Are higher pre-diagnosis follicle stimulating hormone levels associated with long-term prostate cancer risk?

BACKGROUND: Follicle stimulating hormone (FSH) is a pituitary hormone that helps regulate testosterone homeostasis. Although it is generally accepted that FSH levels increase with LHRH-agonist therapy for prostate cancer (PC), the specific impact of FSH levels on risk of PC diagnosis is largely unknown. The objective of this study was to perform a population-level analysis to assess the association between FSH levels and PC diagnosis. METHODS: All men (n = 386,018) who had a pre-PC diagnosis FSH level and complete data were identified within the Veterans Affairs Health System between 1999 and 2018. The association between FSH level and time from FSH test to PC diagnosis was tested using stratified Cox proportional hazards models. Multivariable models were adjusted for age, year, race, body mass index, and Charlson comorbidity index. Due to nonproportional hazards over time, time to PC was modeled separately: ≤4 years after an FSH test and >4 years following an FSH test. RESULTS: Median age at first FSH level was 64 years (interquartile range [IQR]: 54-72), median year of FSH was 2010 (IQR: 2005-2014), and 70% of the cohort was white. Median follow-up was 76 months (IQR: 38-126) during which 17,519 men (4.5%) were diagnosed with PC. On multivariable analysis, in the first 4 years after FSH test, there was no association between FSH and time to PC diagnosis. Starting from 4 years after FSH test, on multivariable analysis, a higher FSH level was associated with lower risk of PC with continuous modeling, but found no association with log continuous and categorical modeling. CONCLUSIONS: In this population-level study among male veterans receiving an FSH test for an unknown clinical indication, associations between FSH levels and PC risk were inconsistent and likely driven by selection bias and confounding variables. Future studies should consider different study designs.

Pituitary Society Delphi Survey: An international perspective on endocrine management of patients undergoing transsphenoidal surgery for pituitary adenomas.

PURPOSE: In adults and children, transsphenoidal surgery (TSS) represents the cornerstone of management for most large or functioning sellar lesions with the exception of prolactinomas. Endocrine evaluation and management are an essential part of perioperative care. However, the details of endocrine assessment and care are not universally agreed upon. METHODS: To build consensus on the endocrine evaluation and management of adults undergoing TSS, a Delphi process was used. Thirty-five statements were developed by the Pituitary Society's Education Committee. Fifty-five pituitary endocrinologists, all members of the Pituitary Society, were invited to participate in two Delphi rounds and rate their extent of agreement with statements pertaining to perioperative endocrine evaluation and management, using a Likert-type scale. Anonymized data on the proportion of panelists' agreeing with each item were summarized. A list of items that achieved consensus, based on predefined criteria, was tabulated. RESULTS: Strong consensus (≥ 80% of panelists rating their agreement as 6-7 on a scale from 1 to 7) was achieved for 68.6% (24/35) items. If less strict agreement criteria were applied (ratings 5-7 on the Likert-type scale), consensus was achieved for 88% (31/35) items. CONCLUSIONS: We achieved consensus on a large majority of items pertaining to perioperative endocrine evaluation and management using a Delphi process. This provides an international real-world clinical perspective from an expert group and facilitates a framework for future guideline development. Some of the items for which consensus was not reached, including the assessment of immediate postoperative remission in acromegaly or Cushing's disease, represent areas where further research is needed.

Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results.

PURPOSE: Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. METHODS: CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. RESULTS: Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. CONCLUSIONS: OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each. Trial registration NCT03252353 (August 2017), NCT01412424 (August 2011).

A Rare Case: Adrenal Corticomedullary Mixed Tumor With Elements of Pheochromocytoma, Cortical Adenoma, and Ganglioneuroma Cells.

Background/Objective: Adrenal corticomedullary mixed tumor (CMMT) are extremely rare single adrenal tumor masses containing a mixture of adrenal cortical adenoma and pheochromocytoma cells. Case Report: A 52-year-old woman presented with clinical and biochemical evidence of cortisol and catecholamine excess and was found to have an adrenal CMMT with intermixed chromaffin, cortical adenoma, and ganglioneuroma components. She underwent a successful unilateral adrenalectomy with subsequent improvement in her symptoms. Discussion: We report the first case of a patient with a CMMT that had symptoms of both catecholamine and cortisol excess from her tumor. Typically, patients with similar tumors have signs of cortisol excess; however, the pheochromocytoma portion is clinically silent. Although most CMMT contain 2 distinct cell types, this is the third ever described case of a single adrenal CMMT containing 3 unique cellular components: (1) intermixed chromaffin, (2) cortical adenoma, and (3) ganglioneuroma cells. Conclusion: Our understanding of these rare tumors is limited, and this case serves to broaden our knowledge about their clinical, biochemical, and pathologic features.

