DefinitionFailure to initiate spontaneous
menses by the age of 16 or evidence of pubertal onset by age of 14.
It is a rare condition seen in less than 0.1% of the general population.
Puberty is a period of transition between
childhood life and adult womanhood life
during which sexual maturation occurs
The hypothalamus is initiator of these
pubertal changes in the following order
adrenarche, gonadarche and menarche.
Introduction
HypothalamusHypothalamus
Hypothalamus
Pituitary Stalk
Pituitary gland
PVNSON
ChiasmaVMN
GnRH
Satiety center
OxytocinADH
U-shaped LH curve
High opioid
High melatonin
Low leptin
This curve is present even in agonadic child
The drop of opioid and melatonin, or rise of leptin allows the release of GnRH
Neonate Child Adult
Exercise
Anorexia
Post-partum
Rever
sal
Two independent events of puberty
Two independent events of puberty
Adrenarche Gonadarche
Stimulus CASH GnRH
Timing Precedes growth spurt
Follows growth spurt
Mediator DHEA E2
Manifestation Pubic hair
Axillary hair
Growth spurt
Menarche
Disease Not in Addison’s Not in Turner’s
Tanner staging of puberty
Stage Age Breasts Pubic hair E2 Pg/ml
I 7 Nipple Nil < 10
II 10 Breast bud Sparse labial 10-20
III 11 Smooth contour Dark curled hair 20-40
IV 13 Secondary mound Adult type hair 40-60
V 14 Mature breast Adult distribution > 60
NB: Menarche coincides with stage IV
Second growth spurt
0 2 4 6 8 10 12 14 16 18 20
BoysGirls
1
2
3
4
Incr
emen
ts in
ches
/yea
rs
Age in years
It is earlier in females
It is higher in males
It is related to GH, IGF-1
Gonadal steroids
Initiates it
Terminates it
For proper menses to occur there should be a
nice integration between the hypothalamus,
pituitary, ovary and responsive uterus as well as
a patent effluent genital tract.
We have four levels; Level 1 (Uterus and outflow
tract), Level II (Ovary), Level III (Pituitary), Level
IV (Hypothalamus)
Leveling of amenorrhea
Based on presence or absence of 2ry sexual characteristics:
1. No 2ry sexual characteristics
2. Breast development, but no pubic and axillary hair
3. Normal 2ry sexual characteristics
4. Incompletely developed 2ry sexual characteristics
Primary amenorrhea
Cholesterol
Acetate LDL-c
4P 3HSD 5P
17OH4P 3HSD 17 OH5P
AD 3HSD DHEA
P450SCC
17O
Has
e
17O
Has
e
Des
mol
ase
Des
mol
ase
TeP450arom
P450arom
E1
E2
17H
SD
Corticosterone
Aldosterone
11OHase21OHase
21OHase 11 desoxy cortisol or compound S
Cortisol
11O
Has
e11
HS
D
Cortisone
DOC
Hypogonadotropic hypogonadism:
Kallmann’s syndrome: 1ry amenorrhea (lack GnRH)+ Anosmia
Craniopharyngioma: either by damaging the hypothalamus or interferes with the transport o hormones
If GnRH stimulation test +ve>>> hypothalamus
Imaging needed for tumors
Craniopharyngioma Rathke’s pouch tumor
Cystic spaces Squamous epitheliumCalcificationEnamel-like
GH (Dwarf, obese)
Gn (Delayed puberty)
ADH (DI)
ICT
Stalk section
Optic chiasm
Hypergonadotropic hypogonadism:
Unresponsive end organs
Differential diagnosis:
Turner’s syndromeSwyer’s syndromePure gonadal agenesis (46XX & 46XY)Mixed gonadal dysgenesisAbnormal X chromosome
Turner syndromeTurner’s stigmata
Sexual infantilism
Short stature
Webbed neck
Spaced nipples
Cubitus valgus
Shield chest
Pigmented nevi
Coarctation of aorta
Renal anomaly
Streak gonads
Turner’s Karyotype
XO
XO/XX
XXp-
XXr
Turner syndrome
Cystic hygromaCystic hygroma
