puberty - including primary amennorhea

1. PUBERTY
MODERATOR: DR. HARISH SHETTY

2. PUBERTY
• Puberty is the period during which secondary
sexual characteristics develop and the
capability of sexual reproduction is attained.
• The physical changes accompanying pubertal
development result directly or indirectly from
maturation of the hypothalamus, stimulation
of the sex organs, and secretion of sex
steroids.

3. Hormonal changes in puberty
• The hypothallamic pitutary gonadal axis becomes
functional even before birth.
• By 10 weeks of GA the hypothalamus contains
significant amount ofGnRH.
• Development of the hypothalamo pituitary portal
venous system begins between 9-10 weeks of GA
and is completed by 19-20 weeks.
• FSH and LH concentrations in fetal pitutary glands
increase thereafter.

4. • Gonadotropin levels rise progressively
reaching a peak between 20 and 24 weeks
and then decrease over the last 10 weeks of
pregnancy
• After birth steriod levels fall due to the loss of
maternal and placental hormones
• Pulsatile pattern of hypothalamic GnRH
secretion emerges and serum gonadotropins
concentrations rise again – increase FSH in
females

5. • Gonadotropins and gonadal steroid levels
peak at 12 – 18 months in girls and steadily
decline there after
• Now it enters a quiscent phase known as the
juvenille phase
• This quiescent HPO axis is then activated 1
year before breast budding.
• The hypothalamus starts secreting GnRH in a
pulsatile manner first at night and later
throughout the day.

6. • In response to GnRH from the hypothalamus,
pitutary release FSH and LH
• LH peaks during sleep under the influence of
the nocturnal pulsatile GnRH release.
• LH peak amplitude increases around 10 fold
and the FSH amplitude doubles
• As puberty progress the diurnal pattern of
gonadotropin secretion changes and pulsatile
gonadotropin secretion with high peaks
occurs through out the day

7. • Due to FSH the Estradiol level increase and
become detectable throughout the day
• After one year of consistently high estradiol
level, menarche occurs.
• The maturation of the zona reticularis of the
adrenal gland results in secretion of adrenal
androgens (DHEA, DHEAS and
androstenedione )
• Development of pubic hair , axillary hair ,
body odour and acne

8. Hormonal Changes
• Growth hormone secretion increases along with
increased gonadotropin secretion at the onset of
puberty.
• Girls have higher basal levels of GH throughout
puberty, reaching maximal levels around the time
of menarche and decreasing thereafter.
• Growth hormone secretion is highly pulsatile,
with most pulses occurring during sleep and with
sex steroids increasing pulse amplitude rather
than altering pulse frequency.

9. Hormonal Changes
• The increase in growth hormone induces
peripheral insulin resistance resulting in
compensatory hyper insulinemia
• This causes a decrease in the different binding
proteins
• A reduction in insulin growth factor binding
protiens leads to an increase in insulin growth
factor therby stimulates somatic growth

10. Factors Affecting Time of Onset
• Time of onset of puberty is genetic, but a
number of other factors influence both the age at
onset and the progression of pubertal
development.
• These influences are nutritional state, general
health , geographic location, exposure to light,
and psychological state .
• The concordance of the age of menarche in
mother–daughter pairs and between sisters and
in ethnic populations illustrates the importance
of genetic factors

11. Factors Affecting Time of Onset
• Blind girls undergo menarche earlier than sighted
girls, suggesting some influence of light
• One of the more controversial hypotheses
centers on the role of total body weight and body
composition on the age of menarche.
• It is found that a girl must reach a critical
bodyweight (47.8 kg) before menarche can occur
• Body fat must increase to 23.5% from the typical
16% of the prepubertal state

12. STAGES OF PUBERTY
• Growth spurt
• Breast development (thelarche)
• Pubic hair growth (Adrenarche)
• Menstruation (menarche)
• Axillary hair growth
• 70% of girls, variation often occur in Tanner
• Definite signs of puberty are usually present by
the age 9 or 10 years

