New Medical Approaches in Pituitary Adenomas

Abstract

Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5–1.0 μg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D₂ receptors using specific radiotracers such as ¹²³I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing’s disease or Nelson’s syndrome.

Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion

“…These data would indicate a stimulatory role for SSTR5 in NFA cell proliferation, suggesting that the use of compounds selectively interacting with SSTR5 in NFA medical therapy might be counterproductive. In addition, this effect might account for the lack of volume reduction (Colao et al 2000, Andersen et al 2001 or the increase in tumor volume (Gasperi et al 1993) observed in NFA patients treated with octreotide or lanreotide, which mainly interacts with SSTR2 and SSTR5. However, this does not seem to be a general mechanism in pituitary adenomas, because previous evidence from somatotroph and corticotroph pituitary tumors suggests that the additional activation of SSTR5 might be responsible for the enhanced efficacy of SRIF analogs in reducing both secretion and cell proliferation (Shimon et al 1997, Hofland et al 2005.…”

In vitro testing of new somatostatin analogs on pituitary tumor cells

“…On the contrary, our data show that the SSTR2 selective agonist did not influence NFA cell viability, which was promoted by the SSTR5 selective agonist. This effect might explain the lack of efficacy of medical treatment by means of octreotide or Lan, compounds mainly interacting with SSTR2 and less with SSTR5, in some NFA (Oppizzi et al 1998, Andersen et al 2001, Colao et al 2000, Gasperi et al 1993. Moreover, our findings might provide a possible …”

Treatment options for Cushing disease after unsuccessful transsphenoidal surgery

“…Side effects from this drug include GI distress and gynecomastia, occurring in fewer than 15% of patients. 19,50 Elevated levels of hepatic transaminases are also common, thus requiring periodic monitoring of liver function tests. Because of its favorable adverse effect profile, twice-daily dosing, and relative effectiveness as a single-agent therapy, ketoconazole has emerged as the agent of choice for the medical treatment of Cushing disease.…”