AMENORRHOEA

Amenorrhoea is a symptom and not a diagnosis and it may be a presenting feature

in a number of disorders. The most common causes are endocrine dysfunction
(99%) but occasionally it is secondary to an anatomical defect (1%). Treatment
should never be instituted before full investigation has been undertaken and a
diagnosis made.

DEFINITIONS:

Amenorrhoea: absence of menstruation

Reproductive years: generally 16 - 40 years of age is regarded as the limit of

normal reproductive years i.e. the upper limit for
menarche and the lower limit for menopause

Primary amenorrhoea: synonymous with delayed menarche and is the failure

to menstruate by the age of 16 years or later. In these
patients menstruation has never occurred
spontaneously.

Secondary amenorrhoea: the absence of menstruation when menses have

previously occurred - even if the patient has only had
one spontaneous menstrual bleed

Galactorrhoea: inappropriate or non-puerperal lactation

WHEN TO INVESTIGATE?

Any woman complaining of amenorrhoea who fulfils the following criteria warrants
investigation:

 Fourteen years of age with no secondary sex characteristics (delayed puberty)

 Sixteen years of age with normal growth and development of secondary sex
characteristics (delayed menarche)
 Amenorrhoea for a period of the time equivalent to at least 3 previous cycles or 3 -
6 months
 Signs of hyperandrogenism
 Dysmorphic features: regardless of duration of menstrual dysfunction
 Ambiguous genitalia: urgent investigation

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AETIOLOGY:

1. Physiological

1. Pregnancy (Important – always consider)

2. Puerperium and lactation
3. Perimenarchae
4. Postmenopausal

2. End organ defects

May involve uterus, cervix or vagina

a) Congenital anatomical abnormalities

( i) Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser

Syndrome)
46XX, normal ovaries, completely absent Müllerian system

(ii) Müllerian anomalies: may affect the Müllerian system at any

level and include cervical and vaginal atresia, transverse
vaginal septa and imperforate hymen
These patients are 46XX, have normal ovaries, and an
anatomical anomaly.

b) Disorders of sex development (DSD)

 Sex Chromosome DSD: (eg Klinefelter Syndrome, 47XXY or Turner

Syndrome, 45XO)

 46 XY DSD:
o Disorders of gonadal development
o Disorders of androgen synthesis eg 5α reductase deficiency:
Testosterone not converted to DHT. Initially apparent female
phenotype but male karyotype and absent uterus. With
androgen increase at puberty → masculinisation.
o Disorders of Androgen action: eg Androgen insensitivity: Female
phenotype with normal male karyotype. Receptors insensitive to
testosterone. Absent uterus. Partial forms of the condition do
exist.

 46XX DSD:
o Disorders of gonadal development: gonadal dysgenesis
o Androgen excess (fetal/ fetoplacental/ maternal)

All above  primary amenorrhoea

c) Acquired abnormalities

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  Obliteration or obstruction of the uterine cavity or cervix secondary
to trauma e.g. dilatation and curettage or infection such as
tuberculosis.

3. Gonadal Causes

a. Aberrant function/dysfunction:
 polycystic ovary syndrome
 resistant ovary syndrome - failure to respond to gonadotrophin
stimulation (may be intermittent)

b. Primary ovarian insufficiency:

 premature menopause
 ovarian dysgenesis/agenesis *
 damage secondary to irradiation, chemotherapy or surgery
 auto-immune disease

c. DSD:
 possibly ovotestis or testis *

d. Functional tumours of ovary

* will present as primary amenorrhoea

4. Pituitary causes

a. Hyperprolactinemia: many causes

 Physiological
 Pharmacological e.g. metoclopramide, phenothiazine
 Psychological
- stress including exercise and tension
- pseudocyesis (phantom pregnancy)
 Pituitary tumours:
- prolactinomas
- acromegaly
- Nelson syndrome
 Peripheral lesions:
i) Disruption of hypothalamic - pituitary connection:
- Granulomas e.g. TB, sarcoidosis
- Tumours e.g. craniopharyngioma (“neighbourhood
syndrome”)
- Irradiation
- stalk section e.g. following trauma
ii Other:
- Primary hypothyroidism (TRH drives prolactin)
- Chronic renal failure
- Irritation of chest wall e.g. herpes zoster, surgery

Pathological hyperprolactinemia is found in about 20% of women with

amenorrhoea and about a third of these patients have galactorrhoea.

b. Hypopituitarism secondary to cellular or anatomic defects:

 isolated gonadotrophin deficiency * - rare

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  post-irradiation/surgery
 Empty Sella Syndrome
 post-infarction (Sheehan’s syndrome)

* Primary amenorrhoea

c. Disruption of hypothalamic - pituitary connections: (see earlier)

 stalk lesions - granulomas
- traumatic section
 Interruption vascular link - infarction

d. Pituitary tumours
 Cushing’s syndrome
 Acromegaly

Invariably the underlying pathology tends to overshadow the

menstrual disturbance in these conditions.

