Browsing by Subject "Ovariectomy"
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Item Eludicating triggers and neurochemical circuits underlying hot flashes in an ovariectomy model of menopause(2016-02-26) Federici, Lauren Michele; Shekhar, Anantha; Goodlett, Charles; Johnson, Philip L.; Oxford, Gerry S.; Rusyniak, Daniel E.Menopausal symptoms, primarily hot flashes, are a pressing clinical problem for both naturally menopausal women and breast and ovarian cancer patients, with a high societal and personal cost. Hot flashes are poorly understood, and animal modeling has been scarce, which has substantially hindered the development of non-hormonal treatments. An emerging factor in the hot flash experience is the role of anxiety and stress-related stimuli, which have repeatedly been shown to influence the bother, frequency, and severity of hot flashes. Causal relationships are difficult to determine in a clinical setting, and the use of animal models offers the ability to elucidate causality and mechanisms. The first part of this work details the development and validation of novel animal models of hot flashes using clinically relevant triggers (i.e., compounds or stimuli that cause hot flashes in clinical settings), which also increase anxiety symptoms. These studies revealed that these triggers elicited strong (7-9 °C) and rapid hot flash-associated increases in tail skin temperature in rats. In a surgical ovariectomy rat model of menopause, which typically exhibit anxiety-like behavior, hot flash provocation revealed an ovariectomy-dependent vulnerability, which was attenuated by estrogen replacement in tested models. An examination of the neural circuitry in response to the most robust flushing compound revealed increased cellular activity in key thermoregulatory and emotionally relevant areas. The orexin neuropeptide system was hyperactive and presented as a novel target; pretreatment with selective and dual orexin receptor antagonists significantly diminished or eliminated, respectively, the response to a hot flash provocation in ovariectomized rats. The insertion/deletion polymorphism of the serotonin transporter has been linked to increased anxiety-associated traits in humans, and subsequent studies prolonged hot flashes in SERT+/- rats, which also caused hot flashes in highly symptomatic women. These studies indicate the orexin system may be a novel non-hormonal treatment target, and future studies will determine the therapeutic importance of orexin receptor antagonists for menopausal symptoms.Item Functional contributions of a sex-specific population of myelinated aortic baroreceptors in rat and their changes following ovariectomy(2014) Santa Cruz Chavez, Grace C.; Schild, John H.; Nicol, Grant D.; Oxford, Gerry S.; Rusyniak, Daniel E.; Vasko, Michael R.Gender differences in the basal function of autonomic cardiovascular control are well documented. Consistent baroreflex (BRx) studies suggest that women have higher tonic parasympathetic cardiac activation compared to men. Later in life and concomitant with menopause, a significant reduction in the capacity of the BRx in females increases their risk to develop hypertension, even exceeding that of age-matched males. Loss of sex hormones is but one factor. In female rats, we previously identified a distinct myelinated baroreceptor (BR) neuronal phenotype termed Ah-type, which exhibits functional dynamics and ionic currents that are a mix of those observed in barosensory afferents functionally identified as myelinated A-type or unmyelinated C-type. Interestingly, Ah-type afferents constitute nearly 50% of the total population of myelinated aortic BR in female but less than 2% in male rat. We hypothesized that an afferent basis for sexual dimorphism in BRx function exists. Specifically, we investigated the potential functional impact Ah-type afferents have upon the aortic BRx and what changes, if any, loss of sex hormones through ovariectomy brings upon such functions. We assessed electrophysiological and reflexogenic differences associated with the left aortic depressor nerve (ADN) from adult male, female, and ovariectomized female (OVX) Sprague-Dawley rats. Our results revealed sexually dimorphic conduction velocity (CV) profiles. A distinct, slower myelinated fiber volley was apparent in compound action potential (CAP) recordings from female aortic BR fibers, with an amplitude and CV not observed in males. Subsequent BRx studies demonstrated that females exhibited