Practical approaches to the use of markers of biochemical hyperandrogenism in women

Literature review

Authors

DOI:

https://doi.org/10.18370/2309-4117.2022.63.25-33

Keywords:

testosterone, sex steroid-binding globulin, androstenedione, dehydroepiandrosterone sulfate, affinity

Abstract

Hyperandrogenism (HA) remains an actual problem that raises a large number of questions, in particular, in cases of discrepancy between the clinical signs of HA and biochemical parameters. This review includes an analysis of recent studies of androgen synthesis and metabolism in healthy women of reproductive age; management of pathologies accompanied by HA; as well as contemporary approaches to the principles of prescribing and evaluating the results of the main available markers of biochemical HA.
There are сoncepts of clinical and biochemical HA. Biochemical HA is an increase in the levels of various circulating androgens. The concept of clinical HA includes hirsutism as assessed by the modified Ferriman–Gallwey scale. The most common causes of HA include polycystic ovary syndrome, non-classical forms of congenital adrenal hyperplasia, other endocrine disorders. It is necessary to carry out a differential diagnosis of these conditions with more rare causes as a primarily tumor pathology. The choice and evaluation of laboratory markers of biochemical HA should be made taking into account clinical data such as puberty history, anovulation, polycystic ovarian morphotype, obesity; presence and degree of hirsutism and/or other androgen-associated dermatopathies, the characteristics of the course of clinical HA (sudden onset, rapid progression), presence of other endocrinopathies, liver and kidney dysfunction; diabetes mellitus.
The objectives of the laboratory assessment of HA are determination of HA severity; determination of the source of excess androgen synthesis (ovaries, adrenal glands); assessment of the free fraction of circulating active androgens; in some cases, assessment of the formation of active androgens in the skin. The following indicators are used to solve the tasks in laboratory diagnostics: total testosterone, free testosterone, free androgen index, androstenedione, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, dihydrotestosterone. A comprehensive assessment of these indicators allows not only assessing the presence of HA and its severity, but also the nature of its leading and secondary components, which determine the presence and prognosis of metabolic risks and allow individualizing therapeutic approaches.

Author Biographies

T.M. Tutchenko, SI “O.M. Lukyanova IPOG of the NAMS of Ukraine”; SSI “CIMT of the NAS of Ukraine”; “DILA” Medical Laboratory, Kyiv

PhD, senior researcher, Endocrine Gynecology Department;
Department of Reproductive Health;
Scientific consultant

O.A. Burka, О.О. Bogomolets National Medical University; “DILA” Medical Laboratory, Kyiv

PhD, associate professor, Obstetrics and Gynaecology Department No. 1;
“DILA” Medical Laboratory, Kyiv

I.V. Sidorova, “DILA” Medical Laboratory, Kyiv

Medical director

I.H. Nohovska, P.L. Shupyk National Healthcare University of Ukraine; “Gynecology center ‘Nadiya’” LLC, Clinical Hospital No. 18, Kyiv

Graduate student, Department of Obstetrics, Gynecology and Perinatology;
obstetrician gynecologist

