurrence of
ovarian cysts, thereby slowing pubertal
.progression
 Delayed puberty
INTRODUCTION — Delayed puberty is
defined clinically by the absence or
incomplete development of
secondary sexual characteristics
bounded by an age at which 95
percent of children of that sex and
culture have initiated sexual
.maturation
 Delayed puberty
Delayed or interrupted puberty
exists in girls who fail to develop
any secondary sex
characteristics by age 13, have
not had menarche by age 16, or
have not attained menarche 5 or
more years since the onset of
.pubertal development
 Etiology
Constitutional delay of puberty in 70
.percent of subjects
Permanent hypogonadotropic
hypogonadism. in 12 percent
Permanent hypergonadotropic
hypogonadism (ie, primary gonadal
failure )in 13 percent
Unclassified, 5 percent
 Evaluation
History — The history helps determine whether pubertal
development is totally absent or had started but then
.stalled
Nutritional habits, exercise intensity, prior medical illness, or
medication usage should be analyzed. Delays in sexual
maturation and growth velocity often can be the first
clinical signs of underlying metabolic disorders, such as
inflammatory bowel disease, hypothyroidism, or
.psychosocial deprivation
The presence of associated congenital abnormalities (eg,
midline defects), suggests congenital GnRH deficiency.
Neurologic symptoms such as headache, visual
disturbances, anosmia, dyskinesia, seizures, and mental
retardation strongly suggest a central nervous system
.disorder
A positive family history of either constitutional delay of
.puberty or congenital GnRH deficiency can be a useful clue
 Evaluation
Physical examination
Both the standing height and the arm span
should be measured. An arm span
exceeding the height by more than 5 cm
(ie, eunuchoidal body habitus) suggests
delayed epiphyseal closure secondary to
.hypogonadism
Secondary sexual characteristics should be
.staged according to the Tanner criteria
Pelvic examination or imaging studies to
 .evaluate internal organs
 Evaluation
Imaging studies
A conventional X-ray of the left hand and wrist to
evaluate bone age may be obtained at the initial
visit to assess skeletal maturation and repeated
.over time if needed
Pelvic or testicular ultrasonography should be
performed when an ovarian or testicular mass is
detected on the physical examination
Pelvic ultrasound also may be performed in girls
with delayed puberty to determine the presence
.or absence of a uterus
Head MRI should be ordered if associated
neurologic symptoms or signs suggest a central
process, or if the laboratory studies are
.consistent with hypothalamic or pituitary disease
Pure gonadal dysgenesis
 Pure gonadal dysgenesis
Bilateral streak gonads are associated
with a
(Normal karyotype (46 XX or 46 XY
Normal stature
Primary amenorrhea
XX pattern if associated with 46
sensineural deafness is known as
.Perrault syndrome
XY pattern is known as Swyer 46
 Delayed puberty
THERAPY — If a specific underlying disorder can be
identified, therapy should be targeted at that disorder. As
examples, thyroid hormone replacement in hypothyroidism,
dopamine agonist treatment of pituitary adenomas, and
excision of craniopharyngiomas can result in prompt
.institution of sexual maturation

In most patients, however, the distinction between congenital

GnRH deficiency and constitutional delay of puberty
remains uncertain, and can be resolved only with serial
.observations

In view of these diagnostic difficulties, the initial therapeutic

approach is similar for both disorders. The two major
options are "watchful waiting" with reassurance and
psychological support for the patient and family or the
.administration of gonadal steroids
 Delayed puberty

Short-term therapeutic goals include: Attainment of age-

appropriate secondary sex characteristics to ameliorate the
patient's concern about his/her appearance relative to
.peers
Induction of a growth spurt without inducing premature
epiphyseal closure. This goal requires frequent (eg, every
six months) longitudinal monitoring of bone age during
.therapy

The long-term goals of therapy, if the diagnosis proves to be

isolated GnRH deficiency, are to maintain the serum
concentrations of sex steroids within the normal adult range
and, eventually, to induce fertility if and when the patient
.desires
 Delayed puberty

Estrogen therapy — In girls, estrogen can be given

orally or transdermally, initially at doses well
below those used for replacement therapy in
adults. A progestin should not be added until
there is substantial breast development as
premature initiation of progestin therapy can
.compromise ultimate breast growth

Once breast growth has plateaued during serial

evaluation and menstruation been established,
estrogen therapy can be discontinued
intermittently for one- to three-month periods to
determine if spontaneous menstruation occurs,
which should happen in girls with constitutional
.delay