Endocrinol Metab.  2024 Dec;39(6):819-826. 10.3803/EnM.2024.2057.

Elucidating Clinical Queries for Tailored Therapy in Patients with Prolactinoma

• Lee MH
• Hong JW
• Kim K
• Ku CR
• Lee EJ

• KMID: 2562708
• DOI: http://doi.org/10.3803/EnM.2024.2057

Abstract

Prolactinomas are the most prevalent type of pituitary neuroendocrine adenomas, primarily affecting women of reproductive age. Unlike other pituitary tumors, the first-line management has traditionally been pharmacological rather than surgical. This preference is due to the effectiveness of dopamine agonists (DAs), which typically reduce tumor size and normalize prolactin levels in most patients. However, this does not imply that there is no room for improvement; the duration of treatment and medication side effects often lead to compliance issues among patients. Recent advances in surgical techniques and molecular biology have paved the way for the development of precision medicine, allowing for more flexible and personalized treatment strategies for prolactinomas. This review aims to enhance clinical decision-making and patient care for endocrinologists by focusing on several key factors: predictive markers of DA sensitivity, clinical characteristics and suitability for transsphenoidal adenomectomy as a potential first-line treatment, factors determining the successful withdrawal of DAs after prolonged use, safety concerns during pre/post-pregnancy and breastfeeding, and determinants of tumor aggressiveness. Through tailored therapy—a patient-focused, multidisciplinary approach— we aim to improve the management of prolactinoma patients.

Keyword

Prolactinoma; Precision medicine; Clinical decision-making

Figure

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  Fig. 1. Presentative biomarkers of sensitivity to dopamine agonists in patients with prolactinomas. DA, dopamine agonist; PRL, prolactin; CS, cavernous sinus; D2R, dopamine 2 receptor; GRK2, G protein-coupled receptor kinase 2; ERα, estrogen receptor alpha; TSA, transsphenoidal adenomectomy; PTTG, pituitary tumor-transforming gene.

Reference

1. Park JS, Yun SJ, Lee JK, Park SY, Chin SO. Descriptive epidemiology and survival analysis of prolactinomas and Cushing’s disease in Korea. Endocrinol Metab (Seoul). 2021; 36:688–96.

2. Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD, et al. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf). 2006; 65:265–73.

3. Colao A, Sarno AD, Cappabianca P, Briganti F, Pivonello R, Somma CD, et al. Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia. Eur J Endocrinol. 2003; 148:325–31.

4. Kim D, Ku CR, Kim K, Jung H, Lee EJ. Prolactin ≤1 ng/ mL predicts macroprolactinoma reduction after cabergoline therapy. Eur J Endocrinol. 2020; 182:177–83.

5. Ku CR, Melnikov V, Zhang Z, Lee EJ. Precision therapy in acromegaly caused by pituitary tumors: how close is it to reality? Endocrinol Metab (Seoul). 2020; 35:206–16.

6. Raverot G, Wierinckx A, Dantony E, Auger C, Chapas G, Villeneuve L, et al. Prognostic factors in prolactin pituitary tumors: clinical, histological, and molecular data from a series of 94 patients with a long postoperative follow-up. J Clin Endocrinol Metab. 2010; 95:1708–16.

7. Hong JW, Lee MK, Kim SH, Lee EJ. Discrimination of prolactinoma from hyperprolactinemic non-functioning adenoma. Endocrine. 2010; 37:140–7.

8. Kim HK, Hong JW, Moon JH, Ahn SS, Kim EH, Lee SK, et al. Efficacy and cerebrospinal fluid rhinorrhea after cabergoline treatment in patients with bioactive macroprolactinoma. Cancers (Basel). 2021; 13:5374.

9. Lee Y, Ku CR, Kim EH, Hong JW, Lee EJ, Kim SH. Early prediction of long-term response to cabergoline in patients with macroprolactinomas. Endocrinol Metab (Seoul). 2014; 29:280–92.

10. Liu Y, Wu J, Yan G, Hou R, Zhuang D, Chen L, et al. Proteomic analysis of prolactinoma cells by immuno-laser capture microdissection combined with online two-dimensional nano-scale liquid chromatography/mass spectrometry. Proteome Sci. 2010; 8:2.

11. Park YW, Eom J, Kim S, Kim H, Ahn SS, Ku CR, et al. Radiomics with ensemble machine learning predicts dopamine agonist response in patients with prolactinoma. J Clin Endocrinol Metab. 2021; 106:e3069–77.

12. Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017; 317:516–24.

13. Shimazu S, Shimatsu A, Yamada S, Inoshita N, Nagamura Y, Usui T, et al. Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels. Eur J Endocrinol. 2012; 166:383–90.

14. Colao A, Savastano S. Medical treatment of prolactinomas. Nat Rev Endocrinol. 2011; 7:267–78.

15. Kim K, Park YW, Kim D, Ahn SS, Moon JH, Kim EH, et al. Biochemical remission after cabergoline withdrawal in hyperprolactinemic patients with visible remnant pituitary adenoma. J Clin Endocrinol Metab. 2021; 106:e615–24.

16. Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BM, et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international consensus statement. Nat Rev Endocrinol. 2023; 19:722–40.

17. Sanchez-Soto M, Boldizsar NM, Schardien KA, Madaras NS, Willette BK, Inbody LR, et al. G protein-coupled receptor kinase 2 selectively enhances β-arrestin recruitment to the D2 dopamine receptor through mechanisms that are independent of receptor phosphorylation. Biomolecules. 2023; 13:1552.

