Central precocious puberty (CPP) is the early activation of the hypothalamic-pituitary-gonadal axis, leading to premature sexual maturation. Peripheral precocious puberty (PPP) involves the appearance of secondary sex characteristics without activation of the HPG axis, instead caused by direct sex steroid production. Evaluation of precocious puberty involves determining which pubertal changes are present to classify it as CPP or PPP, followed by laboratory tests and imaging studies to identify potential underlying causes.
2. NORMAL PUBERTY
The onset of puberty is heralded by high-amplitude pulses
of GnRH released from the hypothalamus.
This causes pulsatile releases of pituitary gonadotrophins –
luteinizing hormone (LH) and follicle stimulating hormone
(FSH).
LH stimulates the production of testicular androgens from
the Leydig cells and oestrogens from the ovarian granulosa
cells in boys and girls respectively.
3. NORMAL PUBERTY contd
Pubertal levels of these sex steroids lead to the physical
changes of puberty beginning with breast enlargement in
females and testicular enlargement in males.
They also mediate the pubertal growth spurt.
FSH leads to gonadal enlargement and promotes
spermatogenesis and follicular maturation.
4. NORMAL PUBERTY contd
The mean age of onset of puberty is 11 years in girls (8-13
years) and 12 years in boys (9-14 years).
In earlier childhood, the onset of puberty is delayed by two
mechanisms
Negative feedback inhibition of the hypothalamic-pituitary-
gonadal axis by small amounts of sex steroids secreted in
prepubertal children.
Central neural pathways suppressing GnRH release.
5. NORMAL PUBERTY contd
The age of onset of puberty varies and is more closely
correlated with osseous maturation than with
chronological age.
In females, the breast bud (thelarche) is usually the first
sign of puberty (10-11 yrs), followed by the appearance
of pubic hair (pubarche) 6-12 months later.
The interval to the onset of menstrual activity (menarche)
is usually 2-2.5 yrs but may be as long as 6 yrs.
6. NORMAL PUBERTY contd
At least one sign of puberty is present in approximately
95% of females by 12 yrs and in 99% of females by 13
yrs.
Peak height velocity occurs early (at breast stage II–III,
typically between 11 and 12 yrs) in females and always
precedes menarche. The mean age of menarche is about
12.75 yr.
However, there are wide variations in the sequence of
changes involving growth spurt, breast bud, pubic hair,
and maturation of the internal and external genitalia.
7. NORMAL PUBERTY contd
In males, growth of the testes (≥4 mL in volume or
2.5 cm in longest diameter) and thinning of the
scrotum are the first signs of puberty (11-12 yrs).
These are followed by pigmentation of the scrotum
and growth of the penis and by pubarche .
Appearance of axillary hair usually occurs in mid-
puberty.
8. NORMAL PUBERTY contd
In males, unlike in females, acceleration of growth
begins after puberty is well underway and is maximal
at genital stage IV-V (typically between 13 and 14
yrs).
In males, the growth spurt occurs approximately 2 yrs
later than in females, and growth may continue
beyond 18 yrs of age.
9. PRECOCIOUS PUBERTY
Precocious puberty refers to the appearance of physical
and hormonal signs of pubertal development at an earlier
age than is considered normal.
Puberty is considered precocious if there is onset of
development of secondary sexual characteristics before the
age of 8 years in girls and 9 years in boys.
10. INTRODUCTION contd
There has been a trend towards lower mean ages of onset
of puberty in otherwise normal children, particularly in girls
and particularly in blacks, some as young as 6 years of age.
This complicates the identification, evaluation and
management of children with precocious puberty.
11. INTRODUCTION contd
Depending on the primary source of the hormonal
production, precocious puberty may be classified as:
Central (also known as gonadotropin dependent, or true )
Peripheral (also known as gonadotropin independent or
precocious pseudopuberty).
Central precocious puberty (CPP) is always isosexual and
stems from HPG activation with ensuing sex hormone
secretion and progressive sexual maturation.
12. INTRODUCTION contd
In peripheral precocious puberty, some of the secondary
sex characters appear, but there is no activation of the
normal hypothalamic-pituitary-gonadal interplay.