I.M. Marynchyna, Bukovinian State Medical University, Chernivtsi

PhD, assistant, Department of Obstetrics, Gynecology and Perinatology

N.M. Shcherbatiei, Kyiv City Center of Reproductive and Perinatal Medicine, Kyiv

Gynecologist

References

  1. Barth, J.H., Field, H.P., Yasmin, E., Balen, A. “Definition of hyperandrogenism.” Curr Manag Polycystic Ovary Syndr 1 (2010): 117–24. DOI: 10.1017/CBO9781107478343.012
  2. Lizneva, D., Gavrilova-Jordan, L., Walker, W., Azziz, R. “Androgen excess: Investigations and management.” Best Pract Res Clin Obstet Gynaecol 37 (2016): 98–118. DOI: 10.1016/j.bpobgyn.2016.05.003
  3. Rao, P., Bhide, P. “Controversies in the diagnosis of polycystic ovary syndrome.” Ther Adv Reprod Heal 14 (2020): 2633494120913032. DOI: 10.1177/2633494120913032
  4. Yildiz, B.O., Bolour, S., Woods, K., et al. “Visually scoring hirsutism.” Hum Reprod Update 16.1 (2010): 51–64. DOI: 10.1093/HUMUPD/DMP024
  5. Martin, K.A., Rox Anderson, R., Jeffrey Chang, R., et al. “Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline.” J Clin Endocrinol Metab 103.4 (2018): 1233–57. DOI: 10.1210/JC.2018-00241
  6. Carmina, E., Dreno, B., Lucky, W.A., et al. “Female Adult Acne and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee.” J Endocr Soc 6.3 (2022). DOI: 10.1210/JENDSO/BVAC003
  7. Carmina, E., Azziz, R., Bergfeld, W., et al. “Female Pattern Hair Loss and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee.” J Clin Endocrinol Metab 104.7 (2019): 2875–91. DOI: 10.1210/jc.2018-02548
  8. Carmina, E., Rosato, F., Jannì, A., et al. “Relative Prevalence of Different Androgen Excess Disorders in 950 Women Referred because of Clinical Hyperandrogenism.” J Clin Endocrinol Metab 91.1 (2006): 2–6. DOI: 10.1210/JC.2005-1457
  9. Dubey, P., Reddy, S.Y., Alvarado, L., et al. “Prevalence of at-risk hyperandrogenism by age and race/ethnicity among females in the United States using NHANES III.” Eur J Obstet Gynecol Reprod Biol 260 (2021): 189–97. DOI: 10.1016/J.EJOGRB.2021.03.033
  10. Teede, H.J., Misso, M.L., Costello, M.F., et al. “Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.” Hum Reprod 33.9 (2018): 1602–18. DOI: 10.1093/humrep/dey256
  11. Azziz, R., Carmina, E., Chen, Z., et al. “Polycystic ovary syndrome.” Nat Rev Dis Primers 2 (2016): 1–18. DOI: 10.1038/nrdp.2016.57
  12. Bozdag, G., Mumusoglu, S., Zengin, D., et al. “The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis.” Hum Reprod 31.12 (2016): 2841–55. DOI: 10.1093/HUMREP/DEW218
  13. Sharma, A., Welt, C.K. “Practical Approach to Hyperandrogenism in Women.” Med Clin 105.6 (2021): 1099–116. DOI: 10.1016/J.MCNA.2021.06.008
  14. Carmina, E. “Cutaneous manifestations of polycystic ovary syndrome.” Curr Opin Endocr Metab Res. 12 (2020): 49–52. DOI: 10.1016/J.COEMR.2020.02.015
  15. Moran, C., Arriaga, M., Arechavaleta-Velasco, F., Moran, S. “Adrenal Androgen Excess and Body Mass Index in Polycystic Ovary Syndrome.” J Clin Endocrinol Metab 100.3 (2015): 942–50. DOI: 10.1210/JC.2014-2569
  16. Sanchez-Garrido, M.A., Tena-Sempere, M. “Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies.” Mol Metab 35 (2020): 100937. DOI: 10.1016/J.MOLMET.2020.01.001
  17. Luque-Ramírez, M., Escobar-Morreale, F.H. “Adrenal Hyperandrogenism and Polycystic Ovary Syndrome.” Curr Pharm Des 22.36 (2016): 5588–5602. DOI: 10.2174/1381612822666160720150625
  18. Bianchi, V.E., Bresciani, E., Meanti, R., et al. “The role of androgens in women’s health and wellbeing.” Pharmacol Res 171 (2021): 105758. DOI: 10.1016/J.PHRS.2021.105758
  19. Schiffer, L., Arlt, W., Storbeck, K.H. “Intracrine androgen biosynthesis, metabolism and action revisited.” Mol Cell Endocrinol 465 (2018): 4–26. DOI: 10.1016/J.MCE.2017.08.016
