Endogenous Cushing's Syndrome and Cancer Risk.

OBJECTIVE: Cancer incidence in patients with endogenous Cushing's syndrome (CS) has never been established. We aimed to assess the cancer risk in patients with CS, as compared with individually matched controls. DESIGN: A nationwide retrospective matched-cohort study of patients with endogenous CS diagnosed between 2000-2023, using the database of Clalit Health Services in Israel. METHODS: Patients with adrenal carcinoma or ectopic CS were excluded. Patients with CS were matched in a 1:5 ratio, with controls individually matched for age, sex, socioeconomic status, and body mass index. The primary outcome was defined as the first diagnosis of any malignancy following a CS diagnosis. Risk of malignancy was calculated using the Cox proportional hazards model with death as a competing event. RESULTS: A total of 609 patients with CS and 3018 controls were included [mean age at diagnosis, 48.0±17.2 years; 2371 (65.4%) women]. The median follow-up 14.7 years (IQR, 9.9-20.2 years).Patients with CS had an increased cancer risk, with hazard ratio (HR) of 1.78 (95% CI 1.44-2.20), compared with their matched controls. The risk of malignancy was elevated in patients with Cushing's disease (251 cases and 1246 controls; HR 1.65, 95% CI 1.15-2.36) and in patients with adrenal CS (200 cases and 991 controls; HR 2.36, 95% CI 1.70-3.29). The increased cancer risk in patients with CS persists after exclusion of thyroid malignancies. CONCLUSION: Endogenous CS is associated with increased malignancy risk. These findings underscore the need for further research to establish recommendations for cancer screening in this population.

Hypopituitarism and bone disease: pathophysiology, diagnosis and treatment outcomes.

Hypopituitarism is a rare but significant endocrine disorder characterized by the inadequate secretion of one or more pituitary hormones. The intricate relationship between hypopituitarism and bone health is a topic of growing interest in the medical community. In this review the authors explore associations between hypopituitarism and bone health, with specific examination of the impact of growth hormone deficiency, central hypogonadism, central hypocortisolism, and central hypothyroidism. Pathogenesis, diagnosis, and treatment options as well as challenges posed by osteopenia, osteoporosis, and fractures in hypopituitarism are discussed.

Impact of etiology, sex, diabetes mellitus and remission status on erythrocytic profile in patients with cushing's syndrome: a large population database study.

PURPOSE: The study aimed to characterize the erythrocytic profile in patients with cushing's syndrome (CS) versus controls from the normal population according to etiology, sex, presence of diabetes mellitus (DM) and hypercortisolemia remission status. METHODS: This retrospective cohort analysis compared erythrocytic parameters between patients with CS of pituitary (CD) and adrenal (aCS) etiology and age, sex, body mass index (BMI) and socioeconomic status-matched controls in a 1:5 ratio. Laboratory values at baseline were calculated as mean values during the year preceding CS diagnosis, and over one year thereafter. RESULTS: The cohort included 397 CS patients (68.26% female; mean age 51.11 ± 16.85 years) and 1970 controls. Patients with CS had significantly higher baseline median levels of hemoglobin (Hgb) (13.70 g/dL vs. 13.12 g/dL [p < 0.0001]) and hematocrit (Hct) (41.64% vs. 39.80% [p < 0.0001]) compared to controls. These differences were observed for both CD and aCS and for both sexes. Patients who attained remission had Hgb and Hct levels comparable to controls (13.20 g/dL and 40.08% in patients with CD and aCS vs. 13.20 g/dL and 39.98% in controls). Meanwhile, those with persistent/recurrent disease maintained elevated levels. Patients with comorbid DM had similar Hgb but higher Hct (p = 0.0419), while patients without DM showed elevated erythrocytic values compared to controls (p < 0.0001). CONCLUSION: Our data illustrates that erythrocytic parameters are directly influenced by glucocorticoid excess as Hgb and Hct are higher in patients with CS, and normalize after remission. We have identified the influence of DM on erythrocytic parameters in patients with CS for the first time.

Long-term effectiveness of zoledronic acid in patients with Paget's disease of bone - a retrospective cohort study.