13. Growth spurt
• It begins around the age of 11yrs in girls
• 6 to 10cms per year for around 2 years
• Effect of estrogen – fusion of end plate of the femur
and growth ceases by the age of 15 yrs
• Boys grow an average of 28cm during the growth
spurt, incomparison to a mean of 25cm for girls.
• Growth hormone (GH), insulin like growth factor 1
(IGF-1), and gonadal steroids play major roles

14. Growth spurt
• The changes in body contour in girls, with
accumulation of fat at the thighs, hips, and
buttocks, occur during the pubertal growth
spurt.
• Testosterone is a potent anabolic steroid and
is responsible for the major changes in boys,
whereas estrogen increases total body fat in a
characteristic distribution at the thighs,
buttocks, and abdomen in girls.

15. Physical Changes during Puberty
• Breast budding is usually the first recognized
pubertal change, followed by the appearance
of pubic hair, peak growth velocity, and
menarche.
• In girls, pubertal development typically takes
place over 4.5 years

16. Tanner staging
• Tanner stage 1 refers to the pre pubertal state
and includes no palpable breast tissue, with the
areolae generally less than 2 cm in diameter .
The nipples may be inverted, flat, or raised.
• Tanner stage 2: breast budding occurs, with a
visible and palpable mound of breast tissue. The
areolae begin to enlarge, the skin of the areolae
thins, and the nipple develops to varying degrees.
• Tanner stage 3: is further growth and elevation of
the entire breast. When the individual is seated
and viewed from the side, the nipple is generally
at or above the midplane of breast tissue.

17. Tanner staging
• Tanner stage 4 is defined by projection of the
areola and papilla above the general breast
contour in a secondary mound.
• Tanner stage 5: in which the breast is mature
in contour and proportion. Montgomery’s
glands are visible around the circumference of
the areola. The nipple is below the midplane
of breast tissue when the woman is seated and
viewed from the side.

18. Tanner staging of breast development
– Marshall and Tanner (1969)
Elevation of papilla
Elevation of papilla & breast
on a small mount, increased
in areola
Further enlargement
Secondary mound of areola
and papilla
Recession of areola to
contour of breast
prepubertal
9-13 yrs
10-14 yrs
11-15 yrs
12-17 yrs
18

19. Pubarche: development of pubic
hair
• Median age 10.5yrs
• Tanner stage 1: there is no sexually
stimulated pubic hair present, but some
nonsexual hair may be present in the genital
area.
• Tanner stage 2 is characterized by the first
appearance of coarse, long, crinkly pubic hair
along the labia majora.
• Tanner stage 3 coarse, curly hair extends onto
the mons pubis

20. • Tanner stage 4 is characterized by adult hair
in thickness and texture, but the hair is not
distributed as widely as in adults and typically
does not extend onto the inner aspects ofthe
thighs.
• Except in certain ethnic groups, including
Asians and American Indians, pubic hair
extends onto the thighs in Tanner stage 5.

21. Tanners staging

22. Abberations of puberty
• I. Delayed or interrupted puberty
• II. Asynchronous pubertal development
• III. Precocious puberty
• IV. Heterosexual puberty

23. Delayed or Interrupted Puberty
• It exists in girls who fail to develop any
secondary sex characteristics by age 13, have
not had menarche by age 15 ,or have not
attained menarche 5 or more years since the
onset of pubertal development.

24. I. Delayed or interrupted puberty
• A. Anatomic abnormalities of the genital
outflow tract
• B. Hypergonadotropic (follicle-stimulating
hormone>30 mIU/mL) hypogonadism
• C. Hypogonadotropic (luteinizing hormone
and follicle-stimulating hormone<10 mIU/mL)
hypogonadism

25. Anatomic Abnormalities of the Genital
OutflowTract
• 1. Mullerian dysgenesis (Rokitansky-K¨uster-
Hauser syndrome)
• 2. Distal genital tract obstruction
• a. Imperforate hymen
• b. Transverse vaginal septum

