1. Clinic of Reproduction and Gynecology Pomeranian Medical Academy
Puberty
Clinic of Reproduction and Gynecology
Pomeranian Medical Academy
Iwona Szydłowska

2. It is a physiological phase lasting 2 to 5 years, during which the genital organs mature

3. SEXUAL MATURATION
Physical, emotional and sexual transition from childhood to adulthood
Gradually. Sequence of physiological changes.

4. The first sign of pubertal development is usually breast growth (thelarche), followed by appearance of pubic hair (pubarche), then axillary hair (adrenarche), then menarche.
The mean interval between breast budding and menarche is 2.5 years with a standard deviation of about one year.

5. Somatic changes dependent on adrenal steroid hormones
ADRENARCHE
Somatic changes dependent on adrenal steroid hormones
means increased activity of the suprarenal cortex at puberty with increased production of adrenal androgens which lead to appearance of pubic and axillary hair.

6. Somatic changes dependent on gonadal sex steroid hormones
GONADARCHE
Somatic changes dependent on gonadal sex steroid hormones

7. CAUSE OF PUBERTY:
During childhood, the hypothalamus is extremely sensitive to the negative feedback exerted by the small quantities of estradiol & testosterone produced by the child's ovaries.
As puberty approaches, the sensitivity of the hypothalamus is decreased and subsequently, it increase the pulsatile GnRH secretion .

8. CNS-Hypothalamus-Pituitary Ovary-Uterus Interaction
Neural control
Chemical control
Dopamine
(-)
Norepinephrine
(+)
Endorphines
(-)
Hypothalamus
Gn-RH ? –
Ant. pituitary
FSH, LH
Ovaries
Estrogen
Progesterone
Uterus
Menses

9. HYPOTHALAMUS-PITUITARY OVARIAN AXIS
Necessary for the normal sexual maturation.
Pulsatile secretion of gonadotropins begins the maturation process.
Important is not the amplitude of Gn pulses, but the frequency.
In the late prepubertal period secretion of Gn is reinforced – subsequent pulses of GnRH reinforce the release of Gn.
Activation of positive and negative feedback loops at puberty.

10. The anterior pituitary responds by progressive secretion of FSH and LH associated with increased secretion of growth hormone.

11. The ovaries respond to the increase Gonadotrophin secretion by follicular development & estrogen secretion.

12. Estrogen causes development of the genital organs and the appearance of the secondary sexual characters.
With increased estrogen secretion, menarche and cyclic estrogen secretion occurs.

13. SECONDARY SEX CHARACTERS INCLUDE:
development of the breast,
appearance of pubic and axillary hair.

14. FACTORS AFFECTING THE INITIATION OF PUBERTAL DEVELOPMENT:
1 - Height and weight ratio- 48 kg (nutritional factors).
2 - Maturation of the hypothalamus.
3 - Increased neurotransmitter output in CNS.
4 - Onset of adrenal androgen activity.

15. DEPOSITION OF SC FAT:
17% to menstruate
&
22% to ovulate

16. PUBERTY
Five stages from childhood to full maturity (P1 to P5), described by Marshall and Tanner. In both sexes, these stages reflect the progressive modifications of the external genitalia and of sexual hair. Secondary sex characteristics appear at a mean age of 10.5 y in girls and 11.5 to 12 y in boys.

17. SEQUENCE AND AGE OF SEXUAL MATURATION AND HORMONES RESPONSIBLE FOR THIS PROCESSES.
Event
Age (mean)
Hormones
Thelarche (breast budding)
Pubarche (sexual hair growth)
Growth spurt
Menarche
Adult breast development
Adult sexual hair
10,5
10,6
12,0
12,7
13,7
14,7
Estradiol
Androgens GH
Progesterone

18. FEMALE PUBERTAL STAGES (TANNER)
P1 Prepubertal
P2 Early development of subareolar breast bud +/- small amounts of pubic hair and axillairy hair
P3 Increase in size of palpable breast tissue and areolae, increased amount of dark pubic hair and/of axillary hair
P4 Further increase in breast size and areolae that protrude above breast level adult pubic hair
P5 Adult stage, pubic hair with extension to upper thigh