PURPOSE: The aims of the current study were to describe clinical and biochemical features of patients with Paget disease of bone (PDB) followed at our medical center, and to examine the long-term effectiveness of zoledronate. METHODS: Retrospective cohort study included consecutive patients≥18 years with a diagnosis of PDB, followed in the Rabin Medical Center (RMC) Institute of Endocrinology from 1973 to 2023. The cohort comprised two groups: patients treated/not treated with zoledronic acid (ZOL/NZOL). The primary outcome was the percentage of patients who achieved a biochemical therapeutic response. RESULTS: Overall, 101 patients with PDB were included, 68 in the ZOL group and 33 in the NZOL group. The mean age was 65.2 ± 10.0 years, and 47% were female. Notably, 77% exhibited monostotic involvement, and only 3% had experienced fractures attributed to PDB. Mean ALP level at diagnosis was 160 ± 70.6 U/L. The median follow-up duration was 17 years since PDB diagnosis, comparable between the groups. Primary outcome was more prevalent in the ZOL compared to the NZOL group [42 patients (88%) VS 11 patients (52%) respectively, P = 0.004]. At the end of follow-up, mean ALP levels in the NZOL group were significantly higher than the levels in the ZOL group irrespective of the number of infusions received. CONCLUSION: The majority of patients with PDB experience a mild disease course, marked by monostotic involvement and a low prevalence of fractures. Zoledronic acid effectively manages PDB, providing sustained biochemical response. The necessity for multiple zoledronic acid injections remains questionable, often implemented due to osteoporosis.

Glucagon-like Peptide 1 Receptor Agonists and Cardiovascular Outcomes in Solid Organ Transplant Recipients With Diabetes Mellitus.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in type 2 diabetes. Limited data are available on diabetes treatment after solid organ transplantation. We aimed to explore the effect of GLP1-RAs on cardiovascular outcomes in transplanted recipients with diabetes. METHODS: We extracted data on adult transplant recipients (kidney, lungs, liver, heart) insured in a large health maintenance organization. Death-censored patients with diabetes treated with GLP1-RAs were matched with nonusers. The primary outcome was a composite of major cardiovascular events (MACEs): a nonfatal cardiac event (myocardial infarction, stable/unstable angina, coronary bypass, and coronary angiography), ischemic stroke and all-cause mortality. Secondary outcomes were MACE or peripheral vascular disease (MACE-PVD), and all-cause mortality. Safety outcomes included biliopancreatic adverse events. RESULTS: We included 318 patients (69% males, average age 58.3 ±â€…11.0 y) with a 3.1-y median follow-up. The incidence of MACE was 101 of 1000 patient-years in GLP1-RAs users compared with 134 of 1000 in controls (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.27-0.78). GLP1-RAs similarly reduced the risk of MACE-PVD (HR 0.53; 95% CI, 0.33-0.88) and the risk of all-cause mortality (HR 0.39; 95% CI, 0.18-0.84). Biliopancreatic adverse events occurred less in GLP1-RA users. CONCLUSIONS: Transplant recipients with diabetes who used GLP1-RAs had lower risks for MACE and all-cause mortality. These results may profoundly implicate the daily management of posttransplant recipients with diabetes, a population with a high prevalence of cardiometabolic risk factors and cardiovascular death. Transplant patients are usually excluded from randomized controlled trials and, hence might be undertreated with disease-modifying drugs. Larger prospective studies are needed in this unique population.

The Association Between Hypothyroidism Treatment and Mortality in Patients Hospitalized in Surgical Wards.

Limited data are available regarding the association between pre-admission thyroid-stimulating hormone (TSH) levels and prognosis in hospitalized surgical patients treated for hypothyroidism. We retrospectively evaluated a cohort of 1,451 levothyroxine-treated patients, hospitalized to general surgery wards. The 30-day mortality risk was 2-fold higher for patients with TSH of 5.0-10.0 mIU/L (adjusted OR, 2.3; 95% CI 1.1-5.1), and 3-fold higher for those with TSH > 10.0 mIU/L (3.4; 95% CI 1.3-8.7). Long-term mortality risk was higher in patients with TSH of 5.0-10.0 and above 10.0 mIU/L (adjusted HR, 1.2; 95% CI, 1.0-1.6, and 1.7; 95% CI 1.2-2.4, respectively). We found that in levothyroxine-treated adults hospitalized to surgical wards, increased pre-admission TSH levels are associated with increased short- and long-term mortality.