26. Mullerian dysgenesis
• This condition is also called Mayer -
Rokintansky- Kuster –Hauser syndrome.
• Exact etilogy unknown
• The karyotype is 46 XX .
• The phenotype is that of a normal female with
normal height and secondary sex characters ,
as the ovaries are normally developed.
• Ovulation will occur normally in these girls

27. Mullerian dysgenesis
• The mullerian ducts fail to form completely and
there is no uterus and so its called mullerian
agenesis
• Sometimes the mullerian ducts may partially
develop and there may be two rudimentary horns
• The external genitalia appear normal but the vagina
is very short and blind
• 1/3rd patients have associated renal anomalies –so
should be evaluated

28. Diagnosis and treatment
• Karyotyping- 46XX and demonstration of non
canalised vagina with absent uterus
• Patients can have their own children by
retrieving their ova for IVF and growing the
embryo in a surrogate mother

29. • For coital function: vaginoplasty may be done
few months before marriage with split skin
graft(Mc Indoe technique) or amniotic
membrane.
• As a alternative to vaginoplasty ,progressive
dilatation with vaginal dilators can be used

32. 2.Distal genital tract obstruction
• Outflow obstructions include imperforate
hymen or transverse vaginal septum
• This causes cyclical pain without menstrual
bleeding in adoloscents
• IMPERORATE HYMEN: diagnosed in the
presence of a bulging membrane (often bluish
in colour)distending on valsalva manuver
• Treatment: cruciate incision to open the
vaginal orifice

33. • Transverse septum if present is surgically
removed
• Frank dilators to be used to distend the vagina
and prevent vaginal adhesions

34. B. Hypergonadotropic hypogonadism
• 1. Gonadal dysgenesis with stigmata of Turner
syndrome-45X
• 2. Pure gonadal dysgenesis
• a. 46,XX
• b. 46,XY
• 3. Early gonadal “failure” with apparent
normal ovarian development

35. Turner Syndrome
• Most affected individuals have a
45,Xkaryotype, while others have mosaic
karyotypes (i.e., 45,X/46,XX; 45,X/46,XY).
• The typical phenotype will be webbed neck,
short stature, shield chest , cubitus valgus ,
low hair line, congenital cardiac defects ,
horse shoe kidney, skeletal anomalies , normal
intelligence, autoimmnune thyroiditis and
diabetes mellitus.

37. Turner Syndrome
• Although they do not develop breasts at puberty,
some pubic or axillary hair may develop because
appropriate adrenarche can occur with failure of
thelarche
• Although less severe short stature and some
adolescent development may occur with
chromosomal mosaicism , it is to be assumed
that any short, slowly growing, sexually infantile
girl has Turner syndrome until proved otherwise
because this disorder is so prevalent about 1 in
2,500 newborn phenotypic females

38. Turner Syndrome
• Presence of Y chromosome is associated with a
12% risk of a gonadoblastoma.
• If a Y chromosome is identified, laparoscopic
prophylactic gonadectomy is recommended at
the time of diagnosis to eliminate the risk of
malignancy.
• Although gonadoblastomas are benign tumors
with no metastatic potential, they can be
precursors to germ cell malignancies, such as
dysgerminomas, teratomas, embryonal
carcinomas, or endodermal sinus tumors

39. Treatment of Turner Syndrome
• To increase adult height, treatment strategies
include use of exogenous Growth Hormone
• It appears that early initiation of therapy
(between 2–8years of age), gradually increasing
the dose, and continuing treatment for a mean of
7 years can lead to achievement of a final height
greater than 150 cm in most patients .
• Weekly doses of Growth Hormone of 0.375
mg/kg divided into seven daily doses are given

40. Treatment of Turner Syndrome
• To promote sexual maturation, therapy with
exogenous estrogen should be initiated at about
12 to 13 years of age, and after GH therapy was
administered for several years.
• 2. Because the intent is to mimic normal pubertal
development, therapy with low-dose estrogen
alone (such as 0.025 mg per day transdermal
estradiol or 0.3–0.625 mg conjugated estrogens
orally each day) should be initiated.