In precocious pseudopuberty, the sex characteristics may
be isosexual or heterosexual (contrasexual).
13. INTRODUCTION contd
Peripheral precocious puberty can also induce maturation
of the hypothalamic-pituitary-gonadal axis and trigger the
onset of central puberty.
This mixed type of precocious puberty occurs commonly in
conditions such as congenital adrenal hyperplasia,
McCune-Albright syndrome, and familial male-limited
precocious puberty, when the bone age reaches the
pubertal range (10.5-12.5 years).
14. INCOMPLETE PRECOCITY
Premature thelarche in females and premature adrenarche
in both sexes may occur and represents variants causing
incomplete precocity.
Premature thelarche is defined as the isolated occurrence
of breast development in young females without
progression of other physical signs of puberty following.
Typically occurs in very young children, less than three
years of age.
15. INCOMPLETE PRECOCITY contd
Premature adrenarche occurs in both sexes and involves
the appearance of pubic hair without other signs of
puberty in young girls or boys less than seven years of age.
There may be associated axillary hair, axillary odour and
mild acne.
These variants need to be differentiated from true puberty
so that unnecessary further evaluation is not done and
parents can simply be reassured.
16. INCOMPLETE PRECOCITY contd
Premature adrenarche may be distinguished from true
puberty by the absence of penile enlargement,
clitoromegaly, testicular enlargement and breast
development. Growth rate is normal.
The levels of the weak adrenal androgen
dehydroepiandrostene sulphate (DHEA-S) are typically
elevated.
In premature thelarche, breast development is non-
progressive, staying the same size over several months.
17. INCOMPLETE PRECOCITY contd
Also there is no acceleration in linear growth.
Only about 1-2% of girls with premature thelarche
progress to develop precocious puberty.
Thus only regular follow up is needed.
Aetiology unclear but believed to be due to small ovarian
cysts which produce small amounts of oestrogen. When
these cysts resolve over time, so does the breast
development.
18. EPIDEMIOLOGY
The prevalence of precocity would vary depending on the
physical features assessed and the age cutoff used to
define precocity. It would also depend on if a population
screening is done or if only those referred for specialist
care were studied.
Current trends all over the world indicate that there is a
decline in the age of puberty in girls. Whether the case is
similar in boys is unclear.
19. EPIDEMIOLOGY contd
In 1997, it was found that 8% and 25% of American boys and
girls respectively exhibited evidence of sexual precocity.
This study has prompted researchers to call for a reduction in
the age used to define precocity in girls to 6 years for black
girls and 7 years for white girls.
Another American study done in 2010 reported that in a cohort
of 1239 girls aged 7-7.99years, the proportion that reached
tanner 2 breast development was 10.4% of white girls, 23.4% of
black girls and 14.9% of Hispanic girls.
20. EPIDEMIOLOGY contd
A follow up of these girls ten years later showed that none
of them were diagnosed or treated for central precocious
puberty.
This finding suggests that the majority of girls who have
breast development before age 8 years do not have the
rapidly progressive form of CPP, which requires treatment.
21. EPIDEMIOLOGY contd
The incidence of precocious puberty is 5-10x higher in girls
than in boys and it is unclear if the trend towards earlier
ages at onset of puberty is also established to be present
in boys.
However, a study from Denmark found that the mean age
of testicular enlargement in boys declined from age 11.92
years to 11.66 years between 1991-1993 and 2006-2008,
suggesting that more boys may be starting puberty before
age 9 years.
22. EPIDEMIOLOGY contd
In Nigeria, the actual prevalence of precocious puberty is
not known. However, a recent study done in Calabar
showed that the mean age for pubic hair onset was 11
years for both sexes, while testicular development and
breast development also occurred at an average age of 11
years. Menarche was at 13 years.
The values reflected significant reductions in age of onset
of puberty from the earliest Nigerian studies from the
1950s.
23. CENTRAL PRECOCIOUS PUBERTY
Defined as the onset of breast development before 8 years
of age in females and onset of testicular development
(testicular volume >4mls) before 9yrs of age in males due
to the early activation of the HPG axis.
Up to 10x more common in females and is typically
sporadic.
90% of cases in females are idiopathic.
