Perimenopausal and Menopausal Mammary Glands In A 4-Vinylcyclohexene Diepoxide Mouse Model.

As both perimenopausal and menopausal periods are recognized critical windows of susceptibility for breast carcinogenesis, development of a physiologically relevant model has been warranted. The traditional ovariectomy model causes instant removal of the entire hormonal repertoire produced by the ovary, which does not accurately approximate human natural menopause with gradual transition. Here, we characterized the mammary glands of 4-vinylcyclohexene diepoxide (VCD)-treated animals at different time points, revealing that the model can provide the mammary glands with both perimenopausal and menopausal states. The perimenopausal gland showed moderate regression in ductal structure with no responsiveness to external hormones, while the menopausal gland showed severe regression with hypersensitivity to hormones. Leveraging the findings on the VCD model, effects of a major endocrine disruptor (polybrominated diphenyl ethers, PBDEs) on the mammary gland were examined during and after menopausal transition, with the two exposure modes; low-dose, chronic (environmental) and high-dose, subacute (experimental). All conditions of PBDE exposure did not augment or compromise the macroscopic ductal reorganization resulting from menopausal transition and/or hormonal treatments. Single-cell RNA sequencing revealed that the experimental PBDE exposure during the post-menopausal period caused specific transcriptomic changes in the non-epithelial compartment such as Errfi1 upregulation in fibroblasts. The environmental PBDE exposure resulted in similar transcriptomic changes to a lesser extent. In summary, the VCD mouse model provides both perimenopausal and menopausal windows of susceptibility for the breast cancer research community. PBDEs, including all tested models, may affect the post-menopausal gland including impacts on the non-epithelial compartments.

Exosome Therapy: A Novel Approach for Enhancing Estrogen Levels in Perimenopause.

Perimenopause significantly impacts women's health globally, often managed with hormone replacement therapy (HRT) despite the associated risks. This study explores a novel alternative exosome therapy, aimed at stimulating estrogen production in ovarian tissues, thus offering a potential non-hormonal treatment for perimenopausal symptoms. Employing ex vivo methodologies, ovarian cortex specimens from perimenopausal women were treated with exosomes derived from human umbilical cord mesenchymal stem cells and cultured under specific conditions (patent number: PCT/US2022/073467). The exosomes were produced under cyclic guanosine monophosphate (cGMP) conditions, ensuring high safety standards. Estrogen levels were quantified using enzyme-linked immunosorbent assay (ELISA), and gene expression changes in estrogen and follicle-stimulating hormone (FSH) receptors were assessed via quantitative polymerase chain reaction (PCR). Immunohistochemistry (IHC) was utilized to evaluate cellular proliferation and apoptotic markers. The results indicated a significant increase in estrogen levels and estrogen receptor-alpha (Erα) expression in treated tissues compared to controls. Additionally, a decrease in apoptotic markers and an increase in cellular proliferation markers were observed. These findings suggest that exosome therapy can effectively enhance estrogen production and modulate receptor sensitivity in perimenopausal ovarian tissues. This approach could serve as a safer alternative to HRT, aligning with the body's natural regulatory mechanisms and potentially offering a more effective treatment option for managing perimenopausal symptoms.

A novel method for quantifying affective sensitivity to endogenous ovarian hormones.

Increased sensitivity to ovarian hormone changes is implicated in the etiology of reproductive mood disorders across the female lifespan, including menstrually-related mood disorders, perinatal mood disorders, and perimenopausal depression. Developing a method to accurately quantify sensitivity to endogenous hormone fluctuations may therefore facilitate the prediction and prevention of these mental health conditions. Here, we propose one such method applying a synchrony analysis to compute time-lagged cross-correlations between repeated assessments of endogenous hormone levels and self-reported affect. We apply this method to a dataset containing frequent repeated assessments of affective symptoms and the urinary metabolites of estradiol (E2) and progesterone (P4) in 94 perimenopausal females. These preliminary findings suggest that, with further refinement and validation, the proposed method holds promise as a diagnostic tool to be used in clinical practice and to advance research investigating the etiology of reproductive mood disorders.

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.

The Cortisol and ACTH Response to Dex/CRH Testing in Women With and Without Perimenopausal Depression.

