1. Prolactin-secreting pituitary tumors Rosario Pivonello Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy

2. Prolactinomas are the most frequent pituitary tumors,with an estimated prevalence in the adult population of 100 per million population Their frequency varies with age and sex, occurring most frequently in females between 20 and 50 yr old, when the ratio between the sexes is estimated to be 10:1. After the fifth decade of life, the frequency of prolactinomas is similar in both sexes. Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. Epidemiology

3. Clinical presentation Women Galactorrhea Oligo-amenhorrea Infertility Hypogonadism Smaller tumors Men Galactorrhea Decreased libido Erectyle dysfunction Hypogonadism Larger tumors Both Headache Visual impairment

9.  Tumor removal, preservation of normal residual function, and prevention of recurrences  Restoration of normal secretion  Relief of symptoms directly caused by PRL excess  Prevention of complications (hypogonadism, osteoporosis) Colao and Lombardi. Lancet. 1998;352:1455.

10. Patients With Micro-, Macroadenomas, and Idiopathic Hyperprolactinemia Primarily Treated With Various Dopamine Agonists Dopamine AgonistTotal No. With Normal PRL % With Normal PRL Bromocriptine 1 99775776 Pergolide 2 988587 Cabergoline 3 61254489 1. Fossati, Friesen, Bergh, Badano, Crosignani, Horowitz, Molitch, Liuzzi, van der Heijden, Brue, Webster, Pascal-V, Pinzone, DiSarno, Sabuncu. 2. Horowitz, Kleinberg, L’Hermite, Freda. 3. Ferrari, Ferrari, Webster, Pascal-V, Muratori, Verhelst, Pinzone, Di Sarno, Sabuncu.

11. Efficacy in PRL Normalization and Tumor Size in Patients With Macroprolactinoma Bromocriptine (n=27) 1 Pergolide (n=22) 2 Cabergoline (n=26) 3 Baseline PRL (µg/L) 226029381013 Normal PRL (% of pts) 6668100 ≥50% tumor shrinkage (% of pts) 648696 Time of assessment (mo) 12 mo27 mo24 mo 1. Molitch et al. J Clin Endocrinol Metab. 1985;60:698; 2. Freda et al. J Clin Endocrinol Metab. 2000;85:8; 3. Colao et al. J Clin Endocrinol Metab. 2000;85:2247.

12. Basal 1180 μg/L 1 week 550 μg/L 4 weeks 55 μg/L Early Changes of Prolactinomas After Cabergoline

13. Basal 1 week 1 month

14. Remission after cabergoline withdrawal

15. 32% (Koppelman et al. Ann Intern Med. 1984;100:115) 33% (Jeffcoate et al. Clin Endocrinol (Oxf). 1996;45:299) 35% (Schlechte et al. J Clin Endocrinol Metab. 1989;68:412) >55% (Sisam et al. Fertil Steril. 1987;48:67)

16.  Normalization of PRL levels  Tumor size at MRI  No tumor  Residual tumor but ≥50% tumor reduction of baseline size in presence of a ≥5 mm distance from optic chiasm and in the absence of invasion of one or both cavernous sinuses or any other cerebral area  Follow-up after withdrawal at least 24 months Cabergoline Withdrawal: Inclusion Criteria Colao et al. N Engl J Med. 2003;349:2023.

17. Recurrence rate 01224364860 0 25 50 75 100 NTH Micro MRI negative Remnant micro Macro MRI negative Remnant macro P=0.0009 Months Recurrence of hyperprolactinemia after withdrawal (%) Colao et al. N Engl J Med. 2003;349:2023.

18. Summary  Recurrence after cabergoline withdrawal was low in patients achieving tumor disappearance and did not differ in NTH (24%), micro-(26.2%) and macroprolactinomas (32.6%)  Recurrence of hyperprolactinemia was higher in patients still presenting small remnant tumors at MRI (41.5% in micro- and 77.5% in macroprolactinomas)  In no case of recurrence of hyperprolactinemia did tumor regrow or symptoms reappear Colao et al. N Engl J Med. 2003;349:2023.

20. Cardiac valve regurgitation after cabergoline withdrawal

24. Colao et al., JCEM 2008

27. No controversies on macroprolactinomas: 1st treatment is pharmacotherapy (cabergoline). Surgery indicated in patients with resistant adenomas In young patients with microprolactinoma, the surgical choice should be offered based on the high likelihood of definitive cure (risk of tricuspid regurgitation!) Patients fully responsive to bromocriptine or cabergoline who showed the disappearance of the tumor in MRI could be withdrawn from the drug and followed up. There is an increased risk for asymptomatic tricuspid regurgitation that should be investigated more carefully Conclusions

28. Thanks