24. CENTRAL PRECOCIOUS PUBERTY contd
Structural CNS abnormality may be seen in up to 75% of
males with precocious puberty.
High incidence has been found in children adopted to
Western countries from developing countries, possibly due
to undefined nutritional and environmental factors.
Has also been suggested to be due to age identification
challenges.
25. AETIOLOGY
Idiopathic true precocious puberty
CNS tumors
Optic glioma associated with neurofibromatosis type 1
Hypothalamic astrocytoma
Developmental abnormalities including hypothalamic hamartoma of the
tuber cinereum
Encephalitis
Static encephalopathy
Brain abscess
Sarcoid or tubercular granuloma
Head trauma
Hydrocephalus
26. AETIOLOGY CONTD
Arachnoid cyst
Myelomeningocele
Vascular lesion
Cranial irradiation
True precocious puberty after late treatment of congenital virilizing adrenal
hyperplasia or other previous chronic
exposure to sex steroids
True precocious puberty due to mutations:
in KISS1R/GRP54 gene
in KISS1 gene
MKRN3 gene
27. CLINICAL MANIFESTATIONS
Sexual development in CPP follows the same trend as in
normal puberty.
Menstrual bleeding is typically irregular and periods are
anovulatory although pregnancy has been reported in a
five-year old.
Height, weight and height velocity are accelerated but final
adult height is typically compromised. This is worse in
females than in males.
28. CLINICAL MANIFESTATIONS contd
Bone age is advanced by a mean of about 2 years above
chronological age. Early skeletal maturation leads to
premature epiphyseal closure and short adult stature.
Mental development is compatible with chronological age.
Child may have emotional upheavals and mood swings but
serious psychological problems are rare.
29. CLINICAL MANIFESTATIONS contd
Three patterns exist:
Rapidly Progressive: rapid physical and osseus
maturation with loss of adult height potential.
Slowly Progressive: osseus maturation at par with
chronological age; height potential is preserved.
Unsustained CPP: spontaneous regression of CPP.
This variability underscores the need for some follow up
after CPP is diagnosed before consideration of treatment
30. PRECOCIOUS PSEUDOPUBERTY
In precocious pseudopuberty (PPP), there is the presence
and development of secondary sexual characteristics
without activation of the HPG axis.
the secondary sex characteristics so developed may be
isosexual or contrasexual in PPP.
The source of sex steroids are directly from the gonads,
adrenals or ectopic sources of gonadotrophins.
36. CLINICAL MANIFESTATIONS
Clinical manifestations and progress of pubertal changes
similar to that in CPP.
However, features of secondary causes such as café-au-lait
spots in McCune Albright syndrome, features of
hypothyroidism, liver enlargement in hepatoblastoma,
ovarian cysts etc. may all be pointers to PPP as a cause for
sexual precocity.
37. EVALUATION OF PRECOCIOUS PUBERTY
The first step is to determine by physical examination which
characteristic of normal puberty are obvious and whether only
estrogen effects or only androgen effects or both are present.
In girls, androgen effect manifests as adult odour, pubic and axillary
hair, and facial skin oiliness and acne, whereas estrogen effect
manifests as breast development, uterine increase, and eventually
menarche.
In boys, androgen effect manifests as adult odour, pubic and axillary
hair, and facial skin oiliness and acne; it is also important to note
whether the testes are enlarged more than 2.5 cm in length, which
implies gonardarche.
38. EVALUATION OF PRECOCIOUS PUBERTY
If the testes are not enlarged, but virilization is progressing, the
source of the androgens may be the adrenal glands or exogenous
sources.
If the testes are slightly enlarged but not consistent with the stage of
pubertal development, ectopic production of HCG or familial Leydig
and germ cell maturation may be the cause. Most of the
enlargement of testes during puberty is the result of seminiferous
tubule maturation.
If only Leydig cells are enlarged as in these conditions, the testes
make considerable testosterone, but show only minimal
enlargement.
39. LABORATORY WORKUP
Determination of sex steroid (testosterone, estradiol, or DHEA) and
baseline gonadotropin concentrations.
The inherent nature of gonadotropin secretion is characterized by
low secretory rates throughout childhood and pulsatile secretion in
adolescents and adults.
