Endocrine Abstracts

Cushing’s disease (CD), caused by a corticotroph pituitary adenoma, is associated with multi-system morbidity and when untreated or suboptimally treated with an increased mortality. Transsphenoidal adenomectomy is the first choice of treatment for CD. Medical treatment is an option in patients in whom surgery is not successful or not feasible. Medical therapy for CD can be classified into pituitary-directed drugs, adrenal-blocking drugs and glucocorticoid receptor antagonists. Dopamine and somatostatin receptors have been identified as targets for pituitary-directed drug therapy. The majority of ACTH-secreting pituitary adenomas express the dopamine receptor subtype-2 (DA2) and somatostatin receptor subtype-5. The DA2 agonist cabergoline can normalize cortisol production in ±30% of patients. Pasireotide, a universal somatostatin analog with high affinity for sst5, normalizes cortisol production in ±25% of patients. A study with longacting pasireotide in CD is underway. Combined targeting of DA2 and sst5 with cabergoline and pasireotide, which may have synergistic effects, showed promising results. Potential new therapeutic targets in corticotroph adenomas include cyclin-dependent kinases (CDK), epidermal growth factor receptor (EGFR) and heat shock protein 90 (HSP90). CDK are upregulated in corticotroph adenomas and can promote cell growth via deregulation of the cell cycle. EGFR signaling, in particular in adenomas with somatic mutations in the USP8 gene, is associated with POMC expression and cell proliferation. Overexpression of HSP90 contributes to glucocorticoid resistance of corticotroph adenomas. Preclinical studies on targeting CDK, EGFR and HSP90 with roscovitine, gefitinib and silibinin respectively showed promising results. Osilodrostat and levoketoconazole are recently developed inhibitors of steroidogenesis and are currently under investigation in multicenter trials. Mifepristone is the only available glucocorticoid receptor antagonist and was recently approved in the USA for treatment of hyperglycemia related to CD. Medical therapy for CD should be tailor-made and future studies should explore the optimal order and combination of medical treatment modalities.