CONTEXT: Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are frequent accompaniments of depression, and studies have documented the role of stress and stressful life events in the ontogeny of perimenopausal depressions (PMD). Because HPA axis function in women is further modulated both by aging and ovarian steroids, it is possible that a dysregulated HPA axis contributes to the increased risk of PMD. OBJECTIVE: We examined HPA axis function in perimenopausal women with and without depression using the combined dexamethasone-corticotropin-releasing hormone (Dex/CRH) test. METHODS: Dex/CRH tests were performed on 20 women with PMD and 20 women who were also perimenopausal but without current or past depression (control women). Main outcome measures were plasma levels of cortisol and adrenocorticotropin (ACTH) and 24-hour urinary free cortisol (UFC). Five women took chronic stable medications, otherwise all women were medically healthy, and both groups were comparable with respect to reproductive stage and age. Standardized symptom rating scales were administered to each woman prior to Dex/CRH testing. RESULTS: No group differences were present in either baseline or stimulated ACTH and cortisol secretion. Baseline plasma measures of estradiol, progesterone, and 24-hour UFC levels similarly did not differ in PMD and control women. CONCLUSION: Despite reports of increased stress responsiveness in PMD, we observed no abnormalities of HPA axis activity associated with PMD compared with women without depression. These findings suggest that PMD is not uniformly associated with HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from women with nonreproductive-related depressions.

Estrogen Receptor ß Contributes to Both Hypertension and Hypothalamic Plasticity in a Mouse Model of Peri-Menopause.

Hypertension susceptibility in women increases at the transition to menopause, termed perimenopause, a state characterized by erratic estrogen fluctuation and extended hormone cycles. Elucidating the role of estrogen signaling in the emergence of hypertension during perimenopause has been hindered by animal models that are confounded by abrupt estrogen cessation or effects of aging. In the present study, accelerated ovarian failure (AOF) in estrogen receptor ß (ERß) reporter mice was induced by 4-vinylcyclohexene diepoxide in young mice to model early-stage ovarian failure (peri-AOF) characteristic of peri-menopause. It was found that administering ERß agonists suppressed elevated blood pressure in a model of neurogenic hypertension induced by angiotensin II (AngII) in peri-AOF, but not in age-matched male mice. It was also found that ERß agonist administration in peri-AOF females, but not males, suppressed the heightened NMDAR signaling and reactive oxygen production in ERß neurons in the hypothalamic paraventricular nucleus (PVN), a critical neural regulator of blood pressure. It was further shown that deleting ERß in the PVN of gonadally intact females produced a phenotype marked by a sensitivity to AngII hypertension. These results suggest that ERß signaling in the PVN plays an important role in blood pressure regulation in female mice and contributes to hypertension susceptibility in females at an early stage of ovarian failure comparable to human perimenopause.

The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease.

The peri-menopause or menopausal transition-the time period that surrounds the final years of a woman's reproductive life-is associated with profound reproductive and hormonal changes in a woman's body and exponentially increases a woman's risk of cerebral ischemia and Alzheimer's disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-ß). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-ß-mediated mechanisms.

Antidepressant-like effects of Xiaochaihutang in perimenopausal mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaochaihutang (XCHT) is a traditional Chinese medicine prescription for thousand years in China. Our previous researches show that XCHT has antidepressant-like effects in several depression models, but effect and mechanism of XCHT in perimenopausal depression are still vague. AIM OF THE STUDY: To reveal the antidepressant-like effect and mechanism of XCHT in perimenopausal mice. MATERIALS AND METHODS: Perimenopausal depression model is executed by ovariectomy combined with chronic unpredictable mild stress (OVX-CUMS). Tail suspension test (TST), forced swim test (FST), elevated plus-maze (EPM), novelty suppressed feeding (NSF) and locomotor activity are used to assess antidepressant-like effects of XCHT. The Level of estradiol (E2), follicle-stimulating hormone (FSH), gonadotrophin releasing hormone (GnRH), corticosterone (CORT), adrenocorticotrophic hormone (ACTH) and corticotropin releasing hormone (CRH) are evaluated by ELISA. Antidepressant mechanisms of XCHT in OVX-CUMS mice are analyzed by 5-hydroxytryptamine (5-HT), tryptophan hydroxylase 2 (TPH2) and estrogen receptor α and ß (ERα/ß). RESULTS: The results show that OVX-CUMS significantly increases the immobility time in TST and FST, increases latency to feed, decreases food consumption in NSF and both the time spend and number of entries in open arms in EPM. While, oral administration of XCHT can significantly normalize above depression-like behaviors in OVX-CUMS mice. Moreover, XCHT also remarkably normalized levels of 5-HT, 5-HIAA, E2, GnRH, CORT, ACTH and CRH in OVX-CUMS mice. Finally, the expression of ERß and TPH2 are decreased by OVX-CUMS in prefrontal cortex and hypothalamus, and XCHT can restore these decrease. CONCLUSION: Current findings suggest XCHT can alleviate perimenopausal depression-like behaviors, restore 5-HT and hormones in OVX-CUMS mice, which may be related to normalizing the functions of HPA/HPO axis and enhancing expression of ERß and TPH2 in prefrontal cortex and hypothalamus.