19. TANNER’S CLASSIFICATION OF SEXUAL MATURITY: BREASTS
Th 1- child (only papillae are elevated)
Th 2 – prepubertal (breast bud and papilla are elevated and a small mount is present; areola diameter is enlarged); age 11,2 yrs (9,0-13,3 yrs)
Th 3 - early pubescent, age 12,2 yrs (10,0-14,3)
Th 4 - late pubescent, age 13,1 yrs (10,8-15,3)
Th 5 - adult mature breast (recession of areola to the mound of breast tissue, rounding of the breast mound, and projection of only the papilla are evident); age 15,3 yrs (11,9-18,8)

20. TANNER’S CLASSIFICATION OF SEXUAL MATURITY: PUBIC HAIR
P1- prepubertal/Pre-adolescent (vellus hair only, no pubic hair)
P2 - presexual hair (sparse growth of long, slightly pigmented, downy hair or only slightly curled hair, appearing along labia) - age 11,7 (9,3-14,1)
P3 - sexual hair (hair is darker, coarser, more curled, and spreads above the syphysis pubis) – age 12,4 (10,2-14,6)
P4 - mild-escutcheon (Adult-type hair; area covered is less than that in most adults; there is no spread to the medial surface of thigh) – age 13,0 (10,8-15,1)
P5 - female escutcheon (Adult-type hair with increased spread to medial surface of thighs; distribution is as an inverse triangle) – age 13,4 ( 12,2-16,7)

21. GENITAL ORGANS CHANGES:
Mons pubes, labia majora & minora: increase in size.
Vagina:
length: increase, appearance of the rugae
epithelium: thick, stratified squamous, containing glycogen
pH: acidic.

22. GENITAL ORGANS CHANGES:
Uterus:
enlarge, Uterus / Cervix :2 / 1
Ovaries:
Increase in size, almond shape
300 thousands primary follicle at menarche (2 million at birth)

23. In prepuberty, the ovarian size volume extends from 0. 3 to 0. 9 cm3
In prepuberty, the ovarian size volume extends from 0.3 to 0.9 cm3. More than 1.0 cm3 indicates that puberty has begun. During puberty, the ovarian size increases rapidly to a mean postpubertal volume of 4.0 cm3 (1.8 to 5.3 cm3).

24. MENARCHE
During puberty, plasma E2 levels fluctuate widely, probably reflecting successive waves of follicular development that fail to reach the ovulatory stage. The uterine endometrium is affected by these changes and undergoes cycles of proliferation and regression, until a point is reached when substantial growth occurs so that withdrawal of estrogen results in the first menstruation (menarche).

25. OVULATION
Plasma progesterone remains at low levels even if secondary sexual characteristics have appeared. A rise in progesterone after menarche is, in general, indicative that ovulation has occured. The first ovulation does not take place until 6-9 months after menarche because the positive feedback mechanism of estrogen is not developed.

26. Puberty represents the first part of adolescence .
Is the period of life during which the child becomes an adult person
i.e. the physical , sexual and psychological development are complete .
Puberty represents the first part of adolescence .

27. ABNORMALITIES OF PUBERTY
1 - Precocious puberty.
2 - Delayed puberty.
3 - Growth problems:
during adolescence e.g. short stature or tall stature, marked obesity and menstrual disorders at puberty .

28. FEMALE PRECOCIOUS PUBERTY

29. DEFINITION:
It means menarche or appearance of any of the secondary sexual characters before the age of 8 years.

30. TYPES: 1 - True precocious puberty.
2 - False (pseudo-precocious puberty).
3 - Incomplete precocious puberty.

31. 1. TRUE (CENTRAL,CEREBRAL) PRECOCIOUS PUBERTY.
It is due to increased production of pituitary gonadotrophins.

32. 2. FALSE (PERIPHERAL) PRECOCIOUS PUBERTY
It is of peripheral origin.
It is due to secretion of sex hormones (estrogen or androgen) which is not dependent on pituitary gonadotrophins as in case of estrogenic or androgenic ovarian tumors.

33. 2. FALSE (PERIPHERAL) PRECOCIOUS PUBERTY
False precocious puberty may be isosexual or heterosexual.
A girl who feminizes early is defined as having isosexual precocious puberty.
A girl who virilize early is defined as having heterosexual precocious puberty. (female pseudohermaphrodite)

34. 3. INCOMPLETE PRECOCIOUS PUBERTY
In this case only one pubertal change as breast development is present before the age of 8 years without the presence of any other pubertal changes and in absence of increased estrogen production.
The other pubertal changes occur at the normal age.

35. 3. INCOMPLETE PRECOCIOUS PUBERTY
Incomplete forms of precocious puberty include premature thelarche (unilateral or bilateral), premature pubarche and premature adrenarche with appearance of pubic and axillary hair.

