Amenorrhea pdf - All Lectures

CLINICAL GUIDELINES

FOR

EVALUATION AND MANAGEMENT

OF AMENORRHEA

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.

Secondary amenorrhea



Absence of menstruation for 3 or more months in a

previously menstruating women of reproductive

age.

CNS-Hypothalamus-Pituitary

Ovary-uterus Interaction

Neural control

Chemical control

Dopamine

(-)

Norepiniphrine

(+)

Endorphines

(-)

Hypothalamus

Gn-RH

Ant. pituitary

FSH, LH

Ovaries

Uterus

Progesterone

Estrogen

Menses

–

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)

Euestrogenic Anovulatory

Amenorrhea

Normal androgens

• Hypothalamic-pituitary

dysfunction (stress, weight

loss or gain, exercise,

pseudocyesis)

• 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)

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)

AMENORRHOEA

AN APPROACH FOR DIAGNOSIS

• HISTORY
• PHYSICAL EXAMINATION
• ULTRASOUND EXAMINATION

Exclude Pregnancy
Exclude Cryptomenorrhea

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
- Bulging bluish membrane at the introitus or absent

vagina (only dimple)

Once Pregnancy and 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

FSH Serum level

Low / normal

High

Hypogonadotropic

hypogonadim

Gonadal

dysgenesis

AMENORRHEA

Absent or poor secondary sex

Characteristics

AMENORRHEA

Normal secondary sex Characteristics

- FSH, LH, Prolactin, TSH
- Provera 10 mg PO daily

x 5 days

+ Bleeding

No bleeing



Prolactin



TSH

Further
Work-up
(Endocrinologist)

- Mild hypothalamic

dysfunction

- PCO (LH/FSH)

Review FSH result

And history

(next slide)

FSH

Low / normal

High

Hypothalamic-pituitary

Failure

Ovarian

failure



If < 25 yrs or primary

amenorrhea  karyoptype


If < 35 yrs R/O

autoimmune disease

?? Ovarian biopsy

head CT- scan or MRI

- Severe hypothalamic

dysfunction

- Intracranial pathology

Amenorrhea

Utero-vaginal absence

Karyotype

46-XX

Mullerian

Agenesis

(MRKH syndrome)

Andogen

Insenitivity

(TSF syndrome)

Gonadal regressioon

. Testocular enzyme

defenciecy

. Leydig cell agenisis

46-XY

Normal breasts

& sexual hair

Normal breasts

& absent sexual

hair

Absent breasts

& sexual hair

Normal FSH, LH; -ve bleeding

history is suggestive of amenorrhea

trumatica

Asherman’s syndrome

• History of pregnancy associated D&C
• Rarely after CS , myomectomy T.B

endometritis, bilharzia

• Diagnosis : HSG or hysterescopy
• Treatment : lysis of adhesions; D&C or

hysterescopy + estrogen therapy ( ? IUCD or

catheter)

Some will prescribe a cycle of Estrogen and

Progesterone challenge Before HSG or Hysterescopy

Asherman’s syndrome

Amenorrhea

Signs of androgen excess

Testosterone, DHEAS, FSH, and LH

DHEAS 500-700 mug/dL

DHEAS >700 mug/dL

TEST. >200 ng/dL

Serum 17-OH
Progesterone level

Late CAH

Adrenal

hyperfunction

U/S ? MRI or CT

Ovarian

Or adrenal

tumor

Lower elevations  PCOS (High LH / FSH)

Amenorrhea

PRIMARY AMENORRHEA

. Ovarian failure 36%
. Hypogonadotrophic 34%

Hypogonadism.

. PCOS 17%
. Congenital lesions

(other than dysgenesis) 4%

. Hypopituitarism                    3%
. Hyperprolactinaemia            3%
. Weight related                       3%

SECONDARY AMENORRHEA

. Polycystic ovary syndrome        30%
. Premature ovarian failure           29%
. Weight related amenorrhoea      19%
. Hyperprolactinaemia                    14%
. Exercise related amenorrhoea    2%
. Hypopituitarism                             2%

Gonadal dysgeneis

• Chromosomally incompetent

- Classic turner’s syndrome (45XO)

- Turner variants (45XO/46XX),(46X-

abnormal

- Mixed gonadal dygenesis (45XO/46XY)

• Chromosomally competent

- 46XX (Pure gonadal dysgeneis)

- 46XY (Swyer’s syndrome)

Gonadal dysgenesis

Classic

Turner’s

Turner

Variant

True gonadal

Dysgenesis

Mixed

Dysgenesis

phenotype

Female

Ambiguous

Gonad

Streak

- Streak

- Testes

Hight

Short

- Short

- Normal

Tall

Short

Somatic
stigmata

Classical

Nil

karyotype

XX/XO or

abnormal X

46-XX(Pure)