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population.

OBJECTIVE: Bone turnover, which regulates bone mass, may exert metabolic consequences, particularly on markers of glucose metabolism and adiposity. To better understand these relationships, we examined cross-sectional associations between bone turnover markers (BTMs) and metabolic traits in a population with high bone mass (HBM, BMD Z-score ≥+3.2). DESIGN: ß-C-terminal telopeptide of type-I collagen (ß-CTX), procollagen type-1 amino-terminal propeptide (P1NP) and osteocalcin were assessed by electrochemiluminescence immunoassays. Metabolic traits, including lipids and glycolysis-related metabolites, were measured using nuclear magnetic resonance spectroscopy. Associations of BTMs with metabolic traits were assessed using generalized estimating equation linear regression, accounting for within-family correlation, adjusting for potential confounders (age, sex, height, weight, menopause, bisphosphonate and oral glucocorticoid use). RESULTS: A total of 198 adults with HBM had complete data, mean [SD] age 61.6 [13.7] years; 77% were female. Of 23 summary metabolic traits, citrate was positively related to all BTMs: adjusted ßß-CTX  = 0.050 (95% CI 0.024, 0.076), P = 1.71 × 10-4 , ßosteocalcin  = 6.54 × 10-4 (1.87 × 10-4 , 0.001), P = .006 and ßP1NP  = 2.40 × 10-4 (6.49 × 10-5 , 4.14 × 10-4 ), P = .007 (ß = increase in citrate (mmol/L) per 1 µg/L BTM increase). Inverse relationships of ß-CTX (ß = -0.276 [-0.434, -0.118], P = 6.03 × 10-4 ) and osteocalcin (-0.004 [-0.007, -0.001], P = .020) with triglycerides were also identified. We explored the generalizability of these associations in 3664 perimenopausal women (age 47.9 [4.4] years) from a UK family cohort. We confirmed a positive, albeit lower magnitude, association between ß-CTX and citrate (adjusted ßwomen  = 0.020 [0.013, 0.026], P = 1.95 × 10-9 ) and an inverse association of similar magnitude between ß-CTX and triglycerides (ß = -0.354 [-0.471, -0.237], P = 3.03 × 10-9 ). CONCLUSIONS: Bone resorption is positively related to circulating citrate and inversely related to triglycerides. Further studies are justified to determine whether plasma citrate or triglyceride concentrations are altered by factors known to modulate bone resorption, such as bisphosphonates.

Reduced serotonin impairs long-term depression in basolateral amygdala complex and causes anxiety-like behaviors in a mouse model of perimenopause.