36. PRECOCIOUS PUBERTY - TERMS
breast development - premature thelarche,
pubic development - premature pubarche
axillary hair development - premature adrenarche
menses - premature menarche

37. ETIOLOGY OF PRECOCIOUS PUBERTY
1.Constitutional or idiopathic:
In most cases of precocious puberty (90%) no cause is found.
For some unknown reason the hypothalamus stimulates the pituitary gland to secrete its gonadotrophic hormones.
There is normal menstruation and ovulation.
Pregnancy can occur at young age.

38. ETIOLOGY OF PRECOCIOUS PUBERTY
2. Organic lesions of the brain:
The next common cause.
Organic lesions affecting the midbrain, hypothalamus, pineal body, or pituitary gland may lead to premature release of pituitary gonadotrophins.
Examples include traumatic brain injury, meningitis, encephalitis, brain abscess, brain tumor as glioma, craniopharyngioma, and hamartomas.
3. McCune-Albright syndrome.

39. McCune-Albright Syndrome:
The disease is found more frequently in girls.
It consists of a triad of :
Precocious puberty,
Cystic changes in bones, and
Cafe-au lait patches of the skin.
The cause of precocious puberty is autonomous production of estrogen by the ovaries.
FSH and LH levels are low.
The treatment is testolactone oral tablets which inhibit ovarian steroidogenesis.

40. ETIOLOGY OF PRECOCIOUS PUBERTY
4. Adrenal causes:
(a) Hyperplasia, adenoma, or carcinoma of suprarenal cortex.
Congenital adrenal hyperplasia and Cushing syndrome lead to precocious puberty in the male direction, i.e. heterosexual precocious puberty;
(b) Estrogen secreting adrenal tumor which is very rare.

41. ETIOLOGY OF PRECOCIOUS PUBERTY
5. Ovarian causes :
(a) Estrogen producing tumors as granulosa and theca cell tumor;
(b) Androgen producing tumors as androblastoma;
(c) Choriocarcinoma because it secretes human chorionic gonadotrophin (HCG) which may stimulate the ovaries to secrete estrogen;
(d) Dysgerminoma if it secretes HCG.

42. ETIOLOGY OF PRECOCIOUS PUBERTY
6. Juvenile hypothyroidism:
Lack of thyroxine leads to increased production of TSH and the secretion of pituitary gonadotrophins may also be increased.
7. Drugs:
Iatrogenic may follow oral or local administration of estrogen.
A long course of estrogen cream used for treatment of vulvovaginitis of children may lead to breast development or withdrawal bleeding.

43. DIAGNOSIS OF PRECOCIOUS PUBERTY
1. History:
It excludes iatrogenic source of estrogen or androgen.
It differentiates between isosexual and heterosexual precocious puberty.

44. DIAGNOSIS OF PRECOCIOUS PUBERTY
2. Physical examination:
It diagnoses McCune-Albright syndrome.
Neurologic and ophthalmologic examinations exclude organic lesions of the brain.

45. DIAGNOSIS OF PRECOCIOUS PUBERTY
3. Special investigations:
These are done according to the history and clinical findings and include:

46. 3. SPECIAL INVESTIGATIONS:
a. X-ray examination of the hand and wrist to determine bone age.
Estrogen stimulates growth of bone but causes early fusion of the epiphysis.
So the child is taller than her peers during childhood, but she is short during adult life.

47. 3. SPECIAL INVESTIGATIONS:
b. Hormonal assay:
including serum FSH, LH, prolactin, estradiol, testosterone, 17α-hydroxy progesterone, TSH, and human chorionic gonadotrophin to diagnose Choriocarcinoma.

48. 3. SPECIAL INVESTIGATIONS:
c. Ultrasonography
to diagnose ovarian or adrenal tumor.
d. CT or MRI :
to diagnose an organic lesion of the brain, or adrenal tumor.

49. Hypothyroidism retards bone age and is the only condition of precocious puberty in which bone age is retarded

50. IDIOPATHIC PRECOCIOUS is diagnosed after excluding all other causes.
PUBERTY:
is diagnosed after excluding all other causes.

