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Fifth stage
Gynecology
Lec-
Dr.Asma
/ /2016
Puberty and it’s disorders
Puberty encompasses the development of secondary sexual characteristics and the
acquisition of reproductive capability. During this transition, usually between 10 and 16
years of age, a variety of physical, endocrinologic , and psychological changes accompany
the increasing levels of circulating sex steroids.
The onset of pubertal changes is determined primarily by:
genetic factors, including race, and is also influenced by geographic location (girls in
metropolitan areas, at altitudes near sea level, or at latitudes close to the equator
tend to begin puberty at an earlier age)
racial differences, with black females showing an earlier age of pubertal onset
compared with white
nutritional status (obese children have an earlier onset of puberty, and those who
are malnourished or have chronic illnesses associated with weight loss have a later
onset of menses).
Excessive exercise relative to the caloric intake can also delay the onset of puberty.
BMI high body mass index is linked to earlier age of maturation, and the relationship
between body fat and the onset of puberty is proposed to be linked to the release of
leptin from adipose sites . Leptin and kisspeptin would seem to act as a primary
signal to the hypothalamus to allow puberty to commence. It has been proposed that
an invariant mean weight of 48 kg (106 lb) is essential for the initiation of menarche
in healthy girls.
Psychological factors, severe neurotic or psychotic disorders, and chronic isolation
may interfere with the normal onset of puberty through a mechanism similar to adult
hypothalamic amenorrhea.
Endocrinologic Changes of Puberty
FETAL AND NEWBORN PERIOD
The fetal hypothalamic–pituitary–gonadal axis is capable of producing adult levels of
gonadotropins and sex steroids.
By 20 weeks’ gestation, levels of gonadotropins—follicle-stimulating hormone (FSH) and
luteinizing hormone (LH)—rise dramatically in both male and female fetuses .
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Late in gestation, a surge in levels of glucocorticoids in the fetal circulation occurs. This is
essential for normal maturation of fetal lungs and critical for the development of the fetal
thyroid, kidney, brain, and pituitary.
Recently, it has been suggested that excessive exposure of the developing fetus to
glucocorticoids or exposure at the wrong time may lead to lifelong alterations in the
function of the hypothalamic–pituitary–adrenal axis.
In both male and female fetuses, serum estradiol is primarily of maternal and placental
origin.
With birth and the acute loss of maternal and placental sex steroids, the negative feedback
action on the hypothalamic-pituitary axis is lost, and gonadotropins are once again released
from the pituitary gland, reaching adult or near-adult concentrations in the early neonatal
period
In the female infant, peak serum levels of gonadotropins are generally seen by 3 months of
age, then they slowly decline until a nadir is reached by the age of 4 years.
In contrast to gonadotropin levels, sex steroid concentrations decrease rapidly to
prepubertal values within 1 week of birth and remain low until the onset of puberty.
During fetal development, the adrenal glands are large in proportion to their size in adult
life (similar to the fetal kidneys). Early in gestation, the fetal adrenal gland produces
abundant dehydroepiandrosterone sulfate (DHEA-S), which serves as a precursor for
estrogen production by the placenta and is also able to convert placental progesterone into
cortisol. It is not until about 23 weeks’ gestation that the fetal adrenal cortex expresses the
enzyme to directly synthesize cortisol from cholesterol or pregnenolone. In the first few
months of postnatal life, the innermost part of the adrenal cortex (the fetal zone) largely
regresses, and there is a rapid decrease in the production of DHEA-S
The hypothalamic–pituitary–gonadal axis in the young child is suppressed between the ages
of 4 and 10 years. The hypothalamic–pituitary system regulating gonadotropin release has
been termed the gonadostat. Low levels of gonadotropins and sex steroids during this
prepubertal period are a function of two mechanisms:
(1) maximal sensitivity of the gonadostat to the negative feedback effect of the low
circulating levels of estradiol present in prepubertal children, and,
(2) intrinsic central nervous system inhibition of hypothalamic gonadotropin-releasing
hormone (GnRH) secretion. These mechanisms occur independently of the presence of
functional gonadal tissue.