41. Treatment of Turner Syndrome
• 3. Progestins (5-10mg medroxy progesterone
acetate or 200mg micronized progesterone
orally for 12 to 14 days every 1 to 2 months)
can be added to prevent endometrial
hyperplasia after the patient first experiences
vaginal bleeding or after 6 to12 months of
unopposed estrogen use if the patient has not
yet had any bleeding

42. Treatment of Turner Syndrome
• 4. The dose of estrogen is increased slowly over 1
to 2 years until the patient is taking about twice
as much estrogen as the amount administered to
post menopausal women.
• 5. Girls with gonadal dysgenesis must be
monitored carefully for the development of
hypertension with estrogen therapy.
• 6. The patients and their parents should be
counseled regarding the emotional and physical
changes that will occur with therapy.

43. Mosaic Forms of Gonadal Dysgenesis
• Individuals with rare mosaic forms of gonadal
dysgenesis may develop normally at puberty.
• The decision to initiate therapy with exogenous
estrogen should be based mainly on circulating
FSH levels. Levels in the normal range for the
patient’s age imply the presence of functional
gonads.
• These individuals can become pregnant, with
success rates of more than 50% using donor
oocytes.

44. Pure Gonadal Dysgenesis
• It refers to 46,XX or 46,XY phenotypic females
who have streak gonads.
• This condition may occur sporadically or may be
inherited as an autosomal recessive trait or as an
X-linked trait in XY gonadal dysgenesis .
• Affected girls typically are of average height and
have none of the stigmata of Turner syndrome,
but they have elevated levels of FSH because the
streak gonads produce neither steroid hormones
nor inhibin.

45. Pure Gonadal Dysgenesis
• When gonadal dysgenesis occurs in
46,XYindividuals, it is sometimes termed
Sweyer syndrome.
• Sweyer syndrome is a 46 XY female with
sexual infantilism
• The gonads do not develop in these
individuals due to mutations in the SRY gene
of the Y chromosome

46. Sweyer syndrome features
• Eunuchoid features
• Phenotypic female
• Secondary sexual characters not developed
• Infantile uterus and vagina

47. Sweyer sydrome
• Because of the absence of anti mullerian
hormone the mullerian duct will persist and
the patients have a rudimentary uterus and
vagina.
• Since these individuals are at high risk of
gonadoblastomas their gonads should be
extirpated.
• Estrogen and progesterone therapy is given
for development of secondary sexual
characters.

48. Hypogonadotropic hypogonadism
1. Constitutional delay
2. Isolated gonadotropin deficiency
a. Kallmann syndrome
b. Prader-Labhart-Willi syndrome
c. Laurence-Moon-Bardet-Biedl syndrome
d. other rare syndromes
3. Multiple hormone deficiencies
4. Neoplasms of the hypothalamus–pituitary
a. Craniopharyngiomas
b. Pituitary adenomas

49. Hypogonadotropic hypogonadism
5. Langerhans cell–type histiocytosis
6. After irradiation of the central nervous system
7. Severe chronic illnesses with malnutrition
8. Anorexia nervosa and related disorders
9. Hyperprolactinemia
10. Primary hypothyroidism
11. Cushing syndrome
12. Use of chemotherapeutic (especially alkylating)
agents

50. Kallman syndrome
• Kallmann syndrome consists of the triad of
anosmia, hypogonadism, and color blindness
• seen in 1 in 50,000 women
• Women may be affected, and other associated
defects may include cleft lip and palate,
cerebellar ataxia, nerve deafness, and
abnormalities of thirst and vasopressin release.
• X-linked recessive, autosomal dominant, and
autosomal recessive.