51. TREATMENT OF PRECOCIOUS PUBERTY
Objectives:
Arrest maturation until normal pubertal age.
Attenuate & diminish established precocious characteristics.
Maximize adult height.
Avoid abuse, reduce emotional & social problems

52. TREATMENT OF PRECOCIOUS PUBERTY
Treatment of the cause, e.g., thyroxin for hypothyroidism, removal of ovarian and adrenal tumors.
Incomplete forms of precocious puberty do not require treatment, as estrogen production is not increased.

53. McCune-Albright syndrome
Is treated with testolactone oral tablets.
The drug inhibits the formation of estrogen from its precursors, so reduces estrogen level.
The dose is 20 mg/kg body weight in 4 divided doses and increased to 40 mg/kg body weight during a 3 week interval.

54. IDIOPATHIC TYPE
is treated by explanation and reassurance and by giving one of the following drugs which inhibit the secretion of gonadotrophins:
(a) Gonadotrophin releasing hormone analogues which are given as daily nasal spray, intramuscular, or subcutaneous injections every 4 weeks.
(b) Medroxyprogesterone acetate tablets (Provera tablets) or intramuscular injection (Depo-Provera);
(c) Danazol capsules;
(d) Cyproterone acetate tablets (Androcur).

55. IDIOPATHIC TYPE
Treatment is given till the age of 12 years (mean age of pubertal development).

56. Gonadotrophin releasing hormone analogues
Drug of choice because it achieves all objectives:
It acts by binding to the anterior pituitary receptors causing down-regulation & desensitization of the pituitary.
Regression of symptoms occurs in the first year
Delayed epiphyseal fusion; treatment more effective if begun before bone age >12 yrs.
Maintain E2 at <10 pg/mL.
Children require higher doses than adults for suppression.
Adrenarche will continue.

57. DELAYED PUBERTY
Secondary Sexual Characters do not develop by the age of
14 yrs or
no menstruation till age of 16yrs

58. DELAYED PUBERTY It is either :
Delayed onset: Breast bud does not appear till 13 years or menarche does not occur till 16 years. or
Delayed progreession: Menarche does not occur within 5 years after breast bud.

59. ETIOLOGY OF DELAYED PUBERTY
1 - Constitutional with +ve family history, short stature & normal fertility.
2 - Hypergonadotropic hypogonadism (FSH > 40) = ovarian causes of Iry amenorrhea = primary ovarian failure & 2ry ovarian failure (if occurs before puberty).
3 - Hypogonadtropic hypogonadism = hypothalamic & pituitary causes of Iry amenorrhea e.g. Kallman's syndrome, Anorexia nervosa.

60. ETIOLOGY OF DELAYED PUBERTY
4 - Normogonadtropic hypogonadism = end organ defects = uterine causes (Mullerian agenesis and testicular feminization syndrome), imperforate hymen (c/o = delayed menarche + normal other aspects of puberty), PCOD and Virilizing ovarian adrenal tumors.
5 - General causes of amenorrhea (endocrinal or non-endocrinal especially malnutrition) if occurred before puberty &↓GH & steroid synthesis defects .

61. INVESTIGATIONS OF DELAYED PUBERTY
History :
1 - Family history, nutritional history, any systemic diseases (e.g. history of endocrinal disturbances).
2 - Clinical picture of space occupying lesion in the ovary, adrenal, pituitary & hypothalamus.
3 - Periodic pain and +ve 2ry sexual characteristics in imperforate hymen .

62. INVESTIGATIONS OF DELAYED PUBERTY
Examination :
(A) Body measurement for causes of amenorrhea + ↑ or ↓ weight, short or tall stature, proportions (upper/lower segment ratio & arm span/height ratio).
(B) Tanner staging of breast, pubic & axillary hair if present.
(C) Clinical picture of Turner, Mullerian agenesis & imperforate hymen.
(D) Neurological examination for smell sense (Kallman's syndrome), visual field & other cranial nerve lesions .

63. SPECIAL INVESTIGATIONS:
1 - FSH & LH assay important to differentiate level of the lesion & progesterone assay in 17 OH deficiency.
2 - Chromosomal study if short stature or hypergonadotropic type.
3 - Radiological bone age study & radiologic study for pituitary adenoma.

64. AMENORRHEA

65. DEFINITIONS Primary amenorrhea
Failure of menarche to occur when expected in relation to the onset of pubertal development.
 No menarche by age 16 years with signs of pubertal development.
 No onset of pubertal development by age 14 years.

