Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats.

BACKGROUND: Borolatonin is a potential therapeutic agent for some neuronal diseases such as Alzheimer's disease (AD). Its administration exerts ameliorative effects such as those induced by the equimolar administration of melatonin in behavioral tests on male rats and in neuronal immunohistochemistry assays. OBJECTIVE: In this study, motivated by sex differences in neurobiology and the incidence of AD, the ability of borolatonin to induce changes in female rats was assessed. METHODS: Effects of borolatonin were measured by the evaluation of both behavioral and immunohistopathologic approaches; additionally, its ability to limit amyloid toxicity was determined in vitro. RESULTS: Surprisingly, behavioral changes were similar to those reported in male rats, but not those evaluated by immunoassays regarding neuronal survival; while pro-brain-derived neurotrophic factor (BDNF) immunoreactivity and the limitation of toxicity by amyloid in vitro were observed for the first time. CONCLUSION: Borolatonin administration induced changes in female rats. Differences induced by the administration of borolatonin or melatonin could be related to the differences in the production of steroid hormones in sex dependence. Further studies are required to clarify the possible mechanism and origin of differences in disturbed memory caused by the gonadectomy procedure between male and female rats.

Tamoxifen Suppresses the Immune Response to Plasmodium berghei ANKA and Exacerbates Symptomatology.

Malaria is the most lethal parasitic disease in the world. Mortality and severity in symptoms are higher in men than women, suggesting that oestrogens, which are in higher concentration in females than in males, may regulate the immune response against malaria. Tamoxifen, a selective oestrogen receptor modulator used in breast cancer treatment due to its antagonistic effect on oestrogen receptors α and ß, is also studied because of its potential therapeutic use for several parasitic diseases. However, most studies, including one in malaria, have not addressed the immunomodulatory role of tamoxifen. In this work, we evaluated the effect of tamoxifen on the immune response of CBA/Ca mice against Plasmodium berghei ANKA. This study showed for the first time that tamoxifen increased parasite load, aggravated symptoms by decreasing body temperature and body weight, and worsened anaemia. Additionally, tamoxifen significantly increased the splenic index and the percentages of CD4+ and NK+ cells on day eight post-infection. By contrast, tamoxifen decreased both CD8+ and B220+ populations in the spleen and decreased the serum levels of IL-2, IL-6, and IL-17. Our findings support the notion that tamoxifen is a potent immunomodulator in malaria-infected mice and suggest caution when administering it to malaria-infected women with breast cancer.

Puberty and oestral cycle length in captive female jaguars Panthera onca.

Habitat loss and fragmentation have been leading jaguars to constant conflicts with humans, and as a result, jaguar populations have been declining over the last decades. Captive breeding is often a tool for species conservation, and it is not different for jaguars. However, success is far from optimal due to the lack of basic knowledge about species' reproductive biology. In the present study, we assessed gonadal hormonal profiles of natural oestral cycles and puberty and compared our data to those of other wild felids. We collected faecal samples from two to seven times per week for 18 months from two adults and three pre-pubertal females. We defined baseline levels for progestins and oestrogens in order to estimate oestrous cycle length and age at puberty. We compared our data with 16 other species through generalized linear model, using weight and genus as two explanatory variables. Cycle length was 38.28 ± 2.52 days, ranging from 25 to 44 days, while sexual maturity was attained within 22 months. Due to our analysis of both hormonal and behavioural data, there is a variation between this research from other studies that employed only behavioural observations. Such difference may be caused by the absence of behavioural oestrous at the peri-pubertal period. When compared to wild felids of similar size, puberty and oestral cycle durations of the jaguar females fell within the same range. Our modelling showed that age at maturity was influenced mostly by size and only Leopardus partially explained the observed variation. Conversely, oestral cycle length did not differ among genera or size categories. Our study adds to the body literature in the reproductive endocrinology of wild felids, and because female gametes are more challenging to collect and preserve, a strong understanding on the female reproductive physiology is essential to assisted reproduction and wild population viability assessment.

Effect of ovariectomy on maxilla and mandible dimensions of female rats.