  20. Bienenfeld, A., Azarchi, S., Lo Sicco, K., et al. “Androgens in Women: Androgen mediated skin disease and patient evaluation (Part I).” J Am Acad Dermatol (2018) Oct 10. DOI: 10.1016/J.JAAD.2018.08.062
  21. Walters, K.A., Handelsman, D.J. “Role of androgens in the ovary.” Mol Cell Endocrinol 465 (2018): 36–47. DOI: 10.1016/J.MCE.2017.06.026
  22. Qu, X., Donnelly, R. “Sex Hormone-Binding Globulin (SHBG) as an Early Biomarker and Therapeutic Target in Polycystic Ovary Syndrome.” Int J Mol Sci 21 (2020): 8191. DOI: 10.3390/IJMS21218191
  23. Dunn, J.F., Nisula, B.C., Rodbard, D. “Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma.” J Clin Endocrinol Metab 53.1 (1981): 58–68. DOI: 10.1210/JCEM-53-1-58
  24. Dumoulin, S.C., Perret, B.P., Bennet, A.P., Caron, P.J. “Opposite effects of thyroid hormones on binding proteins for steroid hormones (sex hormone-binding globulin and corticosteroid-binding globulin) in humans.” Eur J Endocrinol 132.5 (1995): 594–8. DOI: 10.1530/EJE.0.1320594
  25. Skałba, P., Zieba, M., Olejek, A. “Testosterone and SHBG levels in blood serum in women with anorexia nervosa.” Wiad Lek 54.9–10 (2001): 532–6.
  26. Miller, K.K., Lawson, E.A., Mathur, V., et al. “Androgens in Women with Anorexia Nervosa and Normal-Weight Women with Hypothalamic Amenorrhea.” J Clin Endocrinol Metab 92.4 (2007): 1334–9. DOI: 10.1210/JC.2006-2501
  27. Pasquali, R., Vicennati, V., Bertazzo, D., et al. “Determinants of sex hormone-binding globulin blood concentrations in premenopausal and postmenopausal women with different estrogen status.” Metabolism 46.1 (1997): 5–9. DOI: 10.1016/S0026-0495(97)90159-1
  28. Wei, S., Schmidt, M.D., Dwyer, T., et al. “Obesity and Menstrual Irregularity: Associations With SHBG, Testosterone, and Insulin.” Obesity 17.5 (2009): 1070–6. DOI: 10.1038/OBY.2008.641
  29. Slominski, A.T., Manna, P.R., Tuckey, R.C. “On the role of skin in the regulation of local and systemic steroidogenic activities.” Steroids 103 (2015): 72–88. DOI: 10.1016/j.steroids.2015.04.006
  30. Zouboulis, C.C., Chen, W.C., Thornton, M.J., et al. “Sexual hormones in human skin.” Horm Metab Res 39.2 (2007): 85–95. DOI: 10.1055/s-2007-961807
  31. Slominski, A.T., Zmijewski, M.A., Zbytek, B., et al. “Key Role of CRF in the Skin Stress Response System.” Endocr Rev 34.6 (2013): 827–84. DOI: 10.1210/ER.2012-1092
  32. Wagner, I.V., Savchuk, I., Sahlin, L., et al. “De Novo and Depot-Specific Androgen Production in Human Adipose Tissue: A Source of Hyperandrogenism in Women with Obesity.” Obes Facts 15.2 (2022): 281–91. DOI: 10.1159/000521571
  33. Lösel, R.M., Falkenstein, E., Feuring, M., et al. “Nongenomic steroid action: Controversies, questions, and answers.” Physiol Rev 83.3 (2003): 965–1016. DOI: 10.1152/physrev.00003.2003
  34. Heinlein, C.A., Chang, C. “The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions.” Mol Endocrinol 16.10 (2002): 2181–7. DOI: 10.1210/ME.2002-0070
  35. Hodgson, T.K., Braunstein, G.D. “Physiological Effects of Androgens in Women.” Androg Excess Disord Women (2006) Nov 7: 49–62. DOI: 10.1007/978-1-59745-179-6_4
  36. Escobar-Morreale, H.F., Carmina, E., Dewailly, D., et al. “Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society.” Hum Reprod Update 18.2 (2012): 146–70. DOI: 10.1093/HUMUPD/DMR042
  37. Pasch, L., He, S.Y., Huddleston, H., et al. “Clinician vs Self-ratings of Hirsutism in Patients With Polycystic Ovarian Syndrome: Associations With Quality of Life and Depression.” JAMA Dermatology 152.7 (2016): 783–8. DOI: 10.1001/JAMADERMATOL.2016.0358