Fluid Restriction Reduces Delayed Hyponatremia and Hospital Readmissions After Transsphenoidal Surgery.

CONTEXT: Postoperative hyponatremia leads to prolonged hospital length of stay and readmission within 30 days. OBJECTIVE: To assess 3 strategies for reducing rates of postoperative hyponatremia and analyze risk factors for hyponatremia. DESIGN: Two retrospective analyses and 1 prospective study. SETTING: Tertiary referral hospital. PATIENTS: Patients undergoing transsphenoidal surgery for pituitary adenomas and other sellar and parasellar pathologies. INTERVENTION(S): Phase 1: no intervention. Phase 2: postoperative day (POD) 7 sodium testing and patient education. Phase 3: fluid restriction to 1 L/day on discharge in addition to phase 2 interventions. MAIN OUTCOME MEASURES: Rates of early and delayed hyponatremia and readmissions. Secondary outcomes were risk factors for hyponatremia and readmission costs. RESULTS: In phase 1, 296 patients underwent transsphenoidal surgery. Twenty percent developed early and 28% delayed hyponatremia. Thirty-eight percent underwent POD 7 sodium testing. Readmission rates were 15% overall and 4.3% for hyponatremia. In phase 2 (n = 316), 22% developed early and 25% delayed hyponatremia. Eighty-nine percent complied with POD 7 sodium testing. Readmissions were unchanged although severity of hyponatremia was reduced by 60%. In phase 3 (n = 110), delayed hyponatremia was reduced 2-fold [12.7%, relative risk (RR) = 0.52] and readmissions 3-fold [4.6%, RR = 0.30 (0.12-0.73)]; readmissions for hyponatremia were markedly reduced. Hyponatremia readmission increased costs by 30%. CONCLUSIONS: Restricting fluid to 1 L/day on discharge decreases rates of delayed hyponatremia and readmissions by 50%. Standardized patient education and POD 7 sodium testing decreases severity of hyponatremia but does not impact readmission rates. These protocols should be considered standard practice for patients undergoing transsphenoidal surgery.

Are higher follicle-stimulating hormone levels before androgen deprivation therapy for prostate cancer associated with oncological and cardiac outcomes and overall survival?-a population-level analysis.

Background: Androgen deprivation therapy (ADT), commonly delivered via a luteinizing hormone-releasing hormone (LHRH) agonist, is the standard treatment for advanced prostate cancer (PC). While quite effective, it has been associated with an increased risk of major adverse cardiovascular events (MACE). The exact mechanisms are not clear. However, it has been theorized that follicle-stimulating hormone (FSH), a pituitary hormone that is involved in controlling normal testosterone levels, which is decreased with LHRH-agonist therapy, may be the culprit. We performed a retrospective population-level study to test the link of FSH levels on the development of MACE, castrate-resistant PC (CRPC), and death among men starting ADT. Methods: All men (n=1,539) who had an FSH level between 1999 and 2018 within 2 years prior to starting ADT and complete data were identified within the Veterans Affairs (VA) Health System. FSH was dichotomized as low/normal (≤8 IU/mL) and high (>8 IU/mL), using established cut-points. The associations between FSH and time to MACE, death, and CRPC were tested using log-rank tests and multivariable Cox proportional hazards models. Results: Patients with high FSH were older (median 76 vs. 73 years, P<0.001), started ADT earlier (median 2007 vs. 2009, P=0.027), and had lower body mass index (BMI) (median 29.1 vs. 30.1 kg/m2, P=0.004) compared to those with low/normal FSH. On multivariable analysis, there was no association between FSH and time from ADT to MACE, CRPC, or death. Conclusions: In this population-level study of men receiving an FSH test prior to starting ADT, there was no association between FSH levels and time from ADT to MACE, CRPC, or death. Although further studies are needed, these results do not support a link between pre-ADT FSH and long-term oncological or cardiovascular outcomes.

