Differential diagnoses
Hirsutism and/or hyperandrogenaemia
Oligomenorrhea or amenorrhea
Distinctive characteristics
Clinical features
Laboratory tests
Hyperprolactinaemia; prolactinoma
Mild or absent
Present
Galactorrhoea; macroprolactinomas may cause visual disturbances headache, cranial nerve palsies and hypopituitarism symptoms
Increased plasma levels of prolactin
Primary hypothyroidism
Mild or absent
Potentially present
Slow relaxing tendon reflexes; periorbital oedema; bradycardia; hypothermia; dry-coarse skin; deep voice-hoarseness; potentially thyroid goitre
Increased plasma levels of TSH; decreased T4 levels; potentially increased prolactin levels (in secondary hypothyroidism TSH levels can be low or normal)
Nonclassic (late-onset; adult onset) congenital adrenal hyperplasia (21-hydroxylase deficiency)
Present
Not often present
Common in women of Ashkenazi Jewish, Hispanic, Slavic and central European ancestry; family history of hirsutism and/or infertility
Increased levels of 17-hydroxyprogesterone at 8 am or after stimulation (60 min after intravenous ACTH)
Androgen-secreting adrenal or ovarian tumours
Markedly present
Present
Virilization with severe manifestations (e.g., clitoral enlargement, male pattern alopecia, deepening of voice, decreased breast size, increased muscle mass); usually recent/sudden onset and rapid progression of symptoms
Markedly increased levels of testosterone (>2–3 upper normal range) and androstenedione; markedly increased DHEAS levels suggest an adrenal tumour and should prompt imaging of the adrenals (CT or MRI)
Cushing’s syndrome
Present
Present
Facial plethora; cervical, thoracic, and/or central obesity; violaceous/red striae >1 cm wide; easy bruising; progressive proximal muscle weakness; thin skin especially in young patients
24-h urinary free cortisol levels and midnight salivary cortisol levels are increased; failure to suppress morning plasma cortisol by an overnight dexamethasone suppression test
Acromegaly
Mild or absent
Often present
Prognathism; tooth separation; gradual acral enlargement (e.g., increased shoe/glove size); coarsening of facial features (e.g., lower lip and nose); hypertension; potentially compressive effects from a macroadenoma
Increased plasma levels of insulin-like growth factor-1 and failure to suppress GH levels or paradoxical rise in GH levels after an oral glucose tolerance test
Premature ovarian failure
Absent
Present
Estrogen deficiency symptoms (e.g., hot flashes, urogenital atrophy); potential presence of other autoimmune endocrinopathies (e.g., autoimmune thyroiditis, autoimmune adrenal failure)
Increased plasma levels of FSH with normal or decreased estradiol levels
Simple obesity
Often present
Not often present
Diagnosis of exclusion
Absent
Idiopathic hirsutism (hirsutism with regular menstrual cycles and without increased circulating androgens)
Present
Absent
Diagnosis of exclusion; usually mild hirsutism (Ferriman-Gallwey hirsutism score: 8–15); more common in women of Mediterranean heritage
Absent
Drug-induced androgen excess (e.g., anabolic or androgenic steroids, danazol, valproic acid)
Often present
Potentially present
Detailed history to rule out exogenous androgen use and drug-induced androgen excess
Absent
Hyperprolactinaemia. Measurement of early morning prolactin levels is essential to exclude hyperprolactinaemia. Clinicians should also look for symptoms/signs indicating a prolactinoma (e.g. galactorrhoea).
Primary hypothyroidism. Measurement of thyroid-stimulating hormone (TSH) plasma levels is usually sufficient to exclude hypothyroidism.
Nonclassic congenital adrenal hyperplasia (NC-CAH; 21-hydroxylase deficiency). Early morning plasma levels of 17-hydroxyprogesterone (17-OHP) should be measured to rule out NC-CAH due to 21-hydroxylase deficiency. NC-CAH can be detected in approximately 1.5–6.8 % of women presenting with androgen excess. Its clinical presentation may not differ from that of PCOS and heightened clinical suspicion is required in women with a positive family history or in those of high-risk ethnic group (e.g., Ashkenazi Jewish ancestry). Early morning 17-OHP levels in the range of 200–400 ng/dL are considered abnormal (this applies to the early follicular phase of a normal menstrual cycle, because 17-OHP levels increase with ovulation, and also depends on the assay). However, if the early morning 17-OHP levels are at the lower end of this range, an ACTH stimulation test should be used for diagnosis (stimulated increase to 17-OHP levels of >1,000 ng/dL 60 min after the intravenous injection of ACTH).
Androgen-secreting tumours. Androgen-secreting tumours are present in about 0.2 % of women with androgen excess (more frequently are ovarian; >50 % are malignant). Markedly increased testosterone levels that exceed two to three times the upper limit of the laboratory reference range suggest an androgen-secreting tumour (testosterone reference ranges vary depending on the lab/method). Significantly raised testosterone levels with acute onset and rapid progression of clinical hyperandrogenism should be evaluated as an androgen-secreting tumour until proven otherwise. Virilization can develop in less than a few months with marked androgen excess, while a longer period might be required in the presence of persistent modest hyperandrogenaemia. Rapid progression of clinical hyperandrogenism and virilization are rarely seen in PCOS. In PCOS the ovarian secretion of both androstenedione and testosterone is increased, while the adrenal synthesis of dehydroepiandrosterone sulfate (DHEAS) may also be enhanced. DHEAS is secreted almost exclusively from the adrenals and should be measured if there is clinical suspicion of an androgen-secreting tumour. Markedly increased plasma DHEAS levels must prompt imaging studies of the adrenals.
What laboratory tests would help in confirming the diagnosis?