OBJECTIVE: The role of oestrogen in craniofacial growth still remains unclear. Therefore, the present study aimed to assess the effect of oestrogen deficiency on maxilla and mandible dimensions. SETTING AND SAMPLE POPULATION: The study was conducted at the Department of Pediatric Dentistry at the School of Dentistry of Ribeirão Preto, University of São Paulo, and used forty female Wistar rats. MATERIAL AND METHODS: Ovariectomy (OVX) and placebo surgery (Sham) were performed when animals were twenty-one days old (prepubertal stage). Dimensions of the maxilla and mandible were assessed by craniometric analysis using radiographs, during and after puberty of the animals (45 and 63 days old, respectively). Quantitative real-time PCR and immunohistochemical analyses were performed to determine the expression and localization, respectively, of oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERß) in different growth sites of the evaluated structures at puberty. The differences between the groups for each outcome were evaluated using the t test with an established alpha error of 5%. RESULTS: There were significant differences between the OVX and Sham groups for horizontal and vertical linear measurements in the maxilla and the mandible at both pubertal and post-pubertal stages (P < .05). The ovariectomized rats showed significantly greater measures for all dimensions assessed. No differences in gene expression of ERα and ERß were identified at the different growth sites between the OVX and Sham groups (P > .05). Immunohistochemical analyses revealed the presence of both oestrogen receptors in osteoblasts and chondrocytes in the midpalatal suture and mandibular condyle, respectively, in the OVX and Sham groups. CONCLUSION: Our results suggest that oestrogen deficiency from the prepubertal stage might increase the growth of the maxilla and mandible in female rats.

Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds.

The high concentrations of free fatty acids as a consequence of obesity and being overweight have become risk factors for the development of different diseases, including neurodegenerative ailments. Free fatty acids are strongly related to inflammatory events, causing cellular and tissue alterations in the brain, including cell death, deficits in neurogenesis and gliogenesis, and cognitive decline. It has been reported that people with a high body mass index have a higher risk of suffering from Alzheimer's disease. Hormones such as oestradiol not only have beneficial effects on brain tissue, but also exert some adverse effects on peripheral tissues, including the ovary and breast. For this reason, some studies have evaluated the protective effect of oestrogen receptor (ER) agonists with more specific tissue activities, such as the neuroactive steroid tibolone. Activation of ERs positively affects the expression of pro-survival factors and cell signalling pathways, thus promoting cell survival. This review aims to discuss the relationship between lipotoxicity and the development of neurodegenerative diseases. We also elaborate on the cellular and molecular mechanisms involved in neuroprotection induced by oestrogens.

Sex hormone replacement therapy in periodontology-A systematic review.

OBJECTIVE: To analyse whether sex hormone replacement therapy (HRT) improves periodontal parameters and dental implants osseointegration in humans. MATERIALS AND METHODS: Electronic databases and hand searches were performed from June to August 2018 in SciELO, LILACS and PubMed/MEDLINE. Human observational and interventional studies that evaluated the following parameters were included: clinical attachment loss (CAL), probing pocket depth (PPD), bleeding on probing (BOP), radiographic bone loss (RBL) or osseointegration. RESULTS: Initial search retrieved 1,282 non-duplicated articles. Fifteen studies were selected after inclusion criteria were applied. All studies were performed in postmenopausal women. Mean differences for PPD reduction ranged from 0.02 to 0.2 mm in HRT-positive patients; mean CAL gain -0.18 to 0.54 mm; mean RBL reduction -0.87 to 0.15 mm; and mean BOP reduction 9%-30.3%. Failure rate of dental implants increased -5.5% to 11.21% when HRT was used. CONCLUSIONS: Very low but consistent evidence suggests a reduction in BOP and no impact on RBL in postmenopausal women receiving HRT. There are inconsistent reports that suggest that HRT in postmenopausal women: (a) improves or does not impact PPD reduction and CAL gain; and (b) does not impact or increase implant loss. In summary, there is no evidence to support HRT prescription for either men or women for periodontal/implant placement purposes.

