Untargeted Metabolomics Revealed that Quercetin Inhibited Ferroptosis by Improving Metabolic Disorder in the Hippocampus of Perimenopausal Depression Model Rats.

Perimenopausal depression is often accompanied by metabolic disorders, which have long-term harmful effects on women's physical and mental health. Quercetin, a kind of phytoestrogen, has anti-inflammatory, antioxidant, and nerve-protective effects, and can regulate various metabolic disorders. This study aims to investigate the effect of quercetin on hippocampal metabolic disorder in perimenopausal depression rat models based on untargeted metabolomics technology. The rat model of perimenopausal depression was established by ovariectomy combined with chronic unpredictable mild stress (OVX-CUMS). Rats with no difference in sucrose preference were randomly divided into four groups (n = 12): sham group, OVX-CUMS group (model group), model plus quercetin group, and model plus 17ß-estradiol group. At the end of the experiment, hippocampal tissues were collected for untargeted metabolomics analysis, morphological analysis, and detection of related indicators. Metabolomics identified 23 differential metabolites in the model group, and the pathway analysis discovered hippocampus metabolic abnormalities including the metabolism of arachidonic acid metabolism, glycerophospholipid metabolism, and ubiquinone biosynthesis, accompanied by an increase in oxidative stress, inflammation, and lipid peroxidation indicators. At the same time, the morphological characteristics of ferroptosis occurred in the hippocampus in the model group. These abnormal changes were reversed by treatment with quercetin or 17ß-estradiol. Quercetin can improve perimenopausal depression by regulating hippocampal metabolic disorders and reducing hippocampal ferroptosis in rats. These findings provide a new strategy for the use of quercetin in the prevention and treatment of perimenopausal depression.

Exploring the Feasibility of Estrogen Replacement Therapy as a Treatment for Perimenopausal Depression: A Comprehensive Literature Review.

Perimenopausal depression (PMD) is a psychological disorder that occurs in women during perimenopause. In addition to the common clinical symptoms of depression, it often manifests as a perimenopausal complication, and its notable cause is the decline in estrogen levels. Despite numerous studies and trials confirming the benefits of estrogen replacement therapy (ERT) for PMD, ERT remains unapproved for treating PMD. Therefore, we conducted a literature search using selected keywords in PubMed and Google Scholar to write a review discussing the feasibility of using ERT for PMD. This review examines the potential of ERT for PMD in terms of its underlying mechanisms, efficacy, safety, and time window. These four aspects suggest that ERT is a viable option for PMD treatment. However, the risk of thrombosis and stroke with ERT is a matter of contention among medical experts, with a paucity of clinical data. Consequently, further clinical trial data are required to ascertain the safety of ERT.

Tao-Hong-Si-Wu-Tang Improves the Depressive-like Behaviors in Mice Experiencing Perimenopausal Depression Through Modulating Activity of the Hypothalamic-Pituitary-Adrenal-Ovary Axis and Activating the BDNF-TrkB-CREB Signaling Pathway.

Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.

Effects of Chaihu Shugan San on Brain Functional Network Connectivity in the Hippocampus of a Perimenopausal Depression Rat Model.

In this study, we used Chaihu Shugan San (CSS), a traditional Chinese herbal formula, as a probe to investigate the involvement of brain functional network connectivity and hippocampus energy metabolism in perimenopausal depression. A network pharmacology approach was performed to discover the underlying mechanisms of CSS in improving perimenopausal depression, which were verified in perimenopausal depression rat models. Network pharmacology analysis indicated that complex mechanisms of energy metabolism, neurotransmitter metabolism, inflammation, and hormone metabolic processes were closely associated with the anti-depressive effects of CSS. Thus, the serum concentrations of estradiol (E2), glutamate (Glu), and 5-hydroxytryptamine (5-HT) were detected by ELISA. The brain functional network connectivity between the hippocampus and adjacent brain regions was evaluated using resting-state functional magnetic resonance imaging (fMRI). A targeted metabolomic analysis of the hippocampal tricarboxylic acid cycle was also performed to measure the changes in hippocampal energy metabolism using liquid chromatography-tandem mass spectrometry (LC-MS/MS). CSS treatment significantly improved the behavioral performance, decreased the serum Glu levels, and increased the serum 5-HT levels of PMS + CUMS rats. The brain functional connectivity between the hippocampus and other brain regions was significantly changed by PMS + CUMS processes but improved by CSS treatment. Moreover, among the metabolites in the hippocampal tricarboxylic acid cycle, the concentrations of citrate and the upregulation of isocitrate and downregulation of guanosine triphosphate (GTP) in PMS + CUMS rats could be significantly improved by CSS treatment. A brain functional network connectivity mechanism may be involved in perimenopausal depression, wherein the hippocampal tricarboxylic acid cycle plays a vital role.