The hypothalamus–pituitary–gonadal axis is active during fetal life and quiescent during
childhood. It is the reactivation of this axis that leads to sexual maturation.The arcuate
nucleus in the basal hypothalamus is responsible for secretion of gonadotrophin-releasing
hormone (GnRH) into the hypothalamus–pituitary portal circulation.
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As puberty commences, the arcuate nucleus begins to secrete GnRH in a pulsatile manner,
initially solely at night; however, as time progresses GnRH release adopts a low-frequency
low-amplitude pulsatile pattern that starts to induce release of luteinizing hormone (LH)
from the pituitary.
The low-amplitude pulsatile pattern gradually extends to include day time secretion and
gonadotrophin levels themselves start to increase, reflecting higher pulse amplitude and
increasing frequency of GnRH production.
The female fetus acquires the lifetime peak number of oocytes (in utero) by mid-gestation
and also has a brief period of follicular maturation and sex steroid production in response
to elevated gonadotropin levels in utero.
This transient increase in serum estradiol (a sex steroid) acts on the fetal hypothalamic-
pituitary unit, resulting in a reduction of gonadotropin secretion (a negative feedback
effect), which in turn reduces estradiol production. This indicates that the inhibitory effect
of sex steroids on gonadotropin release is operative before birth.
As the pattern of follicle-stimulating hormone (FSH) and LH Release Becomes established,
so ovarian activity commences and initially this is totally chaotic as it is uncoordinated. This
means that there is follicular growth without coordinated ovulation and although oestradiol
levels start to rise, there is no evidence of ovulation. The ovary may have appearances that
are multicystic due to this chaotic gonadotrophin stimulation and, over time (about 5–10
years), coordinated pulsatile release of GnRH leads to adult frequency of FSH release
(approximately every 90min). At this stage the ovulatory cycle is established.From age 7,
most girls will begin activation of adrenal androgen production, a phenomenon known as
adrenarche. As with ovarian oestradiol production ,androgen production is initially at
extremely low levels and increases over time.
Serum concentrations of DHEA, DHEA-S, and androstenedione rise between the ages of 8
and 11 years. This rise in adrenal androgens induces the growth of both axillary and pubic
hair and is known as adrenarche or pubarche. This increase in adrenal androgen production
occurs independently of gonadotropin secretion or gonadal steroid levels, and the
mechanism of its initiation is not understood at this time.
Stages of pubertal development
The first physical sign of puberty is usually breast budding (thelarche), followed by the
appearance of axillary or pubic hair (adrenarche/pubarche).
Unilateral breast development is not uncommon in early puberty and may last up to 6
months before the development of the contralateral breast.
Maximal growth or peak height velocity is usually the next stage, followed by menarche
(the onset of menstrual periods).
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The final somatic changes are the appearance of adult pubic hair distribution and adult-
type breasts.
In approximately 15% of normally developing girls, the development of pubic hair occurs
before breast development.
The sequence of pubertal changes generally occurs over a period of 4.5 years, with a
normal range of 1.5 to 6 years
Physical changes of puberty
Growth
An increase in vertical growth is the initial physical sign of the onset of puberty. Growth
during infancy is relatively rapid until age 3–4 years and then it rapidly decelerates when
the childhood phase begins. Growth velocity during infancy is approximately 15cm/year but
in middle childhood , until the onset of puberty, slows to 5–6cm/year.
Interestingly, childhood growth rates are usually at their slowest in the 12–18 Months
immediately preceding puberty and thus if puberty is delayed this effect is exaggerated. At
puberty, girls may reach a peak growth velocity of 10 cm/year and girls will gain
approximately 25 cm of growth during puberty. Males in contrast have their growth spurt
approximately 2 years later than females but eventually gain approximately 28 cm of added
height. Once the final stage of growth. Velocity decreases, epiphyseal fusion occurs which
prevents further growth.
During the adolescent growth phase , bone density increases rapidly ,Control of the growth
spurt is primarily through growth hormone and its major secondary messenger insulin-
like growth factor (IGF)-1.