G protein-coupled oestrogen receptor stimulation ameliorates iron- and ovariectomy-induced memory impairments through the cAMP/PKA/CREB signalling pathway.

Iron accumulation in the brain has been associated with neurodegenerative disorders, and imaging studies in humans indicate that iron content in brain regions correlates with poor performance in cognitive tasks. In rats, iron overload impairs memory retention in a variety of memory tasks. Although the effects of iron on cognition in rodents are extensively reported, no previous study has been conducted in female rats. The incidence of certain dementias, such as Alzheimer's disease, is higher in women after menopause compared to aged-matched men. The role of oestrogen depletion in memory deficits in menopausal women is still a matter of debate. The present study aimed to characterise the effects of iron overload on memory in female rats by investigating the effects of ovariectomy (OVX, an experimental model of oestrogen depletion) in rats submitted to iron overload, as well as examining the effects of G protein-coupled oestrogen receptor (GPER) agonism on memory impairments induced by iron and OVX. Female rats received iron (30 mg kg-1 , orally) or vehicle at postnatal days 12-14 and were submitted to OVX in adulthood. Results showed that either iron or OVX impaired memory for object placement and inhibitory avoidance. The selective GPER agonist G1, administered immediately after training, reversed both iron- and OVX-induced memory impairments. G1 effects were abolished by protein kinase A (PKA) inhibition, suggesting the involvement of the cAMP/PKA/CREB signalling pathway. The search for novel oestrogen agonists with positive effects on cognition may be promising for the development of treatments for memory disorders.

Disturbed testicular expression of the estrogen-metabolizing enzymes CYP1A1 and COMT in infertile men with primary spermatogenic failure: possible negative implications on Sertoli cells.

Estradiol (E2 ) is normally metabolized to hydroxyestradiols and methoxyestradiols by CYP1A1, CYP1B1 and COMT. However, an altered production of these metabolites by a disturbed expression of these enzymes is associated with reproductive and non-reproductive pathologies. In vitro studies suggest that increased hydroxyestradiols and methoxyestradiols intratesticular generation is related to male infertility, but no studies have explored whether infertile men have a disturbed testicular expression of the enzymes that generate these E2 metabolites. The aim of this study was to assess CYP1A1, CYP1B1 and COMT testicular expression at mRNA and protein level in men with spermatogenic impairment. Seventeen men with primary spermatogenic failure (13 with Sertoli cell-only syndrome and four with maturation arrest) and nine controls with normal spermatogenesis were subjected to testicular biopsy. mRNA was quantified using real-time RT-PCR and protein expression was evaluated using western blot and immunohistochemistry followed by integrated optic density analysis. Besides, the effects of hydroxyestradiols and methoxyestradiols on testosterone-induced transcriptional activity were evaluated in TM4 cells using a luciferase reporter assay system. Our results show that patients with Sertoli cell-only syndrome had significantly elevated COMT expression at the mRNA level, higher COMT immunoreactivity in their seminiferous tubules and increased protein expression of the soluble COMT isoform (S-COMT), whereas patients with maturation arrest had significantly elevated CYP1A1 mRNA levels and higher CYP1A1 immunoreactivity in interstitial space. Finally, 2-hydroxyestradiol decreased testosterone-induced transcriptional activity in Sertoli cells in vitro. In conclusion, male infertility is related to disturbed testicular expression of the enzymes responsible for producing hydroxyestradiols and/or methoxyestradiols. If these changes are related with increased intratesticular hydroxyestradiols and methoxyestradiols concentrations, they could elicit an impaired Sertoli cell function. Our results suggest CYP1A1 and COMT as new potential targets in treating male infertility.

Changes in microscopic analysis of the urinary sediment in postmenopausal women who receive vaginal conjugated oestrogens.

