Contemporary approaches to the diagnosis of hyperprolactinemia




hyperprolactinemia, prolactinoma, hormone-secreting pituitary adenomas, macroprolactin, stress, hypothyroidism


Hyperprolactinemia (HP) is a persistent prolactin increase in serum. HP is a common endocrinopathy that impairs reproductive function, long term HP may lead to the metabolic disorders and a decrease in bone mineral density.

Prolactin increase may be result of many physiological and pathological conditions, the diagnosis of which directly affects treatment approaches.

Evaluation of prolactin is not only the basis for the HP diagnosis but also an indirect indicator of its cause. For this reason it is important to recognize the possible difficulties in the

HP diagnosis associated with the following factors: pulsate nature of prolactin secretion; sensitivity to various exogenous and endogenous factors; presence of various molecular prolactin forms (macroprolactinemia) and rare laboratory artifacts (hook effect). Laboratory studies are also used to evaluate other endocrinopathies that can be the primary HP cause (hypothyroidism) or coexisting conditions (mixed pituitary adenomas, polycystic ovary syndrome). Stress-induced HP has to be differentiated from physiological HP via repeated prolactin tests is gaining increasing clinical importance.

The article provides an overview of modern research and relevant clinical guidelines for the diagnosis of various HP causes and offers an algorithmic approach for this clinical problem, the main principles are: to exclude iatrogenic causes, pregnancy and hypothyroidism at the initial stage of diagnosis; in the absence of neuroophthalmic symptoms and prolactin levels under 50–80 ng/ml repeated prolactin testing may be necessary to exclude physiological HP; screening for macroprolactinemia in all cases of prolactin level under of 200 ng/ml allows diagnosing macroprolactinemia or non-functioning pituitary adenoma; if MRT shows on macroprolactinoma and/or there are neuroophthalmic symptoms in combination with a normal or slightly elevated prolactin level it is necessary to exclude possible hook effect; in order to exclude mixed pituitary adenomas based on clinical features it is necessary to evaluate growth hormone, insulin-like growth factor 1, adrenocorticotrophic and thyroid-stimulating hormones in addition to prolactin

Author Biographies

О. А. Бурка, О.О. Bogomolets National Medical University; “DILA” Medical Laboratory, Kyiv

PhD, associate professor of the Obstetrics and Gynecology Department No. 1;

scientific consultant

Т. М. Тутченко, SI “O.M. Lukyanova IPOG of the NAMS of Ukraine”; “DILA” Medical Laboratory, Kyiv

PhD, senior researcher of the Endocrine Gynecology Department;

