## 4 Discussion
For example, hPITOs generated from patients with sparsely granulated corticotroph adenomas (hPITOs 10; 25; 34; 35) and [PERSON]'s cell adenomas (hPITOs 7; 33) showed variable responses regardless of similar pathologically defined subtypes. In addition, the response of the tumor cells within the organoids to the standard of care drugs that directly target the pituitary in the body, including mifepristone and cabergoline, was only 50% in hPITO34 and hPITO35, and almost 0% in the other lines, including hPITO7, 10, and 25. These data clearly demonstrate that the inherent patient difference to drug response that is often observed among CD patients is reflected in the organoid culture. This culture system may be an approach that will provide functionaldata revealing actionable treatment options for each patient. Patient-derived organoids from several tumors have served as a platform for testing the efficacy of anticancer drugs and predicting responses to targeted therapies in individual patients [27; 46; 48; 49; 50]. An example of the use of organoids in identifying drug responsiveness within an endocrine gland is that of papillary thyroid cancer [51]. Organoids developed from PTC patients were used as a preclinical model for studying responsiveness to anticancer drugs in a personalized approach [51]. However, our study is the first report of the use of hPITOs for drug screening. Connecting genetic and drug sensitivity data will further categorize corticotroph subtypes associated with CD. WES analysis of each hPITO line was compared to the results for the corresponding primary adenoma tissues. We showed the concordance rate of exonic variants between the primary tumor tissues obtained from CD patients and the corresponding organoid line. On average, approximately 80% of the variants observed in the CD patients' adenoma tissues were retained in the corresponding hPITOs. Pituitary organoids were also developed from iPSCs generated from PBMCs of a CD patient expressing a germline genetic alteration in adcherrin-related 23 (iPSC\({}^{\textit{CDH23}}\)), a CD patient expressing an MEN1 mutation (iPSC\({}^{\textit{MEN1}}\)), and a healthy individual (iPSC\({}^{\textit{ctrl}}\)). Foundational studies performed by investigators at the genome level have revealed significant knowledge regarding the pathophysiology of CD [36; 37; 52; 53]. In some instances, CD is a manifestation of genetic mutation syndromes that include multiple endocrine neoplasia type 1 (MEN1), familial isolated pituitary adenoma (FIPA), and Carney complex [54; 55]. _CDH23_ syndrome is clinically associated with the development of Usher syndrome, deafness, and vestibular dysfunction [56]. Several mutations in _CDH23_ are associated with inherited hearing loss and blindness [57]. However, none of the variants found in this study were linked to any symptoms of deafness or blindness. A possible explanation is that deafness-related _CDH23_ mutations are caused by either homozygous or compound heterozygous mutations [57]. In a study that linked mutations in _CDH23_ with familial and sporadic pituitary adenomas, it was suggested that these genetic alterations could play important roles in the pathogenesis of CD [38]. Genomic screening in a total of 12 families with familial PitNETs, 125 individuals with sporadic pituitary tumors, and 260 control individuals showed that 33% of the families with familial pituitary tumors and 12% of individuals with sporadic pituitary tumors expressed functional or pathogenic _CDH23_ variants [38]. Consistent with the expected pathology and function of a PitNET from a patient with CD, iPSC\({}^{\textit{CDH23}}\) organoids exhibited hypersecretion of ACTH, and expression of transcription factors and cell markers were reported in the pathology report for corticotroph PitNETs. Collectively, these findings warrant further investigation to determine whether carriers of _CDH23_ mutations are at a high risk of developing CD and/or hearing loss.