Progesterone receptor expression in orbital cavernous hemangiomas

Orbital cavernous hemangiomas (OCH) have thick and highly cellular vascular walls. Ultrastructural studies have demonstrated the smooth muscle nature of these cells. Vascular neoplasms can modify their morphological and clinical features under hormonal stimulation. The purpose of the present study was to investigate the presence of smooth muscle markers and sex steroid receptors in 12 cases of OCH. Orbital cases were compared with cutaneous hemangiomas and subcutaneous angioleiomyomas. Smooth muscle actin (SMA) and desmin were localized in spindle cells of the vascular walls of all 12 cases studied. OCH showed immunohistochemical positivity with progesterone receptor (PR) antibody both in smooth muscular and in endothelial cells. For comparison, sex steroid receptors were studied in 10 cases of cutaneous cavernous hemangioma and in 10 cases of subcutaneous angioleiomyoma. PR was found in smooth muscle and endothelial cells of 6 out of 10 cases of subcutaneous angioleiomyoma and in none of the cases of cutaneous cavernous hemangioma. No positivity was obtained with estrogen receptor (ER) antibody in any of the cases tested. The present data suggest that OCH share morphological and immunohistochemical features with subcutaneous angioleiomyomas. Furthermore, immunohistochemical positivity with PR antibody indicates that OCH have to be added to the list of mesenchymal lesions that express sex steroid receptors. Received: 15 July 1999 / Accepted: 14 September 1999     

Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice

Although μ-receptor opioids are clinically important analgesics, they can also paradoxically cause hyperalgesia independently of opioid receptor activity, presumably via the action of neuroexcitatory glucoronide metabolites. However, it is unknown whether the commonly used μ-receptor opioid analgesic fentanyl, which is not subject to glucuronidation, can also induce hyperalgesia independently of opioid receptor activity. Thus, here we examined whether fentanyl increases nociception on the tail-withdrawal test in CD-1 mice concurrently treated with the opioid receptor antagonist naltrexone or in opioid receptor triple knock-out mice lacking μ, δ, and κ opioid receptors. For both groups, an acute fentanyl bolus dose (0.25 mg/kg, s.c.) and continuous fentanyl infusion (cumulative daily dose: 10 mg/kg) did not cause analgesia at any time. Instead, fentanyl significantly decreased withdrawal latencies relative to pre-drug values for the next 15–60 min and for six days, respectively. MK-801 blocked and reversed hyperalgesia caused by the acute injection and continuous infusion of fentanyl, respectively, in naltrexone-treated CD-1 mice, indicating the contribution of NMDA receptors to fentanyl hyperalgesia. These data show that the synthetic opioid fentanyl causes hyperalgesia independently of prior or concurrent opioid receptor activity or analgesia. Since the biotransformation of fentanyl does not yield any known pronociceptive metabolites, these data challenge assumptions regarding the role of neuroexcitatory metabolites in opioid-induced hyperalgesia.     

Lack of estradiol modulation of sleep deprivation-induced c-Fos in the rat brain

Women recover from sleep deprivation more efficiently than men, but the mechanism for this difference is unknown. Effects of estrogen on sleep suggest that it could play a role, but the brain targets on which estrogen may act to have this effect have not been identified. Sleep deprivation increases levels of the immediate-early gene protein c-Fos in selected brain regions, but it is unknown whether estrogen modulates this response. We investigated the influence of different levels of exogenous estradiol on the c-Fos response to sleep deprivation in ovariectomized female rats. Female rats were treated with low or high levels of estradiol (mimicking diestrous and proestrous levels, respectively) delivered via subcutaneous silastic tubes. Control ovariectomized females and sham-operated males were implanted with tubes filled with cholesterol. One week after surgery, half of the rats underwent a 3 h period of sleep deprivation during the light phase in a motorized Wahmann activity wheel that rotated constantly at a slow speed, while half were confined to fixed wheels. Immediately after sleep deprivation, animals were killed and their brains processed to detect c-Fos using immunohistochemistry. Sleep deprivation increased the number of c-Fos positive cells in a number of brain areas, including the caudate putamen, medial preoptic area, perifornical hypothalamus, and anterior paraventricular thalamic nucleus. Other areas, including the suprachiasmatic nucleus, posterior paraventricular hypothalamic nucleus, posterior paraventricular thalamic nucleus, arcuate nucleus, and central amygdala, did not respond to 3 h sleep deprivation with a significant increase in c-Fos levels. Levels of c-Fos induced in the selected brain regions by sleep deprivation were not modulated by estrogen levels, nor by sex.     