Molecular targets in acromegaly.

Molecular therapeutic targets in growth hormone (GH)-secreting adenomas range from well-characterized surface receptors that recognize approved drugs, to surface and intracellular markers that are potential candidates for new drug development. Currently available medical therapies for patients with acromegaly bind to somatostatin receptors, GH receptor, or dopamine receptors, and lead to attainment of disease control in most patients. The degree of control is variable: however, correlates with both disease aggressiveness and tumor factors that predict treatment response including somatostatin receptor subtype expression, granulation pattern, kinases and their receptors, and other markers of proliferation. A better understanding of the mechanisms underlying these molecular markers and their relationship to outcomes holds promise for expanding treatment options as well as a more personalized approach to treating patients with acromegaly.

Endocrine Autoantibodies Determine Immune Checkpoint Inhibitor-induced Endocrinopathy: A Prospective Study.

CONTEXT: Incidence and awareness of endocrine-related adverse events (ERAE) associated with use of immune checkpoint inhibitors (ICI) has grown with increased ICI use, yet mechanisms for ERAE prediction, surveillance, and development are not well established. OBJECTIVE: We prospectively evaluated the impact of endocrine autoimmunity on ERAE development and overall survival (OS). METHODS: Adults ≥ 18 years of age prescribed ICI treatment for advanced or metastatic solid tumors and no known active/past endocrine disorders were eligible for enrollment. Thyroid, adrenal, and pancreatic antibodies as well as hormone levels were assessed prior to ICI treatment and at 8 to 9 weeks and 36 weeks after treatment for ERAE in relation to presence and changes in endocrine-specific antibodies, hormone levels, and OS. RESULTS: Sixty patients were enrolled and ERAE were detected in 14 (23.3%), with a median onset of 52 days (IQR, 38.5-71.5) after first ICI dose. Hypothyroidism occurred in 12 (20%) patients, and 2 (3.33%) patients developed hypophysitis. Diabetes and primary adrenal insufficiency were not observed. Antibodies were detected in 14 patients (11 at baseline, 3 developed during follow-up) and their presence was significantly associated with ERAE (R2 59.3%, P < 0.001). Thyroid peroxidase antibody (20%) and thyroid-stimulating immunoglobulin (3.3%) were most common, and anti-GAD was present in 1 patient. The presence of ERAE was associated with a more favorable OS (P = 0.001). CONCLUSION: Endocrine-specific autoantibodies play an important role in ERAE pathogenesis and may serve as predictive markers for early identification and treatment of ICI-induced endocrinopathies.

DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas.

Drivers of sporadic benign pituitary adenoma growth are largely unknown. Whole-exome sequencing of 159 prospectively resected pituitary adenomas showed that somatic copy number alteration (SCNA) rather than mutation is a hallmark of hormone-secreting adenomas and that SCNAs correlate with adenoma phenotype. Using single-gene SCNA pathway analysis, we observed that both cAMP and Fanconi anemia DNA damage repair pathways were affected by SCNAs in growth hormone-secreting (GH-secreting) somatotroph adenomas. As somatotroph differentiation and GH secretion are dependent on cAMP activation and we previously showed DNA damage, aneuploidy, and senescence in somatotroph adenomas, we studied links between cAMP signaling and DNA damage. Stimulation of cAMP in C57BL/6 mouse primary pituitary cultures using forskolin or a long-acting GH-releasing hormone (GHRH) analog increased GH production and DNA damage measured by H2AX phosphorylation and a comet assay. Octreotide, a somatostatin receptor ligand that targets somatotroph adenoma GH secretion in patients with acromegaly, inhibited cAMP and GH and reversed DNA damage induction. In vivo long-acting GHRH treatment also induced pituitary DNA damage in mice. We conclude that cAMP, which induces somatotroph proliferation and GH secretion, may concomitantly induce DNA damage, potentially linking hormone hypersecretion to SCNA and genome instability. These results elucidating somatotroph adenoma pathophysiology identify pathways for targeted treatment.

Maintenance of Acromegaly Control in Patients Switching From Injectable Somatostatin Receptor Ligands to Oral Octreotide.

