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PRECOCIOUS PUBERTY

Puberty is the process of biologic change and physical development


after which sexual reproduction becomes possible
 this is a time of accelerated linear skeletal growth and
development of secondary sexual characteristics, such as
breast development and the appearance of axillary and pubic
hair

both categories have increased circulating levels of estrogen

GnRH Independent Precocious Puberty secretion of estrogens is


independent of hypothalamicpituitary control
 prolonged ollow-up is sometimes necessary to rule out subtle,
slow-growing lesions of the brain, ovary, or adrenal gland

Precocious Puberty appearance of any signs of secondary


sexual maturation at an early age

puberty is a time of accelerated growth, skeletal maturation, and


resulting epiphyseal closure

the vast majority of females with precocious puberty develops a


GnRH-dependent process
 causes:
idiopathic (70%)
CNS disease (30%)

early in the course of the disease the girls are taller and heavier than
their chronologic peers who have not experienced the growth spurt
 however, although the patient is tall as a child, her eventual
adult height will be shorter than normal
 without therapy, approximately 50% of females with
precocious puberty will not reach a height of 5 feet

a definitive definitive diagnosis is established more often for


pseudoprecocious puberty, which is usually related to an ovarian or
adrenal disorder

heterosexual precocious puberty if the secondary sex


characteristics are discordant with the genetic and
phenotypic sex
 this is premature virilization in a female child and includes
development of masculine secondary sexual characteristics
 the androgens usually come from the adrenal gland

the pathophysiology of this short stature is related to the limited


duration of the rapid growth spurt
 there is accelerated bone maturation and premature closure
of the distal epiphyseal growth centers

categories of precocious puberty:


 GnRH dependent (complete or true)
 GnRH independent (incomplete or pseudo)
 Isosexual
 Heterosexual

Premature Thelarche

GnRH Dependent Precocious Puberty involves: premature


maturation of the hypothalamicpituitaryovarian axis and includes
normal menses, ovulation, and the possibility of pregnancy

GnRH Independent Precocious Puberty involves: premature


female sexual maturation, which may lead to estrogen-induced
uterine stimulation and bleeding without any normal ovarian
follicular activity

Premature thelarche is defined as isolated unilateral or bilateral


breast development as the only sign of secondary
sexual maturation
it is not accompanied by other associated evidence of pubertal
development, such as axillary or pubic hair or changes in vaginal
epithelium
 breast hyperplasia is a normal physiologic phenomenon in the
neonatal period, and it may persist up to 6 months of age
 breast buds enlarge to 2 to 4 cm, and sometimes this process
is asymmetrical
 nipple development is absent
 this is a benign self-limiting condition that does not require
treatment
 often the breast enlargement spontaneously regresses

COMPREHENSIVE GYNECOLOGY

PRECOCIOUS PUBERTY




usually occurs between 1 and 4 years of age


caused by a slight increase in circulating estrogen levels, these levels
are normally low to undetectable
this disorder may be associated with female infants who had
extremely low birth weights




Premature Pubarche and Adrenarche












Premature pubarche is early isolated development of pubic hair


without other signs of secondary sexual
maturation
Premature adrenarche is isolated early development of axillary
hair
neither of these conditions is progressive, and the girls do not have
clitoral hypertrophy
 it is important to differentiate premature pubarche from the
virilization produced by congenital adrenal hyperplasia
some children with premature pubarche have abnormal
electroencephalograms (EEGs) without significant neurologic disease
the bone age should not be advanced in this disorder
believed to be related to increased androgen production by the
adrenal glands (DHEA and DHEA-S)
the child should have periodic follow-up visits to confirm that the
condition is not progressive




