Online Supplementary Material for Table 1

Online supplementary information forBox 1. Rare disorders in the differential diagnosis of hirsutism.

Hyperandrogenism, insulin resistance and acanthosis nigricans (HAIR-AN):

These patients will present with marked acanthosis and extreme degrees of hyperandrogenism. Normal or low luteinizing hormone levels accompany increased levels of androgen. The clinical distinction between HAIR-ANand PCOS is not very clear and some authors believe that HAIR-AN is an extreme variant of PCOS. Nevertheless, HAIR-ANis defined, in a patient with hyperandrogenism and acanthosis, by the presence of severe insulin resistance determined arbitrarily by insulin levels greater than 2100–3500 pmol/l (>300-500 µIU/ml).

Androgen-secreting tumors:

The onset of these tumors is usually sudden and they may rapidly lead to virilization and masculinization. Adrenal tumors can be suspected when serum dehydroepiandrosterone levels are greater than 18.9 μmol/l (>7000 ng/ml), whereas circulating testosterone levels of more than 6.9nmol/l(>200 ng/dl) should raise the suspicion of an ovarian tumor although clinical presentation is the most sensitive indicator of an androgen-producing tumor. In cases of high clinical and biochemical suspicion of an adrenal or ovarian androgen-producing tumor, imaging studies and venous sampling could be of value in identifying the tumor.

Hyperthecosis:

Individuals with hyperthecosis present with severe hirsutism, usually associated with obesity and signs of virilization. Androgen levels are higher than those usually observed in polycystic ovary syndrome. Severe insulin resistance and hyperinsulinemia are observed. The ovaries are enlarged, with proliferating islands of luteinized theca cells in the ovarian stroma, but not cystic which might distinguish this condition from polycystic ovary syndrome.

Cushing’s syndrome and acromegaly:

Clinical suspicion of these disorders requires the measurement of 24h free urinary cortisol and insulin-like growth factor 1 levels respectively.

Online supplementary information forBox 3. Initial investigations for a patient with hirsutism.

Exclusion of related disorders by measuring 17-hydroxyprogesterone (17-OHP) levels:

A normal basal or stimulated 17-OHP level excludes non-classic congenital adrenal hyperplasia. If baseline 17-OHP levels are above 6.06 nmol/l (200 ng/dl), a stimulation test, using adrenocorticotropic hormone, should be performed to establish the diagnosis. For this test, 250 µg of adrenocorticotropic hormone is injected intravenously and 17-OHP levels are measured after 60 minutes. The diagnosis of 21-hydroxylase-deficient non-classic congenital adrenal hyperplasia is made biochemically if the stimulated levels are above 30.3 nmol/l (1000 ng/dl).17,18

Exclusion of related disorders by measuring TSH and prolactin levels:

TSH and prolactin levels are measured in hirsute patients with oligomenorrhea to exclude thyroid dysfunction and hyperprolactinemia, respectively.

Confirmation of ovulatory function:

Many women with hirsutism present with oligomenorrhea or with amenorrhea. In some women hirsutism can, however, be accompanied by regular menstrual cycles (albeit anovulatory in up to 40% of the patients). In these women normal ovulatory function should be confirmed by obtaining a luteal phase progesterone level 20–22 days after the start of menstruation. Ovulatory dysfunction may be evidenced by a luteal phase progesterone level which is greater than 9.5–15.9 nmol/l (>3-5 ng/ml) in a eumenorrheic patient.

Pelvic ultrasonography:

All patients with hirsutism should undergo pelvic ultrasonography to check whether they have polycystic ovaries according to 2003 Rotterdam or 2006 Androgen Excess Society criteria for the diagnosis of polycystic ovary syndrome.

References

16. Azziz R et al. (1999) Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study Fertil Steril72: 915–925

17. New MI et al. (1983) Genotyping steroid 21-hydroxylase deficiency: hormonal reference data J Clin Endocrinol Metab57: 320–326