If baseline gonadotropin values are elevated into the normal
pubertal range, central precocious puberty is likely.
If baseline gonadotropins are low, however, the distinction between
CPP and PPP often requires assessment of gonadotropin
responsiveness to GnRH stimulation.
40. LABORATORY WORKUP contd
Serum testosterone levels in boys: < 30ng/dl(prepubertal), 30-100ng/dl
(early pubertal), 100-300ng/dl (mid to late pubertal), > 300ng/dl (adult).
for girls, oestradiol measurements are less reliable indicators of the stage
of puberty. Generally, levels > 20pg/ml indicate puberty though some
girls who are clearly pubertal may have levels <20pg/ml.
DHEA-S usually elevated in boys and girls with premature adrenarche
with levels of 20-100mcg/dl. In virilizing adrenal tumours, levels
>500mcg/dl).
serum OH-progesterone if CAH is suspected.
Random LH is the best screening test for CPP. Prepubertal levels <
0.1IU/l. LH levels ≥4.1IU/l in boys and ≥3.3IU/l in girls in CPP.
41. LABORATORY WORKUP contd
A prepubertal GnRH response is FSH predominant,
whereas a pubertal response is more LH predominant.
Thyroid hormone determination also is useful because
severe primary hypothyroidism can cause incomplete
precocious puberty.
Bone age is typically advanced (>2-3 SD).
42. LABORATORY WORKUP contd
Pelvic ultrasonography in females reveals progressive
enlargement of the ovaries, followed by enlargement of
the fundus and then of the whole uterus to pubertal size.
An MRI scan usually demonstrates physiologic
enlargement of the pituitary gland, as seen in normal
puberty; it may also reveal CNS pathology.
An MRI of the brain is required in all cases of CPP.
44. TREATMENT
A decision on treatment needs to be made carefully. Most
children would only require observation with counseling
and 6-monthly follow ups particularly if:
Age is borderline (7-8 years).
Child and family are coping well.
Bone age is only slightly advanced.
Puberty is slowly progressive.
45. TREATMENT contd
Long-acting, superactive analogues of GnRH (Histrelin,
Leuprolide) are the treatment of choice for central
precocious puberty because they suppress gonadotropin
secretion by down-regulating GnRH receptors in the
pituitary gonadotropes.
After a brief (2 to 3 days) increase in gonadotropin
secretion, values decrease, and the pubertal process
reverts to the prepubertal state.
46. TREATMENT contd
Psychological support or even counseling for children and
families is critical as children with precocious puberty may
suffer emotional distress.
Surgical resection of CNS tumours causing CPP (excluding
harmatomas) should be attempted. Follow up radiotherapy
may also be required.
Surgical resection rarely causes regression of precocious
puberty.
48. PROGNOSIS
There is no increased risk of mortality with CPP. However
children with precocious puberty who have CNS, adrenal
or ovarian tumours are at risk of complications of such
tumours.
Some studies have found an association between early
puberty and a higher risk of breast cancer in girls.
Very young girls may find early menarche difficult to cope
with and may become withdrawn.
49. PROGNOSIS contd
Generally, children with sexual precocity may be teased or
bullied because of their physical difference. Behavioural
disorders are common and some persist into adulthood.
Increased libido in boys may lead to masturbation and
inappropriate sexual behaviours at a young age.
Girls with early puberty may have their sexual debut at an
earlier age than usual
50. PROGNOSIS contd
Accelerated osseous maturation increases the risk of adult
short stature. This risk is higher with earlier onset of
puberty (<6years).
However, most untreated girls with idiopathic CPP reach an
adult height within normal range.
Determination of bone age can predict adult height and
select those at risk for short stature so treatment is
instituted.
51. PROGNOSIS contd
Accelerated osseous maturation increases the risk of adult
short stature. This risk is higher with earlier onset of
puberty (<6years).
However, most untreated girls with idiopathic CPP reach an
adult height within normal range.
Determination of bone age can predict adult height and
select those at risk for short stature so treatment is
instituted.
52. DELAYED PUBERTY
May be defined as the absence of any signs of pubertal
development by age 13 in females and age 14 in males.