Scientific consultant


  1. Tronko, M.D., Antypkin, Y.G., Kaminskyi, V/V/, et al. “National consensus on Management of Patients with Hyperprolactinemia.” Reproductive Endocrinology 4.30 (2016): 8–18.
  2. Melmed, S., Casanueva, F.F., Hoffman, A.R., et al. “Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline.” J Clin Endocrinol Metab 96 (2011): 273–88. doi:10.1210/jc.2010-1692
  3. Chiloiro, S., Giampietro, A., Bianchi, A., De Marinis, L. “Prolactinoma and Bone.” Curr Opin Endocr Metab Res 3 (2018): 21–4. doi:10.1016/J.COEMR.2018.02.006
  4. Ben-Jonathan, N., Hugo, E.R., Brandebourg, T.D., LaPensee, C.R. “Focus on prolactin as a metabolic hormone.” Trends Endocrinol Metab 17 (2006): 110–6. doi:10.1016/J.TEM.2006.02.005
  5. Vilar, L., Abucham, J., Albuquerque, J.L., et al. “Controversial issues in the management of hyperprolactinemia and prolactinomas – An overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism.” Arch Endocrinol Metab 62 (2018): 236–63. doi:10.20945/2359-3997000000032
  6. Tirosh, A., Shimon, I. “Management of macroprolactinomas.” Clin Diabetes Endocrinol 1 (2015): 5. doi:10.1186/s40842-015-0006-4
  7. Pekić, S., Medic Stojanoska, M., Popovic, V. “Hyperprolactinemia/Prolactinomas in the Postmenopausal Period: Challenges in Diagnosis and Management.” Neuroendocrinology 109 (2019): 28–33. doi:10.1159/000494725
  8. Matalliotakis, M., Koliarakis, I., Matalliotaki, C., et al. “Clinical manifestations, evaluation and management of hyperprolactinemia in adolescent and young girls: a brief review.” Acta Biomed 90 (2019): 149–57. doi:10.23750/abm.v90i1.8142
  9. Hughes, E.G., Garner, P.R. “Primary amenorrhea associated with hyperprolactinemia:
  10. Coulam, C.B., Laws, E.R., Abboud, C.F., Randall, R.V. “Primary amenorrhea and pituitary adenomas.” Fertil Steril 35 (1981): 615–9. doi:10.1016/S0015-0282(16)45551-2
  11. Freeman, M.E., Kanyicska, B., Lerant, A., Nagy, G.“Prolactin: Structure, Function, and Regulation of Secretion.” Physiol Rev 80 (2000): 1523–1631. doi:10.1152/physrev.2000.80.4.1523
  12. Grattan, D.R., Kokay, I.C. “Prolactin: A Pleiotropic Neuroendocrine Hormone.” J Neuroendocrinol 20 (2008): 752–63. doi:10.1111/j.1365-2826.2008.01736.x
  13. Tritos, N.A., Klibanski, A. “Prolactin and Its Role in Human Reproduction.” Yen Jaffe’s Reprod Endocrinol (2019): 58–74.e8. doi:10.1016/B978-0-323-47912-7.00003-2
  14. Mancini, T., Casanueva, F.F., Giustina, A. “Hyperprolactinemia and Prolactinomas.” Endocrinol Metab Clin North Am 37 (2008): 67–99. doi:10.1016/j.ecl.2007.10.013
  15. Ciccarelli, A., Daly, A.F., Beckers, A. “The Epidemiology of Prolactinomas.” Pituitary 8 (2005): 3–6. doi:10.1007/s11102-005-5079-0
  16. Pivonello, R., Salzano, C., Galdiero, M., Colao, A. “Male Hypogonadism Due to Disorders of the Pituitary and Suprasellar Region.” In: Male Hypogonadism. Springer International Publishing. Cham (2017): 169–86. doi:10.1007/978-3-319-53298-1_8
  17. Corona, G., Mannucci, E., Fisher, A.D., et al. “Effect of Hyperprolactinemia in Male Patients Consulting for Sexual Dysfunction.” J Sex Med 4 (2007): 1485–93. doi:10.1111/j.1743-6109.2007.00569.x
  18. Molitch, M.E. “Diagnosis and Treatment of Pituitary Adenomas.” JAMA 317 (2017): 516. doi:10.1001/jama.2016.19699
