The Cushing Reflex: Oliguria as a Reflection of an Elevated Intracranial Pressure.

Oliguria is one of the clinical hallmarks of renal failure. The broad differential diagnosis is well known, but a rare cause of oliguria is intracranial hypertension (ICH). The actual knowledge to explain this relationship is scarce. Almost all literature is about animals where authors describe the Cushing reflex in response to ICH. We hypothesize that the Cushing reflex is translated towards the sympathetic nervous system and renin-angiotensin-aldosterone system with a subsequent reduction in medullary blood flow and oliguria. Recently, we were confronted with a patient who had complicated pituitary surgery and displayed multiple times an oliguria while he developed ICH.

Akt2/LDLr double knockout mice display impaired glucose tolerance and develop more complex atherosclerotic plaques than LDLr knockout mice.

AIM: To characterize the phenotype of Akt2/low-density-lipoprotein receptor double knockout (dKO) (Akt2/LDLr dKO) mice with respect to insulin resistance and features of atherosclerotic plaque progression. METHODS AND RESULTS: Metabolic profile and atherosclerotic plaque progression were compared between LDLr KO mice and Akt2/LDLr dKO mice. Total cholesterol, glucose, and insulin levels were significantly higher and oral glucose tolerance test (GTT) was more impaired in Akt2/LDLr dKO mice than in LDLr KO mice. Although atherosclerotic plaques at both the carotid artery and the aortic root of Akt2/LDLr dKO mice were significantly smaller (P < 0.05) compared with LDLr KO controls, plaque composition in these mice was more complex, showing 34-50% reduced collagen content (P < 0.01), 1.4-fold larger necrotic cores (P < 0.05) and six-fold more TUNEL-positive cells (P < 0.01). In situ zymography revealed a more than two-fold higher gelatinolytic activity in Akt2/LDLr dKO mice (P < 0.05). In vitro analyses showed that deletion of Akt2 caused decreased migration, proliferation, and collagen content of vascular smooth muscle cells (VSMCs) and disturbed the balance of metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) mRNA expression in macrophages and VSMCs. CONCLUSION: Akt2/LDLr dKO mice develop insulin resistance and complex atherosclerotic lesions. These phenotypic characteristics make Akt2/LDLr dKO mice an interesting mouse model to study the effects of insulin resistance on the development and progression of atherosclerosis.

Microcirculation and atherothrombotic parameters in prolactinoma patients: a pilot study.

Atherothrombosis is a multifactorial process, governed by an interaction between the vessel wall, hemodynamic factors and systemic atherothrombotic risk factors. Recent in vitro, human ex vivo and animal studies have implicated the hormone prolactin as an atherothrombotic mediator. To address this issue, we evaluated the anatomy and function of various microvascular beds as well as plasma atherothrombosis markers in patients with elevated prolactin levels. In this pilot study, involving 10 prolactinoma patients and 10 control subjects, sidestream dark field (SDF) imaging revealed a marked perturbation of the sublingual microcirculation in prolactinoma patients compared to control subjects, as attested to by significant changes in microvascular flow index (2.74 ± 0.12 vs. 2.91 ± 0.05, respectively; P = 0.0006), in heterogeneity index (0.28 [IQR 0.18-0.31] vs. 0.09 [IQR 0.08-0.17], respectively; P = 0.002) and lower proportion of perfused vessels (90 ± 4.0% vs. 95 ± 3.0%, respectively; P = 0.016). In the retina, fluorescein angiography (FAG) confirmed these data, since prolactinoma patients more often have dilatated perifoveal capillaries. In plasma, prolactinoma patients displayed several pro-atherogenic disturbances, including a higher endogenous thrombin potential and prothrombin levels as well as decreased HDL-cholesterol levels. Prolactinoma patients are characterized by microvascular dysfunction as well as plasma markers indicating a pro-atherothrombotic state. Further studies are required to assess if prolactin is causally involved in atherothrombotic disease.

Functional consequences of prolactin signalling in endothelial cells: a potential link with angiogenesis in pathophysiology?