Prophylactic Effects of Hemp Seed Oil on Perimenopausal Depression: A Role of HPA Axis.

Hemp seed, the dried fruit of Cannabis sativa L. (Moraceae), has been extensively documented as a folk source of food due to its nutritional and functional value. This study evaluated the antidepressant effect of hemp seed oil (HSO) during its estrogen-like effect in Perimenopausal depression (PMD) rats induced by ovariectomy combined with chronic unpredictable mild stress (OVX-CUMS). Female SD rats (SPF, 10 weeks, sham operated group, ovariectomy (OVX) model group, ovariectomy - chronic unpredictable mild stress (OVX-CUMS) group, HSO + OVX-CUMS group, fluoxetine (FLU) + OVX-CUMS group, n=8) were subjected to treatment with HSO (4.32 g/kg) or fluoxetine (10 mg/kg) for 28 days (20 mL/kg by ig). Sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), estrogen receptor α (ERα) and estrogen receptor ß (ERß) expression, estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), cortisol (CORT), adrenocorticotropic hormone (ACTH), corticotropin releasing hormone (CRH), norepinephrine (NE), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5HIAA) levels are measured to evaluate the function of the hypothalamic-pituitary-ovarian (HPO) and hypothalamic-pituitary-adrenal (HPA) axis. The results showed that OVX-CUMS significantly decrease sucrose preference rate in SPT, increase immobility time in FST and OFT, and decrease movement distance and stand-up times in OFT. HSO treatment significantly improves depression-like behaviors, upregulates the expression of ERα and ERß, improves HPO axis function by increasing E2 levels and decreasing FSH and LH levels, reverses HPA axis hyperactivation by decreasing CORT, ACTH, and CRH levels, and upregulates NE, 5-HT, and 5HIAA levels in model rats. The findings suggested that HSO could improve depression-like behavior in OVX-CUMS rats by regulating HPO/HPA axis function and neurotransmitter disturbance.

Exosome-sheathed ROS-responsive nanogel to improve targeted therapy in perimenopausal depression.

The development of natural membranes as coatings for nanoparticles to traverse the blood-brain barrier (BBB) presents an effective approach for treating central nervous system (CNS) disorders. In this study, we have designed a nanogel loaded with PACAP and estrogen (E2), sheathed with exosomes and responsive to reactive oxygen species (ROS), denoted as HA NGs@exosomes. The objective of this novel design is to serve as a potent drug carrier for the targeted treatment of perimenopausal depression. The efficient cellular uptake and BBB penetration of HA NGs@exosomes has been demonstrated in vitro and in vivo. Following intranasal intervention with HA NGs@exosomes, ovariectomized mice under chronic unpredictable mild stress (CUMS) have shown improved behavioral performance, indicating that HA NGs@exosomes produced a rapid-onset antidepressant effect. Moreover, HA NGs@exosomes exhibit notable antioxidant and anti-inflammatory properties and may regulate the expression of pivotal proteins in the PACAP/PAC1 pathway to promote synaptic plasticity. Our results serve as a proof-of-concept for the utility of exosome-sheathed ROS-responsive nanogel as a promising drug carrier for the treatment of perimenopausal depression.

Neuroendocrine pathogenesis of perimenopausal depression.

With the development of social economics and the increase of working pressure, more and more women are suffering from long-term serious stress and showing symptoms of perimenopausal depression (PMD). The incidence rate of PMD is increasing, and the physical and mental health are seriously affected. However, due to the lack of accurate knowledge of pathophysiology, its diagnosis and treatment cannot be accurately executed. By consulting the relevant literature in recent years, this paper elaborates the neuroendocrine mechanism of perimenopausal depression from the aspects of epigenetic changes, monoamine neurotransmitter and receptor hypothesis, glial cell-induced neuroinflammation, estrogen receptor, interaction between HPA axis and HPG axis, and micro-organism-brain gut axis. The purpose is to probe into new ways of treatment of PMD by providing new knowledge about the neuroendocrine mechanism and treatment of PMD.