51. Kallman syndrome
• unilateral renal agenesis
• bimanual synkinesia
• sensorineural hearing loss.
• sexual infantilism and an eunuchoid habitus,
but some degree of breast development may
occur

52. Kallman syndrome
• Primary amenorrhea . The ovaries are usually
small, with follicles seldom developing beyond
the primordial stage
• Affected individuals respond to pulsatile
administration of exogenous GnRH, and this is
the most physiologic approach to ovulation
induction

53. Prader-Labhart-Willi syndrome
Characterized by
• obesity
• short stature
• hypogonadism
• small hands and feet (acromicria)
• mental retardation
• infantile hypotonia.

54. Prader-Labhart-
Willi syndrome
Characterized by
 obesity
 short stature
 hypogonadism
small hands and feet
(acromicria)
mental retardation
 infantile hypotonia.

55. Laurence-Moon-Bardet-Biedl
syndrome
• retinitis pigmentosa
• postaxial polydactyly
• obesity
• hypogonadism

56. Tumors of the Hypothalamus and
Pituitary
• Except for craniopharyngiomas, other tumors are
uncommon in children.
• A craniopharyngioma is a tumor of the Rathke’s
pouch.
• It is the most common neoplasm associated with
delayed puberty, and it accounts for 10% of all
childhood central nervous system tumors.
• Craniopharyngiomas are usually suprasellar in
location and maybe asymptomatic well into the
second decade of life.

57. Tumors of the Hypothalamus and
Pituitary
• Laboratory evaluation should document
hypogonadotropism and may reveal
hyperprolactinemia as a result of interruption of
hypothalamic dopamine inhibition of prolactin
release.
• Radiographically, the tumor may be either cystic
or solid and may show areas of calcification.
Appropriate therapy for hypothalamic–pituitary
tumors may involve surgical excision or
radiotherapy

58. Anorexia Nervosa and Bulimia
• Significant weight loss and psychological
dysfunction occur simultaneously with
anorexia nervosa .
• Although many anorectic girls experience
amenorrhea after pubertal development
begins, if the disorder begins sufficiently early

59. Anorexia Nervosa
• The following findings confirms anorexia nervosa
in most individuals:
• 1. Relentless pursuit of thinness
• 2. Amenorrhea, sometimes preceding the weight
loss
• 3. Obsessive-compulsive personality
• 4. Distorted and bizarre attitude toward eating,
food, or weight
• 5. Distorted body image

60. Anorexia Nervosa
• Girls with anorexia nervosa may have, in addition to
hypogonadotropic hypogonadism,
• partial diabetes insipidus
• abnormal temperature regulation
• Hypotension
• chemical hypothyroidism with low serum tri
iodothyronine (T3) and high reverse T3 levels
• elevated circulating cortisol levels in the absence of
evidence of hypercortisolism

61. Anorexia Nervosa Management
• A team approach involving the primary
clinician, psychiatrist, and nutritionist is most
effective.
• anorexia nervosa has the highest mortality of
any psychiatric disorder.
• Deaths are often sudden and unexpected.
Cause of death can include hypoglycemia and
electrolyte imbalance.

63. Hyperprolactinemia
• Low levels of LH and FSH may be associated
with hyperprolactinemia.
• Galactorrhea cannot occur in the absence of
complete breast development.
• Pituitary prolactinomas are rare during
adolescence but must be considered when
certain signs and symptoms are present.

65. Asynchronous Puberty
• It is characterised by pubertal development
that deviates from the normal pattern of
puberty
• A. Complete androgen insensitivity syndrome
(testicular feminization)
• B. Incomplete androgen insensitivity
syndrome

66. Complete AIS
• This was previously called testicular feminisation
syndrome and is inherited as an X linked trait.
• The main pathology is the absence of the cytosol
receptor which is necessay for the actions of
testosterone .
• The genotype is 46XY
• The testis may be situated intra abdominally or
in the labia or as inguinal hernia.
• The testes produce both testosterone and anti
mullerian hormone.