  19. Voogt, J.L., Lee, Y., Yang, S., Arbogast, L. “Chapter 12. Regulation of prolactin secretion during pregnancy and lactation.” Prog Brain Res 133 (2001): 173–85. doi:10.1016/S0079-6123(01)33013-3
  20. Glezer, A., Bronstein, M.D. “The Pituitary Gland in Pregnancy.” Pituitary (2017): 397–411. doi:10.1016/B978-0-12-804169-7.00013-1.
  21. Levine, S., Muneyyirci-Delale, O. “Stress-Induced Hyperprolactinemia: Pathophysiology and Clinical Approach.” Obstet Gynecol Int 2018 (2018): 9253083. doi:10.1155/2018/9253083
  22. La Torre, D., Falorni, A. “Pharmacological causes of hyperprolactinemia.” Ther Clin Risk Manag 3 (2007): 929–51. Available from: [], last accessed Oct 17, 2019.
  23. Molitch, M.E. “Drugs and prolactin.” Pituitary 11 (2008): 209–18. doi:10.1007/s11102-008-0106-6
  24. Vilar, L., Vilar, C.F., Lyra, R., et al. “Pitfalls in the Diagnostic Evaluation of Hyperprolactinemia.” Neuroendocrinology 109 (2019): 7–19. doi:10.1159/000499694
  25. Ajmal, A., Joffe, H., Nachtigall, L.B. “Psychotropic-Induced Hyperprolactinemia: A Clinical Review.” Psychosomatics 55 (2014): 29–36. doi:10.1016/J. PSYM.2013.08.008
  26. Falkai, P., Wobrock, T., Lieberman, J., et al. “Guidelines for Biological Treatment of Schizophrenia, Part 1: Acute treatment of schizophrenia.” World J Biol Psychiatry 6 (2005): 132–91. doi:10.1080/15622970510030090
  27. Reeves, K.W., Okereke, O.I., Qian, J., et al. “Antidepressant use and circulating prolactin levels.” Cancer Causes Control 27 (2016): 853–61. doi:10.1007/s10552-016-0758-x
  28. Petrikis, P., Tigas, S., Tzallas, A.T., et al. “Prolactin levels in drug-naïve patients with schizophrenia and other psychotic disorders.” Int J Psychiatry Clin Pract 20 (2016): 165–9. doi:10.1080/13651501.2016.1197274
  29. Praharaj, S.K. “Euprolactinemic Galactorrhea With Escitalopram.” J Neuropsychiatry Clin Neurosci 26 (2014): E25–E26. doi:10.1176/appi.neuropsych.13070147
  30. Nebhinani, N. “Sertraline-induced galactorrhea: case report and review of cases reported with other SSRIs.” Gen Hosp Psychiatry 35 (2013): 576. e3-576.e5. doi:10.1016/J.GENHOSPPSYCH.2012.10.010
  31. Montejo, Á.L., Arango, C., Bernardo, M., et al. “Multidisciplinary consensus on the therapeutic recommendations for iatrogenic hyperprolactinemia secondary to antipsychotics.” Front Neuroendocrinol 45 (2017): 25–34. doi:10.1016/J. YFRNE.2017.02.003
  32. Jabbar, A., Khan, R., Farrukh, S.N. “Hyperprolactinaemia induced by proton pump inhibitor.” J Pak Med Assoc 60 (2010): 689–90. Available from: [http://www.ncbi.], last accessed Oct 16, 2019.
  33. Romeo, J.H., Dombrowski, R., Kwak, Y.S., et al. “Hyperprolactinaemia and verapamil: prevalence and potential association with hypogonadism in men.” Clin Endocrinol (Oxf) 45 (1996): 571–5. doi:10.1046/j.1365-2265.1996.00859.x
  34. Kelley, S.R., Kamal, T.J., Molitch, M.E. “Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia.” Am J Physiol 270 (1996): E96–100. doi:10.1152/ajpendo.1996.270.1.E96
  35. Baldini, M., Cornelli, U., Molinari, M., Cantalamessa, L. “Effect of methyldopa on prolactin serum concentration.” Eur J Clin Pharmacol 34 (1988): 513–5. doi:10.1007/BF01046712
  36. Murai, L., Ben-Jonathan, N. “Acute Stimulation of Prolactin Release by Estradiol: Mediation by the Posterior Pituitary.” Endocrinology 126 (1990): 3179–84. doi:10.1210/endo-126-6-3179
