Amenorrhoea

This is the absence of menstruation.

It may be physiological as before the menarche, after the menopause or in pregnancy, or it may be post-operative if the patient has had a hysterectomy.
Amenorrhoea can be divided into primary and secondary:

• Primary amenorrhoea is when menses have not occurred by the time of the expected menarche. This may be taken as age 14 years in the absence of secondary sexual characteristics, but it is worth waiting until age 16 years if other features are developing normally.
• Secondary amenorrhoea is when menstruation has previously occurred but it has stopped for at least six consecutive months.

Prevalence (in women of menstruating age) is:

• Primary 0.3%¹
• Secondary 3%² - but the prevalence is higher in college students (3-5%), competitive endurance athletes (5-60%), and ballet dancers (19-44%)

Between 10 and 20% of women presenting with infertility have amenorrhoea.

Primary amenorrhoea can be divided into anatomical, endocrine or constitutional.
For the purpose of investigation it is useful to divide it into those with and those without normal development of secondary sexual characteristics.

Secondary sexual characteristics present

• Constitutional delay:
  This is when there is no abnormality but she is a little later than her peers in reaching her menarche. Ask about the age of menarche in her mother and any older sisters. Reassure that the menarche is the last of the characteristics to develop.
• Genitourinary malformation:
  Malformations, e.g. imperforate hymen or absence of the uterus or vagina are uncommon causes of primary amenorrhoea. Absence of a vagina may have gone unnoticed. If a uterus is present but there is no passage to the outside, there may be cyclical lower abdominal pains.
• Testicular feminisation:
  Also called androgen resistance syndrome, this occurs with an XY karyotype. The external appearance is as a normal adolescent girl but there are no internal female organs.³ The gonads are testes that produce testosterone. There are no ovaries, Fallopian tubes, uterus or upper vagina. The clinical manifestation is variable according to the degree of androgen sensitivity.

Almost every cause of secondary amenorrhoea can also cause primary amenorrhoea, if it is established before the menarche.

Secondary sexual characteristics absent

• Hypothalamic failure:
  This can be due to chronic illness, stress or being significantly underweight. Anorexia nervosa usually develops after the menarche and represents a regression. Obesity is also more likely to cause secondary amenorrhoea.
• Other causes of failure of the hypothalamic-pituitary axis include:
  • Kallmann's syndrome:
    Characterised by failure of secretion of gonadotropin-releasing hormone (GnRH), tumours of the hypothalamus or pituitary along with other causes of hypopituitarism and hydrocephalus.
  • Hyperprolactinaemia:
    This can be due to many causes including hypothyroidism and drugs, especially phenothiazines. If it is due to a pituitary tumour, the level of prolactin (PRL) is usually very high. Hyperprolactinaemia occurs in 60% of secondary amenorrhoea.
  • Gonadal failure:
    This can be due to premature ovarian failure, even before the menarche or ovarian dysgenesis. The latter is usually part of Turner's syndrome that has a characteristic physical appearance.
• Causes of ambiguous genitalia:
  These include androgen-secreting tumours and 5 alpha-reductase deficiency. Congenital adrenal hyperplasia (CAH) can cause precocious puberty or at least pseudoprecocious puberty as the development of sexual characteristics is not followed by menstruation. There may be ambiguous genitalia in testicular feminisation.

Here it is useful to subdivide according to whether or not there is evidence of androgen excess.

No signs of androgen excess

• Pregnancy, lactation and the menopause:
  These are physiological causes. Secondary amenorrhoea is due to pregnancy until proved otherwise. Even denial of sexual activity should be taken with a degree of circumspection.
• Premature ovarian failure:
  This is a poorly understood condition that may represent an autoimmune phenomenon.⁴ It can also follow radiotherapy or chemotherapy. With all these causes, menstruation and fertility can sometimes resume spontaneously. Ovarian failure will cause elevation of gonadotrophins and so hot flushes are likely. Premature menopause is defined as occurring before the age of 40.⁵
• Depot and implant contraception:
  This often produces amenorrhoea and the progestogen-only pill can do so less often. Intrauterine contraceptive devices usually increase menstrual flow but Mirena® reduces it and may stop it.
• Cervical stenosis and intrauterine adhesions:
  These are known as Asherman's syndrome and should be considered.
• Loss of weight:
  This can cause amenorrhoea, especially if rapid. Body mass index (BMI) is rarely above 19 and at least 10% of normal body weight has been lost. Anorexia nervosa and other eating disorders including bulimia nervosa should be considered. The female athlete triad is well recognised. It consists of eating disorder, amenorrhoea and osteoporosis, predisposing to stress fractures.⁶ The triad affects not just distance runners, but gymnasts and dancers. Amenorrhoea is probably mostly related to weight but, in endurance athletes, excessive endorphin production may play a part,⁷ although this has also been disputed.⁸ Of women who have been given a place to run the London Marathon, the most common reason for failing to start is pregnancy.
• Pituitary disease and hyperprolactinaemia:
  Drugs, especially phenothiazines and metoclopramide raise PRL. Prolonged amenorrhoea is very common in heroin abusers. They are usually underweight but there may also be a pharmacological effect.
• Sheehan's syndrome:
  The pituitary may be damaged by tumours, trauma, cranial irradiation, sarcoidosis or tuberculosis.
• "Post pill amenorrhoea":
  This is when stopping oral contraceptives does not lead to a resumption of a normal menstrual cycle. It usually settles spontaneously in around three months but, if not, it requires investigation. The condition is probably not a true entity but the cause of amenorrhoea started whilst taking the contraceptives that induced an artificial cycle until they were stopped.