Primary Fibromatosis of the Breast in a Patient with Multiple Desmoid Tumors: Report of a Case with Evaluationof Estrogen and Progesterone Receptors

Fibromatosis (or desmoid tumor) is an infiltrative fibroblastic/myofibroblastic lesion presenting a moderate risk for local recurrence and no metastatic potential. Classically, these lesions are classified whether in abdominal or extra-abdominal sites, and may be multicentric or familial. Primary fibromatosis of the breast (PFB) is an uncommon lesion that shows histological similarities with abdominal fibromatosis (AF), and frequently poses difficulties in the differential diagnosis with other spindle cell tumors of the breast. It has been demonstrated that AF usually shows immunoreactivity for estrogen (ER) and progesterone (PR) receptors; conversely, in most of the studies, the cells from PFB are consistently negative for both receptors. We report on a case of a 41-year-old female with two desmoid tumors, affecting the abdominal wall and the breast tissue. To the best of our knowledge, there is no previous report in which hormonal receptors were evaluated in abdominal and mammary desmoid tumors in the same patient. We assessed the immunohistochemical expression of ER and PR in both lesions; while the AF showed immunoreactivity for both receptors, the cells from PFB were all negative. Although we have considered just this case, we still believe that these findings could support a distinctive etiopathogenesis of abdominal and mammary fibromatosis.     

ER、PR及其相应拮抗剂与甲状腺癌的相关性研究进展

雌激素受体(ER)、孕激素受体(PR)在甲状腺癌中的异常表达说明性激素受体在甲状腺癌的发病机制中起重要作用.ER、PR通过经典的基因途径及非基因途径对甲状腺癌的发生、发展及生物学特征产生重要影响.性激素受体拮抗剂抑制甲状腺癌细胞增殖作用的研究,将为甲状腺癌的治疗提供新的选择方案.     

Effects of sex, phase of the menstrual cycle and gonadal hormones on pain in healthy humans

Sex differences in pain have been noted; women typically report more pain than men. Gonadal hormones may influence pain reports, and, moreover, such hormones may help to explain sex differences and menstrual cycle differences in pain. This study measured venipuncture and intravenous catherization pain during the follicular and luteal phases of the menstrual cycle in regularly menstruating women. Pain was also assessed in a group of men. Pain ratings were higher in women than men. In women, pain ratings did not differ between the follicular and luteal phases. Estradiol and progesterone increased from follicular to luteal phases. Within-phase analyses revealed that pain ratings were positively correlated with estradiol and progesterone during the luteal phase. Moreover, increases in estradiol and progesterone across the menstrual cycle were positively correlated with increases in pain. These findings suggest that variations in gonadal hormones during the menstrual cycle influence the experience of pain in healthy women.     

Social conflict activates status-dependent endogenous analgesic or hyperalgesic mechanisms in male mice: effects of naloxone on nociception and behaviour

The concept of environmentally-induced activation of endogenous analgesia mechanisms rests, almost exclusively, upon studies which have involved the use of rather intense artificial stimuli. The current study was therefore designed to assess the validity of this concept under the more naturalistic conditions of social conflict between isolated resident mice and group-housed intruders. Agonistic experience was found to result in a potent, naloxone-reversible (10 mg/kg) analgesia in intruder mice while, in residents, it produced a moderate hyperalgesic reaction which was very sensitive to naloxone antagonism (0.1 mg/kg). Detailed videotape analyses revealed that only the behaviour of residents was significantly altered by naloxone treatment, with a highly selective inhibition of attack observed at 10 mg/kg. These data suggest that (1) social conflict in mice is a potent, and biologically-relevant, stimulus in the activation of endogenous naloxone-sensitive pain control mechanisms, (2) social status is an important determinant of nociceptive response to such experience and (3) inescapability from attack may be a critical factor in the development of encounter-induced analgesia.     

NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinociceptive tolerance

N-methyl-d-aspartate (NMDA) receptors and c-Jun N-terminal kinase (JNK) have been shown to be involved in morphine antinociceptive tolerance. However, whether chronic morphine-induced activation of the spinal JNK is NMDA receptor-dependent is unknown. The present study investigated the link between the spinal NMDA receptor NR2B subunit and the JNK activation during morphine antinociceptive tolerance in rats. Our results showed that chronic morphine treatment induced upregulation of the NR2B expression and activation of JNK in the spinal cord. Moreover, the increased NR2B-immunoreactivity (IR) and phosphorylated JNK-IR were observed mainly at the superficial dorsal horn laminae of the spinal cord; the spinal p-JNK was mainly expressed in astrocytes and NR2B in neurons. SP600125, a selective inhibitor of JNK, significantly attenuated morphine tolerance. MK-801, a noncompetitive NMDA receptor antagonist, not only suppressed morphine antinociceptive tolerance and the increase in NR2B, but also reduced the spinal JNK activation induced by chronic morphine treatment. These findings demonstrated for the first time that NMDA receptor-dependent activation of the spinal JNK contributes to morphine antinociceptive tolerance and that MK-801 attenuates morphine tolerance partly due to its inhibition on the spinal JNK activation.     

Progesterone at plasma levels lower than those of mid-pregnancy decreases sexual behavior in ovariectomized rats

Progesterone was measured by radioimmunoassay in the plasma of Day 10 pregnant rats and in the plasma of ovariectomized rats injected with doses of progesterone that result in a decrease in sexual receptivity. Doses of progesterone (1–2.5 mg) that result in behavioral refractoriness to further progesterone treatment result in lower plasma levels of progesterone than those measured on the tenth day of pregnancy, a time of naturally-occurring behavioral inhibition. These data re-assert the possibility that endogenous progesterone produced during pregnancy in the rat is at least partially responsible for the decrease in female sexual behavior seen during pregnancy in this species.     

Mental stress-induced hemoconcentration: Sex differences and mechanisms

Given the possible role of hemoconcentration in myocardial infarction and apparent sex differences in susceptibility, three studies examined sex differences in mental stress-induced hemoconcentration, and explored possible underlying mechanisms. Blood pressure, heart rate, and hematocrit were monitored at rest and in response to a mental stress task that was contrived to be increasingly provocative across the three studies. This was confirmed by self-report, performance, and cardiovascular reactivity data. The most convincing evidence for hemoconcentration effects and sex differences in hemoconcentration emerged from exposure to the more provocative of the stress tasks, with men also showing greater hemoconcentration than women. Blood pressure reactivity was a strong and consistent predictor of stress-induced hemoconcentration. These findings may help to explain sex differences in susceptibility to myocardial infarction.     

Sex differences in GABA/benzodiazepine receptor changes and corticosterone release after acute stress in rats

Since many hormonal indices of stress responsiveness are sexually dimorphic in rats, we examined sex differences and the effects of gonadectomy on the stress-related changes in GABA_A/benzodiazepine receptors in rats. Intact or ovariectomized female rats displayed a markedly greater corticosterone response and a more pronounced increase in benzodiazepine receptors than males (intact or orchidectomized) after acute handling or swim stress. Swim stress increased benzodiazepine receptor density without modifying affinity in cortex, hippocampus, and hypothalamus. Corticosterone treatment induced benzodiazepine receptor levels comparable to those seen after swim stress in all hormone groups. Handling stress also enhanced cortical low-affinity GABA_A receptor levels in males and ovariectomized females. Both GABA and benzodiazepine receptor levels were positively correlated with circulating corticosterone levels in female, but not male, groups. GABA/benzodiazepine coupling was unaffected by stress or hormonal status. These sexual dimorphisms in hormonal responses to stress may help elucidate the causes and consequences of stress-induced changes in the GABA_A/benzodiazepine receptor complex.     

Gonadal hormones and body temperature in rats: effects of estrous cycles, castration and steroid replacement.

The effects of estrous cycles, castration, subcutaneous steroid replacement, and intracranial steroid implants on the colonic temperatures were examined in 3 experiments. In Experiment 1 a rise in colonic temperature was observed at proestrus in intact females, and castration lowered the colonic temperatures of both males and females 1–2 hr before lights out. In Experiment 2 we tested the effects of 3 doses of progesterone and estradiol benzoate on the colonic temperatures of ovariectomized rats. Both hormones raised colonic temperature. The rise in colonic temperature was directly related to the progesterone dose, but it was inversely related to the dose of estradiol benzoate. In Experiment 3, progesterone and estradiol benzoate were implanted in the preoptic area of ovariectomized rats. Although estradiol benzoate in this site had no effect on colonic temperature, there was some suggestion that progesterone may increase colonic temperature when implanted in the preoptic area.     