Perimenopause is characterized by a gradual depletion of ovarian follicles with increased vulnerability to anxiety. However, the underlying mechanisms remain poorly understood. Herein, we show that chronic exposure to 4-vinylcycloxene diepoxide (VCD) in adult female mice (VCD-mice) caused follicles depletion and decline of serum estradiol (E2) and progesterone levels. Serotonin (5-HT) synthesis in dorsal raphe nucleus (DRN) and serotonergic afferents to basolateral amygdala complex (BLA) were reduced in VCD-mice, which were recovered by the supplement E2. VCD-mice appeared anxiety-like behaviors, which was relieved by the treatment with E2 or the co-administration of 5-HT1Ar agonist 8-OH-DPAT and 5-HT2A/Cr agonist DOI. The bath-application of 8-OH-DPAT in the slices obtained from VCD-mice (VCD-slices) corrected the increase in presynaptic glutamate release at external capsule-BLA synaptic transmission. Threshold to induce NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) was declined in VCD-mice with elevation of CaMKII phosphorylation, which was sensitive to 8-OH-DPAT. Notably, the bath-application of 8-OH-DPAT in VCD-slices caused a decrease in the GABAergic feedback inhibition, which was restored by adding DOI. In addition, NMDAr-independent long-term depression (LTD) could not be induced in VCD-mice, which was rescued by the co-application of 8-OH-DPAT with DOI or the GABAA receptor agonist muscimol. Furthermore, the treatment of VCD-mice with E2 could prevent the facilitation of LTP and recover the LTD induction. Thus, the results indicate that the 5-HT deficiency in the BLA of VCD-mice causes the facilitation of LTP via enhanced glutamate release and impairs the LTD induction through diminished GABAergic inhibition, leading to anxiety-like behaviors.

Bilberry anthocyanin improves the serum cholesterol in aging perimenopausal rats via the estrogen receptor signaling pathway.

With aging, there is an increasing risk for women to develop perimenopause syndrome, which is harmful to women's physical and mental health. The present study investigated the health benefits of bilberry anthocyanin (BA) on aging perimenopausal Sprague-Dawley rats. Rats that entered into perimenopause through natural aging were treated for 8 weeks with BA, and received either a low dose (LD, 35 mg per kg of bodyweight), medium dose (MD, 70 mg per kg of bodyweight), or high dose (HD, 140 mg per kg of bodyweight). The experimental results suggested that all three dosages of BA, especially the high dose, significantly reduced the serum total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) levels. In addition, BA supplementation markedly reduced the serum malondialdehyde (MDA), effectively increased the activity of hepatic total superoxide dismutase (T-SOD), significantly raised the high density lipoprotein cholesterol (HDL-C), increased the number of estrogen receptors, and effectively up-regulated the expression levels of G protein-coupled receptor 30 (GPR30), protein kinase B (AKT), and extracellular regulated protein kinase 2 (ERK2). In summary, BA has a great effect on improving the serum cholesterol in natural aging perimenopausal rats via the estrogen receptor signaling pathway, and it may be used as a dietary supplement for perimenopause women to decrease the risk of cardiovascular disease.

Efficacy of self-made Gengnian decoction on phosphatidylinositol 3-kinases/protein kinase B/mammalian target of rapamycin signaling pathway in perimenopausal rats.

OBJECTIVE: To investigate the efficacy of self-made Gengnian decoction on expressions of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) in ovarian tissues of perimenopausal rats. They were identified with symptom pattern of kidney-Yang deficiency in terms of Traditional Chinese Medicine. METHODS: Female Sprague-Dawley rats aged 10-12 months were selected. Estrous cycle was observed by vaginal smears of keratinocytes to screen the perimenopausal model rats. The chosen rats were randomly divided into five groups, including perimenopausal model of kidney-Yang deficiency group (24 rats), self-made Gengnian decoction of high-dose group (24 rats), self-made Gengnian decoction of middle-dose group (24 rats), self-made Gengnian decoction of low dose group (24 rats) and tibolone control group (24 rats). In addition, rats aged 4-6 months were selected as young control group. The perimenopausal model rats of kidney-Yang deficiency were prepared by alternative intramuscular injection of hydrocortisone 5 mg·kg－1·d－1 The successfully prepared models in self-made Gengnian decoction of high-dose, middle-dose and low-dose groups and tibolone control group were given self-made Gengnian decoction 26.4, 13.2 and 6.6 mg·kg－1·d－1, and tibolone tablets solvent 0.22 mg·kg－1·d－1, respectively, through intragastric administration. Models group and young control group were given the same dose of normal saline, 1 time a day for 15 consecutive days. 24 h after the last administration, blood and ovarian tissues were collected after anesthesia with 20% ethyl carbamate. The follicles of different levels in ovarian tissue were observed and counted by histopathological hematoxylin-eosin staining. Enzyme linked immunosorbent assay was applied to test insulin-like growth factor-1 (IGF-1) level in the serum of experimental rats. The expression levels of PI3K, phosphorylated-Akt (p-Akt) and phosphorylated-mTOR (p-mTOR) mRNA in ovarian tissue were detected by quantitative real-time polymerase chain reaction. RESULTS: The total follicle counts of perimenopausal model rats with kidney-Yang deficiency were significantly reduced, and the number of follicles (mainly increased in preantral follicles and antral follicles) in perimenopausal model rats with kidney-Yang deficiency was significantly increased after intervention of high and middle doses of Gengnian decoction and tibolone (P < 0.05). Compared with normal rats in young control group, the levels of IGF-1 in serum of perimenopausal rats with kidney-Yang deficiency were significantly decreased (P < 0.01), and those intervened by high dose of Gengnian decoction and tibolone were significantly up-regulated. The relative expression levels of PI3K, p-Akt, p-mTOR mRNA in ovarian tissues of perimenopausal rats with kidney-Yang deficiency were significantly lower than those of young rats (P < 0.01), and those intervened by high dose of Gengnian decoction and tibolone were significantly up-regulated (P < 0.05). CONCLUSION: Self-made Gengnian decoction can increase the levels of IGF-1, PI3K, Akt and mTOR mRNA expression in serum.