INTRODUCTION: Microscopic haematuria is common in adults and it has been reported in 13% of postmenopausal women. OBJECTIVE: To evaluate the changes in urinary sediment after the use of vaginal conjugated oestrogens. MATERIAL AND METHODS: Postmenopausal women with vaginal dryness were studied. In all them a urinalysis was done, looking for density, pH, and the presence of leukocytes and erythrocytes. In order to be included in the study, all of the women had to have microscopic haematuria, considered as the presence of 3 or more erythrocytes in the urinary sediment. All received vaginally 1 g of conjugated equine oestrogens cream 3 times per week for one month, moment in which a new urinalysis was carried out and the same parameters were evaluated. RESULTS: Twenty-four women were studied. The median age was 62 years (40-83), and the time since menopause was 144 months (24-336). When comparing the values between baseline and end of treatment urinalyses, no significant differences in pH and urinary density were found. The number of leukocytes significantly decreased after treatment (3.0 [1-6] vs. 1.0 [1-6], p < 0.026), and the erythrocytes number decreased (4.5 [3-12] vs. 0.0 [0-2], p < 0.001). CONCLUSION: In postmenopausal women with microscopic haematuria and vaginal dryness, it is worth considering administration of local oestrogen for one month, and after repeat the urine exam, before deciding to begin the microscopic haematuria study protocol.

Dietary whey reduces energy intake and alters hypothalamic gene expression in obese phyto-oestrogen-deprived male rats.

Removing dietary phyto-oestrogens in adult male rats causes obesity and diabetes. As whey proteins have been reported to reduce food intake and improve glucose homoeostasis, we investigated whether they could attenuate susceptibility to obesity and diabetes due to phyto-oestrogen deprivation. To this end, thirty male Wistar rats were fed a high-phyto-oestrogen (HP) or a phyto-oestrogen-free (PF) diet for 10 weeks; six rats from each group were killed. The remaining HP animals (six animals) continued receiving the HP diet for 6 weeks. The remaining PF rats (twelve rats) were divided in two groups: one was given the PF diet and the other a variation of the PF diet plus whey protein (PF-W). Body weight, food intake and adipose tissue weights were recorded. Hypothalamic mRNA expressions of orexigenic (neuropeptide Y, agouti-related protein (AgRP)) and anorexigenic (pro-opiomelanocortin (POMC), cocaine-amphetamine-related transcript (CART)) neuropeptides were quantified by real-time PCR. Serum glucose, insulin and total thyroxine (T4), thyroid-stimulating hormone, testosterone and oestradiol were assessed. After 10 weeks of PF diet, increased body weight, adiposity and energy intake, with up-regulation of AgRP and down-regulation of POMC', were observed. Longer treatment exacerbated these results, increased total T4 levels, reduced oestradiol levels and impaired glucose homoeostasis. PF-W reduced energy intake and increased POMC expression; however, body weight and adiposity remained unchanged. PF-W could not prevent the hormonal changes or the high circulating glucose levels induced by phyto-oestrogen deprivation, but reduced fasting insulin. These data demonstrate that, although 6 weeks of whey administration could not prevent obesity in phyto-oestrogen-deprived rats, the reduction in energy intake and circulating insulin could be beneficial with longer treatments.

Developmental and Functional Effects of Steroid Hormones on the Neuroendocrine Axis and Spinal Cord.

This review highlights the principal effects of steroid hormones at central and peripheral levels in the neuroendocrine axis. The data discussed highlight the principal role of oestrogens and testosterone in hormonal programming in relation to sexual orientation, reproductive and metabolic programming, and the neuroendocrine mechanism involved in the development of polycystic ovary syndrome phenotype. Moreover, consistent with the wide range of processes in which steroid hormones take part, we discuss the protective effects of progesterone on neurodegenerative disease and the signalling mechanism involved in the genesis of oestrogen-induced pituitary prolactinomas.

Lack of Oestrogenic Inhibition of the Nuclear Factor-κB Pathway in Somatolactotroph Tumour Cells.