[Plasma components of Danzhi Xiaoyao Formula and its mechanism of action in treating perimenopausal depression based on UPLC-Q-TOF-MS~E integrated with network pharmacology].

In this study, ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS~E) was used to analyze the plasma components of Danzhi Xiaoyao Formula after oral administration. Forty-nine plasma components were found in the serum of rats by comparing the compound extract, drug-containing serum, and blank serum. Components, such as 6-hydroxycoumarin, poricoic acid F, deoxoglabrolide, 30-norhederagenin, kanzonol R, 3',6'-di-O-galloylpaeoniflorin, 16α-hydroxytrametenolic acid, 16-deoxyporicoic acid B, 3-O-acetyl-16α-hydroxytrametenolic acid, and 16α,25-dihydroxydehydroeburiconic acid, were first found in rat serum. Behavioral tests, including the tail suspension test, novel object recognition test, and novelty-suppressed feeding test, were conducted for behavioral analysis. It was confirmed that this formula had therapeutic effects on perimenopausal depression. Furthermore, in combination with the network pharmacology method, 53 core targets including MAPK1, HRAS, AKT1, EGFR, and ESR1 were screened, and these targets participated in 165 signaling pathways, including PI3K-AKT, AMPK, VEGFA, MAPK, and HIF-1. In summary, the potential effects of Danzhi Xiaoyao Formula in treating perimenopausal depression are associated with mechanisms in accelerating inflammation repair, improving neuroplasticity, affecting neurotransmitters, regulating estrogen levels, and promoting new blood vessel formation.

Global hotspots and prospects of perimenopausal depression: A bibliometric analysis via CiteSpace.

Background: Perimenopausal depression (PMD) is characterized by affective symptoms as well as menopause-specific somatic complaints and has attracted increasing attention over the past few decades. Using a bibliometric tool, this study aims to evaluate the origin, current hotspots, and research trends on PMD. Methods: Articles with research on PMD were retrieved from Web of Science Core Collection (WoSCC). We used the bibliometric method to analyze publication years, journals, countries, institutions, authors, research hotspots, and trends. We plotted the reference co-citation network and used keywords to analyze the research hotspots and trends. Results: A total of 209 publications related to PMD were identified from WoSCC on May 8, 2022. The number of publications concerning PMD every year shows an upward trend. Further analysis indicated that 209 articles were contributed by 45 countries, 288 institutions, and 501 authors. The United States contributed the most significant number of publications, followed by China. Harvard University is the core institution of PMD research, and Cohen's work has had an important impact on another research. The occurrence and pathological mechanisms of depression during the menopausal transition from the knowledge base of PMD. All of them belong to the category of gynecology and psychosis, which reflects the focus of the research topics. Major depression, postmenopausal women, symptoms like hot flashes, and prevalence and risk factors are research hotspots in the PMD field. The frontiers in PMD field that will impact future research are anxiety, meta-analysis, association, and Beck Depression Inventory-II (BDI-II). Conclusion: These findings provide us with the core countries, institutions, and authors in PMD research and point out the direction of attention in this field. The current research focuses on depression, postmenopausal women, hot flashes, and other symptoms, as well as the prevalence and risk factors. The frontiers will be anxiety, meta-analysis, related factors, and depression assessment in future research.

Neuroprotective Effects of Estrogen Through BDNF-Transient Receptor Potential Channels 6 Signaling Pathway in the Hippocampus in a Rat Model of Perimenopausal Depression.

Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 µg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 µg/24 µl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.

Astragalin attenuates depression-like behaviors and memory deficits and promotes M2 microglia polarization by regulating IL-4R/JAK1/STAT6 signaling pathway in a murine model of perimenopausal depression.

