Assessment of hirsutism

Ultrasound is not recommended in adolescents, as there are no definitive criteria to define polycystic ovary morphology in this population.[14]Teede HJ, Tay CT, Laven J, et al. Recommendations from the 2023 International Evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2023 Oct;120(4):767-93. https://www.fertstert.org/article/S0015-0282(23)00719-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/37589624?tool=bestpractice.com ​ However, it may be considered If serum androgen levels or the degree of virilisation is concerning for an ovarian tumour.[24]Screening and Management of the Hyperandrogenic Adolescent: ACOG Committee Opinion, Number 789. Obstet Gynecol. 2019 Oct;134(4):e106-e114. https://www.doi.org/10.1097/AOG.0000000000003475 http://www.ncbi.nlm.nih.gov/pubmed/31568365?tool=bestpractice.com

The best method for evaluation of total testosterone is liquid chromatography with tandem mass spectrometry.[14]Teede HJ, Tay CT, Laven J, et al. Recommendations from the 2023 International Evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2023 Oct;120(4):767-93. https://www.fertstert.org/article/S0015-0282(23)00719-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/37589624?tool=bestpractice.com ​ This has higher specificity and less interference with other androgens, such as androstenedione and dehydroepiandrosterone sulfate (DHEAS).[17]Barth JH, Field HP, Yasmin E, et al. Defining hyperandrogenism in polycystic ovary syndrome: measurement of testosterone and androstenedione by liquid chromatography-tandem mass spectrometry and analysis by receiver operator characteristic plots. Eur J Endocrinol. 2010 Mar;162(3):611-5. http://www.ncbi.nlm.nih.gov/pubmed/20008514?tool=bestpractice.com [25]Sairish A, Mudasar N, Shayaq ul Abeer R et al. Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review. Egypt. J. Med. Hum.Genet. 2019 Nov 20;20(25). https://jmhg.springeropen.com/articles/10.1186/s43042-019-0031-4 ​Endocrine Society guidelines recommend that early morning serum total and free testosterone are measured by calculating free androgen index in premenopausal women who have normal total testosterone but who have moderate to severe sexual hair growth or mild sexual hair growth in the presence of symptoms or signs of a hyperandrogenic endocrine disorder, such as menstrual disturbance.[1]Martin KA, Anderson RR, Chang RJ, et al. Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1233-57. https://academic.oup.com/jcem/article/103/4/1233/4924418 http://www.ncbi.nlm.nih.gov/pubmed/29522147?tool=bestpractice.com

In women with obesity, sex hormone-binding globulin levels are low, resulting in raised free testosterone and often normal total testosterone. Androgen level tests should be performed in the follicular phase (in cycling women), in the morning, and at least 3 months after cessation of any hormonal therapies other than cyclic progestin.

The best method for evaluation of total testosterone is liquid chromatography with tandem mass spectrometry (LC-MS/MS). This has higher specificity and less interference with other androgens, such as androstenedione and dehydroepiandrosterone sulfate (DHEAS).[17]Barth JH, Field HP, Yasmin E, et al. Defining hyperandrogenism in polycystic ovary syndrome: measurement of testosterone and androstenedione by liquid chromatography-tandem mass spectrometry and analysis by receiver operator characteristic plots. Eur J Endocrinol. 2010 Mar;162(3):611-5. http://www.ncbi.nlm.nih.gov/pubmed/20008514?tool=bestpractice.com [25]Sairish A, Mudasar N, Shayaq ul Abeer R et al. Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review. Egypt. J. Med. Hum.Genet. 2019 Nov 20;20(25). https://jmhg.springeropen.com/articles/10.1186/s43042-019-0031-4 If total testosterone is normal, free testosterone can be assessed by measurement of serum total testosterone and sex hormone binding protein, followed by calculation of the free androgen index.[26]Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999 Oct;84(10):3666-72. https://www.doi.org/10.1210/jcem.84.10.6079 http://www.ncbi.nlm.nih.gov/pubmed/10523012?tool=bestpractice.com

Endocrine Society guidelines recommend measuring early morning serum total and free testosterone in premenopausal women who have normal total testosterone, but who have moderate to severe sexual hair growth or mild sexual hair growth in the presence of symptoms or signs suggesting a hyperandrogenic endocrine disorder, such as menstrual disturbance.[1]Martin KA, Anderson RR, Chang RJ, et al. Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1233-57. https://academic.oup.com/jcem/article/103/4/1233/4924418 http://www.ncbi.nlm.nih.gov/pubmed/29522147?tool=bestpractice.com