66. PATHOPHYSIOLOGY OF AMENORRHEA
Inadequate hormonal stimulation of the endomerium “Anovulatory amenorrhea”
- Euestrogenic
- Hypoestrogenic
Inability of endometrium to respond to hormones “Ovulatory amenorrhea”
- Uterine absence - Utero-vaginal agenesis
- XY-Females (e.g T.F.S)
- Damaged endometrium (e.g Asherman’s syndrome)

67. EUESTROGENIC ANOVULATORY AMENORRHEA
Normal androgens
Hypothalamic-pituitary dysfunction (stress, weight loss or gain, exercise)
Hyperprolactinemia
Feminizing ovarian tumour
Non-gonadal endocrine disease (thyroid, adrenal)
Systemic illness
High androgens
PCOS
Musculinizing ovarian tumour
Cushing’s syndrome
Congenital adrenal hyperplasia (late onset)

68. HYPOESTROGENIC ANOVULATORY AMENORRHEA
Normal androgens
- Hypothalamic-pituitary failure
- Severe dysfunction
- Neoplastic,destructive,
infiltrative, infectious &
trumatic conditions
involving hypothalamus or pituitary
- Ovarian failure
- Gonadal dysgenesis
- Premature ovarian failure
- Enzyme defect
- Resistant ovaries
- Radiotherapy, chemotherapy
High androgens
- Musculinizing ovarian tumour
- Cushing’s syndrome
- Congenital adrenal hyperplasia (late onset)

69. DIAGNOSIS
HISTORY
PHYSICAL EXAMINATION
ULTRASOUND EXAMINATION

70. CRYPTOMENORRHEA Outflow obstruction to menstrual blood
Imperforate hymen
Transverse Vaginal septum with functioning uterus
Isolated Vaginal agenesis with functioning uterus
Isolated Cervical agenesis with functioning uterus
Intermittent abdominal pain
Possible difficulty with micturition
Possible lower abdominal swelling

71. IMPERFORATE HYMEN

72. The patient is a bioassay for Endocrine abnormalities
Once cryptomenorrhea are excluded:
The patient is a bioassay for
Endocrine abnormalities
Four categories of patients are identified
1. Amenorrhea with absent or poor secondary sex characters
2. Amenorrhea with normal 2ry sex characters
3. Amenorrhea with signs of androgen excess
4. Amenorrhea with absent uterus and vagina

73. AMENORRHEA Absent or poor secondary sex Characteristics
FSH Serum level
Low / normal
High
Hypogonadotropic
hypogonadim
Gonadal
dysgenesis

74. AMENORRHEA Normal secondary sex Characteristics
- FSH, LH, Prolactin, TSH
Provera 10 mg PO daily
x 5 days
Prolactin  TSH
+ Bleeding
No bleeing
- Mild hypothalamic
dysfunction
- PCO (LH/FSH)
Further
Work-up
(Endocrinologist)
Review FSH result
And history (next slide)

75. Hypothalamic-pituitary
FSH
High
Low / normal
Ovarian failure
Hypothalamic-pituitary
Failure
head CT- scan or MRI
If < 25 yrs or primary amenorrhea  karyoptype If < 35 yrs autoimmune disease
- Severe hypothalamic
dysfunction
- Intracranial pathology
?? Ovarian biopsy

76. AMENORRHEA Utero-vaginal absence Andogen Insenitivity (TFS syndrome)
Karyotype
46-XY
46-XX
. Gonadal regression
. Testicular enzymes deficiency
. Leydig cell agenisis
Andogen Insenitivity (TFS syndrome)
Mullerian
Agenesis
(MRKH syndrome)
Normal breasts
& absent sexual
hair
Normal breasts
& sexual hair
Absent breasts
& sexual hair

77. Signs of androgen excess
AMENORRHEA
Signs of androgen excess
Testosterone, DHEAS, FSH, and LH
TEST. >200 ng/dL
DHEAS >700 mug/dL
DHEAS mug/dL
U/S ? MRI or CT
Serum 17-OH
Progesterone level
Ovarian
Or adrenal
tumor
Adrenal
hyperfunction
Late CAH
Lower elevations  PCOS (High LH / FSH)

78. AMENORRHEA PRIMARY AMENORRHEA Ovarian failure 36%
Hypogonadotrophic hypogonadism 34%
PCOS %
Congenital lesions (other than dysgenesis) %
Hypopituitarism %
Hyperprolactinaemia %
Weight related %