5. Hypothalamus and CNS

a Psycho-neuroendocrine:
 nutritional - anorexia nervosa
- simple weight loss
- excessive exercise
 “stress”

b. GnRH deficiency * (+ anosmia = Kallmann’s syndrome)

c. CNS tumours: many compress/destroy hypothalamus

e.g. craniopharyngioma.

* primary amenorrhoea

6. Thyroid disorders

 Hypothyroidism (associated with  prolactin)

 Hyperthyroidism

Both conditions alter steroid hormone metabolism.

7. Adrenal

 Congenital Adrenal Hyperplasia (CAH) (both early and late onset)

 Cushing’s syndrome
 Addison’s disease

8. Metabolic causes

 Cystic fibrosis : absorption problems lead to undernutrition

 Vegans : altered gut flora and therefore altered absorption of oestrogens
 Diabetes mellitus

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  Liver disease

9. Medication
 Multiple mechanisms whereby medication may cause amenorrhoea

SIMPLIFIED AETIOLOGICAL CLASSIFICATION OF MAIN CAUSES OF AMENORRHOEA

Physiological Hyperprolactinemia
Pregnancy Pharmacological
Lactation Psychological
Perimenopausal Pituitary causes
Perimenarchal Peripheral causes

Androgenic Other
PCOS Hypothalamic disturbances
CAH Anatomical abnormalities
Tumours Disturbances of steroid economy
Medication Gonadal failure

Primary amenorrhoea: Causes

 Errors in genital differentiation
 Errors in gonaductal development
 Errors in gonadal development
 Hypothalamic - pituitary disturbances
 Follicles unresponsive to gonadotrophins

INVESTIGATION OF THE PATIENT WITH AMENORRHOEA:

History

1. Presenting complaint
 Define what is troubling the patient e.g. absence of menses or lack of
secondary sexual characteristics or infertility, etc.
 Menstrual history, past and present
 Pubertal development and history
 If relevant: breasts, pubic hair, growth, axillary hair
 Past obstetric and gynaecological history
 Weight/exercise/diet/toxins/infections
 Vaginal dryness/libido/medication
 Hirsutism/acne/skin/symptoms of Cushing’s syndrome
 Polyuria/polydypsia/polyphagia
 Thyroid/skin/weight/flushes/temperature preferences
 Hot flushes/sweats

2. Medical History
 Medication
 Surgery

3. Social History

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  Stress, career aspirations, major upheaval in domestic life, etc.

4. Family History
 Congenital adrenal hyperplasia
 Polycystic ovary syndrome

Examination

 Blood pressure
 Body composition - weight and height and BMI
 General appearance
- stigmata of endocrinopathies or chromosome abnormalities
- hair distribution
- hirsutism/acne/virilization
- breasts (? galactorrhoea)
 Pubertal staging (if indicated)
 General examination
 Vaginal examination: if indicated or appropriate

Special Investigations and Diagnosis

Plan investigations based on clinical findings and history

Primary amenorrhoea

1. Uterus present, no secondary sexual characteristics:

- failure of ovarian or hypothalamic pituitary function

2. Uterus absent, normal secondary sexual characteristics:

- Müllerian agenesis
- 46 XY female e.g. androgen insensitivity

3. DSD

4. Normal internal and external genitalia and normal secondary sexual

characteristics
- constitutional delay in menarche
- failure of ovarian or hypothalamic function after pubertal development
- same causes as for secondary amenorrhoea

Baseline investigations

1. Exclude Pregnancy!

2. Chromosome analysis if
 height less than 1.52m
 primary amenorrhoea
 abnormality suspected

3. FSH and LH
Elevated - ovarian failure
Very low - pituitary or hypothalamic dysfunction
Inverse ratio i.e. LH>FSH - consider PCOS

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 Normal - Investigate further

4. Prolactin:
Elevated  repeat and check thyroid status and medication
TFTs normal  detailed radiology - no medication

5. TSH:
Selected patients

6. Testosterone and DHEAS to investigate hyper androgenic status

7. 17α OH progesterone to exclude CAH. Stimulation tests sometimes required.

8. Progestogen withdrawal test to assess whether sufficient endogenous

oestrogens are produced to prime the endometrium:
Medroxyprogesterone-acetate 10mg/day x 5 days.

No withdrawal bleed - either no endogenous oestrogens or outflow tract

abnormalities. Add in oestrogen and progesterone together (usually the
combined oral contraceptive).
If still no withdrawal bleed – investigate the outflow tract.

NB. Ultrasonographic examination of the ovaries may be an extremely valuable

aid in diagnosis and management in the following circumstances:

1. assessing ovarian physiology and pathology

2. assessing the presence, or absence of the uterus
3. assessing pelvic organs in the young girl where vaginal examination is
preferably avoided
4. assessing endometrial thickness and uterine size (i.e. “bioassay” of
oestrogen effect)
5. diagnosis of polycystic ovaries
6. therapeutic progress may be monitored

Management

Treat the basic pathology and not the amenorrhoea itself. Investigate appropriately
so that you have adequate information to define the prognosis and treatment options.

Do not diagnose “post-pill amenorrhoea”. A cause for the cessation of

menses may usually be identified if the patient is appropriately investigated.

Do not institute therapy without a diagnosis

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