Sex differences in fighting and defense induced in rats by shock and dextro-amphetamine during morphine abstinence

Male and female rats were injected with morphine while a control group received water injections. Four days following the final morphine injection, the animals received d-amphetamine and then were tested for their reaction to a stuffed leather glove. Drugged animals, while not showing a higher incidence of attack, did show increased escape tendencies when compared to controls. Both drugged and control animals were then shocked in the presence of either a same or different sexed conspecific. Nine measures of aggressive behavior were recorded from the pairs. Factor analysis of the nine intercorrelated measures produced two orthogonal aggressive factors — one indicative of defensive-threat behavior and one relating to actual fighting. Male-male pairs under morphine abstinence plus d-amphetamine scored significantly higher than the other groups on the fighting factor while drugged male-female pairs scored significantly higher on the defensive-threat factor. Although the fighting exhibited in this study was essentially restricted to male pairs under the drugged condition, evidence is presented suggesting that the agonistic behavior observed is not the species typical intermale aggression.     

Relationship between salivary cortisol and progesterone levels in humans

In four studies, each with multiple hormone assessments before and after positive emotion-arousing laboratory manipulations, salivary progesterone positively correlated with salivary cortisol in men and women taking hormonal contraceptives but not in freely cycling women. This is consistent with the idea that progesterone in men is largely adrenal in origin, whereas in women its sources are both ovarian and adrenal. In addition, bi-partial correlations revealed that change in cortisol was positively related to change in progesterone levels; this effect was stronger in men than in women. These findings suggest that progesterone is released from the adrenal along with cortisol in humans, due to general adrenal activation and/or possibly as an additional negative feedback mechanism to down-regulate the stress response.     

Assessment of leukocyte activity in mice devoid of the glucocorticoid receptor in the noradrenergic system (GRDBHCre)

Disturbances in brain monoamines, overactivity of the hypothalamo-pituitary adrenal (HPA) axis and pro-inflammatory tendency in the immune system are the key features of depressive disorders. Recently, several murine lines with mutations in glucocorticoid receptors (GRs) have been generated and these animals may be utilized for study depressive-like disorders. In the present study, we have investigated whether selective ablation of GRs in noradrenergic neurons affects functional properties of leukocytes and redirects them towards pro-inflammatory activity.Transgenic mice selectively devoid of GRs on noradrenergic cells were constructed using the Cre/loxP approach. Peritoneal leukocytes were collected from mutant and wild type (WT) animals of both sexes and were cultured in vitro for 24 h both in basal conditions and after application of selected pro- or anti-inflammatory stimuli. Metabolic activity and adherence were measured in basal conditions. Nitric oxide (NO) synthesis and arginase (ARG) activity were assessed as the markers of functional status of the cells. Because adult mutant mice lack adrenal medulla and thereby peripheral adrenaline, we modulated pro- and anti-inflammatory culture conditions by addition of noradrenaline (10–6 M). Finally, effects of in vivo pro-inflammatory challenge (with intraperitoneal administration of lipopolysaccharide) on properties of leukocytes were assessed 24 h (in both sexes) and 48 h later (in males only).The experiments indicated that selective ablation of GR in noradrenergic neurons did not affect fundamental properties of peritoneal leukocytes and exerted effects only under conditions of selected pro- or anti-inflammatory stimuli in vitro. Stronger response to pro-inflammatory stimulation in terms of NO synthesis and ARG activity may suggest pro-inflammatory tendency in mutant mice. In vivo inflammatory challenge failed to show any effect of GR ablation on selected parameters of leukocyte activity. Both in vitro studies and in vivo challenge revealed mainly sex-related differences in leukocyte activity.     