Signs of androgen excess

• Polycystic ovarian syndrome (PCOS):
  PCOS accounts for as many as 30% of cases of amenorrhoea. Both androgens and oestrogens may be normal or slightly raised so that, whilst there are signs of virilisation, there is no evidence of oestrogen deficiency. They are usually, but not always, overweight and may have insulin resistance. Fat is very important in the metabolism of the steroid sex hormones and it accounts for both the excess in PCOS and the deficiency in anorexia.
• Cushing's syndrome:
  This may be spontaneous or iatrogenic.
• Late onset congenital adrenal hyperplasia:
  Produces androgens.
• Adrenal or ovarian carcinoma:
  These also produce androgens.

Examination should include:⁹

• Height, weight and calculation of BMI. In young teenagers, centile charts are more appropriate as a BMI of 20 is overweight at age 14.
• Check secondary sexual characteristics and note any galactorrhoea.
• Pelvic examination should be omitted for a girl who denies previous sexual activity but abdominal examination is mandatory. There may be an unexpected mass arising from the pelvis, and after 16 weeks HCG falls and pregnancy tests are negative. Abdominal masses arising from the pelvis are not necessarily uterine. It may be a large ovarian cyst.

Investigations for primary and secondary amenorrhoea have much overlap but some will be rather more applicable to one than the other. The clinical picture may also point to a diagnosis that will lead to an investigation being done at an early stage.

• Urinary or serum human chorionic gonadotrophin should be measured, as exclusion of pregnancy is a basic initial investigation in all cases of secondary amenorrhoea, and in some cases of primary amenorrhoea.
• Follicle-stimulating hormone (FSH) and luteinising hormone (LH) are raised in ovarian failure; an FSH level ≥20 IU/l in a woman under 40 with secondary amenorrhoea indicates ovarian failure. This affects 1% of women. In PCOS the LH tends to be high compared with FSH. The exact degree of elevated FSH/LH ratio in PCOS is unclear, as the precise definition varies between practitioners, especially between gynaecologists and endocrinologists.⁸ Anyone who is diagnosed with PCOS should be investigated for impaired glucose tolerance or even type 2 diabetes.
  Low gonadotrophin concentrations indicate a hypothalamic cause for amenorrhoea, which is often associated with stress or excessive exercise or weight loss with or without an eating disorder. In cases associated with weight change or excessive exercise, serum gonadotrophin may be normal, and a thorough history may give important clues.
• Thyroid function tests may show an over- or under-active gland. Low T4 with low thyroid-stimulating hormone (TSH) suggests pituitary failure. Low T4 causes the hypothalamus to secrete more thyrotrophin-releasing hormone (TRH) that also stimulates the release of prolactin.
• PRL, estradiol and testosterone should be measured. Pituitary tumours tend to produce values in the thousands. Oestrogens are low when ovaries are not functioning and may be high in PCOS. Low oestrogen with high FSH and LH suggests a primary ovarian problem whilst a low FSH and LH with low oestrogens suggests a problem at the hypothalamic or pituitary level, including stress, exercise and low weight.
• Hyperandrogenaemia is observed in 60-80% of women with secondary amenorrhoea. Testosterone ≥5 nmol/l (female normal range 0-4.1 nmol/l) may indicate an androgen secreting tumour or late onset congenital adrenal hyperplasia and warrants referral for further investigation.
  The free androgen index is raised when sex hormone-binding globulin is suppressed. Thus, free testosterone concentration can be decreased by contraceptive pills and increased by insulin resistance or obesity.
• Pelvic ultrasound is necessary to establish the presence of uterus and ovaries and to exclude outflow obstruction. It can also demonstrate polycystic ovaries and possibly a carcinoma.
• Karyotyping is required to exclude Turner's syndrome, testicular feminisation and rarer conditions like XXX. It is obvious for primary amenorrhoea, but it may also be useful in primary ovarian failure under the age of 30.

Referral for more specialist investigations may be required. These include MRI or CT where pituitary tumour is suspected or investigation of adrenal or ovarian tumours. Hysteroscopy may be required for Asherman's syndrome.

Management depends upon the nature of the problem.

• Fertility is likely to be a concern in the younger woman, whether in the near or more distant future.
• Hormone replacement therapy (HRT) is indicated for women with premature ovarian failure (<40 years) until the average age of natural menopause, i.e. 52 years.⁵ HRT only raises the risk of breast cancer slightly in these women compared to that of their menstruating peers. They should not undergo early mammographic screening. Diabetes complicates the decision.¹⁰
• Constitutional late puberty requires reassurance and waiting.
• Structural abnormalities may be amenable to surgery.
• Eating disorders require psychiatric/psychological intervention, usually with cognitive and behavioural therapy. Obesity also requires dietary modification. Insulin resistance may benefit from metformin.
• If PRL is elevated due to drugs, they should be reviewed. Phenothiazines may possibly be replaced by newer medication. Metoclopramide may be replaced by domperidone. Pituitary tumours require specialist supervision. Bromocriptine and other drugs can be very effective at suppressing PRL from pituitary tumours but advice should be sought from the specialist before embarking on pregnancy as it can cause the tumour to expand. Thyroid abnormalities should be addressed.
• Turner's syndrome needs to be discussed. Oral contraceptives can correct problems of hormone deficiency and provide a menstrual cycle that may be psychologically beneficial. Genetic and psychological counselling may be required.
• In testicular feminisation any residual gonadal tissue should be removed to avoid the risk of malignancy. Explanation of the nature of the condition requires care and tact. For an adolescent girl to be told that she is really a boy would be most traumatic.¹¹ There is no hope of fertility and this should be made clear. The vagina is often short and problems with sexual intercourse are common.¹²

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