Activation of nuclear factor (NF)-κB promotes cell proliferation and inhibits apoptosis. We have previously shown that oestrogens sensitise normal anterior pituitary cells to the apoptotic effect of tumour necrosis factor (TNF)-α by inhibiting NF-κB nuclear translocation. In the present study, we examined whether oestrogens also modulate the NF-κB signalling pathway and apoptosis in GH3 cells, a rat somatolactotroph tumour cell line. As determined by Western blotting, 17ß-oestradiol (E2 ) (10(-9) m) increased the nuclear concentration of NF-κB/p105, p65 and p50 in GH3 cells. However, E2 did not modify the expression of Bcl-xL, a NF-κB target gene. TNF-α induced apoptosis of GH3 cells incubated in either the presence or absence of E2 . Inhibition of the NF-kB pathway using BAY 11-7082 (BAY) (5 µm) decreased the viability of GH3 cells and increased the percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive GH3 cells. BAY also increased TNF-α-induced apoptosis of GH3 cells, an effect that was further increased by an inhibitor of the c-Jun N-terminal protein kinase pathway, SP600125 (10 µm). We also analysed the role of the NF-κB signalling pathway on proliferation and apoptosis of GH3 tumours in vivo. The administration of BAY to nude mice bearing GH3 tumours increased the number of TUNEL-positive cells and decreased the number of proliferating GH3 cells. These findings suggest that GH3 cells lose their oestrogenic inhibitory action on the NF-κB pathway and that the pro-apoptotic effect of TNF-α on these tumour pituitary cells does not require sensitisation by oestrogens as occurs in normal pituitary cells. NF-κB was required for the survival of GH3 cells, suggesting that pharmacological inhibition of the NF-κB pathway could interfere with pituitary tumour progression.

Long-term effects of early-life exposure to environmental oestrogens on ovarian function: role of epigenetics.

Oestrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is considered that developmental exposure to environmental oestrogens can disrupt neural and reproductive tract development, potentially resulting in long-term alterations in neurobehaviour and reproductive function. Many chemicals have been shown to have oestrogenic activity, whereas others affect oestrogen production and turnover, resulting in the disruption of oestrogen signalling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on oestrogen-sensitive target tissues. Hence, alternative mechanisms are assumed to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including oestrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying the disruption of ovarian follicular development. In addition, we discuss how exposure to environmental oestrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology.

Effects of the oestrogen receptor antagonist Fulvestrant on expression of genes that affect organization of the epididymal epithelium.

The role of oestrogens in epididymal function is still unclear. Knockout of the oestrogen receptor ESR1 (Esr1(-/-) ) or treatment with the anti-oestrogen Fulvestrant affect epididymal milieu and sperm motility. We investigated the effect of in vivo treatment of rats with Fulvestrant on: (i) expression of genes that may be important for the architecture and function of the epididymal epithelium: prominins 1 and 2, metalloproteinase 7, claudin 7, beta-catenin and cadherin 13, and (ii) levels of oestradiol and testosterone, and expression of oestrogen and androgen receptors, in the initial segment (IS), caput, corpus and cauda epididymis. Fulvestrant (i) reduced gene expression of prominin 1 (variant 1) in the caput, reduced prominin 1 protein content in the caput epididymis and in the efferent ductules, and increased the localization of prominin 1 in microvilli of the caput and corpus; (ii) reduced gene expression of prominin 2 in the corpus and cauda epididymis; (iii) increased the metalloproteinase 7 content in the apical region of principal cells from IS/caput; (iv) reduced in the corpus epididymis, but increased in the efferent ductules, the cadherin 13 mRNA level; (v) reduced testosterone but increased oestradiol levels in the corpus and cauda; (vi) increased the androgen receptor protein content in all regions of the epididymis, and the oestrogen receptor GPER in the corpus and cauda epididymis. In conclusion, treatment with Fulvestrant induced regional-specific changes in hormonal and steroid receptor content, and affected expression of proteins important for epithelial organization and absorption/secretion. The mechanisms of oestrogen action may differ among epididymal regions, which may contribute to determine region-specific sperm functions.

17α-Oestradiol-induced neuroprotection in the brain of spontaneously hypertensive rats.