Prolactin levels increase proportionally to the size of the tumour.[27]Schlechte JA. Clinical practice. Prolactinoma. N Engl J Med. 2003 Nov 20;349(21):2035-41. http://www.ncbi.nlm.nih.gov/pubmed/14627789?tool=bestpractice.com

CT may be an alternative, but MRI is more sensitive for small lesions.[27]Schlechte JA. Clinical practice. Prolactinoma. N Engl J Med. 2003 Nov 20;349(21):2035-41. http://www.ncbi.nlm.nih.gov/pubmed/14627789?tool=bestpractice.com

Should be measured in the morning, during follicular phase; levels may be higher in the afternoon. For women with amenorrhoea/infrequent menses it can be done on a random day. In women considered to have a high risk of non-classical congenital adrenal hyperplasia this screening test is recommended even if serum total and free testosterone are normal.[1]Martin KA, Anderson RR, Chang RJ, et al. Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1233-57. https://academic.oup.com/jcem/article/103/4/1233/4924418 http://www.ncbi.nlm.nih.gov/pubmed/29522147?tool=bestpractice.com

Diagnosis should be confirmed by ACTH stimulation test.[29]White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000 Jun;21(3):245-91. https://www.doi.org/10.1210/edrv.21.3.0398 http://www.ncbi.nlm.nih.gov/pubmed/10857554?tool=bestpractice.com

Tetracosactide, a synthetic form of ACTH, is injected (250 micrograms intravenously/intramuscularly), and measurements of 17-hydroxyprogesterone are done before administration and after 30 and 60 minutes. The diagnosis of non-classical congenital adrenal hyperplasia is confirmed when levels are >45 nanomol/L (1500 nanograms/dL).[21]Azziz R, Dewailly D, Owerbach D. Clinical review 56: nonclassic adrenal hyperplasia: current concepts. J Clin Endocrinol Metab. 1994 Apr;78(4):810-5. http://www.ncbi.nlm.nih.gov/pubmed/8157702?tool=bestpractice.com

An intramuscular depot formulation of tetracosactide is used in cases of suspected adrenocortical insufficiency where the original tests yield inconclusive results.

One of the first-line tests to consider in any patient with suspected Cushing syndrome.[30]Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00235-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/34687601?tool=bestpractice.com

Collected at 11 p.m.

Obtaining multiple (at least two) samples may increase sensitivity, and initial testing should be performed with sampling on two separate nights.[31]Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-40. http://www.ncbi.nlm.nih.gov/pubmed/18334580?tool=bestpractice.com [32]Carroll T, Raff H, Findling JW. Late-night salivary cortisol for the diagnosis of Cushing syndrome: a meta-analysis. Endocr Pract. 2009 May-Jun;15(4):335-42. https://www.endocrinepractice.org/article/S1530-891X(20)41041-9/fulltext http://www.ncbi.nlm.nih.gov/pubmed/19502211?tool=bestpractice.com [33]Raff H. Utility of salivary cortisol measurements in Cushing's syndrome and adrenal insufficiency. J Clin Endocrinol Metab. 2009 Oct;94(10):3647-55. https://academic.oup.com/jcem/article/94/10/3647/2596462 http://www.ncbi.nlm.nih.gov/pubmed/19602555?tool=bestpractice.com [34]Zhang Q, Dou J, Gu W, et al. Reassessing the reliability of the salivary cortisol assay for the diagnosis of Cushing syndrome. J Int Med Res. 2013 Oct;41(5):1387-94. https://journals.sagepub.com/doi/10.1177/0300060513498017 http://www.ncbi.nlm.nih.gov/pubmed/24065452?tool=bestpractice.com Value greater than the upper limit of normal is considered positive. Normal values vary greatly depending on the assay and clinical laboratory used. Positive results should be confirmed with dexamethasone suppression testing or 24-hour urinary free cortisol.​​​​​​

Assay-specific reference range.[30]Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00235-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/34687601?tool=bestpractice.com ​ Variability may be 50% between samples, thus 2 to 3 collections are required.[30]Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00235-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/34687601?tool=bestpractice.com

1 mg of dexamethasone given at 11 p.m. and serum cortisol collected at 8 a.m. the next morning.​[30]Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00235-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/34687601?tool=bestpractice.com [31]Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-40. http://www.ncbi.nlm.nih.gov/pubmed/18334580?tool=bestpractice.com ​​​​[35]Elamin MB, Murad MH, Mullan R, et al. Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab. 2008 May;93(5):1553-62. http://www.ncbi.nlm.nih.gov/pubmed/18334594?tool=bestpractice.com

Should not be used in patients taking drugs affecting dexamethasone metabolism (e.g., phenytoin, carbamazepine, rifampin, cimetidine).