67. Complete AIS
• The presence of the mullerian inhibiting factor
prevents development of the mullerian
structures and so there is no uterus.
• As the androgen receptor is absent, there is
insensitivity to testosterone and the wolffian
structures do not develop and so there are no
male internal genital organs.
• External genitalia are of the female type and the
phenotype is female.
• The result is a female with normal stature and
adequate breast development, but no uterus

68. Complete AIS
• Breast development occurs by the oestrogen
produced from the peripheral conversion of
testosterone to estrogen.
• The inheritance is X linked in two-thirds. The
rest are thought to be due to new mutations.
The androgen receptor gene is found to lie
along the long arm of the X chromosome

69. Complete AIS
• Female child presenting with an inguinal
hernia is very typical of this condition and
almost always necessitates a karyotyping.
• The diagnosis is confirmed by finding a male
karyotype.
• Testosterone levels, if done will be found to
be in the normal male range.

70. Complete AIS- management
• Most cases of complete AIS present only at puberty
as primary amenorrhoea. The sex of rearing would
usually have been female and it is best not to change
it.
• In such cases the gonads are removed after
completion of puberty as there is the risk of
malignant change in the presence of a Y
chromosome.If removed earlier breast development
may not occur
• Exogenous estrogens are prescribed to prevent
osteoporosis.

71. Partial AIS
• For complete masculinisation to occur the
androgen receptor should be present for
testostrone to act.
• Here there is partial sensitivity of this receptor
• Hence phenotypically they are different from
complete AIS

72. Sinnecker’s classification of AIS
Grade Phenotype
Type1 Normal male phenotype with impaired
spermatogenesis
Type 2 Male genitalia with hypospadiasis , micropenis
and bifid scrotum (reifenstein syndrome)
Type 3 Ambiguous genitalia
Type 4 Female genitalia with virilisation like
clitoromegaly and partial labial fusion
Type 5 Complete AIS

73. Precocious puberty
• Tanner stage 2 of breast development prior
the age of 7 yrs in white and 6 yrs in black
• In 90% of girls precocious puberty is
idiopathic.

76. Precocious puberty
A. Central (true) precocious puberty
1. Constitutional or idiopathic precocious puberty
2. Hypothalamic neoplasms (most commonly
hamartomas)
3. Congenital malformations like hydrocephalus,
cranistenosis , arachnoid cyst , septooptic dysplasia
4. Infiltrative processes (Langerhans cell–type
histiocytosis)
5. After irradiation
6. Trauma
7. Infection

77. Central precocious puberty
• It is due to activation of the hypothalamo-pitutary
unit
• In this GnRH prematurely stimulates
premature gonadotropin secretion
• A common etiology (2% to 28%) of central
precocious puberty is a hypothalamic
hamartoma.

78. Central precocious puberty
Classification: Idiopathic or organic brain
disease
Idiopathic :
Most common
90%
Underlying etiology unknown

79. Central precocious puberty
Organic brain disease (10%)
• Extreme precocity (usually before 3 years of
age) and the absence of tumor markers, such
as β-human chorionic gonadotropin and α-
fetoprotein, suggest a hamartoma.
• Hamartomas can be associated with laughing
(gelastic) seizures, behavioral disturbances,
mental retardation, and dysmorphic
syndromes

80. Central precocious puberty-hamartomas
• hamartomas produce GnRH in a pulsatile
manner and thus stimulate gonadotropin
secretion
• Growth spurt is rapid with short duration
• General health is not impaired
• diagnosis – MRI, CT scan

81. Central precocious puberty treatment
Idiopathic – GnRH analogs are reported as
being sucessful in the treatment of IPP and
central nervous system .
Therapy – early – increase the height
Buserelin 6.3mg every 2 months
Goserelin 3.6 mg every month or 10.8 mg every
3 months
Lueprolide 3.75-7.5mg monthly or 11.25 mg
every 3 months
Triptorelin 3-3.75mg monthly or 11.25mg every
3 months.

