Intended for healthcare professionals

Practice Rational testing

Investigating hirsutism

BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b912 (Published 28 April 2009) Cite this as: BMJ 2009;338:b912
  1. T Sathyapalan, specialist registrar in diabetes1,
  2. Stephen L Atkin, professor of academic endocrinology2
  1. 1Endocrinology and General Medicine, Michael White Diabetes Centre, Hull Royal Infirmary, Hull HU3 2RW
  2. 2Diabetes and Metabolism, Hull-York Medical School, Hull Royal Infirmary
  1. Correspondence to: S L Atkin Stephen.Atkin{at}hyms.ac.uk

    When should we test for clinical hyperandrogenism and what are the best tests?

    Learning points

    • Clinical hirsutism is usually caused by polycystic ovary syndrome or is idiopathic (has no other clinical or biochemical abnormality)

    • Initial tests should: assess biochemical hyperandrogenaemia by measuring total testosterone, sex hormone binding globulin, and free androgen index; include thyroid function tests and prolactin measurements; and if clinically indicated, rule out non-classic congenital adrenal hyperplasia by measuring 17-hydroxyprogesterone and Cushing’s syndrome by measuring 24 hour urinary cortisol

    • Ultrasonographic imaging of ovaries is not needed to diagnose polycystic ovary syndrome in patients with menstrual disturbances and clinical or biochemical evidence of hyperandrogenism

    The patient

    A 29 year old woman presented to her general practitioner because of facial hair that had worsened over the past three years. Her menarche had been at the age of 13 and her menstrual cycle was regular at 30 days. Her weight had been stable over the past two years, but she had previously put on 10 kg in weight over 18 months. She had an unremarkable medical history and was not taking any drugs. She had a body mass index of 34 and coarse terminal hair on her upper lip, chin, and stomach. No signs of virilisation (deepening of the voice, clitoromegaly, and loss of female body shape) were seen.

    What is the next investigation?

    Hirsutism is the presence of excess hair growth in women as a result of increased androgen production or increased skin sensitivity to androgens, or both. It should be distinguished from hypertrichosis, which is androgen independent and causes uniform growth of non-terminal (vellus) hair over the body, particularly in non-sexual areas; this condition can be familial, related to drugs (such as phenytoin or ciclosporin), or caused by non-endocrine disorders such as anorexia nervosa. The initial consultation should take into account ethnic differences (even mild hirsutism in Asian women may indicate excess androgen production),1 any cultural norms, and the patient’s expectations during assessment.

    The most common causes of clinical hyperandrogenism are PCOS (72%), idiopathic (no other clinical or biochemical abnormalities) hyperandrogenism (23%), non-classic adrenal hyperplasia (4.3%), and androgen secreting tumours (0.2%).2 For a diagnosis of PCOS—the most common cause of hirsutism—other causes of clinical or biochemical hyperandrogenism and menstrual disturbance (which was not present in this case) need to be excluded and the revised 2003 consensus criteria fulfilled (box 1).3 The initial laboratory investigations include thyroid function tests and measurement of free androgen index, prolactin, 17-hydroxyprogesterone, and 24 hour urine cortisol (to rule out Cushing’s syndrome if suspected). Pregnancy should be ruled out in women with “irregular” or absent menstrual cycles.

    Box 1 Revised 2003 criteria for diagnosing polycystic ovary syndrome (PCOS)3

    • Two of the following three criteria must be fulfilled for a diagnosis of PCOS:

    • A clinical diagnosis of oligomenorrhoea or amenorrhoea—menstrual cycles longer than 35 days or fewer than 10 periods a year

    • Clinical (hirsutism, acne, or androgen alopecia) or biochemical (raised free androgen index) evidence of hyperandrogenism

    • Polycystic ovaries on ultrasound examination (box 2)

    Late onset congenital adrenal hyperplasia, androgen secreting tumours, and Cushing’s syndrome must be excluded in women with raised androgens; thyroid disorders and raised prolactin should be excluded in women with menstrual disturbances.

    Sex hormone evaluations

    Serum analysis fails to detect biochemical hyperandrogenism in about 20-40% of women with PCOS.4 The table shows the diagnostic accuracy of these biochemical parameters. Measurement of total testosterone, even using modern immunoassays, has a low sensitivity for diagnosing PCOS.5 High (for example, with the use of oral contraceptive pills) or low (for example, in insulin resistance7 or obesity) concentrations of sex hormone binding globulin may affect total testosterone values. Measurement of sex hormone binding globulin enables calculation of the free androgen index (total testosterone concentration divided by sex hormone binding globulin concentration multiplied by 100).8 In practice, total testosterone is often normal in PCOS but the free androgen index—a measure of bioavailable testosterone—is raised because sex hormone binding globulin is suppressed.