17ß-oestradiol is a powerful neuroprotective factor for the brain abnormalities of spontaneously hypertensive rats (SHR). 17α-Oestradiol, a nonfeminising isomer showing low affinity for oestrogen receptors, is also endowed with neuroprotective effects in vivo and in vitro. We therefore investigated whether treatment with 17α-oestradiol prevented pathological changes of the hippocampus and hypothalamus of SHR. We used 20-week-old male SHR with a blood pressure of approximately 170 mmHg receiving s.c. a single 800 µg pellet of 17α-oestradiol dissolved in cholesterol or vehicle only for 2 weeks Normotensive Wistar-Kyoto (WKY) rats were used as controls. 17α-Oestradiol did not modify blood pressure, serum prolactin, 17ß-oestradiol levels or the weight of the testis and pituitary of SHR. In the brain, we analysed steroid effects on hippocampus Ki67+ proliferating cells, doublecortin (DCX) positive neuroblasts, glial fibrillary acidic protein (GFAP)+ astrocyte density, aromatase immunostaining and brain-derived neurotrophic factor (BDNF) mRNA. In the hypothalamus, we determined arginine vasopressin (AVP) mRNA. Treatment of SHR with 17α-oestradiol enhanced the number of Ki67+ in the subgranular zone and DCX+ cells in the inner granule cell layer of the dentate gyrus, increased BDNF mRNA in the CA1 region and gyrus dentatus, decreased GFAP+ astrogliosis in the CA1 subfield, and decreased hypothalamic AVP mRNA. Aromatase expression was unmodified. By contrast to SHR, normotensive WKY rats were unresponsive to 17α-oestradiol. These data indicate a role for 17α-oestradiol as a protective factor for the treatment of hypertensive encephalopathy. Furthermore, 17α-oestradiol is weakly oestrogenic in the periphery and can be used in males.

Hiperestrogenismo em cadela: dermatose secundária a hormôniosexual – relato de caso / Hyperestrogenism in a female dog: dermatosis secondary to sex hormone - case report

O hiperestrogenismo em fêmeas caninas é uma condição raramente descrita que se apresenta como umaalopecia simétrica bilateral com início na região perineogenital e membros pélvicos, podendo se estenderaté o flanco, acompanhada de hipertrofia de vulva e ginecomastia. Seu diagnóstico é realizado atravésdos achados clínicos, exames laboratoriais, histopatologia para confirmação do quadro endócrino e resposta ao tratamento. Este artigo apresenta um caso de hiperestrogenismo em um cão fêmea inteira daraça Pinscher com 7 anos de idade.

The hyperestrogenism in a female dog is a condition that has rarely been described as a bilaterally symmetricalalopecia beginning in the perineogenital region and hindlimbs, and may extend to the flank, accompanied by hypertrophy of the vulva and gynecomastia. The diagnosis is made by clinical findings,laboratory tests, histopathology for confirmation of endocrine disease and response to treatment. Thisarticle presents a case of hyperestrogenic in a female dog of breed Pinscher, 7 years old, not spayed.

Hiperestrogenismo em cadela: dermatose secundária a hormôniosexual relato de caso / Hyperestrogenism in a female dog: dermatosis secondary to sex hormone - case report

O hiperestrogenismo em fêmeas caninas é uma condição raramente descrita que se apresenta como umaalopecia simétrica bilateral com início na região perineogenital e membros pélvicos, podendo se estenderaté o flanco, acompanhada de hipertrofia de vulva e ginecomastia. Seu diagnóstico é realizado atravésdos achados clínicos, exames laboratoriais, histopatologia para confirmação do quadro endócrino e resposta ao tratamento. Este artigo apresenta um caso de hiperestrogenismo em um cão fêmea inteira daraça Pinscher com 7 anos de idade.(AU)

The hyperestrogenism in a female dog is a condition that has rarely been described as a bilaterally symmetricalalopecia beginning in the perineogenital region and hindlimbs, and may extend to the flank, accompanied by hypertrophy of the vulva and gynecomastia. The diagnosis is made by clinical findings,laboratory tests, histopathology for confirmation of endocrine disease and response to treatment. Thisarticle presents a case of hyperestrogenic in a female dog of breed Pinscher, 7 years old, not spayed. (AU)