Amenorrhoea is nearly always endocrine in origin, and associated with anovulation and infertility.
Anatomical defects account for about 1% of cases. Some of these patients may be ovulating normally, but the bleeding is concealed.
Congenital causes include:
intersex states - usually the effect of an underlying endocrine order such as congenital adrenal hyperplasia; for example, true hermaphroditism, and male or female pseudohermaphroditism
malformation of the female genital tract - such as uterine agenesis, vaginal atresia, imperforate hymen
Acquired causes include:
endometrial fibrosis - Asherman's syndrome, tuberculosis; both rare in the UK
cervical stenosis - usually due to surgery, especially cautery or conization
Many endocrine disorders can cause amenorrhoea. The most common causes are functional disorders of the hypothalamus and hyperprolactinaemia.
hypogonadotrophic hypogonadism - e.g. Kallmann's syndrome
psychogenic - associated with emotional stress, shift work especially, night / day shifts
excessive weight gain / weight loss
tumours - e.g. craniopharyngioma
post-oral contraceptive use - "post-pill amenorrhoea"
tumours - with or without hyperprolactinaemia; includes prolactin secreting pituitary adenomas, non-functional pituitary adenomas with suprasellar extension impairing blood flow down the pituitary stalk; growth hormone secreting tumours - 30% secrete prolactin
infarction necrosis - Sheehan's syndrome
granulomatous infiltration - e.g. sarcoidosis
ovarian dysgenesis - Turner's syndrome / mosaic
polycystic ovarian syndrome
resistant ovary syndrome
premature ovarian failure
androgen secreting ovarian tumours
surgery - oophorectomy; ovarian suppression by pelvic irradiation
Other endocrine lesions:
thyroid - primary hypothyroidism; hyperthyroidism
pancreas - poorly controlled diabetes
adrenal - Cushing's syndrome; advanced Addison's disease
primary versus secondary amenorrhoea
The causes of primary and secondary amenorrhoea overlap but the distinction is informative. Secondary amenorrhoea indicates a patent lower genital tract, an endometrium which has responded to ovarian hormones, and ovaries which have responded to gonadotrophins. Exceptions include surgery to the endometrium or cervix which rarely cause intrauterine adhesions or cervical stenosis respectively.
Congenital disorders usually present as primary amenorrhoea, for example:
congenital malformations of the genital tract
congenital adrenal hyperplasia
However, any cause of secondary amenorrhoea may present as primary amenorrhoea if it occurs before the age of 16 years.
This is the failure to start menstruating. If this occurs in a 16 year old (or in a 14 year old who has growth failure or absence of secondary sexual characteristics) then this requires investigation. For menstruation to occur there must be a functioning hypothalmic-pituitary axis and no structural abnormalities that may prevent menstruation e.g. uterine agenesis, imperforate hymen.
This occurs when there have been no periods for a period of more than 6 months in a female who has previously had periods (other than due to pregnancy). Commonly secondary amenorrhoea is due to dysfunction of the hypothalmic-pituitary axis. Rarely this condition may due to ovarian or endometrial causes.
A combination of both stress on the brain and reduced fat mass leading to reduced oestrogen metabolism may lead to amenorrhoea.
This condition is particularly prevalent in ballet schools and college sports. A principal concern in the management is the prevention of osteoporosis, this is combatted using hormone replacement therapy or the oral contraceptive pill - the latter being more socially acceptable to young people with the added advantage of contraception. If restoration of fertility is a main objective, the best treatment is to gain weight.
amenorrhoea (weight loss)
Weight loss leads to reduced fat mass, reduced oestrogen metabolism, and amenorrhoea.
The effects of weight loss on menstruation may be estimated from the Ponteral index which is defined as: Weight in Kg / (Height in Metres, squared)
A ponteral index less than 17 or greater than 25 - 27 predicts amenorrhoea. The range of values at the upper limit arises from the greater unpredictability of obesity on menstruation, except in cases of the polycystic ovarian syndrome.
Congenital causes of amenorrhoea can be ignored in patients with secondary amenorrhoea but a patient with primary amenorrhoea may have any of the conditions associated with primary or secondary amenorrhoea. Pregnancy must always be excluded.
