Estrogen and Progesterone Integration in an in vitro Model of RP3V Kisspeptin Neurons.

Positive feedback on gonadotropin release requires not only estrogen but also progesterone to activate neural circuits. In rodents, ovarian estradiol (E2) stimulates progesterone synthesis in hypothalamic astrocytes (neuroP), needed for the luteinizing hormone (LH) surge. Kisspeptin (kiss) neurons are the principal stimulators of gonadotropin-releasing hormone neurons, and disruption of kiss signaling abrogates the LH surge. Similarly, blocking steroid synthesis in the hypothalamus or deleting classical progesterone receptor (PGR) selectively in kiss neurons prevents the LH surge. These results suggest a synergistic action of E2 and progesterone in kiss neurons to affect gonadotropin release. The mHypoA51, immortalized kiss-expressing neuronal cell line derived from adult female mice, is a tractable model for examining integration of steroid signaling underlying estrogen positive feedback. Here, we report that kiss neurons in vitro integrate E2 and progesterone signaling to increase levels of kiss translation and release. mHypoA51 neurons expressed nonclassical membrane progesterone receptors (mPRα and mPRß) and E2-inducible PGR, required for progesterone-augmentation of E2-induced kiss expression. With astrocyte-conditioned media or in mHypoA51-astrocyte co-culture, neuroP augmented stimulatory effects of E2 on kiss protein. Progesterone activation of classical, membrane-localized PGR led to activation of MAPK and Src kinases. Importantly, progesterone or Src activation induced release of kiss from E2-primed mHypoA51 neurons. Consistent with previous studies, the present results provide compelling evidence that the interaction of E2 and progesterone stimulates kiss expression and release. Further, these results demonstrate a mechanism though which peripheral E2 may prime kiss neurons to respond to neuroP, mediating estrogen positive feedback.

Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes.

Despite affecting millions of individuals, the etiology of hot flushes remains unknown. Here we review the physiology of hot flushes, CNS pathways regulating heat-dissipation effectors, and effects of estrogen on thermoregulation in animal models. Based on the marked changes in hypothalamic kisspeptin, neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes. In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R), the primary receptor for NKB. Furthermore, activation of NK3R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature. Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation. These data suggest that arcuate KNDy neurons relay estrogen signals to preoptic structures regulating heat-dissipation effectors, supporting the hypothesis that KNDy neurons participate in the generation of flushes.

Validation of the 12-item stroke-specific quality of life scale in a biethnic stroke population.

The 12-item Stroke-Specific Quality of Life Scale (SSQOL), a shortened version of the original SSQOL, was developed to be an efficient and valid outcome in stroke research. We aimed to assess the validity of this scale in a biethnic ischemic stroke population. Patients with validated ischemic stroke who completed the original 49-item SSQOL at 90 days poststroke were identified from a population-based study, the Brain Attack Surveillance in Corpus Christi Project. Cronbach's α was used to assess the internal consistency of the scales. Intraclass correlation coefficients and linear regression were used to assess agreement between the 2 scales. The study cohort comprised 45 patients with ischemic stroke, 56% female and 51% Mexican American, with a mean age of 66.0±11.3 years. The mean score for the 49-item scale was 3.33±0.84, compared with 3.31±0.95 for the 12-item scale. Internal consistency was 0.96 for the 49-item scale and 0.88 for the 12-item scale. The 2 scales were highly correlated (intraclass correlation coefficient, 0.98; R2=0.97). This study in patients with ischemic stroke from diverse racial/ethnic backgrounds found that the more efficient 12-item SSQOL is a valid alternative to the full 49-item SSQOL for the assessment of health-related quality of life.

The prevalence of spirituality, optimism, depression, and fatalism in a bi-ethnic stroke population.

