Claudia E. Ramirez

Expression of Ki-67, PTTG1, FGFR4, and SSTR 2, 3, and 5 in nonfunctioning pituitary adenomas: a high throughput TMA, immunohistochemical study.

CONTEXT Nonfunctioning pituitary adenomas (NFPA) are the most common pituitary neoplasms. There is no clinical, biochemical, or histopathological marker that would accurately predict recurrence of NFPA. OBJECTIVE The aim of this study was to evaluate a large group of NFPA for the presence of potential markers of biological behavior. DESIGN AND SETTING A cross-sectional study using a high throughput tissue microarray technology was conducted at tertiary care centers. MATERIALS AND METHODS Seventy-four gonadotroph and null cell adenomas were included in the tissue microarray. Using highly specific antibodies and appropriate controls, we determined the expression of Ki-67, pituitary tumor transforming gene 1, the N-terminally truncated pituitary tumor-derived fibroblast growth factor receptor-4 (FGFR4), as well as somatostatin receptor subtypes 2, 3, and 5 (SSTR2, -3, and -5), in an attempt to establish correlations and/or associations with clinical characteristics of the patients. RESULTS Median Ki-67 index was 1.49 (interquartile range, 0.62-2.49). Pituitary tumor transforming gene 1 nuclear immunoreactivity was found in all but one tumor (median percentage of positive nuclei, 11.44); immunopositivity for FGFR4 was found in the majority of the tumors, with variable levels of expression. The immunostaining score for SSTR2 was significantly higher than that for SSTR3 or SSTR5. FGFR4 expression correlated positively with SSTR2 and SSTR5 immunostaining scores (r = 0.59; P < 0.001; and r = 0.46; P < 0.001, respectively). Multivariate analysis revealed that the Ki-67 index was significantly associated with a tumor size greater than 3 cm (odds ratio, 2.32; 95% confidence interval, 1.17-4.58) as well as with tumor recurrence (odds ratio, 1.4; 95% confidence interval, 1.03-1.89). CONCLUSIONS Ki-67 is the most consistent marker of biological behavior in NFPA. The finding of significant amounts of SSTR2 and SSTR5 may have therapeutic implications regarding the use of somatostatin analogs in preventing tumor recurrence.

Successful Mortality Reduction and Control of Comorbidities in Patients With Acromegaly Followed at a Highly Specialized Multidisciplinary Clinic

CONTEXT Acromegaly is usually due to the excessive secretion of GH by a pituitary adenoma. It is frequently accompanied by comorbidities that compromise quality of life and results in elevated mortality rates. OBJECTIVE To evaluate mortality and morbidity in patients with acromegaly receiving multimodal care. SETTING Tertiary care center. DESIGN, PATIENTS, AND METHODS Retrospective evaluation of 442 patients (65.4% women; mean age, 43.5 ± 13.1 y) followed for a median of 6 years (interquartile range [IQR], 3-10). RESULTS Twenty-two patients died during the study period (4.9%), representing a total standardized mortality ratio (SMR) of 0.72 (95% confidence interval [CI], 0.41-1.03). Standardized mortality ratios were 1.5 and 0.44 for patients whose last GH was above and below 2.5 ng/mL, respectively; 1.17 and 0.16 for those whose last GH was above and below 1 ng/mL, respectively; and 0.94 and 0.46 for those whose last IGF-1 was above and below 1.2 times the upper limit of normal (ULN), respectively. The prevalence of diabetes mellitus, hypertension, heart disease, and cancer was 30%, 35%, 8%, and 4.7%, respectively. The most common cause of death was cancer. On multivariate analysis, diabetes, heart disease, and cancer were related to a baseline GH > 10 ng/mL; the presence of cancer and the last IGF-1 were significant predictors of mortality. Survival decreased as the latest GH levels increased from < 1 ng/mL to > 5 ng/mL and as IGF-1 increased from < 1.2 to > 2 times the ULN. CONCLUSIONS Mortality in acromegaly can be successfully reduced, provided patients are treated using a multimodal approach with careful management of comorbidities.