Effects of dehydroepiandrosterone on the ovarian reserve and pregnancy outcomes in perimenopausal rats (DHEA and fertility in perimenopausal rats).

BACKGROUND: Dehydroepiandrosterone (DHEA) is a weak androgen and a crucial precursor of sex steroids. Exogenous supplementation of DHEA is now being commonly used to augment ovarian stimulation in women with diminished ovarian reserve. However, the effects of DHEA are controversial. AIMS: This study verifies the effects of pharmacologic doses of DHEA on the ovarian reserve variables, follicular development, reproductive function, and pregnancy outcomes of perimenopausal rats. MAIN METHODS: The reproductive function was studied by monitoring the estrous cycle and hormones. The ovarian reserve was studied by testing the anti-mullerian hormone and ovarian histology. The follicular development was studied histologically and immunohistochemically. KEY FINDINGS: DHEA supplementation at a dose of at 50 mg/kg improved the ovarian reserve and pregnancy outcomes. Higher doses of DHEA caused PCOs-like symptoms manifested by the development of cystic follicles and low ovarian reserve and pregnancy outcomes. SIGNIFICANCE: DHEA is a promising treatment that improves the ovarian reserve parameters and pregnancy outcomes. Further studies are needed to determine the optimal dose and duration.

Effects of Estrogen Therapy on the Serotonergic System in an Animal Model of Perimenopause Induced by 4-Vinylcyclohexen Diepoxide (VCD).

Chronic exposure to 4-vinylcycloxene diepoxide (VCD) in rodents accelerates the natural process of ovarian follicular atresia modelling perimenopause in women. We investigated why estrogen therapy is beneficial for symptomatic women despite normal or high estrogen levels during perimenopause. Female rats (28 d) were injected daily with VCD or oil for 15 d; 55-65 d after the first injection, pellets of 17ß-estradiol or oil were inserted subcutaneously. Around 20 d after, the rats were euthanized (control rats on diestrus and estradiol-treated 21 d after pellets implants). Blood was collected for hormone measurement, the brains were removed and dorsal raphe nucleus (DRN), hippocampus (HPC), and amygdala (AMY) punched out for serotonin (5-HT), estrogen receptor ß (ERß), and progesterone receptor (PR) mRNA level measurements. Another set of rats was perfused for tryptophan hydroxylase (TPH) immunohistochemistry in the DRN. Periestropausal rats exhibited estradiol levels similar to controls and a lower progesterone level, which was restored by estradiol. The DRN of periestropausal rats exhibited lower expression of PR and ERß mRNA and a lower number of TPH cells. Estradiol restored the ERß mRNA levels and number of serotonergic cells in the DRN caudal subregion. The 5-HT levels were lower in the AMY and HPC in peristropausal rats, and estradiol treatment increased the 5-HT levels in the HPC and also increased ERß expression in this area. In conclusion, estradiol may improve perimenopause symptoms by increasing progesterone and boosting serotonin pathway from the caudal DRN to the dorsal HPC potentially through an increment in ERß expression in the DRN.