  37. Luciano, A.A., Sherman, B.M., Chapler, F.K., et al. “Hyperprolactinemia and contraception: a prospective study.” Obstet Gynecol 65 (1985): 506–10. Available from: [http://www.], last accessed Oct 17, 2019.
  38. Davis, J.R.E., Selby, C., Jeffcoate, W.J. “Oral contraceptive agents do not affect serum prolactin in normal women.” Clin Endocrinol (Oxf) 20 (1984): 427–34. doi:10.1111/j.1365-2265.1984.tb03438.x
  39. Foth, D., Römer, T. “Prolactin Serum Levels in Postmenopausal Women Receiving Long-Term Hormone Replacement Therapy.” Gynecol Obstet Invest 44 (1997): 124–6. doi:10.1159/000291502
  40. Schlegel, W., Petersdorf, L.I., Junker, R., et al. “The effects of six months of treatment with a low-dose of conjugated oestrogens in menopausal women.” Clin Endocrinol (Oxf) 51 (1999): 643–51. doi:10.1046/j.1365-2265.1999.00857.x
  41. Cicero, T.J. “Neuroendocrinological Effects of Alcohol.” Annu Rev Med 32 (1981): 123–42. doi:10.1146/
  42. Vilar, L., Freitas, M.C., Naves, L.A., et al. “Diagnosis and management of hyperprolactinemia: Results of a Brazilian multicenter study with 1234 patients.” J Endocrinol Invest 31 (2008): 436–44. doi:10.1007/BF03346388
  43. Cocks Eschler, D., Javanmard, P., Cox, K., Geer, E.B. “Prolactinoma through the female life cycle.” Endocrine 59 (2018): 16–29. doi:10.1007/s12020-017-1438-7
  44. Chanson, P., Maiter, D. “Prolactinoma.” Pituitary (2017): 467–514. doi:10.1016/B978-0-12-804169-7.00016-7
  45. Morselli, L.L., Schlechte, J.A. “Prolactin-Secreting Pituitary Adenomas: Epidemiology
  46. Tjörnstrand, A., Gunnarsson, K., Evert, M., et al. “The incidence rate of pituitary adenomas in western Sweden for the period 2001–2011.” Eur J Endocrinol 171 (2014): 519–26. doi:10.1530/EJE-14-0144
  47. Raappana, A., Koivukangas, J., Ebeling, T., Pirilä, T. “Incidence of Pituitary Adenomas in Northern Finland in 1992–2007.” J Clin Endocrinol Metab 95 (2010): 4268–75. doi:10.1210/jc.2010-0537
  48. Agustsson, T.T., Baldvinsdottir, T., Jonasson, J.G., et al. “The epidemiology of pituitary adenomas in Iceland, 1955–2012: a nationwide population-based study.” Eur J Endocrinol 173 (2015): 655–64. doi:10.1530/EJE-15-0189
  49. Haddad, R.A., Giacherio, D., Barkan, A.L. “Interpretation of common endocrine laboratory tests: technical pitfalls, their mechanisms and practical considerations.” Clin Diabetes Endocrinol 5 (2019): 12. doi:10.1186/s40842-019-0086-7
  50. Krysiak, R., Kowalska, B., Szkróbka, W., Okopień, B. “The effect of oral contraception on macroprolactin levels in women with macroprolactinemia: A pilot study.” Pharmacol Reports 67 (2015): 854–7. doi:10.1016/J.PHAREP.2015.02.001
  51. Kalsi, A.K., Halder, A., Jain, M., et al. “Prevalence and reproductive manifestations of macroprolactinemia.” Endocrine 63 (2019): 332–40. doi:10.1007/s12020-018-1770-6
  52. Dellal, F.D., Ozdemir, D., Aydin, C., et al. “Gigantomastia and Macroprolactinemia Responding to Cabergoline Treatment: A Case Report and Minireview of the Literature.” Case Rep Endocrinol 2016 (2016): 3576024. doi:10.1155/2016/3576024
  53. Krysiak, R., Marek, B., Okopień, B. “Cardiometabolic risk factors in young women with macroprolactinaemia.” Endokrynol Pol 70 (2019): 336–41. doi:10.5603/EP.a2019.0013



How to Cite

Бурка, О. А., & Тутченко, Т. М. (2019). Contemporary approaches to the diagnosis of hyperprolactinemia. REPRODUCTIVE ENDOCRINOLOGY, (49), 35–42.