Faculty Bibliography

Cushing's disease (CD) is an endogenous hypercortisolism state caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Medical therapy is an important second-line treatment for CD. New pharmacologic agents for the treatment of patients with CD are under development. New possible intervention targets include various receptors and pathways in the corticotroph tumor, the hormone ACTH, and its receptor and enzymes involved in cortisone metabolism. This part of the article will focus on tailoring pharmacologic therapy according to patient specific characteristics, long-term medical therapy and development of new drugs for CD.

Cushing's disease (CD) is an endogenous hypercortisolism state caused by an adrenocorticotropic hormone secreting pituitary adenoma. CD is associated with vast comorbidities and has a significant detrimental effect on quality of life as well as longevity. First line treatment for CD is transsphenoidal surgery (TSS) while medical therapy is an important second line treatment in cases of TSS failure or infeasibility. Current existing medications for CD target different processes related to CD including the corticotroph adenoma, cortisol adrenal manufacturing mechanisms, and glucocorticoid receptor blockage and widely differ in advantages as well as adverse effects. In depth acquaintance with the specific characteristics of each drug is needed in order to provide patients with the appropriate therapy according to their specific needs.

PURPOSE/OBJECTIVE:Data on mortality risk in patients with hyperprolactinemia is limited. This study aimed to evaluate all-cause mortality in a cohort of dopamine agonist (DA)-treated patients with hyperprolactinemia. METHODS:A nationwide retrospective study (2000-2023) using the Clalit Health Services database evaluated all-cause mortality in patients with DA-treated hyperprolactinemia, matched 1:5 with controls by age, sex, socioeconomic status, and BMI. The primary outcome was all-cause mortality. Secondary outcomes included the impact of hyperprolactinemia severity, prolactin (PRL) normalization, and other mortality risk factors. RESULTS:The study included 2,492 patients with hyperprolactinemia (mean age ± SD:38.7 ± 14.8 years, 59.6% women) and 12,456 controls (38.7 ± 14.8 years, 59.6% women). Over > 17 years of follow-up, 182 patients (7.3%) and 936 controls (7.5%) died (HR = 0.972, 95% CI 0.829-1.139), with similar mean age at death. Causes of death in both groups were mainly infectious, cardiovascular, and malignancies. Compared to controls, patients achieving PRL normalization within 1 year had lower mortality (HR = 0.730), while those without normalization had similar risk. Patients with baseline PRL < 5×ULN had lower mortality (6.9% vs. 7.9%, HR = 0.725) than those with ≥ 5×ULN. Mortality was higher in men than in women with hyperprolactinemia but not versus controls. Independent predictors for all-cause mortality included older age, higher BMI, male sex, heart failure, malignancy, hypertension, diabetes, and ischemic heart disease. CONCLUSION/CONCLUSIONS:All-cause mortality in patients with DA-treated hyperprolactinemia is not increased compared to matched controls, however is higher in men vs. women. Mortality is primarily influenced by age, sex, BMI, and comorbidities. Achieving PRL normalization within a year decreases mortality compared with controls.

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.

PURPOSE/OBJECTIVE:Clinical screening systems (CSSs) for Cushing syndrome (CS) validated in Europe have not been evaluated for CS or Cushing disease (CD) in the United States (US). We aimed to evaluate existing CSSs in US patients and develop two new symptom-based CSSs to identify patients with high pre-test probability of disease warranting referral for definitive biochemical workup-one for broad CS screening and one specifically for CD. METHODS:Data were obtained from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID)-comprising 615 patients who underwent transnasal transsphenoidal resection for CD at one of 11 US pituitary centers, the Centers for Disease Control and Prevention's 2019 National Health Interview Survey (NHIS)-comprising 31,997 US respondents, and a single institution CD-NFA cohort-comprising 468 US patients diagnosed with either CD (n = 385) or nonfunctioning adenoma (n = 83). The RAPID Community Cushing CSS was derived from differences between the RAPID and NHIS cohorts, and the RAPID CD CSS from differences between patients with CD versus NFA. RESULTS:In external validation using US-based cohorts, the RAPID Community CSS achieved an AUC of 0.707, compared to the Spanish (AUC = 0.691) and Italian (AUC = 0.685) models, and the RAPID CD CSS demonstrated greater external sensitivity (0.836, threshold = 0.5) at the Youden-optimized threshold than the Spanish (0.605, threshold = 4) and Italian (0.735, threshold = 6) CSSs. CONCLUSIONS:In US patient populations, the RAPID Community Cushing CSS demonstrated superior discriminative ability for CD compared to the Italian and Spanish CSSs, and the RAPID CD CSS achieved the highest sensitivity for CD among all CSSs evaluated.

First-line treatment of endogenous Cushing's syndrome (CS) is surgical removal of the tumor responsible for cortisol excess. However, medical therapy has an established role in treatment when patients are not surgical candidates or decline surgery, residual or recurrent disease is present and not amenable to repeat resection, and control of hypercortisolism is needed either preoperatively or while awaiting the effects of radiotherapy. The approach to medical therapy should be tailored based on the etiology, degree of hypercortisolism, and patient characteristics. Currently available medical therapy for all etiologies of CS either blocks adrenal production of cortisol or blocks its action at the level of the glucocorticoid receptor. Currently available medical therapy for Cushing's disease (CD) targets the adrenocorticotropic hormone-secreting pituitary tumor through activation of somatostatin and dopamine receptors, alkylating DNA damage, or immune system activation. More focused therapy with greater efficacy and fewer adverse effects is needed, particularly in the case of CD, with potential targets and drugs identified and in development.