46-XY (Swyer)

XO/XY

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

Ovarian dysgenesis

None-dysgenesis ovarian failure

• Steroidogenic enzyme defects (17-hydroxylase)
• Ovarian resistance syndrome
• Autoimmune oophoritis
• Postinfection (eg. Mumps)
• Postoopherectomy
• Postradiation
• Postchemotherapy

Premature ovarian failure

• Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on

repeated occasions

• 10% of secondary amenorrhea
• Few cases reported, where high dose estrogen or

HMG therapy resulted in ovulation

• Sometimes immuno therapy may reverse autoimmue

ovarian failure

• Rarely  spont. ovulation (resistant ovaries)
• Treatment: HRT (

osteoporosis, atherogenesis

)

Polycystic ovary syndrome

• The most common cause of chronic anovulation
• Hyperandrogenism ;  LH/FSH ratio
• Insulin resitance is a major biochemical feature

( blood insulin level hyperandrogenism )

• Long term risks: Obesity, hirsutism, infertility,

type 2 diabetes, dyslipidemia, cardiovasular

risks, endometrial hyperplassia and cancer

• Treatment depends on the needs of the patient

and preventing long term health problems

Hypogonadotrophic

Hypogonadism

•

Normal hight

• Normal external and internal

genital organs (infantile)

• Low FSH and LH
• MRI to R/O intra-cranial pathology.
• 30-40% anosmia (kallmann’s

syndrome)

• Sometimes  constitutional delay
• Treat according to the cause (HRT),

potentially fertile.

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)

Sheehan’s syndrome

• Pituitary inability to secrete gonadotropins
• Pituitary necrosis following massive obstetric

hemorrhage is most common cause in women

• Diagnosis : History and

 E2,FSH,LH

+ other pituitary deficiencies (MPS test)

• Treatment :

Replacement of deficient hormones

Weight-related amenorrhoea

Anorexia Nervosa

• 1

or 2

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 13-14 yrs (range 10-21 yrs)
• Low estradiol → risk of osteoporosis
• Bulemics less commonly have amenorrhea

due to fluctuations in body wt, but any
disordered eating pattern (crash diets) can
cause menstrual irregularity.

• Treatment :

 body wt. (Psychiatrist referral)

Exercise-associated

amenorrhoea

• Common in women 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

Contraception related

amenorrhea

• Post-pill amenorrhea is not an entity
• Depot medroxyprogesterone acetate

Up to 80 % of women will have amenorrhea

after 1 year of use. It is reversible

(oestrogen deficiency)

• A minority of women taking the progestogen-

only pill may have reversible long term

amenorrhoea due to complete suppression of

ovulation

• Autosomal recessive trait
• Most common form is due to 21-

hydroxylase deficiency

• Mild forms Closely resemble PCO
• Severe forms show Signs of

severe androgen excess

• High 17-OH-progesterone blood

level

• Treatment : cortisol replacement

and ? Corrective surgery

Late onset congenital adrenal

hyperplasia

Cushing’s syndrome

• Clinical suspicion : Hirsutism,

truncal obesity, purple striae, BP

• If Suspicion is high :

dexamethasone suppression test

(1 mg PO 11 pm ) and obtaine
serum cortisol level at 8 am :

< 5 µg/ dl excludes cushing’s

• 24 hours total urine free cortisol

level to confirm diagnosis

• 2 forms ; adrenal tumour or ACTH

hypersecretion (pituitary or ectopic
site)

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 : STERILE ? Vaginal creation

( Dilatation VS Vaginoplasty)

Androgen insensitivity

Testicular feminization syndrome

• X-linked trait
• Absent cytosol receptors
• 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

Vaginoplasty )

General Principles of management

of Amenorrhea

Attempts to restore ovulatory function

If this is not possible HRT (oestrogen and

progesterone) is given to hypo-estrogenic
amenorrheic women (

to prevent osteoporosis; atherogenesis

)

Periodic progestogen should be taken by euestrogenic

amenorrheic women (

to avoid endometrial cancer

)

If Y chromosome is present gonadectomy is indicated

Many cases require frequent re-evaluation

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

Summary

• Although the work-up of amenorrhea may seem to be

complex, a carefully conducted physical examination with the
history, and Looking to the patient as a bioassay for
endocrine abnormalities, should permit the clinician to narrow
the diagnostic possibilities and an accurate diagnosis can be
obtained quickly.

• Management aims at restoring ovulatory cycles if possible,

replacing estrogen when deficient and Progestogegen to
protect endometrium from unopposed estrogen.

• Frequent re-evaluation and reassurance of the patient.

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