Oestradiol plays an important role in the increased secretion of growth hormone during
puberty, particularly in the early stages. As bone growth and height are maximally achieved
,oestradiol initiates epiphyseal fusion as it reaches its maximum towards the end of
puberty.
Thyroid hormone also plays a key role in growth and development as illustrated in severe
childhood Hypothyroidism , which results in a dramatic decrease in the velocity of growth.
Breast development
Although the growth spurt is usually the first sign of the onset of puberty, in females it is
breast change that is usually used as an indicator of development. The initiation of breast
development is known as thelarche and this has been classified by Tanner into five stages
[5].
Breast growth is often unequal between the two breasts and Tanner stage 5 represents the
mature end stage of breast development. This takes approximately 5 years.
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Pubic and axillary hair growth:
The adolescent development of female pubic hair Occurs in conjunction with androgen
release and it is the presence of androgen that determines bothpubic and axillary hair
growth. In approximately 20% of females, pubic hair growth may precede breast
development.
Precocious puberty
Refers to the development of any sign of secondary sexual maturation at an age 2.5
standard deviations earlier than the expected age of pubertal onset. In North America,
these ages are 8 years for girls and 9 years for boys.
The incidence of precocious puberty is 1 in 10,000 children in North America, and it is
approximately five times more common in girls. In 75% of cases of precocious puberty in
girls, the cause is idiopathic. A thorough evaluation to eliminate a serious disease process,
and to arrest potential premature osseous maturation that may affect the normal growth
pattern, is mandatory.
The early development of secondary sexual characteristics may promote psychosocial
problems for the child and should be addressed carefully. Typically, these girls are taller
than their peers as children but ultimately are shorter as adults, due to the premature
fusion of the long bone epiphyses.
Differential diagnosis of early onset of puberty:
Premature adrenarche
This is due to the precocious increase in adrenal androgen secretion and is the most
common cause of referral for precocious puberty. There seems to be an association
between premature adrenarche and increased BMI ,and in the overweight child referred
with precocious puberty it is important not to assume that breast tissue is truly breast
development and not adipose tissue. Signs of virilization such as clitoral enlargement,
severe acne or increased muscle mass would lead to concerns of a virilizing ovarian or
adrenal tumour or late-onset congenital adrenal hyperplasia (CAH). Late-onset CAH can
present with pubic hair growth from the age of 1 and should be appropriately investigated.
Premature thelarche
Here, breast growth tends to appear earlier than age 8 And progresses very slowly and
usually occurs in isolation Of the growth spurt or any other secondary sexual characteristic.
The cause of this condition remains unknown and although it is appropriate to exclude an
ovarian cyst, these are rarely found
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Central precocious puberty
This refers to progressive breast development Prematurely due to early activation of the
hypophyseal–Pituitary–ovarian axis and is accompanied by the growth spurt; pubic hair is
frequently but not always found. This therefore mimics normal onset of puberty but at a
veryearly age. A positive family history of early onset of puberty may be discovered but in
the majority of casesthe aetiology is idiopathic. Brain imaging is important,especially in girls
with an onset of puberty before the age of 6, where 20% will be found to have a central
nervous system (CNS) tumour.
Peripheral precocious puberty
This is far less common than central precocious puberty and is usually Induced by excess
production of sex steroids.
Causes include the following.
• Androgen secretion from a virilizing adrenal tumour.
• Late-onset CAH.
• Oestrogen-secreting tumour causing rapid breast development. If a large ovarian
cyst is present, this may be part of McCune–Albright syndrome, With Associated
classical features of irregular café-au-lait spots and cysticbone lesions called
polyostotic fibroid dysplasia.
• Exposure to exogenous hormones, e.g. inadvertent ingestion of birth control pills
by children causing excess levels of oestrogens; topical androgen exposure.
Precocious puberty may be divided into two major subgroups:
*heterosexual precocious puberty (development of secondary sexual characteristics
opposite those of the anticipated phenotypic sex) heterosexual precocity results from:
1.virilizing neoplasms either ovarian (most commonly an arrhenoblastoma) adrenal in
origin and are exceedingly rare in childhood .