Clinicians must first exclude (1) pregnancy by a urine or serum test for human chorionic gonadotropin (hCG); and (2) exogenous androgen use and drug-induced androgen excess by asking the patient to list all prescribed and over the counter medications, including any herbal supplements and injections. Our case patient listed only a multivitamin tablet and denied any other medications or supplements. Furthermore, her urine hCG test was negative. Thus, a set of biochemical and hormonal assessments, including a standard 2 h oral glucose tolerance test (OGTT), was requested for this patient and was subsequently done early in the morning (8 am) after overnight fasting.
Biochemical hyperandrogenism. Testosterone is found in the circulation in three fractions: (1) tightly bound to sex hormone binding globulin (SHBG; 65–68 % of the total testosterone); (2) weakly bound to albumin (30–33 %); and (3) free testosterone (1–2 %). The latter two fractions constitute the bioavailable testosterone (non SHBG-bound) which can be readily diffused into target tissues where it is converted to dihydrotestosterone by the enzyme 5α-reductase. Thus, SHBG is a crucial regulator of the bioavailable testosterone levels. SHBG is synthesised primarily in the liver and high levels of testosterone and insulin suppress its production, whereas thyroxine and estrogen enhance it. Accordingly, circulating SHBG levels are decreased in hyperandrogenaemia and hyperinsulinaemia, leading to increased free/bioavailable testosterone levels. In PCOS this creates a feed-forward vicious cycle between androgen excess, hyperinsulinaemia and low SHBG levels. Measurement of circulating androgens may not be necessary for PCOS diagnosis in cases of clinical hyperandrogenism without any signs of virilization, since either clinical or biochemical hyperandrogenism satisfy the PCOS diagnostic criteria. Establishing biochemical hyperandrogenism for the diagnosis of PCOS has limitations because there is no diagnostic level of circulating testosterone, while the existing normative data in women are not clearly defined. Furthermore, the different assays for testosterone measurement in women are not standardised across laboratories. Particularly measurement of free testosterone with direct tracer immunoassays can be problematic compared to the gold standard methods (e.g., equilibrium dialysis). If a reliable measurement of free testosterone cannot be obtained, the free androgen index (FAI) can be calculated based on total testosterone and SHBG levels (FAI: 100 × total testosterone/SHBG; levels in nmol/L). FAI has been shown to correlate well with the free testosterone levels measured by equilibrium dialysis.
Gonadotropins. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) are not necessarily required for the diagnosis of PCOS, since neither their ratio nor their absolute circulating levels are included in PCOS diagnostic criteria. Raised LH levels with low-normal FSH levels and an increased LH/FSH ratio (>2) are more frequently noted in lean PCOS women. These findings are less common in overweight/obese PCOS women, presumably due to effects of hyperinsulinaemia on LH secretion. Thus, a high LH/FSH ratio supports the diagnosis of PCOS but the absence of such findings has no diagnostic value.
Glucose tolerance. The current PCOS clinical practice guidelines by the Endocrine Society recommend an initial assessment of glucose tolerance by a standard OGTT in PCOS patients. Measurement of fasting glucose levels may not be sufficient to detect impaired glucose tolerance (IGT) in PCOS women. In patients that are unable or unwilling to complete an OGTT, measurement of haemoglobin A1c (HbA1c) is recommended instead, although it appears less sensitive for detecting IGT.
In our case patient, testosterone levels were 2.5 nmol/L (local laboratory normal reference: <1.8 nmol/L) with normal levels of prolactin, TSH, 17-OHP, DHEAS, androstenedione, LH and FSH. SHBG levels were at the lower limit of the laboratory reference range. Normal complete blood count, liver enzymes, and fasting lipid panel were also noted. Based on the OGTT results, plasma glucose increased from fasting levels of 5 mmol/L (90 mg/dL) to 8.6 mmol/L (155 mg/dL) after 2 h. Finally, pelvic ultrasonography revealed: (1) left ovary of 24 × 20 × 22 mm with 12 follicles of 2–9 mm; and (2) right ovary of 18 × 16 × 18 mm with 4 follicles of 2–9 mm (with absence of a dominant follicle >10 mm; and without any visible endometrial or adrenal pathology).
How would you interpret these results and what is the final diagnosis?
To date, there are three definitions that can be used to establish the diagnosis of PCOS (Table 13.2). PCOS remains a diagnosis of exclusion, hence all definitions require the exclusion of other disorders which are associated with symptoms/signs of androgen excess in women (see Tables 13.1 and 13.2). According to current guidelines by the Endocrine Society, early morning plasma levels of prolactin, TSH and 17-OHP should be routinely measured in the diagnostic evaluation of PCOS in order to exclude hyperprolactinaemia, thyroid disease (particularly hypothyroidism), and NC-CAH (primarily 21-hydroxylase deficiency), respectively. Depending on the clinical suspicion and presenting symptoms/signs, further laboratory tests may be required in selected patients to exclude other relevant disorders (see Table 13.1).
Table 13.2
Definitions and proposed criteria for establishing the diagnosis of the polycystic ovary syndrome (PCOS)
NIH [6] | Rotterdam ESHRE [9] | AE-PCOS society [1] |
|---|---|---|
(A) BOTH of the following: | (A) At least TWO of the following: | (A) BOTH of the following: |
Hyperandrogenism: clinical and/or biochemical (not specified) | Hyperandrogenism: clinical (hirsutism) and/or biochemical (free testosterone or FAI) | Hyperandrogenism: clinical (hirsutism) and/or biochemical (free testosterone by sensitive assays) |
Ovarian dysfunction: Chronic anovulation or oligo-ovulation (≤6 menses per year)
Related posts: Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Get Clinical Tree app for offline access
|