RATIONALE: Neuroinflammation can be alleviated via M2 microglia polarization, which could promote the recovery of perimenopausal depression. Astragalin (AST) possesses anti-neuroinflammatory activity. However, the effects of AST on perimenopausal depression and the molecular mechanism in regulating microglia polarization remained unknown. OBJECTIVES: The purpose was to investigate the effects of AST on mice with simulated perimenopausal depression through regulating microglia polarization. It was aimed to clarify the molecular mechanism related to the interleukin-4 receptor (IL-4R)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 6 signaling pathway. METHODS: The ovariectomy (OVX)/chronic unpredictable mild stress (CUMS)-induced murine model of perimenopausal depression was established and treated with AST. Then the depression-like behaviors and cognitive ability of mice were examined. After that, we detected the markers of microglia polarization and its regulatory signals. In addition, lipopolysaccharides (LPS)/adenosine triphosphate (ATP)-induced inflammatory BV2 model were used to verify the potential molecular mechanism. RESULTS: AST alleviated perimenopausal depression-like behaviors and memory deficits. AST alleviated microglia activation and increased Ki67-positive cells in dentate gyrus (DG). The viability of BV2 decreased by LPS/ATP was raised by AST. Moreover, both in vivo and in vitro, AST switched microglia from M1 phenotype caused by OVX/CUMS or LPS/ATP to M2 phenotype. The IL-4R/JAK1/STAT6 signaling was restored, and the levels of inducible nitric oxide synthase (iNOS), nuclear NF-KappaB-p65 were reduced by AST. Importantly, AST showed prevention against the ubiquitination modification and degradation of STAT6. CONCLUSIONS: Our results revealed new insights into molecular mechanism associated with microglia polarization in the effect of AST on the mouse model of perimenopausal depression.

Exploration of a Brain-Liver-Communication-Related Mechanism Involved in the Experimental Perimenopausal Depression Rat Model using Chaihu-Shugan-San.

Existing research suggests the involvement of a brain-liver-communication-related mechanism in the occurrence of depression. In this study, we selected Chaihu-Shugan-San (CSS), a traditional Chinese herbal medicine that can simultaneously affect liver and depression, as a probe to investigate the involvement of the brain-liver-communication-related mechanism in perimenopausal depression. A total of 50 experimental perimenopausal depression rat models were established by ovariectomy surgery (PMS) followed by chronic unpredictable mild stress (CUMS) processes. Animals underwent CSS treatment or treatments with CSS + Ly294002, an inhibitor of the PI3K/Akt signalling pathway. We observed the behavioural performances of depression and anxiety, serum concentrations of biochemical indices, serum estrogen two levels, hippocampal 5-HT and NE levels and the morphological changes in liver tissues. The protein and mRNA expressions of PI3K and Akt were also evaluated. CSS treatment significantly ameliorated the behavioural performance, partial biochemical indices and the morphological changes in the liver tissues of PMS + CUMS rats. Ly294002 partially inhibited the CSS effects. The expressions of PI3K and Akt were significantly downregulated by PMS + CUMS processes but upregulated by CSS treatment, which could be significantly suppressed by Ly294002. A brain-liver-communication-related mechanism may be involved in perimenopausal depression, where the PI3K/Akt signalling pathway plays a vital role.

The role of estradiol fluctuation in the pathophysiology of perimenopausal depression: A hypothesis paper.

The menopause transition, which constitutes the five or so years surrounding the final menstrual period, has been established as a time of increased risk for depressive symptoms. While mounting research suggests that exposure to more extreme and fluctuating levels of estradiol (E2) plays a role, it remains unclear which specific trigger is most strongly implicated in the development of depressive mood: acute E2 withdrawal or extreme increases in E2. The current review summarises the literature supporting the role of each, considering research pertaining to perimenopausal depression as well as other reproductive mood disorders in which ovarian hormone change is believed to play a key role, namely premenstrual dysphoric disorder and postpartum depression. Taking together the available research pertaining to the various reproductive mood disorders, we propose that women may exhibit one of four E2 sensitivity profiles, each of which may have important implications for the expected timing and severity of depressive mood during the menopause transition: the E2-increase sensitive profile, developing depressive mood in response to elevations in E2, the E2-decrease sensitive profile, for whom E2 withdrawal triggers negative mood, the E2-change sensitive profile, characterised by mood sensitivity to E2 change in either direction, and the E2 insensitive profile for whom changes in E2 have negligible psychological effects. The evidence supporting the existence of such profiles are summarised, potential biological mechanisms are briefly highlighted, and implications for future research are discussed.