    Biochemical parameter used to test for hyperandrogenism

    View this table:

    A high total testosterone concentration indicates that hyperandrogenaemia may be caused by an ovarian or adrenal tumour. Raised testosterone concentrations are seen in 60-80% of women with PCOS.9 If the total testosterone is normal (<4.1 nmol/l) or only slightly raised (<5 nmol/l), then an androgen secreting tumour can be excluded. Testosterone concentrations more than 1.5-2 times the upper limit of normal or a history of rapid virilisation are likely to be associated with tumour associated hyperandrogenism. In such cases dehydroepiandrosterone sulphate and androstenedione should be measured to identify an adrenal or ovarian source of the hyperandrogenaemia.

    Ultrasound imaging

    Patients with either menstrual disturbances or clinical or biochemical evidence of hyperandrogenism alone should have transvaginal ultrasonographic imaging of the ovaries to look for polycystic ovaries (box 2). Because our patient had clinical hyperandrogenism only, to fulfil the 2003 revised diagnostic criteria for PCOS she will therefore need ovarian imaging.

    Box 2 Ultrasound imaging

    Women with either menstrual irregularities or clinical or biochemical hyperandrogenaemia only should undergo pelvic ultrasound. Visualisation of the ovaries is better when the transvaginal route is used rather than the transabdominal route.

    A polycystic ovary has at least one of the following:

    • Twelve or more follicles in each ovary, each follicle measuring 2-9 mm in diameter

    • Ovarian volume >10 ml

    One polycystic ovary is sufficient for the diagnosis of polycystic ovary syndrome.

    Thyroid function and prolactin

    Other diseases that could result in a similar clinical picture need to be excluded before the diagnosis of PCOS can be confirmed. Thyroid function should be measured because defective functioning can affect menstruation and hypothyroidism is associated with changes in hair, although this is usually a coarsening and dryness of the hair rather than true hirsutism. Prolactin should be measured because it affects the menstrual cycle, and it has been associated with hirsutism through an effect on the production of adrenal androgens. If prolactin concentrations are more than 1.5-2 times the upper limit of normal, other causes of hyperprolactinaemia—including the use of drugs, especially antipsychotic agents, and pituitary tumours—should be considered.

    Serum 17-hydroxyprogesterone

    Around 1-10% of women with hyperandrogenaemia will have non-classic congenital adrenal hyperplasia,10 which is caused by partial 21-hydroxylase deficiency and is clinically indistinguishable from PCOS. The prevalence is higher in Hispanics, Yugoslavs, Eastern European Jews, and people from the southern Mediterranean. In patients belonging to these ethnic groups, 17-hydroxyprogesterone—a precursor of 21-hydroxyprogesterone—can be used to screen for this condition. Blood should be taken in the follicular phase (the first half of the menstrual cycle) around 9 am to avoid diurnal variation. Under these circumstances, a 17-hydroxyprogesterone value of 5 nmol/l has a sensitivity of 100% and specificity of 88.6% for diagnosing non-classic congenital adrenal hyperplasia.11 If 17-hydroxyprogesterone concentrations are raised, referral to an endocrinologist is warranted—the diagnosis will be confirmed if the 17-hydroxyprogesterone concentrations are higher than 30 nmol/1 after an adrenocorticotrophin stimulation test.12 Our patient did not belong to an ethnic group with a high prevalence of non-classic congenital adrenal hyperplasia.

    Twenty four hour urinary cortisol

    Cushing’s disease is a rare cause of hirsutism and its routine exclusion is not warranted unless the patient has cushingoid features. Estimation of 24 hour urinary cortisol excretion is a useful screening test. Basal 24 hour urinary cortisol excretion of more than three times the upper limit of normal (50-250 nmol/24 h) has a sensitivity of 100% and specificity of 98% in the diagnosis of Cushing’s syndrome.13 Our patient had no clinical signs of Cushing’s syndrome.

    Diagnostic outcome

    Our patient’s symptoms of clinical hyperandrogenaemia (hirsutism) and a regular menstrual cycle were not sufficient for a diagnosis of PCOS (box 1). Laboratory tests showed biochemical hyperandrogenaemia—total testosterone was normal (2.4 nmol/l; normal 0.5-3.4), sex hormone binding globulin was low (24 mmol/l; 32-58), so the free androgen index was high (10; <9). Thyroid stimulating hormone and prolactin concentrations were normal. To confirm a diagnosis of PCOS, she underwent ultrasound examination, which demonstrated polycystic ovaries (box 2). Because PCOS is associated with an increased risk of other long term problems—such as type 2 diabetes mellitus, hypertension, and dyslipidaemia—these should be considered during the patient’s long term care.

    Notes

    Cite this as: BMJ 2009;338:912

    Footnotes

    • This is a series of occasional articles outlining initial diagnostic approaches to clinical presentations.

    • Contributors: Both authors wrote and revised the article.

    • Competing interests: None declared.

    • Provenance and peer review: Commissioned; externally peer reviewed.

    • Patient consent not required (patient anonymised, dead, or hypothetical).

    References