definition failure to initiate spontaneous menses by the age of 16 or evidence of pubertal onset by...

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.