83. B. Precocious puberty of peripheral
origin
1. Autonomous gonadal hypersecretion
a. small ovarian Cysts
b. McCune-Albright syndrome
2. Congenital adrenal hyperplasia
3. Iatrogenic ingestion/absorption of estrogens or
androgens
4. Hypothyroidism
5. Gonadotropin-secreting neoplasms
6.Gonadal neoplasms

84. Precocious Puberty of Peripheral
Origin
• In gonadotropin-independent precocious
puberty, production of estrogens or androgens
from the ovaries, adrenals, or rare steroid-secreting
neoplasms leads to early pubertal
development.
• Small functional ovarian cysts, typically
asymptomatic, are common in children and may
cause transient sexual precocity .
• Simple cysts can be observed and usually resolve
over time.

85. McCune-Albright Syndrome
• The Mc Cune-Albright syndrome is
characterized by the classic triad of
polyostotic fibrous dysplasia of bone, irregular
caf´e-au-lait spots on the skin, and GnRH-independent
sexual precocity.
• The caf´e-au-lait spots are usually large, do
not cross the midline, and have irregular
“coast of Maine” margins.

86. McCune-Albright Syndrome
• They are often located on the same side as
the bony lesions.
• Sexual precocity often begins in the first 2
years and usually presents with menstrual
bleeding.
• Girls develop sexual precocity as a result of
functioning ovarian cysts.
• Serum estradiol is elevated.

88. Mc Cune Albright syndrome-treatment
• Testolactone – total daily oral dose of 20
mg/kg body in four divided doses-
• over a 3 weeks interval the total daily dose is
increased to 40 mg/kg body wt
• Continue till the sign regress
• Side effects: diarrhoea , abdominal cramping
• Bisphosphonate therapy –in treatment of
fibrous dysplasia of bone that causes pain and
fractures.

89. Congenital Adrenal Hyperplasia
• Three adrenal enzyme defects—
• 21-hydroxylase deficiency
• 11β-hydroxylase deficiency and
• 3β-hydroxysteroid dehydrogenase deficiency
• It can lead to heterosexual precocity and to
virilization of the external genitalia because of
increased androgen production beginning in
utero

90. Congenital Adrenal Hyperplasia
• Most patients with classic CAH have 21-
hydroxylase deficiency
• incidence :1 in 15,000 births.

91. Congenital Adrenal Hyperplasia
• 1.simple virilizing(classic form) :typically
identified at birth because of genital
ambiguity
• 2. salt-wasting (in which there is impairment
of mineralocorticoid and glucocorticoid
secretion-classic form)
• 3.late-onset or nonclassic (in which
heterosexual development occurs at the
expected age of puberty).

92. Congenital Adrenal Hyperplasia
• Deficiency of 21-hydroxylase results in the
impairment of the conversion of 17α-
hydroxyprogesterone to 11-deoxycortisol and
of progesterone to deoxycorticosterone
• Because the development of the external
genitalia is controlled by androgens, in the
classic form of this disorder, girls are born
with ambiguous genitalia

95. Congenital Adrenal Hyperplasia
• The internal female organs(including the
uterus, fallopian tubes, and ovaries)develop
normally because they are not affected by the
increased androgen levels.
• In three-quarters of cases with classic 21-
hydroxylase deficiency, salt-wasting occurs, as
defined by hyponatremia, hyperkalemia, and
hypotension.

96. Congenital Adrenal Hyperplasia
• Mildly virilized newborn with 21-hydroxylase
deficiency should be observed for signs of a
life-threatening crisis within the first weeks of
life
• The classic forms of 21-hydroxylase deficiency
are easily diagnosed based on the presence of
genital ambiguity and markedly elevated
levels of 17α-hydroxyprogesterone.

97. Treatment of Congenital Adrenal
Hyperplasia
• The treatment of CAH involves providing
replacement doses of the deficient steroid
hormones.
• Hydrocortisone (10 to 20 mg/m2bodysurface
area) is given daily in divided doses to
suppress the elevated levels of pituitary
corticotropin present and thus suppress the
elevated androgen levels.