Orcinol glucoside improves the depressive-like behaviors of perimenopausal depression mice through modulating activity of hypothalamic-pituitary-adrenal/ovary axis and activating BDNF- TrkB-CREB signaling pathway.

Orcinol Glucoside (OG), a phenolic glucoside isolated from C. orchioides, showed the antidepressant-like effect on chronic unpredictable mild stress (CUMS)-induced rats previously. This study was designed to determine whether OG could improve the depressive-like symptoms of perimenopausal depression (PMD) and the possible mechanisms involved. This research was performed on a PMD mice model established by a two-steps method of ovariectomy (OVX) followed CUMS. OG treatment effectively improved the depressive-like behaviors of OVX-CUMS mice, as indicated by increased sucrose intake in sucrose preference test (SPT), reduced immobility time in forced swimming test (FST), and tail suspension test (TST), lower frequency of grooming and defecation, increased actions of rearing, and prolonged duration in the center in open field test (OFT). OG treatment alleviated the OVX-CUMS induced dysfunction of hypothalamic-pituitary-ovarian (HPO) axis by increased serum estradiol (E2) and decreased ovarian hormones follicle stimulating hormone (FSH), luteinizing hormone (LH), and gonadotropin-releasing hormone (GnRH) in serum. Meanwhile, OG reversed the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis as evidenced by decreased CORT and ACTH in serum, reduced as well as the mRNA and protein expression of corticotropin-releasing hormone (CRH) in hypothalamus and hippocampus. Moreover, OG up-regulated the protein expression of BDNF, TrkB, and phosphorylation level of CREB and ERK1/2 in hippocampus. These findings demonstrated that OG improves depressive behaviors of OVX-CUMS mice by modulating of HPO/HPA axis dysfunction, and activating BDNF-TrkB-CREB signaling pathway.

Acupuncture as an Independent or Adjuvant Management to Standard Care for Perimenopausal Depression: A Systematic Review and Meta-Analysis.

Background: Many women with perimenopausal depression (PMD) have sought alternative therapies such as acupuncture because of concerns about risks associated with antidepressant and hormone replacement therapy (HRT). This systematic review aimed to clarify if acupuncture is effective for PMD compared with waitlist control or placebo/sham acupuncture, and if acupuncture alone or combined with standard care (antidepressant and/or HRT) is more effective in ameliorating PMD in comparison with standard care alone. Methods: Randomized controlled trials (RCTs) of PMD treatment via acupuncture vs. waitlist control or placebo/sham acupuncture, and RCTs of PMD treatment via acupuncture alone or combined with Western pharmacotherapy vs. Western pharmacotherapy were searched for from seven databases from inception to December 2020. Cochrane criteria were followed. Results: Twenty-five studies involving 2,213 women were analyzed. Meta-analyses indicated that acupuncture significantly reduced the global scores of Hamilton Depression Scale (HAMD) [standardized mean difference (SMD) = -0.54, 95% CI (-0.91, -0.16), p < 0.01], compared with standard care. The therapeutic effect of acupuncture maintained at 2-, 4-, and 12-week follow-ups. Acupuncture combined with standard care was more effective than standard care alone in decreasing HAMD scores [SMD = -0.82, 95% CI (-1.07, -0.58), p < 0.01]. Too few RCTs were available to assess the clinical efficacy differences between acupuncture and placebo/sham acupuncture or HRT alone. Acupuncture also showed better effects in decreasing Kupperman index (KI) scores, whether compared with antidepressant alone [MD = -4.55, 95% CI (-8.46, -0.65), p = 0.02] or antidepressant combined with HRT [MD = -0.89, 95% CI (-1.34, -0.43), p < 0.01]. Conclusions: In comparison with standard care, acupuncture alone or combined with standard care was associated with significant improvements in PMD and reductions of other menopausal symptoms. This finding suggests that acupuncture may be a useful addition to treatment for PMD.

Erxian Decoction, a Famous Chinese Medicine Formula, Ameliorate Depression- Like Behavior in Perimenopausal Mice.