a wide range of inflammatory, degenerative, neoplastic, or congenital


defects that involve the CNS may produce GnRH-dependent
precocious puberty
usually, symptoms of a neurologic disease, especially headaches and
visual disturbances, precede the manifestations of precocious puberty
a most unusual neurologic symptom that may be associated with
precocious puberty is seizures with inappropriate laughter (gelastic
seizures)
anatomically most CNS lesions are located near the hypothalamus in
the region of the third ventricle, tuber cinereum, or mammillary
bodies.
major CNS diseases associated with true precocious puberty include
tuberculosis, encephalitis, trauma, secondary hydrocephalus,
neurofibromatosis, granulomas, hamartomas of the hypothalamus,
teratomas, craniopharyngiomas, cranial irradiation, and congenital
brain defects, such as hydrocephalus and cysts in the area of the third
ventricle
these children have markedly fluctuating estrogen levels and low
gonadotropin concentrations that are independent of GnRH
stimulation
these CNS space-occupying masses are most difficult to successfully
treat surgically
pathophysiology: hamartomas may secrete GnRH; this secretion
is not subject to the normal physiologic inhibition that occurs
during childhood

GnRH Depedent Precocious Puberty


GnRH Independent Precocious Puberty








idiopathic development is responsible for approximately 70% of the


cases of GnRH-dependent precocious puberty
some of these children are simply at the earliest limits of the normal
distribution of the biologic curve
these girls have no genital abnormality except for early development
occasionally, follicular cysts of the ovary may form secondary to
increased levels of pituitary gonadotropins
 in these cases the cysts are the result of, not the cause, of
precocious puberty
gonadotropin levels, sex steroid levels, and response of LH after
administration of GnRH are similar to those in normal puberty
may appear as early as age 3 to 4 years

the most common cause of pseudoprecocious puberty is an estrogensecreting ovarian tumor


 granulosa cell tumors most common type
 these tumors are usually greater than 8 cm in diameter when
associated with precocious puberty; 80% can be palpated
abdominally
other ovarian tumors that may be associated with precocious puberty
include thecomas, luteomas, teratomas, SertoliLeydig tumors,
choriocarcinomas, and benign follicular cysts


COMPREHENSIVE GYNECOLOGY

PRECOCIOUS PUBERTY
thecomas and luteomas are usually much smaller than
granulosa cell tumors and usually cannot be palpated
 these tumors are rare during childhood, with only 5% of
granulosa cell tumors and 1% of thecomas occurring before
puberty
infrequently, follicular cysts of the ovary may emerge spontaneously
and secrete enough estrogen to be the cause, rather than the result, of
precocious puberty
the ability of many tumors, including teratomas, choriocarcinomas,
and dysgerminomas, to secrete estrogen, human chorionic
gonadotropin (HCG), -fetoprotein, and other markers has been
established
McCune-Albright Syndrome is a rare triad of cafau-lait spots,
fibrous dysplasia, and cysts of the skull and long bones
 a.k.a. polyostotic fibrous dysplasia
 these patients also have facial asymmetry
40% of girls with MAS have associated isosexual precocious puberty
adrenocortical neoplasms may produce either isosexual or
heterosexual precocious puberty
the relationship between congenital adrenal hyperplasia and puberty
depends on the time of initial diagnosis and therapy
 if the disease is diagnosed in the neonatal period and treated,
normal puberty ensues
 if the disease is untreated, the girl over time usually develops
heterosexual precocious puberty (signs of androgen excess)
from the adrenal androgens
 if congenital adrenal hyperplasia is diagnosed late in
childhood, isosexual precocious puberty may follow initial
treatment of the adrenal disease
hypothyroidism most commonly is associated with delayed pubertal
development
 in RARE cases, untreated hypothyroidism results in isosexual,
GnRH-dependent, or GnRH-independent precocious puberty
the hypothyroidism associated with precocious puberty is due to
primary thyroid insufficiency, usually Hashimoto's thyroiditis, and not
a deficiency in pituitary TSH
 pathophysiology: diminished negative feedback of
thyroxine, resulting in an increased production of TSH,
which may be accompanied by an increase in production
of gonadotropins









hypothyroidism is the only cause of precocious puberty in


which the bone age is retarded
observed usually in girls between the ages of 6 and 8 years