  38. Azziz, R., Carmina, E., Sawaya, M.E. “Idiopathic Hirsutism.” Endocr Rev 21.4 (2000): 347–62. DOI: 10.1210/EDRV.21.4.0401
  39. Amiri, M., Fallahzadeh, A., Sheidaei, A., et al. “Prevalence of idiopathic hirsutism: A systematic review and meta-analysis.” J Cosmet Dermatol (2021). DOI: 10.1111/JOCD.14313
  40. Trüeb, R.M. “Causes and Management of Hypertrichosis.” Am J Clin Dermatology 3.9 (2002): 617–27. DOI: 10.2165/00128071-200203090-00004
  41. Carmina, E., Azziz, R., Bergfeld, W., et al. “Female pattern hair loss and androgen excess: a report from the Multidisciplinary Androgen Excess and PCOS Committee.” J Clin Endocrinol Metab 104.7 (2019): 2875–91. DOI: 10.1210/jc.2018-02548
  42. Uysal, G., Sahin, Y., Unluhizarci, K., et al. “Is acne a sign of androgen excess disorder or not?” Eur J Obstet Gynecol Reprod Biol 211 (2017): 21–5. DOI: 10.1016/J.EJOGRB.2017.01.054
  43. Rocha, M.A., Bagatin, E. “Adult-onset acne: Prevalence, impact, and management challenges.” Clin Cosmet Investig Dermatol 11 (2018): 59–69. DOI: 10.2147/CCID.S137794
  44. Kircik, L.H. “Androgens and acne: perspectives on clascoterone, the first topical androgen receptor antagonist.” Expert Opin Pharmacother 22.13 (2021): 1801–6. DOI: 10.1080/14656566.2021.1918100
  45. Ding, T., Hardiman, P.J., Petersen, I., et al. “The prevalence of polycystic ovary syndrome in reproductive-aged women of different ethnicity: a systematic review and meta-analysis.” Oncotarget 8.56 (2017): 96351. DOI: 10.18632/ONCOTARGET.19180
  46. O’Reilly, M.W., Taylor, A.E., Crabtree, N.J., et al. “Hyperandrogenemia Predicts Metabolic Phenotype in Polycystic Ovary Syndrome: The Utility of Serum Androstenedione.” J Clin Endocrinol Metab 99.3 (2014): 1027–36. DOI: 10.1210/JC.2013-3399
  47. Lerchbaum, E., Schwetz, V., Rabe, T., et al. “Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype.” PLoS One 9.10 (2014): e108263. DOI: 10.1371/JOURNAL.PONE.0108263
  48. Yildiz, B.O., Azziz, R. “The adrenal and polycystic ovary syndrome.” Rev Endocr Metab Disord 8.4 (2007): 331–42. DOI: 10.1007/s11154-007-9054-0
  49. Goodarzi, M.O., Carmina, E., Azziz, R. “DHEA, DHEAS and PCOS.” J Steroid Biochem Mol Biol 145 (2015): 213–25. DOI: 10.1016/J.JSBMB.2014.06.003
  50. Münzker, J., Hofer, D., Trummer, C., et al. “Testosterone to Dihydrotestosterone Ratio as a New Biomarker for an Adverse Metabolic Phenotype in the Polycystic Ovary Syndrome.” J Clin Endocrinol Metab 100.2 (2015): 653–60. DOI: 10.1210/JC.2014-2523
  51. Speiser, P.W., Arlt, W., Auchus, R.J., et al. “Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society. Clinical Practice Guideline.” J Clin Endocrinol Metab 103.11 (2018): 4043–88. DOI: 10.1210/jc.2018-01865
  52. Speiser, P.W., Azziz, R., Baskin, L.S., et al. “Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline.” J Clin Endocrinol Metab 95.9 (2010): 4133–60. DOI: 10.1210/jc.2009-2631
  53. Witchel, S.F., Azziz, R. “Nonclassic Congenital Adrenal Hyperplasia.” Int J Pediatr Endocrinol 1 (2010): 1–11. DOI: 10.1155/2010/625105
  54. Jha, S., Turcu, A.F. “Nonclassic Congenital Adrenal Hyperplasia: What Do Endocrinologists Need to Know?” Endocrinol Metab Clin 50.1 (2021): 151–65. DOI: 10.1016/J.ECL.2020.10.008
  55. Papadakis, G., Kandaraki, E.A., Tseniklidi, E., et al. “Polycystic ovary syndrome and NC-CAH: Distinct characteristics and common findings. A systematic review.” Front Endocrinol (Lausanne) 10 (2019): 388. DOI: 10.3389/FENDO.2019.00388
  56. Hannah-Shmouni, F., Morissette, R., Sinaii, N., et al. “Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians.” Genet Med 19.11 (2017): 1276–9. DOI: 10.1038/GIM.2017.46