AIMS: The present study was performed in order to find out the anti-depression effect of Erxian Decoction in perimenopausal mice. BACKGROUND: Erxian Decoction (EXD) has been used in folk medicine for the treatment of perimenopausal syndrome, but it has not been researched on perimenopausal depression. OBJECTIVE: The present study aimed to evaluate the effect of extraction of Erxian Decoction on perimenopausal depressive mice. METHODS: In this study, female ICR mice were randomly divided into 6 groups: Low, medium and high dose of EXD groups (0.5, 1.5, and 4.5 g/kg), soy isoflavones group (250 mg/kg) and Sham group. The mice in the Sham group received sham surgery (within ovaries), and the others were excised with bilateral ovaries and exerted by 28-day chronic mild unpredictable stimulation for the establishment of a perimenopausal depression model. RESULTS: Behavioral tests showed that EXD could relieve depression symptoms and improve spatial memory in mice. Western blotting showed that EXD significantly up-regulated the expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 in hippocampus and estrogen receptors (ERs) in the uterus and adrenals, protecting hippocampal tissue and antagonizing the symptoms of estrogen deficiency in mice, which was further proved within a uterine morphology test. In addition, EXD reduced the serum levels of follicle-stimulating hormone, luteinizing hormone, and interleukin- 6. CONCLUSION: These results indicated that EXD can regulate hormone secretion and recover hippocampal damage in perimenopausal depressed mice. Besides, it can antagonize the symptoms of ovarian hormone deficiency as well as relieve perimenopausal syndrome.

Endocrine and psychosocial moderators of mindfulness-based stress reduction for the prevention of perimenopausal depressive symptoms: A randomized controlled trial.

BACKGROUND: The menopause transition is associated with an increased risk of depressive symptoms. The current study aimed to test whether Mindfulness-Based Stress Reduction, an 8-week group intervention involving meditation and yoga, might reduce the risk of depressive symptoms among perimenopausal women. A secondary aim was to examine baseline characteristics, including sensitivity to estradiol fluctuation, as a moderator of treatment effects. METHODS: 104 healthy women from the community in the menopause transition were enrolled and randomized to MBSR (n = 52) or a waitlist control condition (n = 52). Randomization was carried out using a random number generator and opaque sealed envelopes. Depressive symptoms, the main outcome, were assessed every two weeks for 6 months using the Center for Epidemiologic Studies Depression Scale (CES-D). The occurrence of an elevated CES-D score (≥16) and of a major depressive episode were pre-identified secondary outcomes. The following surveys were used to assess additional outcomes of interest every two months: the Perceived Stress Scale, Spielberger Trait Anxiety Inventory, Connor-Davidson Resilience Scale, and Pittsburgh Sleep Quality Index. Baseline characteristics examined as potential moderators of treatment benefit included: baseline CES-D score, past depressive episodes, recent stressful life events, a history of physical or sexual abuse, and emotional sensitivity to reproductive hormone fluctuation. Outcome assessors were blinded to the participants' assigned treatment arm. RESULTS: Outcome data were available for 44 women assigned to MBSR and 51 women in the waitlist condition. Women randomized to MBSR reported fewer depressive symptoms, less perceived stress, less anxiety, increased resilience, and improved sleep (ps < 0.001). Furthermore, several baseline characteristics predicted a greater mood benefit of MBSR, including: a history of major depression (p for the interaction <0.001), a greater number of recent stressful life events (p < .001), being in the early menopause transition (p = .002), and an increased emotional sensitivity to reproductive hormone fluctuation (p = .004). There were no group differences in the occurrence of major depressive episodes (p > .05). CONCLUSIONS: MBSR appears to be an effective intervention for the prevention of depressive symptoms in the menopause transition.

Mood sensitivity to estradiol predicts depressive symptoms in the menopause transition.