Prolactin is best known as the polypeptide anterior pituitary hormone, which regulates the development of the mammary gland. However, it became clear over the last decade that prolactin contributes to a broad range of pathologies, including breast cancer. Prolactin is also involved in angiogenesis via the release of pro-angiogenic factors by leukocytes and epithelial cells. However, whether prolactin also influences endothelial cells, and whether there are functional consequences of prolactin-induced signalling in the perspective of angiogenesis, remains so far elusive. In the present study, we show that prolactin induces phosphorylation of ERK1/2 and STAT5 and induces tube formation of endothelial cells on Matrigel. These effects are blocked by a specific prolactin receptor antagonist, del1-9-G129R-hPRL. Moreover, in an in vivo model of the chorioallantoic membrane of the chicken embryo, prolactin enhances vessel density and the tortuosity of the vasculature and pillar formation, which are hallmarks of intussusceptive angiogenesis. Interestingly, while prolactin has only little effect on endothelial cell proliferation, it markedly stimulates endothelial cell migration. Again, migration was reverted by del1-9-G129R-hPRL, indicating a direct effect of prolactin on its receptor. Immunohistochemistry and spectral imaging revealed that the prolactin receptor is present in the microvasculature of human breast carcinoma tissue. Altogether, these results suggest that prolactin may directly stimulate angiogenesis, which could be one of the mechanisms by which prolactin contributes to breast cancer progression, thereby providing a potential tool for intervention.

The prolactin receptor is expressed in macrophages within human carotid atherosclerotic plaques: a role for prolactin in atherogenesis?

Atherosclerotic vascular disease is the consequence of a chronic inflammatory process, and prolactin has been shown to be a component of the inflammatory response. Additionally, recent studies indicate that prolactin contributes to an atherogenic phenotype. We hypothesized that this may be the result of a direct effect of prolactin on atherogenesis through activation of the prolactin receptor. Human carotid atherosclerotic plaques were obtained from patients by endarteriectomies. The mRNA of prolactin receptor, but not of prolactin, was detected in these atherosclerotic plaques by quantitative real-time PCR. In situ hybridization confirmed the expression of the prolactin receptor in mononuclear cells. Analysis at the protein level using immunohistochemistry and immunoelectron microscopy revealed that the prolactin receptor was abundantly present in macrophages near the lipid core and shoulder regions of the plaques. Our findings demonstrate that the prolactin receptor is present in macrophages of the atherosclerotic plaque at sites of most prominent inflammation. We therefore propose that prolactin receptor signaling contributes to the local inflammatory response within the atherosclerotic plaque and thus to atherogenesis.

Prolactin fragmentation by trophoblastic matrix metalloproteinases as a possible contributor to peripartum cardiomyopathy and pre-eclampsia.

Although peripartum cardiomyopathy (PPCM) is a rare disease, it has very serious consequences for both mother and child. No single cause has been held responsible for the pathogenesis. Recent studies have indicated that increased proteolytic cathepsin D activity in cardiomyocytes results in16kDa prolactin fragments with anti-angiogenic and apoptotic properties, which may contribute to the development of PPCM. In support of these findings, lowering full-length prolactin production by bromocriptine therapy has been reported to prevent impairment of cardiac function. PPCM is associated with an increased co-existence of pre-eclampsia, however, a causal relationship has been disputed. We hypothesize that the pathophysiology of PPCM and pre-eclampsia share the same molecular pathway: increased activity of trophoblastic matrix metalloproteinases at the feto-maternal interface may aggravate proteolysis of full-length prolactin, and subsequently the formed 16kDa prolactin fragments may contribute to deterioration of PPCM and pre-eclampsia. Therefore, we argue that it may be worthwhile to explore wether prolactin inhibition is not only beneficial for PPCM patients, but also for the much more prevalent pre-eclamptic women.

Should anterior pituitary function be tested during follow-up of all patients presenting at the emergency department because of traumatic brain injury?