98. Treatment of Congenital Adrenal
Hyperplasia
• Mineralocorticoid replacement is generally
required in individuals with 21-hydroxylase
deficiency whether or not they are salt losing.
• The intent of glucocorticoid therapy should be to
suppress morning 17α-hydroxyprogesterone
levels to between 300 and 900 ng/dL.
• Sufficient fludrocortisone should be given daily
to suppress plasma renin activity to less than 5
mg/mL per hour

99. Prenatal Diagnosis
• The diagnosis is established by documenting
elevated levels of 17α-hydroxyprogesterone
or 21-deoxycortisol in amniotic fluid.

100. • Dexamethasone(20μg/kg/day in three divided
doses) can be administered to the pregnant
women beginning before the ninth week of
gestation because the urogenital sinus begins
to form at nine weeks of gestation.
• If the fetus is determined to be a male or an
unaffected female upon DNA analysis,
treatment is discontinued.
• Otherwise, treatment is continued to term.

102. Premature thelarche – development of breast <
7yrs in white and <6yrs in black
This is a bilateral enlargement of breasts in 1-2 yr olds that is
common. There are no other signs of puberty development
and the growth is normal. As long as the vulva, labia, vagina
are normal infantile, and there is no pubic hair, then nothing is
done.

103. Premature thelarche
It can be unilateral/ bilateral without other signs
of sexual maturation
No significant nipple or areola development
Commonly occurs between 2and 4 yrs of age.
Benign and needs no therapy
Caused due to increase sensitivity of breast to
low levels of estrogens or increased estradiol
secretion by follicular cyst
GnRH stimulation: FSH increases and LH no
response

104. Premature Adrenarche
Appearance of pubic hair <8
yrs
No other pubertal changes
No evidence of systemic
estrogen
Other androgen mediated
clinical findings- axillary hair
growth, oily skin, and acne
One half children have
organic brain disease.

105. Indications of evaluation of
precocious puberty
• Family history
• Rapidity with which secondary sexual
characters are developing
• Presence of central nervous system diseases

106. The evaluation of precocious puberty
1.Measurement of basal gonadotropin levels is the
first step in the evaluation of a child with sexual
precocity
2. Thyroid function should be evaluated
3.High levels of LH (which really may be human
chorionic gonadotropin detected because of
cross-reactivity with LH in immunoassays)
suggest a gonadotropin-producing neoplasm,
most often a pinealoma or choriocarcinoma or,
less often, a hepatoblastoma.

107. Evaluation of precocious puberty …
4. Low or pubertal levels of gonadotropins indicate the
need to determine circulating estradiol concentrations
in girls with isosexual development and to assess
androgen levels, specifically testosterone, DHEAS, and
17α-hydroxyprogesterone in girls with heterosexual
development.
5. Increased estradiol levels suggest an estrogen-secreting
neoplasm, probably of ovarian origin
6. Increased testosterone level suggest an androgen-producing
neoplasm of the ovary or the adrenal gland.

108. Evaluation of precocious puberty …
• Increased 17α-hydroxyprogesterone levels are
diagnostic of 21-hydroxylase deficiency i.e.
congenital adrenal hyperplasia . Levels of
DHEAS are elevated in various forms of CAH.
• 7. If the estradiol levels are compatible with
the degree of pubertal development
observed, evaluation of the central nervous
system by MRI or CT scanning .

109. Evaluation of precocious puberty …
• 8. Bone age should always be assessed in
evaluating an individual with sexual precocity.
• 9. A GnRH stimulation test can be used to
confirm central precocious puberty. After 100
μg GnRH, an LH peak of greater than 15
mIU/mL is suggestive of gonadotropin-dependent
precocious puberty

111. Heterosexual puberty
• Characterised by a pattern of development
that is typical of opposite sex occuring at
expected age of normal puberty.

112. Heterosexual pubertal development
A. Polycystic ovarian syndrome
B. Nonclassic forms of congenital adrenal
hyperplasia
C. Idiopathic hirsutism
D. Mixed gonadal dysgenesis
E. Rare forms of male pseudohermaphroditism
F. Cushing syndrome (rare)
G. Androgen-secreting neoplasms (rare)