Hemoglobin decline as a signal for hyperprolactinemia onset prior to prolactinoma diagnosis in hypogonadal men.

BACKGROUND: Men harboring prolactinomas frequently suffer from central hypogonadism with secondary anemia. They present insidious and nonspecific symptoms of hypogonadism, making it difficult to diagnose the disease and determine its duration. The result is a delay in diagnosis, which may have harmful hormonal and metabolic consequences. We hypothesized that a decrease in hemoglobin (HB) levels prior to prolactinoma diagnosis, may signal hyperprolactinemia onset and estimate disease duration. METHODS: We retrospectively evaluated the prediagnosis temporal trends in HB levels of 70 males with prolactinoma, diagnosed from January 2010 to July 2022. Men without hypogonadism, patients that received testosterone, and those with unrelated anemia were excluded. RESULTS: Sixty-one of seventy men (87%) with prolactinoma presented with hypogonadism, and forty men (57%) had HB levels ≤13.5 g/dL at diagnosis. We identified 25 patients with "informative" HB curves (mean age, 46.1±14.9 years; median prolactin, 952 ng/mL; median follow-up, 14.0 years), demonstrating an obvious prediagnosis HB decrease (greater than 1.0 g/dL), from a prediagnosis baseline HB of 14.4 ± 0.3 to 12.9 ± 0.5 g/dL at diagnosis. The median "low-HB duration" (from the first low HB measurement to hyperprolactinemia diagnosis) was 6.1 years (IQR, 3.3-8.8 years). In symptomatic patients, we identified a correlation between "low-HB duration" and patient-reported sexual dysfunction duration (n = 17, R = 0.502, p = 0.04). The "low-HB duration" was significantly longer than the reported sexual dysfunction duration (7.0 ± 4.5 vs. 2.9 ± 2.5 years, p = 0.01). CONCLUSIONS: In our cohort of men with prolactinomas and hypogonadism, we found a marked decrease in HB levels that preceded prolactinoma diagnosis by a median of 6.1 years, with a mean delay of 4.1 years between HB decrease and hypogonadal symptoms appearance. These results suggest that HB decline prior to prolactinoma diagnosis may serve as a marker for hyperprolactinemia onset in a subset of hypogonadal men and allow a more accurate assessment of disease duration.

The Role of Aromatase Inhibitors in Male Prolactinoma.

BACKGROUND: dopamine agonists are the recommended treatment for male prolactinomas, but some patients may develop dopamine-agonist-resistant hyperprolactinemia, leading to persistent hypogonadism that requires treatment with testosterone. However, testosterone replacement therapy may be associated with a decrease in the efficacy of dopamine agonists due to the aromatization of testosterone to estradiol, which can stimulate the proliferation and hyperplasia of lactotroph cells in the pituitary, inducing resistance to dopamine agonists. OBJECTIVE: this paper systematically reviewed the role of aromatase inhibitors for men with prolactinoma and dopamine-agonist-resistant or persistent hypogonadism following treatment. METHOD: we performed a systematic review of all studies (according to PRISMA guidelines), assessing the role of aromatase inhibitors, including anastrozole and letrozole, for male prolactinoma. An English-language search for relevant studies was conducted on PubMed from its inception to 1 December 2022. The reference lists of the relevant studies were also reviewed. RESULTS: our systematic review identified six articles (nine patients), including five case reports and a single case series, on the use of aromatase inhibitors for male prolactinomas. Reducing estrogen levels with an aromatase inhibitor improved sensitivity to dopamine agonists, as the addition of anastrozole or letrozole improves the control of prolactin levels and may lead to the shrinkage of tumors. CONCLUSION: aromatase inhibitors are of potential value to patients with dopamine-agonist-resistant prolactinoma, or when hypogonadism persists while using high-dose dopamine agonists.

Cushing's syndrome in women: age-related differences in etiology and clinical picture.