2.congenital adrenal hyperplasia : most commonly results from a defect of the adrenal
enzyme 21-hydroxylase that leads to excessive androgen production. More severe forms of
this defect cause the birth of a female with ambiguous genitalia. If untreated, progressive
virilization during childhood and short adult stature will result., A less severe form of this
defect, referred to as nonclassic (late onset) adrenal hyperplasia can cause premature
pubarche and an adult disorder resembling PCOS.
treatment: replacement of cortisol with a related glucocorticoid and surgical correction of
any anatomic abnormalities in the first few years of life.
3.exposure to exogenous androgens.
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*Isosexual precocious puberty (premature sexual maturation that is appropriate for the
phenotype of the affected individual).
It may arise from premature activation of the normal process of pubertal development
involving the hypothalamic–pituitary–gonadal axis, which is called true isosexual precocity.
Exposure to estrogen, independent of the hypothalamic–pituitary axis (such as from an
estrogen-producing tumor), is called pseudoisosexual precocity.
True Isosexual Precocity
In females, 75% of cases are constitutional. True isosexual precocity may be diagnosed by
the administration of exogenous GnRH (a GnRH stimulation test) with a resultant rise in LH
levels equivalent to those seen in older girls who are undergoing normal puberty.
In approximately 10% of girls with the true form of precocious puberty, a central nervous
system disorder is the underlying cause.
This includes tumors, obstructive lesions (hydrocephalus), granulomatous diseases
(sarcoidosis, tuberculosis), infective processes (meningitis, encephalitis, or brain abscess),
neurofibromatosis, and head trauma. It is postulated that these conditions interfere with
the normal inhibition of hypothalamic GnRH release. Children with precocious puberty
secondary to organic brain disease often exhibit neurologic symptoms before the
appearance of premature sexual maturation. Evaluation of true isosexual precocity Should
include MRI of the head for lesions.
Pseudoisosexual Precocity
Pseudoisosexual precocity occurs when estrogen levels are elevated and cause
characteristic sexual maturation without activation of the hypothalamic– pituitary axis. In
these girls, a GnRH stimulation test does not induce pubertal levels of gonadotropins.
Causes include :
• ovarian tumors and cysts,
• exogenous estrogenic compound use,
• McCune-Albright syndrome,
• severe prolonged hypothyroidism,
• Peutz- Jeghers syndrome.
The McCune-Albright syndrome (polyostotic fibrous dysplasia) represents 5% of cases of
female precocious puberty. This syndrome consists of sexual precocity, multiple cystic bone
defects that fracture easily, café au lait spots with irregular borders (most frequently on the
face, neck, shoulders, and back), and adrenal hypercortisolism. Hyperthyroidism and
acromegaly may also occur in this syndrome. The pathophysiology involves a somatic
mutation in affected postzygotic tissues that causes them to function independently of
their normal stimulating hormones.
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Prolonged, severe hypothyroidism has been hypothesized to cause pituitary gonadotropin
release in response to the persistently elevated secretion of thyroid-releasing hormone.
Concomitant elevation of prolactin may also occur with the development of galactorrhea.
Ovarian cysts may occasionally develop, and bone age may be retarded. This is the only
form of precocious puberty associated with delayed bone age. Treatment is with thyroid
replacement therapy.
The Peutz-Jeghers syndrome has been associated with a rare sex cord tumor with annular
tubules, which may secrete estrogen. Because this syndrome of gastrointestinal tract
polyposis and mucocutaneous pigmentation has also been reported in association with
granulosa-theca cell tumors, children with this disorder should be screened for the
development of gonadal neoplasms.
Incomplete isosexual precocity is the early appearance of a single secondary sexual
characteristic.
These conditions include premature thelarche, the isolated appearance of breast
development before the age of 4 years (unilateral or bilateral) that resolves spontaneously
within months and that is probably secondary to transient estradiol secretion; premature
adrenarche, the isolated appearance of axillary hair before the age of 7 years that is the
result of premature androgen secretion by the adrenal gland; and premature pubarche, the
isolated appearance of pubic hair in girls before the age of 8 years.