CONTEXT: A wide range (15-56%) of prevalences of anterior pituitary insufficiency are reported in patients after traumatic brain injury (TBI). However, different study populations, study designs, and diagnostic procedures were used. No data are available on emergency-department-based cohorts of TBI patients. OBJECTIVE: To assess the prevalence of pituitary dysfunction in an emergency-department-based cohort of TBI patients using strict endocrinological diagnostic criteria. METHODS: Of all the patients presenting in the emergency department with TBI over a 2-year period, 516 matched the inclusion criteria. One hundred and seven patients (77 with mild TBI and 30 with moderate/severe TBI) agreed to participate. They were screened for anterior pituitary insufficiency by GHRH-arginine testing, evaluation of fasting morning hormone levels (cortisol, TSH, free thyroxine, FSH, LH, and 17beta-estradiol or testosterone), and menstrual history 3-30 months after TBI. Abnormal screening results were defined as low peak GH to GHRH-arginine, or low levels of any of the end-organ hormones with low or normal pituitary hormone levels. Patients with abnormal screening results were extensively evaluated, including additional hormone provocation tests (insulin tolerance test, ACTH stimulation test, and repeated GHRH-arginine test) and assessment of free testosterone levels. RESULTS: Screening results were abnormal in 15 of 107 patients. In a subsequent extensive endocrine evaluation, anterior pituitary dysfunction was diagnosed in only one patient (partial hypocortisolism). CONCLUSION: By applying strict diagnostic criteria to an emergency-department-based cohort of TBI patients, it was shown that anterior pituitary dysfunction is rare (<1%). Routine pituitary screening in unselected patients after TBI is unlikely to be cost-effective.

Hormones and cardiovascular disease: a shift in paradigm with clinical consequences?

Several endocrine disorders have been associated with an increased risk of cardiovascular disease (CVD) and mortality. In addition, even subtle hormonal disturbances may modulate the function of cardiovascular organs. In this article, we discuss in detail the contribution of thyroid hormones, cortisol, the somatotropic hormones, and prolactin in the development of CVD. We do not only discuss epidemiological evidence on the association between hormones and cardiovascular disease, but we also address possible pathophysiological mechanisms underlying this association. In fact, hormones can contribute to the development of CVD both indirectly by inducing secondary metabolic changes such as hypertension, insulin resistance, or dyslipidemia, and directly by modulation of cellular pathways that are important in the process of atherosclerotic plaque formation (atherogenesis), plaque instability, and thrombosis. To date several new therapeutic approaches that focus on the control of hormones at the tissue level, independently of their circulating levels, are being developed. These may offer new possibilities for cardiovascular risk reduction.

Pregnancy in women suffering from familial hypercholesterolemia: a harmful period for both mother and newborn?

PURPOSE OF REVIEW: The present review aims to highlight the consequences for mother and child of profound hypercholesterolemia during pregnancy of women with familial hypercholesterolemia. RECENT FINDINGS: Familial hypercholesterolemia is increasingly diagnosed in younger patients due to the existence of screening programs and more widespread cholesterol testing. Increasing numbers of young female patients with familial hypercholesterolemia raise the issue of pregnancy and its consequences for the familial hypercholesterolemia patient herself but also for her offspring. When pregnancy is considered, lipid-lowering drugs are often discontinued because of the fear for teratogenic effects. The evidence for teratogenesis associated with statin use is scant and conflicting. On the other hand, several studies do suggest that pronounced hypercholesterolemia during pregnancy has adverse effects on both fetus and mother. In fact, human and animal studies reveal an enhanced tendency toward atherosclerosis in the offspring of women who suffer from hypercholesterolemia during pregnancy. In animal studies, some evidence exists that this can be reversed by treatment with lipid-lowering and antioxidative agents. Until today, however, no human studies exist that have evaluated efficacy or safety of lipid-lowering interventions in pregnant women with familial hypercholesterolemia. SUMMARY: Altogether, the suggested relationship between severe hypercholesterolemia and enhanced atherosclerosis in offspring and possibly the mother warrants further confirmation and, consequently, studies that focus on therapeutic strategies that can safely lower cholesterol levels during pregnancy in these women.

Prolactin does not affect human platelet aggregation or secretion.