OBJECTIVE: To evaluate the clinical presentation, biochemical profile, and etiology of Cushing's syndrome (CS) in women stratified by age. METHODS: Retrospective study of patients with CS, treated at Rabin Medical Center from 2000 to 2020, or Maccabi Healthcare Services in Israel from 2005 to 2017. Disease etiology, presentation and biochemical profile were compared according to age at diagnosis: ≤ 45, 46-64, or ≥ 65 years. Study was approved by the Ethics Review Boards of both facilities with waiver of consent. RESULTS: The cohort included 142 women (mean age, 46.0 ± 15.1 years):81 (57.0%) with Cushing's disease (CD), and 61 (43.0%) with adrenal CS. Pituitary etiology was more common among women < 45 (70.6%), compared with patients ≥ 65 years (31.6%) (P < 0.05). Among CS patients, hypercortisolism was diagnosed in the context of screening after an adrenal incidentaloma detection in 15.0% of patients < 45 and 53.8% of ≥ 65 years (P < 0.001). Weight gain was evident in 57.4% of women < 45 (56.3% CD, 60.0% CS), and 15.8% of women ≥ 65 years (50% CD, 0% CS) (P = 0.011). Mean UFC levels were highest for women < 45 (3.8 × ULN) and lowest for ≥ 65 years (2.3 × ULN) (P < 0.001). CONCLUSION: We have shown for the first time that women with CS ≥ 65 years of age more commonly have adrenal etiology. The initial presentation of CS also differs between age groups, where women < 45 years are likely to present with weight gain, while those ≥ 65 years are frequently diagnosed incidentally, when screening for hypercortisolism in the presence of an adrenal incidentaloma.

Predicting hypogonadotropic hypogonadism persistence in male macroprolactinoma.

PURPOSE: To study the baseline characteristics predicting hypogonadotropic hypogonadism (HH) persistence in men with macroprolactinoma that achieved prolactin normalization. DESIGN: Retrospective cohort study. METHODS: Male patients diagnosed with macroprolactinoma and HH that received cabergoline treatment with subsequent prolactin normalization were included: men that achieved eugonadism, and men that remained hypogonadal. Patient's demographic, clinical and biochemical parameters, sellar imaging, and visual fields tests were obtained. Univariate and multivariate models were used to identify predictors of HH persistence. RESULTS: Fifty-eight male patients (age 49.2 ± 12.6 years) with a median baseline prolactin of 1154 ng/mL (IQR 478-2763 ng/mL) and adenoma (maximal) diameter of 25.9 ± 14.8 mm were followed for a median of 5.6 years (IQR 3.0-10.7). Twelve men (21%) suffered from HH persistence at the end of follow-up and 46 men achieved eugonadism. Forty-two out of 46 men (91%) accomplished eugonadism within the first year following prolactin normalization. In a multivariate logistic regression model, hypopituitarism (OR 10.1; 95% CI 1.10-101.94), visual field defect (OR 9.9; 95% CI 1.07-92.33), and low baseline testosterone levels (OR 0.5; 95% CI 0.29-0.93) were independent predictors of HH persistence. CONCLUSION: In our cohort of men with macroprolactinoma that reached prolactin normalization with cabergoline treatment, 21% had HH persistence. Pituitary hormone deficiency, visual field defects, and low baseline testosterone levels were independently associated with HH persistence. 91% of men achieved eugonadism within the first year following prolactin normalization. These findings may support informed clinical decision-making regarding the initiation of testosterone replacement in men with macroprolactinomas.

Long-term response to cabergoline and multi-modal treatment in men with macroprolactinoma: Does size really matter?

OBJECTIVE: To study the outcome of men with macroprolactinoma following cabergoline treatment based on tumour size. DESIGN: Retrospective cohort study. METHODS: The study included 94 men, divided into three groups according to adenoma diameter: 10-19 mm (Group A, n = 36); 20-39 mm (Group B, n = 41); or ≥40 mm (Group C, giant prolactinomas, n = 17). Patients were followed for a mean of 7.5 years with sellar magnetic resonance imaging, visual fields and hormone measurements. RESULTS: Mean baseline prolactin was 767, 2090 and 24,806 ng/ml in Groups A, B and C, respectively (p < .01). Prolactin suppression below three times the upper limit of normal (ULN) was achieved in 34 (94%; mean weekly cabergoline dose of 1.2 mg), 37 (90%; cabergoline dose, 2.1 mg) and 15 (88%; cabergoline dose, 2.8 mg) men (p = .31) in each group. After excluding patients who underwent surgery and radiotherapy, cabergoline suppressed prolactin below three times ULN in 32/35 (91%), 29/37 (78%) and 11/14 (79%) men in Groups A, B and C, respectively (p = .27). Visual deficits were observed in 5 (14%), 12 (29%) and 10 (59%) patients (p < .01); improvement was achieved in 5/5 (100%), 11/12 (92%) and 10/10 (100%) of men in Groups A, B and C. Low baseline testosterone was measured in 26 (72%), 39 (95%) and 17 (100%) patients in the three groups (p < .01). Following multi-modal treatment, hypogonadism persisted in 3 (8%), 5 (12%) and 2 (12%) men, respectively (p = .85). CONCLUSION: Macroprolactinomas in men were controlled with cabergoline in 84% of cases, independent of tumour size. Pituitary surgery and adjuvant radiotherapy further improved long-term response to 91%.