Sex difference in the effect of dexamethasone on open-field behavior in rats: Gonadal hormones

Previous experiments indicated that dexamethasone phosphate (DEX) increases open-field defecation in females but not in males. To examine the question of whether this sex difference in response to DEX is due to sex differences in gonadal hormones, female rats were (a) ovariectomized; (b) ovariectomized and injected with testosterone propionate prior to and during open-field testing; or (c) sham operated. Half the females in each group received DEX in their drinking water during the 4 day period of testing. DEX produced the expected reductions in body weight, adrenal weight, and plasma corticosterone levels. Despite the differences between the three groups on a variety of physiological measures, DEX produced comparable increases in open-field defecation in all cases. This indicates that the sex difference in the response of open-field defecation to DEX is not dependent on sex differences in circulating gonadal hormones.     

Sex differences in learning processes of classical and operant conditioning

Males and females learn and remember differently at different times in their lives. These differences occur in most species, from invertebrates to humans. We review here sex differences as they occur in laboratory rodent species. We focus on classical and operant conditioning paradigms, including classical eyeblink conditioning, fear-conditioning, active avoidance and conditioned taste aversion. Sex differences have been reported during acquisition, retention and extinction in most of these paradigms. In general, females perform better than males in the classical eyeblink conditioning, in fear-potentiated startle and in most operant conditioning tasks, such as the active avoidance test. However, in the classical fear-conditioning paradigm, in certain lever-pressing paradigms and in the conditioned taste aversion, males outperform females or are more resistant to extinction. Most sex differences in conditioning are dependent on organizational effects of gonadal hormones during early development of the brain, in addition to modulation by activational effects during puberty and adulthood. Critically, sex differences in performance account for some of the reported effects on learning and these are discussed throughout the review. Because so many mental disorders are more prevalent in one sex than the other, it is important to consider sex differences in learning when applying animal models of learning for these disorders. Finally, we discuss how sex differences in learning continue to alter the brain throughout the lifespan. Thus, sex differences in learning are not only mediated by sex differences in the brain, but also contribute to them.     

Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease

Dyskinesias represent a major complication of dopamine replacement therapy in Parkinson's disease (PD) and have prompted a search for alternative treatments. The most radical advances in this field have been provided by surgical manipulations of the deep basal ganglia nuclei, and particularly by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Although being very effective, high-frequency stimulation (HFS) of the STN is a poorly understood treatment. Besides its anti-akinetic activity, it can be pro-dyskinetic above a certain stimulation intensity. Accumulating evidence indicates that dyskinesias induced by STN-HFS and dopamine replacement therapy are linked to dysregulation of glutamate transmission in the basal ganglia. In rat models of PD, both types of dyskinesia are associated with increased concentrations of extracellular glutamate and altered expression of glutamate transporters in the substantia nigra pars reticulata and the striatum. Furthermore, a vast and ever growing literature has revealed changes in the expression, phosphorylation state, and/or subcellular distribution of specific subtypes of glutamate receptors in these dyskinetic conditions. Both types of dyskinesias are linked to an increased phosphorylation of NR2B-containing NMDA receptors in critical basal ganglia circuits. We conclude that disruption of glutamate homeostasis and activation of perisynaptic and extra-synaptic glutamate receptors are an important pathophysiological component of these treatment-induced dyskinesias in PD. These findings lay the ground for therapeutic development initiatives targeting dysfunctional components of glutamate transmission in the basal ganglia.     

Calcium dysregulation in Alzheimer's disease: From mechanisms to therapeutic opportunities

Calcium is involved in many facets of neuronal physiology, including activity, growth and differentiation, synaptic plasticity, and learning and memory, as well as pathophysiology, including necrosis, apoptosis, and degeneration. Though disturbances in calcium homeostasis in cells from Alzheimer's disease (AD) patients have been observed for many years, much more attention was focused on amyloid-β (Aβ) and tau as key causative factors for the disease. Nevertheless, increasing lines of evidence have recently reported that calcium dysregulation plays a central role in AD pathogenesis. Systemic calcium changes accompany almost the whole brain pathology process that is observed in AD, including synaptic dysfunction, mitochondrial dysfunction, presenilins mutation, Aβ production and Tau phosphorylation. Given the early and ubiquitous involvement of calcium dysregulation in AD pathogenesis, it logically presents a variety of potential therapeutic targets for AD prevention and treatment, such as calcium channels in the plasma membrane, calcium channels in the endoplasmic reticulum membrane, Aβ-formed calcium channels, calcium-related proteins. The review aims to provide an overview of the current understanding of the molecular mechanisms involved in calcium dysregulation in AD, and an insight on how to exploit calcium regulation as therapeutic opportunities in AD.