Platelets play an important role in the development of plaque formation and in the events after rupture of the atherosclerotic plaque, leading to atherothrombosis. Multiple hormones, either in excess or when deficient, are involved in the development of atherothrombotic disease, but, to which extent such hormones affect platelet function, is still controversial. It was the objective of this study to assess the ability of the pituitary hormone prolactin to affect platelet functions. Venous blood was collected from six healthy males. Platelet activation was studied by (i) flow cytometry in whole blood (exposure of P-selectin as a measure of platelet secretion, and binding of PAC-1 as a measure of ligand-binding conformation of alpha(IIb)beta(3)), and by (ii) optical aggregation and whole blood aggregation. All studies were performed without and with exposure to several concentrations of ADP (0.1, 0.5 and 1.0 microM) and prolactin (50 and 1,000 microg/l). The presence of the prolactin receptor was investigated by Western blot and flow cytometry. In response to either 50 or 1,000 microg/l prolactin, no evidence of platelet activation or aggregation was found. In addition, ADP-induced platelet activation or aggregation was not enhanced by prolactin. Finally, prolactin receptors could not be detected on the surface of platelets. The present data indicate that prolactin does not directly modulate platelet function.

Hypercoagulable state in Cushing's syndrome: a systematic review.

CONTEXT: It has been debated whether an increased risk of venous thromboembolism (VTE) exists in patients with Cushing's syndrome. OBJECTIVE: We aimed to summarize published literature on the effects of endogenous hypercortisolism on coagulation and fibrinolysis, as well as on the clinical outcome of VTE. DATA SOURCES: We searched the MEDLINE and EMBASE databases up to July 2008. Review of reference lists further identified candidate studies. STUDY SELECTION: Two investigators independently performed study selection and data extraction. Eligible studies had to include Cushing's syndrome patients and either evaluate hemostatic parameters in comparison with control persons or posttreatment levels or describe the occurrence of VTE. DATA EXTRACTION: The Newcastle-Ottawa Scale was used to assess study quality. A scoring system divided studies into categories of low, medium and high quality. DATA SYNTHESIS: Of 441 identified publications, 15 reports were included. They contained information on eight cross-sectionals, two intervention, and eight cohort studies. No high-quality studies were identified. Hypercoagulability was suggested by high levels of factor VIII, factor IX, and von Willebrand factor and by evidence of enhanced thrombin generation. A risk of 1.9 and 2.5% was reported for VTE not provoked by surgery, whereas risk of postoperative VTE varied between 0 and 5.6%, with one outlier of 20%. VTE was reported as the cause of death in 0-1.9% of Cushing's syndrome patients. CONCLUSIONS: Available studies suggest a high risk of venous thrombosis in patients with Cushing's syndrome. Glucocorticoid-induced hypercoagulability as well as surgery and obesity almost certainly contribute to this thrombotic tendency.

Mechanistic insights and clinical relevance of the interaction between acute coronary syndromes and lipid metabolism.

As part of the acute phase reaction, lipid metabolism is significantly altered in patients with unstable coronary syndromes. The clinical relevance and the mechanisms underlying this phenomenon are discussed in this article. Cholesterol reduction takes place in the first hours of an acute coronary event; thus, plasma levels determined at this point should be interpreted with caution. This reduction may be just a consequence of the inflammatory response, or it may be also related to an increase in cellular uptake of cholesterol for tissue repair and hormonal synthesis. A synergistic effect between this predisposition to cholesterol reduction and statin therapy appears to exist during acute coronary syndromes. Triglyceride changes are variable during acute coronary syndromes, and recent data indicate that the pattern of triglyceride variation is a potential risk marker in those patients, possibly because it reflects neurohumoral changes related to the acute phase.

High-density lipoprotein as a key component in the prevention of premature atherosclerotic disease in the insulin resistance syndrome.

The occurrence of insulin resistance syndrome (IRS), which is also called the metabolic syndrome, has rapidly increased over the last decade. IRS involves such major clinical features as premature atherosclerosis and its related complications. The major proatherogenic phenotype includes elevated plasma levels of apolipoprotein B-containing lipid particles. Another lipid particle of high-density lipoprotein (HDL) plays a key role in the prevention of atherosclerotic disease. Decreased levels of HDL cholesterol are found in IRS; however, little is known about metabolic pathways related to HDL antiatherogenic properties in this pathological condition. Hitherto, in other dyslipidemic populations, the antiatherogenic properties of HDL have been most frequently characterized in vitro. Recently, knowledge about antiatherogenic pathways in which HDL particles are involved in vivo has been accumulating. Consistent with these developments, new therapeutic strategies can be envisaged for IRS, including treatment with recombinant HDL particles and inhibitors of cholesteryl ester transfer protein.