Efficacy of Atomoxetine Versus Midodrine for the Treatment of Orthostatic Hypotension in Autonomic Failure

The clinical presentation of autonomic failure is orthostatic hypotension. Severely affected patients require pharmacological treatment to prevent presyncopal symptoms or frank syncope. We previously reported in a proof of concept study that pediatric doses of the norepinephrine transporter blockade, atomoxetine, increases blood pressure in autonomic failure patients with residual sympathetic activity compared with placebo. Given that the sympathetic nervous system is maximally activated in the upright position, we hypothesized that atomoxetine would be superior to midodrine, a direct vasoconstrictor, in improving upright blood pressure and orthostatic hypotension–related symptoms. To test this hypothesis, we compared the effect of acute atomoxetine versus midodrine on upright systolic blood pressure and orthostatic symptom scores in 65 patients with severe autonomic failure. There were no differences in seated systolic blood pressure (means difference=0.3 mm Hg; 95% confidence [CI], −7.3 to 7.9; P=0.94). In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P=0.03) compared with midodrine. Furthermore, atomoxetine (means difference=0.4; 95% CI, 0.1 to 0.8; P=0.02), but not midodrine (means difference=0.5; 95% CI, −0.1 to 1.0; P=0.08), improved orthostatic hypotension–related symptoms as compared with placebo. The results of our study suggest that atomoxetine could be a superior therapeutic option than midodrine for the treatment of orthostatic hypotension in autonomic failure.

Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial

CONTEXT Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance. OBJECTIVE The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function. DESIGN This was a randomized, double-blind, placebo-controlled study. SETTING This trial was conducted at Vanderbilt Clinical Research Center. PARTICIPANTS Participants included overweight individuals with prediabetes. INTERVENTIONS Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment. MAIN OUTCOME MEASURES The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion. RESULT Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per μU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per μU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 μg/mg Cr. This effect persisted 3 months after sildenafil discontinuation. CONCLUSIONS Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.

Clinical Characteristics and Treatment Outcome of 485 Patients with Nonfunctioning Pituitary Macroadenomas

Background. Nonfunctioning pituitary adenomas (NFPAs) are the most common benign lesions of the pituitary gland. Objective. To describe our experience with the management of NFPA. Study Design and Methods. Retrospective evaluation of NFPA patients managed between 2008 and 2013. We analyzed data regarding clinical presentation, imaging diagnosis, hormonal status, surgical, radiotherapeutic, and pharmacological treatment, and outcome. Results. 485 patients (54% men, mean age 53 ± 14 years) were followed for a median of 6.5 years. Visual field abnormalities and headaches were the presenting complaints in 87% and 66%, respectively. The diagnosis of NFPA was made incidentally in 6.2%, and 8% presented with clinical evidence of apoplexy. All patients harbored macroadenomas, with a median volume of 10306 mm3; 57.9% had supra- or parasellar invasion and 19.6% had tumors larger than 4 cm. Central hypothyroidism, hypogonadism, and hypocortisolism were present in 47.2%, 35.9%, and 27.4%, respectively. Surgical resection was performed at least once in 85.7%. Tumor persistence was documented in 27% and was related to the size and invasiveness of the lesion. In selected cases, radiotherapy proved to be effective in controlling or preventing tumor growth. Conclusions. The diagnosis and treatment of NFPA are complex and require a multidisciplinary approach.

Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema

Background The B2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time‐to‐resolution of angiotensin‐converting enzyme (ACE) inhibitor‐associated angioedema in 1 study of European patients. Objective We sought to test the hypothesis that a bradykinin B2 receptor antagonist would shorten time‐to‐resolution from ACE inhibitor‐associated angioedema. Methods Patients with ACE inhibitor–associated angioedema (defined as swelling of lips, tongue, pharynx, or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and patients with bowel edema only were excluded. Patients were randomized within 6 hours of presentation to subcutaneous icatibant 30 mg or placebo at 0 and 6 hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge. Results Thirty‐three patients were randomized and 31 received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded from analyses. Two‐thirds of patients were black and two‐thirds were women. Time‐to‐resolution of symptoms was similar in placebo and icatibant treatment groups (P = .19 for the primary symptom and P > .16 for individual symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the 2 treatment groups. Time‐to‐resolution of symptoms was similar in black and white patients. Conclusions This study does not support clinical efficacy of a bradykinin B2 receptor antagonist in ACE inhibitor‐associated angioedema.

Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans

Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p=0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p=0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p=0.022). Plasma EETs correlated with insulin sensitivity index (r=0.64, p=0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs.

Combination ergotamine and caffeine improves seated blood pressure and presyncopal symptoms in autonomic failure.

Severely affected patients with autonomic failure require pressor agents to counteract the blood pressure fall and improve presyncopal symptoms upon standing. Previous studies suggest that combination ergotamine and caffeine may be effective in the treatment of autonomic failure, but the efficacy of this drug has not been evaluated in controlled trials. Therefore, we compared the effects of ergotamine/caffeine on seated blood pressure and orthostatic tolerance and symptoms in 12 primary autonomic failure patients without history of coronary artery disease. Patients were randomized to receive a single oral dose of placebo, midodrine (5–10 mg), or ergotamine and caffeine (1 and 100 mg, respectively) in a single-blind, crossover study. Blood pressure was measured while patients were seated and after standing for up to 10 min, at baseline and at 1 h post-drug. Ergotamine/caffeine increased seated systolic blood pressure (SBP), the primary outcome, compared with placebo (131 ± 19 and 95 ± 12 mmHg, respectively, at 1 h post-drug; p = 0.003 for time effect). Midodrine also significantly increased seated SBP (121 ± 19 mmHg at 1 h post-drug; p = 0.015 for time effect vs. placebo), but this effect was not different from ergotamine/caffeine (p = 0.621). There was no significant effect of either medication on orthostatic tolerance; however, ergotamine/caffeine improved presyncopal symptoms (p = 0.034). These findings suggest that combination ergotamine and caffeine elicits a seated pressor response that is similar in magnitude to midodrine, and improves symptoms in autonomic failure. Thus, ergotamine/caffeine could be used as an alternate treatment for autonomic failure, in carefully selected patients without comorbid coronary artery disease.

A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition

CONTEXT The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction. OBJECTIVE To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil. DESIGN IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2). SETTING Two-center study. PARTICIPANTS Obese AA women. INTERVENTION A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks. MAIN OUTCOME IS, FMD. RESULTS G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], -0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, -0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, -2.6 (95% CI, -5.1 to -0.1; P = .04). CONCLUSIONS The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.

The multimodal treatment of acromegaly: current status and future perspectives.

Acromegaly is a chronic systemic disorder caused by a GH-secreting pituitary adenoma. Active acromegaly results in a poor quality of life due to symptoms such as headache, fatigue, arthralgia, depression, sexual dysfunction and hyperhidrosis; an increased prevalence of co-morbidities like diabetes, hypertension as well as cancer risk and a reduced life expectancy. Appropriate, modern, multimodal treatment of acromegaly has led to a significant improvement in quality of life, an adequate control of co-morbidities and a drastic reduction in the mortality rates that used to prevail in the past. This multimodal strategy includes an adequate selection of patients who are likely to benefit from surgical treatment (which has to be performed by a skilled pituitary neurosurgeon), the use of pharmacological interventions such as somatostatin analogs and dopamine agonists, which target the pituitary adenoma; and pegvisomant, a GH mutant acting as a competitive antagonist of the GH receptor. Radiation therapy is an important tool, particularly in parts of the World where resources are limited. The ultimate outcome of the individual patient depends on the judicious use of all these treatment options, which are critically analyzed in this mini-review.