To provide insight into the reduced post-stroke all-cause mortality among Mexican Americans, we explored ethnic differences in the pre-stroke prevalence of (1) spirituality, (2) optimism, (3) depression, and (4) fatalism in a Mexican American and non-Hispanic white stroke population. The Brain Attack Surveillance in Corpus Christi (BASIC) project is a population-based stroke surveillance study in Nueces County, Texas. Seven hundred ten stroke patients were queried. For fatalism, optimism, and depression scales, unadjusted ethnic comparisons were made using linear regression models. Regression models were also used to explore how age and gender modify the ethnic associations after adjustment for education. For the categorical spirituality variables, ethnic comparisons were made using Fisher's exact tests. Mexican Americans reported significantly more spirituality than non-Hispanic whites. Among women, age modified the ethnic associations with pre-stroke depression and fatalism but not optimism. Mexican American women had more optimism than non-Hispanic white women. With age, Mexican American women had less depression and fatalism, while non-Hispanic white women had more fatalism and similar depression. Among men, after adjustment for education and age, there was no ethnic association with fatalism, depression, and optimism. Spirituality requires further study as a potential mediator of increased survival following stroke among Mexican Americans. Among women, evaluation of the role of optimism, depression, and fatalism as they relate to ethnic differences in post-stroke mortality should be explored.

Fatalism, optimism, spirituality, depressive symptoms, and stroke outcome: a population-based analysis.

BACKGROUND AND PURPOSE: We sought to describe the association of spirituality, optimism, fatalism, and depressive symptoms with initial stroke severity, stroke recurrence, and poststroke mortality. METHODS: Stroke cases from June 2004 to December 2008 were ascertained in Nueces County, TX. Patients without aphasia were queried on their recall of depressive symptoms, fatalism, optimism, and nonorganizational spirituality before stroke using validated scales. The association between scales and stroke outcomes was studied using multiple linear regression with log-transformed National Institutes of Health Stroke Scale and Cox proportional hazards regression for recurrence and mortality. RESULTS: Six hundred sixty-nine patients participated; 48.7% were women. In fully adjusted models, an increase in fatalism from the first to third quartile was associated with all-cause mortality (hazard ratio, 1.41; 95% CI, 1.06-1.88) and marginally associated with risk of recurrence (hazard ratio, 1.35; 95% CI, 0.97-1.88), but not stroke severity. Similarly, an increase in depressive symptoms was associated with increased mortality (hazard ratio, 1.32; 95% CI, 1.02-1.72), marginally associated with stroke recurrence (HR, 1.22; 95% CI, 0.93-1.62), and with a 9.0% increase in stroke severity (95% CI, 0.01-18.0). Depressive symptoms altered the fatalism-mortality association such that the association of fatalism and mortality was more pronounced for patients reporting no depressive symptoms. Neither spirituality nor optimism conferred a significant effect on stroke severity, recurrence, or mortality. CONCLUSIONS: Among patients who have already had a stroke, self-described prestroke depressive symptoms and fatalism, but not optimism or spirituality, are associated with increased risk of stroke recurrence and mortality. Unconventional risk factors may explain some of the variability in stroke outcomes observed in populations and may be novel targets for intervention.

Neurokinin B and the hypothalamic regulation of reproduction.

Loss-of-function mutations in the genes encoding either neurokinin B (NKB) or its receptor, NK3 (NK3R), result in hypogonadotropic hypogonadism, characterized by an absence of pubertal development and low circulating levels of LH and gonadal steroids. These studies implicate NKB and NK3R as essential elements of the human reproductive axis. Studies over the last two decades provide evidence that a group of neurons in the hypothalamic infundibular/arcuate nucleus form an important component of this regulatory circuit. These neurons are steroid-responsive and coexpress NKB, kisspeptin, dynorphin, NK3R, and estrogen receptor α (ERα) in a variety of mammalian species. Compelling evidence in the human indicates these neurons function in the hypothalamic circuitry regulating estrogen negative feedback on gonadotropin-releasing hormone (GnRH) secretion. Moreover, in the rat, they form a bilateral, interconnected network that projects to NK3R-expressing GnRH terminals in the median eminence. This network provides an anatomical framework to explain how coordination among NKB/kisspeptin/dynorphin/NK3R/ERα neurons could mediate feedback information from the gonads to modulate pulsatile GnRH secretion. There is substantial (but indirect) evidence that this network may be part of the neural circuitry known as the "GnRH pulse generator," with NK3R signaling as an important component. This theory provides a compelling explanation for the occurrence of hypogonadotropic hypogonadism in patients with inactivating mutations in the TAC3 or TACR3 genes. Future studies will be needed to determine whether NKB signaling plays a permissive role in the onset of puberty or is part of the driving force initiating the maturation of reproductive function.