Dexamethasone levels are measured simultaneously with cortisol to ensure that appropriate levels are achieved. This may help in severely obese patients whose dexamethasone levels may be sub-optimal.

Positive results should be confirmed with late-night salivary cortisol or 24-hour urinary free cortisol.

Transvaginal pelvic ultrasound is the preferred imaging modality to evaluate a clinically suspected ovarian mass, providing both qualitative and quantitative information valuable in management. Combined transvaginal and transabdominal ultrasound may be useful for evaluating larger masses.

Ultrasound with Doppler imaging can characterise the mass (e.g., cystic, solid, complex), and in most cases can triage the mass into benign or malignant categories.

Serum CA-125 levels are raised in >80% of women with advanced-stage disease. However, this biomarker is not diagnostic because CA-125 levels can be raised as a result of non-malignant conditions (e.g., endometriosis, uterine fibroids, pregnancy, pelvic inflammatory disease, appendicitis, and ovarian cysts) and other malignant conditions (e.g., pancreatic, breast, lung, gastric, and colon cancers). Furthermore, normal CA-125 levels are observed in approximately 50% of patients with early-stage ovarian cancer.[36]Tuxen MK, Sölétormos G, Dombernowsky P. Tumor markers in the management of patients with ovarian cancer. Cancer Treat Rev. 1995 May;21(3):215-45.

The best method for evaluation of total testosterone is liquid chromatography with tandem mass spectrometry. This has higher specificity and less interference with other androgens, such as androstenedione and dehydroepiandrosterone sulfate (DHEAS).[17]Barth JH, Field HP, Yasmin E, et al. Defining hyperandrogenism in polycystic ovary syndrome: measurement of testosterone and androstenedione by liquid chromatography-tandem mass spectrometry and analysis by receiver operator characteristic plots. Eur J Endocrinol. 2010 Mar;162(3):611-5. http://www.ncbi.nlm.nih.gov/pubmed/20008514?tool=bestpractice.com [25]Sairish A, Mudasar N, Shayaq ul Abeer R et al. Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review. Egypt. J. Med. Hum.Genet. 2019 Nov 20;20(25). https://jmhg.springeropen.com/articles/10.1186/s43042-019-0031-4 If total testosterone is normal, free testosterone can be assessed by measurement of serum total testosterone and sex hormone binding protein, followed by calculation of the free androgen index.[26]Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999 Oct;84(10):3666-72. https://www.doi.org/10.1210/jcem.84.10.6079 http://www.ncbi.nlm.nih.gov/pubmed/10523012?tool=bestpractice.com

Endocrine Society guidelines recommend measuring early morning serum total and free testosterone in premenopausal women who have normal total testosterone, but who have moderate to severe sexual hair growth or mild sexual hair growth in the presence of symptoms or signs suggesting a hyperandrogenic endocrine disorder, such as menstrual disturbance.[1]Martin KA, Anderson RR, Chang RJ, et al. Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1233-57. https://academic.oup.com/jcem/article/103/4/1233/4924418 http://www.ncbi.nlm.nih.gov/pubmed/29522147?tool=bestpractice.com

Ovaries may be very small and not visible. In menopausal women, may be discovered only after oophorectomy.

Characterisation of primary adrenal lesion and evaluation for loco-regional and distant metastases; sensitivity 100% and specificity 94%.[37]Yun M, Kim W, Alnafisi N, et al. 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. J Nucl Med. 2001 Dec;42(12):1795-9. https://jnm.snmjournals.org/content/42/12/1795.long http://www.ncbi.nlm.nih.gov/pubmed/11752075?tool=bestpractice.com [Figure caption and citation for the preceding image starts]: 18-fluoro-2-deoxyglucose (FDG) PET-CT: adrenocortical carcinoma. 51-year-old woman with Cushing's syndrome and large, multilobulated and intensely 18-F-FDG avid left adrenal mass and metastatic aortocaval and left para-aortic lymph nodesGross MD, Avram A, Fig LM, et al. Q J Nucl Med Mol Imaging. 2007 Sep;51(3):272-83; used with permission [Citation ends].