Basic investigations are:
history and physical examination
hormone measurements - PRL, FSH, LH, thyroid function, testosterone
pelvic ultrasound scan - indicates size of ovaries, presence of follicles and their size, may reveal polycystic ovaries, presence of uterus in cases of vaginal atresia
Other investigations are conducted as indicated:
chromosomal studies - if primary amenorrhoea without any obvious basis or if abnormal phenotype
radiologic studies - intravenous urogram if uterine or vaginal malformation to exclude associated renal abnormalities
CT - to visualise pituitary fossa for tumours
laparoscopy and gonadal biopsy - indicated only if the nature of the gonads or the presence of primary oocytes is in dispute
The most important measurements are serum LH, FSH, PRL (x2) and TFTs.
LH is often raised in polycystic ovarian syndrome.
An elevated serum FSH indicates ovarian failure.
Prolactin is raised by stress, prolactinomas and secondary to some drugs e.g. phenothiazines.
A normal FSH may occur in conditions such as PCO, hypothalamic - pituitary lesions, and outflow tract disorders. A progesterone challenge will help discriminate these conditions. A withdrawal bleed after a progesterone challenge indicates anovulation e.g. PCO. No withdrawal bleed after a regime of oestrogen for 21 days then progestogen for 5 days indicates an outflow tract disorder e.g. Asherman's syndrome. A withdrawal bleed will occur after endometrial stimulation with oestrogens then a progestogen if there is a hypothalamic - pituitary lesion.
Measurement of plasma testosterone is indicated in amenorrhoea associated with hirsutism. Levels greater than 6 nmol/litre suggest ovarian malignancy which must be investigated further. An elevated LH/FSH ration with raised testosterone - but less than 6 nmol/litre - suggests polycystic ovarian syndrome.
This is used to assess the ability of the endometrium to respond to steroid hormones.
Medroxyprogesterone acetate - MPA - is given at 10 mg/day p.o. for 5 days.
If withdrawal bleeding occurs 5-7 days later then the endometrium must have been previously exposed to adequate levels of oestrogen, and the endometrium is able to proliferate in response to progesterone. Polycystic ovarian syndrome and hypothalamic dysfunction are the most likely causes of the amenorrhoea, the former being indicated by polycystic ovaries on ultrasound scan.
If no withdrawal bleeding occurs, give oestrogen prior to MPA. A typical regimen would be ethinyloestradiol, 50 æg daily for 21 days with MPA 10 mg daily on days 16-21.
Withdrawal bleeding indicates an oestrogen deficiency state. This may be due to ovarian failure, indicated by raised FSH, or hypothalamic-pituitary failure.
No withdrawal bleeding after the oestrogen / progesterone regime indicates a uterine disorder.
The treatment of amenorrhoea is of the cause.
Testicular feminisation requires gonadectomy to prevent the risk of malignancy with subsequent hormone replacement. The latter is indicated also, in gonadal dysgenesis and uterine agenesis. These two conditions cannot be "cured" but hormone replacement may lessen their psychological impact considerably. An appropriate low dose combined oral contraceptive pill may be used.
Clomiphene is often effective in cases of the polycystic ovarian syndrome but in extreme cases, surgical intervention e.g. wedge resection or electrodiathermy, may be needed.
In cases of hyperprolactinaemia, a repeat assay is advised as prolactin level may be raised temporarily by stress. Hyperprolactinaemia due to hypothyroidism or drugs resolves resolves on correction of the underlying cause although in the case of phenothiazine, this may take several weeks. In other cases, bromocriptine may be necessary.
Patients with ovarian failure require oestradiol replacement up to the age of the expected menopause. Combined oestrogen and progestogen are advised in women with a uterus to ensure hormone replacement and avoid the risks of endometrial carcinoma.
If spontaneous menstruation does not resume following the attainment of a satisfactory body weight, or cessation of the pill or exercise, clomiphene citrate should be used if the patient wishes to become pregnant.
If the cause is uncertain and either the patient wishes to become pregnant or is anxious about the amenorrhoea, ovulation may be induced using clomiphene, pulsatile GnRH or human gonadotrophins.