LABORATORY TESTS USED SELECTIVELY TO EVALUATE
FEMALE PRECOCIOUS PUBERTY
• Radiologic Serial bone age Radiological studies have somewhat limited value
(isosexual precocity) Magnetic resonance imaging (MRI) or computed tomog-raphy
(CT) of the brain with optimal visualization of hypothalamic region and sella turcica
(true isosexual precocity) .
• MRI, CT, may be used in those children with extreme precocious puberty, where the
chances of a positive finding are around 20%.
• ultrasonography of abdomen and pelvic ultrasound may be used if an abdominal
tumour is suspected, (heterosexual precocity, pseudoisosexual precocity)
• Laboratory investigation:
(1) Luteinizing hormone (LH) LH may be used to distinguish between premature
thelarche and central precocious puberty.
(2) follicle-stimulating hormone (FSH) is of limited value.
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(3) Oestradiol is usually elevated in girls with precocious puberty but very high
(4) levels may suggest a tumour.
(5) Dehydroepiandrosterone sulfate, is always elevated in children with
premature adrenarche;
(6) testosterone (hetero-sexual precocity) when markedly elevated would
suggest an androgen-secreting tumour;
(7) 17-hydroxyprogesterone, 11-deoxycortisol (suspected congenital adrenal
hyperplasia causing heterosexual precocity)
(8) Thyroid function tests (thyroid-stimulating hormone, free thyroxine) (isosexual
precocious puberty)
(9) Gonadotropin-releasing hormone (GnRH) stimula-tion test: LH measurement
after 100 μg of GnRH is given intravenously (to differentiate gonadotropin-
dependent from gonadotropin-independent isosexual precocity)
Treatment of precocious puberty
The majority of girls with central precocious puberty do not require hormonal treatment,
because most development is extremely slow and will result in maturity at an age which
would be expected even though onset has been early.
It is therefore prudent to review children with precocious development of secondary sexual
characteristics 6 months later to see whether there has been rapid development
of secondary sexual characteristics or not. In these cases, there is a high chance that sexual
maturity will be reached By age 9 and therefore suppression of the progress of Puberty
would be sensible. While it is possible to suppress The pituitary, growth hormone cannot be
suppressed and therefore treatment will result in adult height that is significantly greater
than would be expected than if the child were left untreated.
Children with extremely early puberty are often tall at the time of diagnosis and they tend
to finish their growth early and achieve normal adult height. It is therefore pertinent in
these young children to suppress the development of secondary sexual characteristics.
The standard treatment for central precocious puberty is GnRH analogues, which may be
given nasally or by intramuscular injection. Three-monthly preparations are now available
and therefore four injections a year is all that is required to suppress Puberty. GnRH
analogues can then be administered until such time as the child reaches approximately age
11, when withdrawal will result in the normal resumption of pubertal changes. Peripheral
precocious puberty, when due to an ovarian or adrenal tumour, requires surgical
intervention; however, for girls with androgen excess due to CAH, suppression of the
adrenal with Hydrocortisone will reverse the changes.
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Delayed puberty
Delayed puberty is usually considered when girls have no secondary sexual characteristics
by age 13.5 years.
Delay in puberty occurs in only 2.5% of the population but the identification of those
children who do have a significant aetiology for this may be extremely important.
However, it is mandatory to take a detailed history as the presence of chronic medical
conditions or excessive athletic participation may be an obvious explanation for delay in
the onset of puberty. In females, approximately 50% will have constitutional delay that is
presumably genetically based.
In the presence of secondary sexual characteristics menstruation ought to occur within 2
years of the establishment of Tanner stage 2 breast change.
However, any child presenting at any stage because of concern over failure to establish
either secondary sexual characteristics or menstruation should be investigated at that
time.
There are often extremely good reasons why a mother will bring her daughter for
investigation and this often relates to the fact that a sibling completed her pubertal
development at an earlier age or she herself went through puberty at an earlier age.
While investigations may not lead to a diagnosis of abnormality, proof of Normality is
extremely important.
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