Acromegaly - Emerging treatments

Oestrogens and selective oestrogen receptor modulators (SERMs)

Oestrogens and selective oestrogen receptor modulators (SERMs) up-regulate the expression of the suppressor of cytokine signalling-2 (SOCS2) in a dose-dependent way. The SOCS2 protein impairs growth hormone (GH)-induced Janus kinase 2 phosphorylation, thus attenuating intracellular GH signalling, and, as a consequence, reduces IGF-1 production. Oestrogens per se, as well as SERMs (e.g., tamoxifen, raloxifene, and clomifene), have all been shown to decrease plasma IGF-1 levels in acromegalic patients, and normalise them in 25% to 50% of cases. It appears that this effect requires rather low biochemical activity of the disease, with pre-treatment IGF-1 levels not exceeding approximately 2.5 fold of the upper limit of normal. In addition, SERMs increase plasma testosterone levels in men. Clinical benefits of oestrogen/SERM therapy in acromegaly have not been assessed, and such studies would be of importance.[49][50][51]

Preoperative treatment of GH-producing somatotropinomas

The issue of preoperative treatment of GH-producing somatotropinomas with somatostatin analogues as a means of improving the efficacy of surgical intervention has been studied extensively in uncontrolled trials with variable results. A single meta-analysis concluded that in randomised, placebo-controlled trials, pre-treatment with somatostatin analogues almost doubled the rate of surgical normalisation of both GH and IGF-1.[52] However, these conclusions should be interpreted with caution. First, the rate of biochemical control in placebo-treated patients was exceedingly low, and the pre-treatment increased it to the level customarily observed in the outcome studies reported by experienced pituitary neurosurgeons. A second meta-analysis, however, could not confirm these conclusions.[53] While initial randomised trials assessed the biochemical control rate in the short term (i.e., 3-4 months), later studies also found higher control rates short term, but failed to document durability of control long term. A potential explanation might be that there was a carry-over effect of long-acting octreotide or lanreotide used preoperatively on the postoperative GH and IGF-1 concentrations. Thus, preoperative therapy is most likely to be useful in patients who do not have access to an expert neurosurgeon and in patients with severe complications (severe pharyngeal thickness and sleep apnoea, or high-output heart failure).[12][54] Long-term beneficial effect of somatostatin analogues preoperative treatment has not been shown.

Paltusotine

Paltusotine, an oral somatostatin receptor type 2 agonist, was effective in maintaining IGF-I values in patients with acromegaly who switched from injectable somatostatin analogue in a phase 2 clinical trial.[55] A phase 3 trial is in progress.[56]

Subcutaneous octreotide depot

A monthly subcutaneous depot formulation of octreotide that has greater bioavailability with faster onset and stronger suppression of IGF-1 compared to long-acting intramuscular octreotide is in phase 3 clinical trials.[57][58]