Estrogens and selective estrogen receptor modulators (SERMs)
Estrogens and selective estrogen receptor modulators (SERMs) upregulate the expression of the suppressor of cytokine signaling-2 (SOCS2) in a dose-dependent way. The SOCS2 protein impairs growth hormone (GH)-induced Janus kinase 2 phosphorylation, thus attenuating intracellular GH signaling, and, as a consequence, reduces IGF-1 production. Estrogens per se, as well as SERMs (e.g., tamoxifen, raloxifene, and clomiphene), have all been shown to decrease plasma IGF-1 levels in acromegalic patients, and normalize them in 25% to 50% of cases. It appears that this effect requires rather low biochemical activity of the disease, with pretreatment 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 estrogen/SERM therapy in acromegaly have not been assessed, and such studies would be of importance.[50]Stone JC, Clark J, Cuneo R, et al. Estrogen and selective estrogen receptor modulators (SERMs) for the treatment of acromegaly: a meta-analysis of published observational studies. Pituitary. 2014 Jun;17(3):284-95.
http://www.ncbi.nlm.nih.gov/pubmed/23925896?tool=bestpractice.com
[51]Balili I, Barkan A. Tamoxifen as a therapeutic agent in acromegaly. Pituitary. 2014 Dec;17(6):500-4.
http://www.ncbi.nlm.nih.gov/pubmed/24243064?tool=bestpractice.com
[52]Duarte FH, Jallad RS, Bronstein MD. Clomiphene citrate for treatment of acromegaly not controlled by conventional therapies. J Clin Endocrinol Metab. 2015 May;100(5):1863-9.
http://www.ncbi.nlm.nih.gov/pubmed/25738590?tool=bestpractice.com
Preoperative treatment of GH-producing somatotropinomas
The issue of preoperative treatment of GH-producing somatotropinomas with somatostatin analogs 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 randomized, placebo-controlled trials, pretreatment with somatostatin analogs almost doubled the rate of surgical normalization of both GH and IGF-1.[53]Pita-Gutierrez F, Pertega-Diaz S, Pita-Fernandez S, et al. Place of preoperative treatment of acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-analysis. PLoS One. 2013 Apr 25;8(4):e61523.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061523
http://www.ncbi.nlm.nih.gov/pubmed/23634209?tool=bestpractice.com
However, these conclusions should be interpreted with caution. First, the rate of biochemical control in placebo-treated patients was exceedingly low, and the pretreatment 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.[54]Zhang L, Wu X, Yan Y, et al. Preoperative somatostatin analogs treatment in acromegalic patients with macroadenomas. A meta-analysis. Brain Dev. 2015 Feb;37(2):181-90.
http://www.ncbi.nlm.nih.gov/pubmed/24815226?tool=bestpractice.com
While initial randomized 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 apnea, or high-output heart failure).[12]Katznelson L, Laws ER Jr, Melmed S, et al; Endocrine Society. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Nov;99(11):3933-51.
http://press.endocrine.org/doi/full/10.1210/jc.2014-2700
http://www.ncbi.nlm.nih.gov/pubmed/25356808?tool=bestpractice.com
[55]Fleseriu M, Hoffman AR, Katznelson L, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: management of acromegaly patients: what is the role of pre-operative medical therapy? Endocr Pract. 2015 Jun;21(6):668-73.
http://www.ncbi.nlm.nih.gov/pubmed/26135961?tool=bestpractice.com
Long-term beneficial effect of somatostatin analogs 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 analog in a phase 2 clinical trial.[56]Gadelha MR, Gordon MB, Doknic M, et al. ACROBAT edge: safety and efficacy of switching injected SRLs to oral paltusotine in patients with acromegaly. J Clin Endocrinol Metab. 2023 Apr 13;108(5):e148-59.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099171
http://www.ncbi.nlm.nih.gov/pubmed/36353760?tool=bestpractice.com
A phase 3 trial is in progress.[57]ClinicalTrials.gov. A study to evaluate the safety and efficacy of paltusotine for the treatment of acromegaly (PATHFNDR-1). ClinicalTrials.gov Identifier: NCT04837040. Sep 2023 [internet publication].
https://clinicaltrials.gov/study/NCT04837040
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.[58]ClinicalTrials.gov. A trial to assess efficacy and safety of octreotide subcutaneous depot in patients with acromegaly. ClinicalTrials.gov Identifier: NCT04076462. Jun 2023 [internet publication].
https://clinicaltrials.gov/study/NCT04076462
[59]ClinicalTrials.gov. A trial to assess the long-term safety of octreotide subcutaneous depot in patients with acromegaly. ClinicalTrials.gov Identifier: NCT04125836. Aug 2023 [internet publication].
https://clinicaltrials.gov/study/NCT04125836