18. Gillam MP, Molitch ME, Lombardi G, Colao A. Advances in the treatment of prolactinomas. Endocr Rev. 2006; 27:485–534.

19. Glezer A, Bronstein MD. Prolactinomas in pregnancy: considerations before conception and during pregnancy. Pituitary. 2020; 23:65–9.

20. Ricci E, Parazzini F, Motta T, Ferrari CI, Colao A, Clavenna A, et al. Pregnancy outcome after cabergoline treatment in early weeks of gestation. Reprod Toxicol. 2002; 16:791–3.

21. Krupp P, Monka C. Bromocriptine in pregnancy: safety aspects. Klin Wochenschr. 1987; 65:823–7.

22. Glezer A, Bronstein MD. Prolactinomas. Endocrinol Metab Clin North Am. 2015; 44:71–8.

23. Cocks Eschler D, Javanmard P, Cox K, Geer EB. Prolactinoma through the female life cycle. Endocrine. 2018; 59:16–29.

24. Molitch ME. Endocrinology in pregnancy: management of the pregnant patient with a prolactinoma. Eur J Endocrinol. 2015; 172:R205–13.

25. Expert Panel on MR Safety; Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG Jr, et al. ACR guidance document on MR safe practices: 2013. J Magn Reson Imaging. 2013; 37:501–30.

26. Trouillas J, Delgrange E, Wierinckx A, Vasiljevic A, Jouanneau E, Burman P, et al. Clinical, pathological, and molecular factors of aggressiveness in lactotroph tumours. Neuroendocrinology. 2019; 109:70–6.

27. Molitch ME. Prolactinoma in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011; 25:885–96.

28. Domingue ME, Devuyst F, Alexopoulou O, Corvilain B, Maiter D. Outcome of prolactinoma after pregnancy and lactation: a study on 73 patients. Clin Endocrinol (Oxf). 2014; 80:642–8.

29. Zarate A, Canales ES, Alger M, Forsbach G. The effect of pregnancy and lactation on pituitary prolactin-secreting tumours. Acta Endocrinol (Copenh). 1979; 92:407–12.

30. Holmgren U, Bergstrand G, Hagenfeldt K, Werner S. Women with prolactinoma: effect of pregnancy and lactation on serum prolactin and on tumour growth. Acta Endocrinol (Copenh). 1986; 111:452–9.

31. Auriemma RS, Perone Y, Di Sarno A, Grasso LF, Guerra E, Gasperi M, et al. Results of a single-center observational 10-year survey study on recurrence of hyperprolactinemia after pregnancy and lactation. J Clin Endocrinol Metab. 2013; 98:372–9.

32. Jeffcoate WJ, Pound N, Sturrock ND, Lambourne J. Long-term follow-up of patients with hyperprolactinaemia. Clin Endocrinol (Oxf). 1996; 45:299–303.

33. Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96:273–88.

34. Dekkers OM, Lagro J, Burman P, Jorgensen JO, Romijn JA, Pereira AM. Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta-analysis. J Clin Endocrinol Metab. 2010; 95:43–51.

35. Hu J, Zheng X, Zhang W, Yang H. Current drug withdrawal strategy in prolactinoma patients treated with cabergoline: a systematic review and meta-analysis. Pituitary. 2015; 18:745–51.

36. Kharlip J, Salvatori R, Yenokyan G, Wand GS. Recurrence of hyperprolactinemia after withdrawal of long-term cabergoline therapy. J Clin Endocrinol Metab. 2009; 94:2428–36.

37. Huda MS, Athauda NB, Teh MM, Carroll PV, Powrie JK. Factors determining the remission of microprolactinomas after dopamine agonist withdrawal. Clin Endocrinol (Oxf). 2010; 72:507–11.

38. Colao A, Di Sarno A, Cappabianca P, Di Somma C, Pivonello R, Lombardi G. Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med. 2003; 349:2023–33.

39. Kim EH, Kim J, Ku CR, Lee EJ, Kim SH. Surgical treatment of prolactinomas: potential role as a first-line treatment modality. Yonsei Med J. 2023; 64:489–96.

40. Lee GY, Kim SH, Kim EH. Role of immediate postoperative prolactin measurement in female prolactinoma patients: predicting long-term remission after complete tumor removal. Brain Tumor Res Treat. 2023; 11:204–9.

41. Honegger J, Nasi-Kordhishti I, Aboutaha N, Giese S. Surgery for prolactinomas: a better choice? Pituitary. 2020; 23:45–51.

42. Tampourlou M, Trifanescu R, Paluzzi A, Ahmed SK, Karavitaki N. Therapy of endocrine disease: surgery in microprolactinomas: effectiveness and risks based on contemporary literature. Eur J Endocrinol. 2016; 175:R89–96.

43. Jethwa PR, Patel TD, Hajart AF, Eloy JA, Couldwell WT, Liu JK. Cost-effectiveness analysis of microscopic and endoscopic transsphenoidal surgery versus medical therapy in the management of microprolactinoma in the United States. World Neurosurg. 2016; 87:65–76.

44. Lasolle H, Ilie MD, Raverot G. Aggressive prolactinomas: how to manage? Pituitary. 2020; 23:70–7.

45. Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab. 1999; 84:761–7.

46. Roche M, Wierinckx A, Croze S, Rey C, Legras-Lachuer C, Morel AP, et al. Deregulation of miR-183 and KIAA0101 in aggressive and malignant pituitary tumors. Front Med (Lausanne). 2015; 2:54.