PURPOSE/OBJECTIVE:Primary aldosteronism (PA) is an underdiagnosed cause of secondary hypertension with significant health consequences. Expanding screening criteria may improve case detection and reduce the number of untreated patients. METHODS:We assessed PA screening rates in a cohort of 457 adults with comorbid obstructive sleep apnea (OSA) and hypertension (HTN). PA screening in a subset of the cohort (n = 97, 21%) was conducted using serum aldosterone, aldosterone-to-plasma renin activity ratio (ARR), and plasma renin activity (PRA). Screening results were compared between the 2016 Endocrine Society guidelines (serum aldosterone and ARR) and the Vaidya & Carey algorithm (serum aldosterone and PRA). RESULTS:The screened patients were predominantly male (mean age 58.6 years), with common comorbidities including hyperlipidemia (80%) and diabetes mellitus (31%). PA positivity rates differed significantly between screening criteria: 7% tested positive using Endocrine Society guidelines, while 33% screened positive using the Vaidya & Carey algorithm. Notably, 26% of patients with negative screens by Endocrine Society criteria were reclassified as positive, and 11 previously indeterminate cases were classified as negative due to absent renin suppression. Using the Vaidya & Carey algorithm with a stricter PRA suppression threshold, 25% of patients screened positive. CONCLUSION/CONCLUSIONS:The Vaidya & Carey algorithm may be an important tool in increasing detection of previously unidentified cases and clarifying the diagnosis of cases that were previously deemed indeterminate. Given the morbidity of untreated PA, more robust screening approaches are warranted. Prospective studies are needed to validate these findings across diverse populations.

This Pituitary Society Consensus article presents an evidence-based consensus on the management of pituitary incidentaloma, defined as an unexpected sellar or parasellar finding incidentally discovered on an imaging study that was not performed for a clinically suspected pituitary lesion. Recommendations are offered for when endocrinology, neurosurgery and ophthalmology consultation, dedicated pituitary imaging, pituitary hormone testing and visual assessment are warranted for macroadenomas, microadenomas, cystic lesions and empty sella, as well as when surgical resection is indicated for incidental pituitary adenomas and cystic sellar lesions. Special considerations in patients with multiple endocrine neoplasia type 1, children and adolescents, older people, and pregnant women are addressed. The Consensus workshop concluded that diagnostic and management approaches should be individualized to the specific clinical context of an incidentally discovered pituitary lesion. Consultation with a multidisciplinary pituitary tumour centre of excellence should be considered in the presence of new or deteriorating lesion-specific signs or symptoms, particularly when surgical or other adjuvant interventions are being considered and when there is uncertainty about the most appropriate subsequent management.

The neurocognitive and psychiatric effects of Cushing's syndrome (CS) are well recognized and negatively impact quality of life. The aim of this systematic review is to compare neurocognitive disease, psychiatric symptoms, and structural brain changes in patients with Cushing's disease (CD)/CS and those with non-functioning pituitary adenoma (NFPA), both before and after surgical treatment, and in comparison to healthy controls. Possible predictors of persistent neurocognitive symptoms and reduced quality of life in patients with CS are highlighted. We reviewed the English literature published in Medline/Pubmed until 2021 to identify eligible studies. This systematic review was registered on Prospero and reported following the PRISMA statement guidelines. The initial literature search yielded 1772 articles, of which 1096 articles remained after removing duplicates. After excluding case reports, animal studies, narrative reviews, comparative reviews, and articles not in English, 86 papers underwent full-text review. Studies eligible for inclusion met the following criteria: (1) described patients with CD/CS, (2) reports of psychiatric symptoms, (3) written in English or with available English translation, and (4) published in a peer-reviewed journal. The full-text review process identified 40 eligible studies. The 40 studies included a total of 2603 participants with CD or CS, with 45.2% of the total participants having CD. The majority of studies were case-control studies and used validated questionnaires such as the Beck's Depression Index, Trail Making Test, Hospital Anxiety and Depression Scale, and Cushing Quality of Life for screening. Compared to NFPA controls, patients with CD who had greater baseline serum cortisol levels had worse cognitive function, even after surgical remission. This suggests a possible association between greater baseline cortisol levels in patients with CS and persistent cognitive impairment. A longer duration of uncontrolled CS was associated with worse cognitive function; however, there was no association found between the length of remission and memory. Overall brain volume was increased in patients in remission from CD compared to active disease. However, temporal and frontal lobe volumes did not recover to normal volumes. Patients with CS experience neurocognitive dysfunction, psychiatric disorders, and diminished quality of life, and symptoms may persist after curative surgery. We found several factors consistently associated with persistent cognitive and neuropsychiatric symptoms in patients with CS including higher pre-operatively baseline cortisol production, longer duration of disease, frontal and temporal lobe atrophy, and the presence of cognitive and neuropsychiatric symptoms at baseline. Larger prospective studies are required to validate these findings.

Craniopharyngiomas are histologically benign central nervous system tumors derived from embryonic epithelial cells of Rathke's pouch. The disease demonstrates a bimodal age distribution, occurring most often in patients 5-14 and 50-74 years of age. Common comorbidities include hypopituitarism, hypothalamic obesity, sleep apnea, visual impairment and neurocognitive disturbances. There are several key differences in the presentation, tumor characteristics and clinical outcomes between age groups. Childhood craniopharyngiomas are mostly adamantinomatous and often present as larger tumors with worse functional outcomes such as rates of obesity and neurological deficits. Adults experience similar but slightly adjusted rates of comorbidity with both the adamantinomatous and papillary subtypes. This review presents a case-based discussion of adult craniopharyngiomas, focusing on recent literature regarding their presentation, pathology and pathogenesis, diagnosis, treatment and long-term sequelae.