Diagnosis:
 begins with a meticulous history and physical examination
 primary emphasis: rule out life-threatening neoplasms of the
ovary, adrenal gland, or CNS
 secondary emphasis: delineate the speed of the maturation process,
for this is crucial in making decisions concerning therapy
 the height of the girl and the exact stage of pubertal development,
including Tanner stage, should be recorded
 a battery of tests, including imaging studies of the brain, serum
estradiol levels, FSH levels, and thyroid function tests, may be needed
to establish the diagnosis
 with this acceleration of development, the sex steroids and adrenal
androgen (DHEA-S) are elevated regardless of the cause
 acceleration of growth is one of the earliest clinical features of
precocious puberty
 bone age should be determined by handwrist films and compared
with standards for a patient's age
 usually these films are repeated at 6-month intervals to
evaluate the rate of skeletal maturation and correspondingly
the need for active treatment of the disease
 advancement of bone age more than 95% of the norm for the
child's chronologic age is indicative of an estrogen effect
 disease of the CNS are suggested during the history by symptoms such
as headaches, seizures, trauma to the head, and encephalitis
 these conditions are confirmed or excluded by a series of
tests, including neurologic and ophthalmologic examinations,
EEGs, and brain imaging
 serum levels of FSH, LH, prolactin, TSH, E2, testosterone, DHEA or
DHEA-S, HCG, androstenedione, 17-hydroxyprogesterone, T3, and T4
may be of value in establishing the differential diagnosis
 sometimes a GnRH stimulation test is diagnostic in differentiating
incomplete from true precocious puberty, but this test does not
specifically identify children with CNS lesions
 LH responses to gonadotropin stimulation after reaching a basal level
are similar in cases of true precocious puberty to the responses of a
mature adult. In contrast, a child with precocious puberty secondary

COMPREHENSIVE GYNECOLOGY

PRECOCIOUS PUBERTY
to a feminizing ovarian neoplasm does not have a significant elevation
in LH response to exogenous gonadotropins. In summary, a
stimulation test with exogenous GnRH is fundamental in helping to
delineate the underlying pathophysiology
Management:
 the treatment of precocious puberty depends on the cause, the extent
and progression of precocious signs, and whether the cause may be
removed operatively
 the present drug of choice for GnRH-dependent precocious puberty is
one of the potent GnRH agonists
 these drugs are typically given by monthly injections or,
rarely, intranasally
 GnRH agonists are safe and effective treatments for children with the
disease second-ary to disturbances in the hypothalamicpituitary
ovarian axis
 therapy should be initiated as soon as possible after the
diagnosis is established in order to achieve maximal adult
height.
 the effect on adult height depends on the chronologic age at
which therapy is initiated
 the therapy is MORE effective in 4- to 6-year-olds
 continuous chronic administration of the drug is maintained
until the median age of puberty
 medical therapy produces involution of secondary sexual
characteristics, with amenorrhea and regression of both breast
development and amount of pubic hair LH and FSH pulsations are
abolished. Most importantly the drug not only reverses the ovarian
cycle but definitely changes the growth pattern
 growth velocity is usually decreased by approximately 50%
 patients with McCuneAlbright syndrome may be treated with
aromatase inhibitors, which prevent the conversion to biologically
active estrogens
 this treatment leads to diminished circulating estrogen levels,
diminished frequency of menses, and a decreased rate of
growth and skeletal maturation
 both the child with precocious puberty and her family need
intensive counseling

the child will have the psychosocial and behavioral


maturation of children of her chronologic age, not the age
reflected by her physical appearance
the child needs extensive sex education and help in
anticipating and confronting various social experiences

Transcribed by: Mike


3A

COMPREHENSIVE GYNECOLOGY