Approach to the Patient With Prolactinoma

Abstract

Prolactinomas are the most common pituitary tumor histotype, with microprolactinomas being prevalent in women and macroprolactinomas in men. Hyperprolactinemia is among the most common causes of hypogonadotropic hypogonadism in both sexes, prompting medical advice for hypogonadism (infertility, oligo-amenorrhea, impotence, osteoporosis/osteopenia) in both sexes, and for signs and symptoms of mass effects (hypopituitarism, visual loss, optic chiasm compression, cranial nerve deficits, headaches) predominantly in men. Diagnostic workup involves a single prolactin measurement and pituitary imaging, but some laboratory artifacts (ie, the "hook effect" and macroprolactin) can complicate or delay the diagnosis. The treatment of choice for prolactinomas is represented by dopamine agonists, mainly cabergoline, which are able to induce disease control, restore fertility in both sexes, and definitively cure one-third of patients, thus permitting treatment discontinuation. Pregnancy and menopause may promote spontaneous prolactin decline and anticipate cabergoline discontinuation in women. Surgery and/or radiotherapy are indicated in case of resistance to cabergoline not overcome by the increase in drug dose up to the maximally tolerated or the patient's personal choice of surgery. The evidence of resistance to cabergoline in invasive and proliferative tumors may indicate biological aggressiveness, thus requiring alternative therapeutic approaches mainly based on temozolomide use as monotherapy or combined with radiotherapy. In uncontrolled patients, new medical approaches (alternative hormonal treatments, cytotoxic drugs, peptide receptor radionuclide therapy, mTOR/Akt inhibitors, tyrosine kinase inhibitors, or immunotherapy) may be offered but the experience collected to date is still very scant. This article reviews different facets of prolactinomas and discusses approaches to the condition in more common clinical situations.

Keywords: cabergoline; dopamine agonists; hyperprolactinemia; menopause; pituitary tumor; pregnancy; prolactin; treatment withdrawal.

Figure 1.

Clinical characteristics of patients with prolactinoma. Pituitary tumor per se exerts several compressive mass effects, leading to headache, visual field defects, and hypopituitarism. Prolactin excess results in both sexes in weight gain, delayed pubertal development, hypogonadism, infertility, galactorrhea, and osteopenia or osteoporosis. Other signs and symptoms are gender-related and include in men libido reduction, erectile dysfunction, and gynecomastia; in women, oligo-amenorrhea, vaginal dryness, irritability, and depression. Created with Biorender.com.

Figure 2.

Diagnostic workup for hyperprolactinemia. Scarceness or absence of the peculiar clinical syndrome of PRL excess in patients with PRL levels <250 μg/L should suggest the screening for macroprolactin before performing a pituitary MRI (left). In patients with overt clinical syndrome of PRL excess and PRL values >250 μg/L, the diagnosis of a prolactinoma can be ruled in and a pituitary gadolinium-enhanced MRI is strongly recommended (right), to investigate for the presence of a microadenoma or a macroadenoma. Discrepancy between PRL levels and tumor size, particularly in case of tumor size > 3 cm, should suggest a potential hook effect and requires the reassessment of the sample with serum dilution (at least 1:100, middle). Created with Biorender.com.

Figure 3.

Biochemical and radiological evolution of clinical case 1. The left panel shows changes in PRL levels from diagnosis to the last follow-up. The right panel shows changes in tumor size from the first available MRI to the last follow-up.

Figure 4.

Biochemical and radiological evolution of clinical case 2. The left panel shows changes in PRL levels from diagnosis to the last follow-up. The right panel shows changes in tumor size from the first available MRI to the last follow-up.

Figure 5.

Biochemical and radiological evolution of clinical case 3. The left panel shows changes in PRL levels from diagnosis to the last follow-up. The right panel shows changes in tumor size from the first available MRI to the last follow-up.

Figure 6.

Alternative medical treatment in resistant prolactinoma: molecular mechanisms explored in murine models. Temozolomide elicits cytotoxicity through the methylation of DNA guanine and adenine residues, leading to single- and double-stranded DNA breaks. Prolonged exposure to estrogens induces the growth of lactotroph cells and PRL synthesis, this latter by binding the estrogen receptors (ER) α and β, abundantly expressed on lactotroph cells, and by activating the estrogen responsive elements (ERE) and other transcription factors (TF). Tamoxifen, by competing with estrogens at the receptor site and blocking the promotional role of estrogens, has been shown to prevent tumor growth and suppress PRL synthesis in the rat pituitary gland. Synthetic progestins have been recently investigated as potential treatments for resistant prolactinomas because of their capability to bind the membrane progesterone receptors, by mediating nongenomic progesterone effects, and inducing a rapid DA release by hypothalamic dopaminergic neurons. The consequent binding of DA to D2DR in the rat pituitary lactotrophs might activate TGFβ1 transcription and decreases the adenylate cyclase (AC) and cAMP levels, leading to the inhibition of PRL secretion. Similarly, somatostatin analogues, with high binding affinity to SSTR5, BIM-23268 and pasireotide, and chimeric compounds, binding SSTR5/D2DR, BIM-23A760, have been demonstrated to reduce PRL synthesis by reducing AC and cAMP levels in rat pituitary cell lines. Everolimus, the mTOR inhibitor, by decreasing the downstream molecules p70S6k and 4eBP1, induces cell proliferation inhibition as a consequence of reduced protein synthesis. The blocking of vascular endothelial growth factor (VEGF) by bevacizumab and of epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (HER2) tyrosine kinase phosphorylation by lapatinib and gefitinib inhibits the activation of proliferative signalling. Finally, the blocking of PD-L1 with nivolumab and of CTLA4 with ipilimumab can prevent the immune escape of lactotroph tumor cells. Created with Biorender.com.