Fetal hydrops
+ve gonadal secretion, no manifestations of androgen secretion
Reflects the absence of androgen receptors “complete androgen insensitivity syndrome” (testicular feminization)
Genotype : 46XY male intra-abdominal testes
Phenotype :female normal contour, no uterus, vaginal dimple….. Due to mullerian-inhibiting substance
Gonadectomy,,,, high malignancy rate
Raise as female and create new vagina
Psychological counseling
Islamic view regarding inheritance
Morris syndrome (XY female)
Male karyotype
Female phenotype
Male level of testosterone
Complete
Receptor failure
5 alpha-reductase defect
With no uterus Mullerian agenesis
(Mayer-Rokitansky) XY female (Morris’)
With a uterus Gynaetresia
– Imperforate hymen – T.S vaginal septum
Hypoplasia uteri Genital TB Systemic illness Constitutional delay
Normal gonadal secretion
Vast majority 46XX, amenorrhea due to anatomical abnormalities
In case of absent vagina and/or uterus: Creation of new vagina is the answer (dilators, vaginoplasty)
With yterine/vaginal abnormalities always think of renal abnormalities
Comparison
Mullerian agenesis XY female
Karyotype XX XY
Heredity -ve XLR
Sexual hair Female distribution Hairless
Te Female range Male range
Anomaly Yes Rare
Tumor No 5%
Obese Frohlich’s syndrome Laurance-Moon-Biedl
syndrome Hand-Schuller-Christian
disease Prader-Willi syndrome Craniopharyngioma Suprasellar-germinoma
Thin Exercise related
– High B-End– High catechol estrogen
Anorexia nervosa Weight loss
Systemic illness
– Tuberculosis
– SCD
– Thalassemia
Primary amenorrhea with sexual infantilism
Tall Pure gonadal agenesis Swyer’s syndrome Kallmann’s syndrome 17 OHase deficiency 17-20 desmolase deficiency
Short Pituitary dwarf
– Sexual– Asexual (Laron)
Turner’s syndrome Hypothyroidism Constitutional delay
of puberty
Primary amenorrhea with sexual infantilism
Comparison
Item Pure gonadal agenesis
Kallmann’s syndrome
Karyotype XX or XY (Swyer’s) XX
FSH High Low
Gonad Streaks Ovary
Humegon No response Good
Association Gonadoblastoma Anosmia
Weight loss amenorrheaSimple Anorexia nervosa
Age Any Young
Psychic No Yes
Weight loss
Added features
20% of IBW
No
More
Dehydration
Hormones Normal GH, rT3, Carotene, DA
PRL, LH, T3, E2, ADH
GnRH therapy Useful Not
Complication No Possible
As the fault extends to the pituitary in anorexia, GnRH pulse therapy is not effective in restoring menstruation.
Turner’s syndrome
Noonan’s syndrome
Karyotype 45/XO 46/XXp-
Gonad Streak Ovary
Stigmata Yes Yes
Heart CoA PS
IQ Normal Low
Comparison
Can Turner cases got pregnancy? Yes
Primary amenorrhea
Ch FSH LH E2 Te PRL PWT
Turner’s XO = = -ve
AIS XY = = -ve
Kallmann XX = -ve
Evaluation of primary amenorrhea
History– Personal history– Family history– Past history
Physical examination– Secondary sex characteristics– Virile manifestations– Weight, height, span
Sonographic assessment Laparoscopy Gonadal biopsy
Buccal smearKaryotyingEndocrine evaluation
–FSH/LH, PRL/TSH
–Estrogen (PWT, C.I, E2 assay)
–Androgen (Te, DHEAS)
Investigation
Management of primary amenorrhea
The aim of treatment is to attain maximum physiologic function of which an individual can attain.
No treatment until the diagnosis is solid.
The majority will be able to achieve satisfactory sexual life but the prospect of fertility may be poor.
HRT may be needed for life.