  57. Carmina, E., Dewailly, D., Escobar-Morreale, H.F., et al. “Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women.” Hum Reprod Update. 23.5 (2017): 580–99. DOI: 10.1093/HUMUPD/DMX014
  58. Bidet, M., Bellanné-Chantelot, C., Galand-Portier, M.B., et al. “Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.” J Clin Endocrinol Metab 95.3 (2010): 1182–90. DOI: 10.1210/JC.2009-1383
  59. Macut, D., Ilić, D., Mitrović Jovanović, A., Bjekić-Macut, J. “Androgen-Secreting Ovarian Tumors.” Frontiers Horm Res 53 (2019): 100–7. DOI: 10.1159/000494906
  60. Pasquali, R., Pignatelli, D. “Hyperandrogenism in women: beyond polycystic ovary syndrome.” Front Horm Res 53 (2019): I–0. DOI: 10.1159/000494912
  61. Libé, R., Coste, J., Guignat, L., et al. “Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing’s syndrome.” Eur J Endocrinol 163.1 (2010): 129–38. DOI: 10.1530/EJE-10-0195
  62. Terzolo, M., Osella, G., Alì, A., et al. “Different patterns of steroid secretion in patients with adrenal incidentaloma.” J Clin Endocrinol Metab 81.2 (1996): 740–4. DOI: 10.1210/JCEM.81.2.8636297
  63. Ramkumar, S., Jyotsna, V.P., Mallick, S., et al. “Bilateral thecoma presenting as premenopausal hirsutism: Laproscopic removal.” Indian J Endocrinol Metab 17.3 (2013): S662. DOI: 10.4103/2230-8210.123561
  64. Iravanloo, G., Nozarian, Z., Sarrafpour, B., Motahhary, P. “Sclerosing stromal tumor of the ovary.” Obstet Gynecol Sci 57.5 (2014): 405. DOI: 10.5468/OGS.2014.57.5.405
  65. Meczekalski, B., Szeliga, A., Maciejewska-Jeske, M., et al. “Hyperthecosis: an underestimated nontumorous cause of hyperandrogenism. Gynecol Endocrinol 37.8 (2021): 677–82. DOI: 10.1080/09513590.2021.1903419
  66. Pivonello, R., Isidori, A.M., De Martino, M.C., et al. “Complications of Cushing’s syndrome: state of the art.” Lancet Diabetes Endocrinol 4.7 (2016): 611–29. DOI: 10.1016/S2213-8587(16)00086-3
  67. Shlomo Melmed Acromegaly. Pituitary (2017): 423–66. DOI: 10.1016/B978-0-12-804169-7.00015-5
  68. Delcour, C., Robin, G., Young, J., Dewailly, D. “PCOS and Hyperprolactinemia: what do we know in 2019?” Clin Med Insights Reprod Heal 13 (2019): 117955811987192. DOI: 10.1177/1179558119871921
  69. Herzog, A.G. “Disorders of reproduction in patients with epilepsy.” Zeitschrift für Epileptol 28.4 (2015): 254–63. DOI: 10.1007/s10309-015-0012-7
  70. Markopoulos, M.C., Kassi, E., Alexandraki, K.I., et al. “Hyperandrogenism after menopause.” Eur J Endocrinol 172.2 (2015): R79–91. DOI: 10.1530/EJE-14-0468
  71. Davis, S.R., Baber, R., Panay, N., et al. “Global Consensus Position Statement on the Use of Testosterone Therapy for Women.” J Clin Endocrinol Metab 104.10 (2019): 4660–6. DOI: 10.1210/JC.2019-01603
  72. Rosner, W., Auchus, R.J., Azziz, R., et al. “Utility, Limitations, and Pitfalls in Measuring Testosterone: An Endocrine Society Position Statement.” J Clin Endocrinol Metab 92.2 (2007): 405–13. DOI: 10.1210/JC.2006-1864

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2022-05-27

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Tutchenko, T., Burka, O., Sidorova, I., Nohovska, I., Marynchyna, I., & Shcherbatiei, N. (2022). Practical approaches to the use of markers of biochemical hyperandrogenism in women: Literature review. REPRODUCTIVE ENDOCRINOLOGY, (63-64), 25–33. https://doi.org/10.18370/2309-4117.2022.63.25-33

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No. 63-64 (2022)

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Endocrinology

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Copyright (c) 2022 Т.М. Тутченко, О.А. Бурка, І.В. Сідорова, I.Г. Ноговська, І.М. Маринчина, Н.М. Щербатєй

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