Delayed puberty may be due to three broad mechanisms
viz;
Constitutional growth delay
Hypogonadotrophic hypogonadism
Hypergonadotrophic hypogonadism
53. AETIOLOGY
1. Constitutional delay in growth and puberty
2. Hypogonadotropic hypogonadism
CNS disorders
Tumors (craniopharyngioma, germinoma, glioma, prolactinoma)
Congenital malformations
Radiation therapy
Other causes
Isolated gonadotropin deficiency
Kallmann syndrome (anosmia-hyposmia)
Other disorders
Idiopathic and genetic forms of multiple pituitary hormone
deficiencies
55. AETIOLOGY contd
3. Hypergonadotropic hypogonadism
Klinefelter syndrome (syndrome of seminiferous tubular dysgenesis) and its
variants
Other forms of primary testicular failure
Anorchia and cryptorchidism
Syndrome of gonadal dysgenesis and its variants (Turner syndrome)
Other forms of primary ovarian failure
XX and XY gonadal dysgenesis
Familial and sporadic XX gonadal dysgenesis and its variants
Familial and sporadic XY gonadal dysgenesis and its variants
Pseudo-Turner syndrome
Galactosemia
56. CONSTITUTIONAL GROWTH DELAY
Short stature secondary to constitutional growth delay usually
occurs with concomitant delayed puberty.
Individuals have delayed bone age compared to chronologic age
but consistent with somatic maturity.
A positive family history is reassuring.
Adult height potential is typically preserved.
Puberty usually ensues once bone age is between 12-13 years
therefore only monitoring and reassurance is typically required.
Diagnosis of exclusion.
57. HYPOGONADOTROPHIC
HYPOGONADISM
Diagnosis is challenging and difficult to distinguish from
constitutional growth delay.
The absence of gonadotrophin release precludes
gonadarche and subsequent puberty. Adrenarche may
occur in certain cases.
Throughout childhood and in early puberty, patients have
normal proportions and growth.
58. HYPOGONADOTROPHIC
HYPOGONADISM contd
When these patients reach adulthood, eunuchoid
proportions may ensue because their long bones grow for
longer than normal, producing an upper-to-lower ratio
below the lower limit of normal of 0.9 and an arm span
greater than their height.
If a patient has concurrent GH deficiency, however, stature
is exceptionally short, and the condition may have been
diagnosed in infancy with a microphallus.
59. HYPERGONADOTROPHIC
HYPOGONADISM
Hypergonadotropic hypogonadism is characterized by
elevated gonadotropin and low sex steroid levels resulting
from primary gonadal failure.
This is a permanent condition almost always diagnosed at
the time of lack of entry into gonadarche and one that
would not have been suspected throughout childhood.
Gonadotropins do not increase to greater than normal
until around the normal time of puberty.
60. DIFFERENTIAL DIAGNOSIS
Primary amenorrhoea with normal pubertal development
may be due to:
Physiologic variation (5 years between pubertal onset
and menarche).
Mayer-Rokitansky-Kuster-Hauser syndrome.
Androgen Insensitivity Syndrome.
Imperforate hymen
61. INVESTIGATION
FBC+ESR, E/U/Cr, Thyroid function tests and Prolactin levels
should be obtained as part of the initial workup.
Insulin-like growth factor-1 level should be done in those with
slow growth.
Testosterone levels in males and Oestradiol in females.
Random FSH/LH and GnRH stimulation test.
X-rays for bone age, Cranial MRI/CT.
Chromosomal karyotyping.
62.
63.
64. TREATMENT
CONSTITUTIONAL DELAY
Appropriate treatment is watchful waiting.
Children with marked growth delays and psychological
compromise may have short course of treatment.
Males are given IM Testosterone 50-100mg every 3
weeks for upwards of 3 months.
Low dose oestradiol for females.
65. TREATMENT contd
Permanent conditions of hypogonadism are treated
with sex hormone replacement.
Females are given low dose ethinyl oestradiol daily till
breakthrough bleeding occurs. Then it is given cyclically
on days 1-25, and for the rest of the cycle,
medroxyprogesterone is added.
Males receive monthly IM doses of Testosterone
enanthate.