BACKGROUND: The risk for depression markedly rises during the 5-6 years leading up to the cessation of menstruation, known as the menopause transition. Exposure to extreme estradiol levels may help explain this increase but few studies have examined individual sensitivity to estradiol in predicting perimenopausal depression. METHOD: The current study recruited 101 perimenopausal women. During Phase 1, we quantified each woman's sensitivity to changes in estradiol using 12 weekly measures of estrone-3-glucuronide (E1G), a urinary metabolite of estradiol, and concurrent depressive symptoms. The weekly cortisol awakening response was measured to examine the hypothalamic-pituitary-adrenal (HPA) axis in mediating mood sensitivity to estradiol. In Phase 2, depressive symptoms and major depression diagnoses were assessed monthly for 9 months. The relationship between Phase 1 E1G sensitivity and Phase 2 depressive symptoms and major depressive episodes was examined. Several baseline characteristics were examined as potential moderators of this relationship. RESULTS: The within-person correlation between weekly E1G and mood varied greatly from woman to woman, both in strength and direction. Phase 1 E1G mood sensitivity predicted the occurrence of clinically significant depressive symptoms in Phase 2 among certain subsets of women: those without a prior history of depression, reporting a low number of baseline stressful life events, and reporting fewer months since their last menstrual period. HPA axis sensitivity to estradiol fluctuation did not predict Phase 2 outcomes. CONCLUSION: Mood sensitivity to estradiol predicts risk for perimenopausal depression, particularly among women who are otherwise at low risk and among those who are early in the transition.

Symptoms assessed in studies on perimenopausal depression: A narrative review.

The menopausal transition constitutes a phase of major biopsychosocial changes associated with an elevated risk for the development of depression. Perimenopausal depression is highly prevalent and usually characterized by core symptoms of a major depressive disorder combined with menopausal complaints such as vasomotor symptoms or other physical complaints. However, a distinct definition of the condition is lacking. The aim of this review is to portray the symptoms assessed in studies on perimenopausal depression in order to provide relevant information on the current understanding of this condition. A literature search was conducted using the databases PubMed, Cochrane Library, and PsycINFO. A total of 37 studies were included. Various assessment tools have been used to measure symptoms related to perimenopausal depression. Fifteen symptoms were identified. Depressed mood was assessed across all studies. Low energy or sleep disturbances, as acknowledged symptoms of a major depressive disorder, were surveyed in most studies. However, the assessment of menopausal complaints was rather heterogeneous. While vasomotor symptoms were often measured, other menopausal symptoms such as mood swings or pain were investigated less frequently. Sexual problems were only rarely assessed. Studies on perimenopausal depression regularly include the assessment of core symptoms of a major depressive disorder, but the assessment of menopausal complaints is inconsistent. While certain symptoms are commonly measured, others are not assessed. Such inconsistencies underline an ambiguous understanding of perimenopausal depression, which in turn affects the evaluation and treatment of the condition. Thus, the use of the existing guidelines on perimenopausal depression is recommended.

Electroacupuncture Promotes Neural Proliferation in Hippocampus of Perimenopausal Depression Rats via Wnt/ß-Catenin Signaling Pathway.

BACKGROUND AND OBJECTIVE: Perimenopausal depression is caused by the impaired function of the ovarium before menopause and with a series of symptoms. Electroacupuncture (EA) therapy has been demonstrated to improve clinically depression. However, the mechanism underlying its therapeutic activity remains unknown. This study aimed to investigat the effects of EA treatment on the hippocampal neural proliferation through Wnt signaling pathway. METHODS: Chronic unpredictable mild stress (CUMS) combined with bilateral ovariectomy (OVX) were used to establish a rat model of perimenopausal depression. The open field test (OFT) and sucrose preference test (SPT) were used to assess depression-like behaviors in rats. ELISAs were used to measure estrogen (E2), luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) levels in the serum. RT-PCR and Western blot assay were utilized for measuring the mRNA expressions and protein expressions of GSK-3ß/ß-catenin. RESULTS: Four-week EA treatment at three points including "Shenshu" (BL23), "Baihui" (GV20) and "Sanyinjiao" (SP6) simultaneously ameliorated depression-like behaviors in rats with CUMS and OVX, whereas rescued the decreased serum level of E2 and prevented the increased serum levels of GnRH and LH. EA treatment ameliorated CUMS and OVX-induced alterations of glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin mRNA levels, ß-catenin and phosphorylated ß-catenin (p-ß-catenin) protein levels. CONCLUSIONS: The results showed that EA treatment promoted hippocampal neural proliferation in perimenopausal depression rats via activating the Wnt/ß-catenin signaling pathway, indicating that EA may represent an efficacious therapy for perimenopausal depression.