True hyperprolactinemia in men without visible pituitary adenoma.

PURPOSE: Men with mild to moderate hyperprolactinemia rarely present with normal pituitary on MRI with no visible adenoma, a condition entitled also "idiopathic hyperprolactinemia" or "non-tumoral hyperprolactinemia". We have characterized a cohort of hyperprolactinemic men with normal pituitary imaging. DESIGN: We have identified 13 men with true hyperprolactinemia and normal pituitary MRI. Baseline clinical and hormonal characteristics and response to medical treatment were retrospectively retrieved from medical records. RESULTS: Mean age at diagnosis was 51 ± 16 years (range, 20-77); mean serum prolactin level at presentation was 91 ng/ml (range, 28-264), eight men presented with low baseline testosterone. Initial complaints leading to diagnosis included sexual dysfunction in ten men and gynecomastia in five. All patients were treated with cabergoline, except for one who was given bromocriptine; none required pituitary surgery. All patients normalized prolactin and testosterone with subsequent clinical improvement reported by most men. Currently, after a mean follow-up of 72 months, ten patients continue treatment with caborgoline (median weekly dose, 0.25 mg), whereas three men discontinued treatment. CONCLUSIONS: Men with symptomatic hyperprolactinemia may rarely present with normal pituitary imaging. Medical treatment can lead to hormonal improvement with clinical benefit.

Elevated blood pressure during emergency departments visit is associated with increased rate of hospitalization for heart failure: A retrospective cohort study.

There is a limited literature discussing the long-term outcome of patients admitted to the emergency department with elevated blood pressure. The aim of the present study was to evaluate outcomes of patients with hypertension who attended an emergency department. All patients with hypertension who attended an emergency department without target organ damage were evaluated. A composite end point at 18 months, which included all-cause mortality, acute coronary syndrome, cerebrovascular accident, or hospitalization for heart failure, were compared between patients with hypertension and those with normotension. Overall, 410 patients were included in the study. Baseline characteristics were similar between patients with hypertension and those with normotension, except chronic renal failure being more prevalent in patients with hypertension. The composite primary end point occurred similarly in both groups; however, hospitalization for heart failure was significantly more common in patients with hypertension. Elevated blood pressure during an emergency department visit is associated with an increased risk for hospitalization for heart failure during an 18-month follow-up period compared with normotension.

High blood pressure variability predicts 30-day mortality but not 1-year mortality in hospitalized elderly patients.

BACKGROUND: The association of blood pressure (BP) variability (BPV) in hospitalized patients, which represents day-to-day variability, with mortality has been extensively reported in patients with stroke, but poorly defined for other medical conditions. AIM AND METHOD: To assess the association of day-to-day blood pressure variability in hospitalized patients, 10 BP measurements were obtained in individuals ≥75 years old hospitalized in a geriatric ward. Day-to-day BPV, measured 3 times a day, was calculated in each patient as the coefficient of variation of systolic BP. Patients were stratified by quartiles of coefficient of variation of systolic BP, and 30-day and 1-year mortality data were compared between those in the highest versus the lowest (reference) group. RESULTS: Overall, 469 patients were included in the final analysis. Mean coefficient of variation of systolic BP was 12.1%. 30-day mortality and 1-year mortality occurred in 29/469 (6.2%) and 95/469 (20.2%) individuals respectively. Patients in the highest quartile of BPV were at a significantly higher risk for 30-day mortality (HR =4.12, CI 1.12-15.10) but not for 1-year mortality compared with the lowest BPV quartile (HR =1.61, CI 0.81-3.23). CONCLUSIONS: Day-to-day BPV is associated with 30-day, but not with 1-year mortality in hospitalized elderly patients.