79. GONADAL DYSGENESIS Chromosomally incompetent
- Classic Turner’s syndrome (45XO)
- Turner variants (45XO/46XX),
(46X-abnormal X)
- Mixed gonadal dygenesis (45XO/46XY)
Chromosomally competent
- 46XX (pure gonadal dysgenesis)
- 46XY (Swyer’s syndrome)

80. TURNER’S SYNDROME
• Sexual infantilism and short stature.
• Associated abnormalities, webbed neck, coarctation of the aorta, high-arched pallate, cubitus valgus, broad shield-like chest with wildely spaced nipples, low hairline on the neck, short metacarpal bones and renal anomalies.
• High FSH and LH levels.
• Bilateral streaked gonads.
• Karyotype - 80% 45, X0
- 20% mosaic forms (46XX/45X0)
• Treatment: HRT

81. TURNER’S SYNDROME
(Classic 45-XO)
Mosaic (46-XX / 45-XO)

82. OVARIAN DYSGENESIS

83. NONE-DYSGENESIS OVARIAN FAILURE
Steroidogenic enzyme defects (17-hydroxylase)
Ovarian resistance syndrome
Autoimmune oophoritis
Postinfection (eg. Mumps)
Postoopherectomy
Postradiation
Postchemotherapy

84. HYPOGONADOTROPHIC HYPOGONADISM
• Normal hight
• Normal external and internal genital organs (infantile)
• Low FSH and LH
• MRI to intra-cranial pathology.
• 30-40% anosmia (Kallmann’s syndrome)
• Sometimes  constitutional delay
• Treat according to the cause (HRT), potentially fertile.

85. CONSTITUTIONAL PUBERTAL DELAY
• Common cause (20%)
• Under stature and delayed bone age
( X-ray Wrist joint)
• Positive family history
• Diagnosis by exclusion and follow up
• Prognosis is good
(late developer)
• No drug therapy is required - Reassurance (? HRT)

86. WEIGHT-RELATED AMENORRHOEA Anorexia Nervosa
1o or 2o Amenorrhea is often first sign
A body mass index (BMI) <17 kg/m² menstrual irregularity and amenorrhea
Hypothalamic suppression
Abnormal body image, intense fear of weight gain, often strenuous exercise
Mean age onset yrs (range yrs)
Low estradiol  risk of osteoporosis
Bulemics less commonly have amenorrhea due to fluctuations in body wt, but crash diets can cause menstrual irregularity.
Treatment :  body wt. (Psychiatrist referral)

87. EXERCISE-ASSOCIATED AMENORRHOEA
Common in girls who participate in sports (e.g. competitive athletes, ballet dancers)
Eating disorders have a higher prevalence in female athletes than non-athletes
Hypothalamic disorder caused by abnormal gonadotrophin-releasing hormone pulsatility, resulting in impaired gonadotrophin levels, particularly LH, and subsequently low oestrogen levels

88. UTERO-VAGINAL AGENISIS Mayer-Rokitansky-Kuster-Hauser syndrome
15% of 1ry amenorrhea
Normal breasts and Sexual Hair development & Normal looking external female genitalia
Normal female range testosterone level
Absent uterus and upper vagina & normal ovaries
Karyotype 46-XX
15-30% renal, skeletal and middle ear anomalies
Treatment : Vaginal creation (Dilatation vs Vaginoplasty)

89. ANDROGEN INSENSITIVITY Testicular feminization syndrome
X-linked trait
Normal breasts but no sexual hair
Normal looking female external genitalia
Absent uterus and upper vagina
Karyotype 46, XY
Male range testosterone level
Treatment : gonadectomy after puberty + HRT
? Vaginal creation (dilatation VS Vaginoplasty)

90. HORMONAL TREATMENT PRIMARY AMENORRHEA WITH ABSENT SECONDARY SEXUAL CHARACTERISTICS
To achieve pubertal development
Premarin 5mg D1-D25 + provera 10mg D15-D25 X 3 months;  2.5mg premarin X 3 months and
 1.25mg premarin X 3 months
Maintenance therapy
0.625mg premarin + provera or ready HRT preparation or 30µg oral contraceptive pill

91. TREATMENT OF DELAYED PUBERTY
* Constitutional: Reassurance.
* Treatment of the cause (if treatable) or cyclic estrogen-progesterone hormone replacement therapy. If the cause is not treatable, for 3 cycles: Norethistrone acetate 5 mg twice daily for 21 d or OCP
* Patient with Y chromosome cell line : Gonadectomy + hormone replacement therapy

92. Thank you