PURPOSE: The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs). METHODS: In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures. RESULTS: Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience. CONCLUSIONS: OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.

THYMIC CARCINOID WITH ADRENOCORTICOTROPIC HORMONE-PRODUCING ECTOPIC CUSHING SYNDROME AND EMPTY SELLA.

OBJECTIVE: Ectopic Cushing's syndrome secondary to thymic carcinoid is a rare disorder that may be difficult to diagnose and manage. METHODS: We describe a case of severe Cushing's syndrome secondary to a large adrenocorticotropic hormone (ACTH) producing thymic carcinoid in a patient with history of primary hyperaldosteronism. RESULTS: A 43-year-old female with a 20-year history of an aldosterone-secreting adrenocortical adenoma status post right adrenalectomy presented with acute onset of proximal muscle weakness, swelling, facial hirsutism, and severe hypokalemia. Ectopic Cushing's Syndrome was suspected based on the sudden symptom onset and markedly elevated 24-hr urine cortisol and ACTH levels. MRI revealed an empty pituitary sella and a large (7.3 cm) mediastinal mass visible on chest CT. The mass was resected by video-assisted thoracoscopic surgery, resulting in resolution of symptoms and cortisol levels. Pathology assessment confirmed well-differentiated thymic carcinoid with positive ACTH staining. CONCLUSION: The case highlights clinical features, challenges in diagnostic work up, treatment modalities, and associated endocrine findings in a thymic carcinoid abutting the heart and presenting with ectopic ACTH secretion.

Insulin Clearance Is Associated with Hepatic Lipase Activity and Lipid and Adiposity Traits in Mexican Americans.

Reduction in insulin clearance plays an important role in the compensatory response to insulin resistance. Given the importance of this trait to the pathogenesis of diabetes, a deeper understanding of its regulation is warranted. Our goal was to identify metabolic and cardiovascular traits that are independently associated with metabolic clearance rate of insulin (MCRI). We conducted a cross-sectional analysis of metabolic and cardiovascular traits in 765 participants from the Mexican-American Coronary Artery Disease (MACAD) project who had undergone blood sampling, oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, dual-energy X-ray absorptiometry, and carotid ultrasound. We assessed correlations of MCRI with traits from seven domains, including anthropometry, biomarkers, cardiovascular, glucose homeostasis, lipase activity, lipid profile, and liver function tests. We found inverse independent correlations between MCRI and hepatic lipase (P = 0.0004), insulin secretion (P = 0.0002), alanine aminotransferase (P = 0.0045), total fat mass (P = 0.014), and diabetes (P = 0.03). MCRI and apolipoprotein A-I exhibited a positive independent correlation (P = 0.035). These results generate a hypothesis that lipid and adiposity associated traits related to liver function may play a role in insulin clearance.

Thyrotoxicosis of Pregnancy.

Thyrotoxicosis presenting during pregnancy is a common clinical problem and can be challenging to differentiate between physiologic patterns of thyroid dysfunction during gestation and intrinsic hyperthyroidism. This review provides a summary of the differential diagnosis, clinical presentation, diagnostic options, potential adverse effects of maternal thyrotoxicosis to the fetus, and treatment recommendations for thyrotoxicosis arising in pregnancy.

Histopathologic evaluation of basilar artery atherosclerosis.

INTRODUCTION: There has been limited attention to pathological features of basilar artery atherosclerosis. It has been assumed that pathology of basilar artery atherosclerosis mimics that of other vascular beds. METHODS: To define the nature of the basilar artery atherosclerotic lesions, we analyzed postmortem intracranial artery samples from eight subjects with history of stroke. RESULTS: Atherosclerotic lesions were present in 7/8 arteries examined, with a mean estimated stenosis of 34%. Lumen thrombus with a disrupted fibrous cap was seen in 1 lesion; the remaining 6 lesions revealed a thick fibrous cap. Neovascularity and calcification were seen in 1 lesion and mild to moderate inflammation was seen in 3 lesions. Necrotic core was present in 4/7 lesions, and was associated with plaque rupture in the only disrupted lesion. CONCLUSIONS: Basilar artery atherosclerotic lesions were relatively benign in this series of patients presenting with stroke. While confirmation is needed with larger sample size, the relative paucity of neovascularity suggests a possibly distinctive histopathological profile.