significantly greater BRx responses compared to males at myelinated-specific intensities. Ovariectomy induced an increased overall temporal dispersion in the CAP of OVX females that may have contributed to their attenuated BRx responses. Interestingly, the most significant changes in depressor dynamics occurred at electrical thresholds and frequencies most closely aligned with Ah-type BR fibers. Collectively, we provide evidence that, in females, two anatomically distinct myelinated afferent pathways contribute to the integrated BRx function, whereas in males only one exists. These functional differences may partly account for the enhanced control of blood pressure in females. Furthermore, Ah-type afferents may provide a neuromodulatory pathway uniquely associated with the hormonal regulation of BRx function.Item Modifications in Bone Matrix of Estrogen-Deficient Rats Treated with Intermittent PTH(Hindawi Publishing Corporation, 2015-01-28) Pacheco-Costa, Rafael; Campos, Jenifer Freitas; Katchburian, Eduardo; de Medeiros, Valquíria Pereira; Nader, Helena Bonciani; Nonaka, Keico Okino; Plotkin, Lilian Irene; Reginato, Rejane Daniele; Department of Anatomy & Cell Biology, IU School of MedicineBone matrix dictates strength, elasticity, and stiffness to the bone. Intermittent parathyroid hormone (iPTH), a bone-forming treatment, is widely used as a therapy for osteoporosis. We investigate whether low doses of intermittent PTH (1-34) change the profile of organic components in the bone matrix after 30 days of treatment. Forty 6-month-old female Wistar rats underwent ovariectomy and after 3 months received low doses of iPTH administered for 30 days: daily at 0.3 µg/kg/day (PTH03) or 5 µg/kg/day (PTH5); or 3 times per week at 0.25 µg/kg/day (PTH025). After euthanasia, distal femora were processed for bone histomorphometry, histochemistry for collagen and glycosaminoglycans, biochemical quantification of sulfated glycosaminoglycans, and hyaluronan by ELISA and TUNEL staining. Whole tibiae were used to estimate the bone mineral density (BMD). Histomorphometric analysis showed that PTH5 increased cancellous bone volume by 6% over vehicle-treated rats. In addition, PTH5 and PTH03 increased cortical thickness by 21% and 20%, respectively. Tibial BMD increased in PTH5-treated rats and this group exhibited lower levels of chondroitin sulfate; on the other hand, hyaluronan expression was increased. Hormonal administration in the PTH5 group led to decreased collagen maturity. Further, TUNEL-positive osteocytes were decreased in the cortical compartment of PTH5 whereas administration of PTH025 increased the osteocyte death. Our findings suggest that daily injections of PTH at low doses alter the pattern of organic components from the bone matrix, favoring the increase of bone mass.Item Sex differences in right ventricular adaptation to pressure overload in a rat model(American Physiological Society, 2022) Cheng, Tik-Chee; Tabima, Diana M.; Caggiano, Laura R.; Frump, Andrea L.; Hacker, Timothy A.; Eickhoff, Jens C.; Lahm, Tim; Chesler, Naomi C.; Medicine, School of MedicineWith severe right ventricular (RV) pressure overload, women demonstrate better clinical outcomes compared with men. The mechanoenergetic mechanisms underlying this protective effect, and their dependence on female endogenous sex hormones, remain unknown. To investigate these mechanisms and their impact on RV systolic and diastolic functional adaptation, we created comparable pressure overload via pulmonary artery banding (PAB) in intact male and female Wistar rats and ovariectomized (OVX) female rats. At 8 wk after surgery, right heart catheterization demonstrated increased RV energy input [indexed pressure-volume area (iPVA)] in all PAB groups, with the greatest increase in intact females. PAB also increased RV energy output [indexed stroke or external work (iEW)] in all groups, again with the greatest increase in intact females. In contrast, PAB only increased RV contractility-indexed end-systolic elastance (iEes)] in females. Despite these sex-dependent differences, no statistically significant effects were observed in the ratio of RV energy output to input (mechanical efficiency) or in mechanoenergetic cost to pump blood with pressure overload. These metrics were similarly unaffected by loss of endogenous sex hormones in females. Also, despite sex-dependent differences in collagen content and organization with pressure overload, decreases in RV compliance and relaxation time constant (tau Weiss) were not determined to be sex dependent. Overall, despite sex-dependent differences in RV contractile and fibrotic responses, RV mechanoenergetics for this degree and duration of pressure overload are comparable between sexes and suggest a homeostatic target. NEW & NOTEWORTHY: Sex differences in right ventricular mechanical efficiency and energetic adaptation to increased right ventricular afterload were measured. Despite sex-dependent differences in contractile and fibrotic responses, right ventricular mechanoenergetic adaptation was comparable between the sexes, suggesting a homeostatic target.Item The Effect of Estrogen Repletion on Osteoblast Differentiation and DNA Synthesis in Ovariectomized Rats(1995) Miller, Ronald L.; Garetto, Lawrence P.; Bidwell, Joseph; Katona, Thomas R.; Roberts, W. Eugene; Shanks, James; Wohlford, Mark E.Previous studies have demonstrated that estrogen plays a significant role in bone mass conservation. To investigate the role that estrogen plays in osteoblast differentiation, the fractional distribution of periodontal ligament (PDL) osteoblast precursor cells was determined. Twenty six-month old female rats (Charles River Co.) were divided into two groups. Both groups were ovariectomized (OVX). Thirty-five days after ovariectomy one group (OVX+E) received supplemental daily injections of estrogen (0. 1 mg/kg Ethinyl Estradiol) for three days. After sacrifice, PDL sections through the mesial root of the maxillary first molar were prepared for microscopic analysis. Using a nuclear morphometric assay, the fibroblast-like cells of the POL were identified as early osteoprogenitor (A+A'), preosteoblast (C+D) or nonosteogenic (B) cells (i.e., A+A'=40-79 μm3; 8=80-119 μm3; C+D>120 μm3). Comparison of the OVX and OVX+E groups showed that treatment with estrogen increased early osteoprogenitor (A+A') cell and decreased preosteoblast (C+D) cell fractional distributions. No changes were seen in the non-osteogenic (B) cell group (expressed as% cell type, mean±SEM for n=4-8 rats/group; *p<0.05). Specimens were also stained with 5-Bromo- 2'-deoxyuridine (BrdU) to localize cells undergoing DNA synthesis. Both OVX and OVX+E groups showed minimal random BrdU staining throughout the PDL. Group= OVX A+A’= 8.8 ± 1.8 B= 30.2 ± 2.3 C+D= 60.8 ± 2.6 Group= OVX+E A+A’= 21.9 ± 2.6* B= 36.0 ± 2.2 C+D= 41.6 ± 3.8* The data suggest a block in proliferation of both less-differentiated precursor cells and preosteoblasts in estrogen-deficient animals. Furthermore, they suggest that estrogen may be required for normal preosteoblast differentiation leading to osteoblast production.Item The Sirtuin1 activator SRT3025 down-regulates sclerostin and rescues ovariectomy-induced bone loss and biomechanical deterioration in female mice(Oxford University Press, 2014) Artsi, Hanna; Cohen-Kfir, Einav; Gurt, Irina; Shahar, Ron; Bajayo, Alon; Kalish, Noga; Bellido, Teresita M.; Gabet, Yankel; Dresner-Pollak, Rivka; Medicine, School of MedicineEstrogen deficiency leads to rapid bone loss and skeletal fragility. Sclerostin, encoded by the sost gene, and a product of the osteocyte, is a negative regulator of bone formation. Blocking sclerostin increases bone mass and strength in animals and humans. Sirtuin1 (Sirt1), a player in aging and metabolism, regulates bone mass and inhibits sost expression by deacetylating histone 3 at its promoter. We asked whether a Sirt1-activating compound could rescue ovariectomy (OVX)-induced bone loss and biomechanical deterioration in 9-week-old C57BL/6 mice. OVX resulted in a substantial decrease in skeletal Sirt1 expression accompanied by an increase in sclerostin. Oral administration of SRT3025, a Sirt1 activator, at 50 and 100 mg/kg·d for 6 weeks starting 6 weeks after OVX fully reversed the deleterious effects of OVX on vertebral bone mass, microarchitecture, and femoral biomechanical properties. Treatment with SRT3025 decreased bone sclerostin expression and increased cortical periosteal mineralizing surface and serum propeptide of type I procollagen, a bone formation marker. In vitro, in the murine long bone osteocyte-Y4 osteocyte-like cell line SRT3025 down-regulated sclerostin and inactive β-catenin, whereas a reciprocal effect was observed with EX-527, a Sirt1 inhibitor. Sirt1 activation by Sirt1-activating compounds is a potential novel pathway to down-regulate sclerostin and design anabolic therapies for osteoporosis concurrently ameliorating other metabolic and age-associated conditions.