Perimenopausal contraception: A practice-based approach.

BACKGROUND: Women who are perimenopausal are at risk of unintended pregnancy despite relatively low fertility at this stage. Contraceptive choice can be limited by increased comorbidities, but the UK Medical Eligibility Criteria (UKMEC) system provides a framework for safe prescribing. OBJECTIVE: This article provides evidence-based guidance on contraceptive options, and information to support decision-making about stopping contraception at menopause. DISCUSSION: Contraceptive choice is determined by several factors, including medical eligibility, side effects and risks, non-contraceptive benefits, cost and personal preference. Long-acting reversible contraceptives (LARCs) are an effective, acceptable and safe choice for many women. For women aged ≥50 years who are using a non-hormonal method, contraception is recommended until after 12 months of amenorrhoea, or 24 months if they are aged 50 years; serial follicle-stimulating hormone (FSH) levels can guide method cessation given amenorrhoea is not a reliable indicator of menopause in this context.

Total glucosides of Curculigo rhizome to perimenopausal period mice model.

To investigate the effects of total glucosides of Curculigo rhizome (TGC) to perimenopausal period (PMS) mice model. After removed the bilateral ovaries induced the PMS mice model, high, medium and low doses of TGC group were partly given TGC solution 400,200,100mg•kg-1, administered once a day, continuously 21 days. Compared with the model group (MG) mices, each dose of TGC group could significantly improve the activities of mice, increase thymus, uterus, spleen index(TI, UI, SI), the levels of testosterone(T), estradiol (E2), reduce the level of luteinizing hormone (LH), the high dose of TGC group(HD-C) group has the best effects. It prompted that TGC has the effect in treatment of PMS mice model, the HD-C group of TGC has the best effects.

Menstrual Cycle Hormone Changes in Women Traversing Menopause: Study of Women's Health Across the Nation.

Context: Menstrual cycle hormone patterns in women approaching menopause are inadequately studied. Objective: To describe day-to-day menstrual cycle hormones in women as they approach menopause from the Study of Women's Health Across the Nation Daily Hormone Study (DHS). Design: DHS enrollees collected daily urine for one entire menstrual cycle or up to 50 days, whichever came first, annually, up to the final menstrual period (FMP) or for up to 10 years. Setting: Seven sites across the United States. Participants: A total of 511 premenopausal or early perimenopausal women at enrollment, within 10 years before menopause. Intervention: Time-to-FMP measurement. Main Outcome Measures: Evidence of luteal activity (ELA), determined using objective algorithms. Menstrual cycle/segment length; whole cycle, and segment integrated urinary luteinizing hormone, follicle-stimulating hormone, estrone conjugates, and pregnanediol glucuronide (Pdg) for each year, organized around the FMP. Results: Mean menstrual cycle length was remarkably preserved at 26 to 27 days in ELA cycles; non-ELA cycles had greater variability. The percentage of cycles that were ELA remained high until 5 years before the FMP (87.9%); only 22.8% of cycles within 1 year of the FMP were ELA. Whole cycle hormones remained relatively stable up to 3 years before the FMP, when gonadotropins began to increase. Pdg excretion declined slowly with progress to the FMP, but Pdg patterns of ELA cycles remained distinguishable from non-ELA. Conclusions: Menstrual cycle hormone patterns in perimenopausal women resemble those of midreproductive-aged women until 5 years before menopause, and presumably ovulatory cycles retain a potentially fertile pattern up to the end of reproductive life.

Effects of essential oil exposure on salivary estrogen concentration in perimenopausal women.

OBJECTIVES: The menopausal transition is the time from the onset of menstrual changes until one year after the final menstrual period. During this phase, perimenopausal women experience a variety of health-related symptoms, which seemingly derive from declining level of estrogen secretion. It has long been recognized that some essential oils have the efficacy of alleviating menopausal symptoms. On the basis of this, it is possible that these essential oils have the potency to facilitate estrogen secretion in women. The present study investigated this possibility by examining if the olfactory exposure to the essential oil increase salivary estrogen concentration. METHODS: We tested the effect of ten essential oils; clary sage, frankincense, geranium, lavender, jasmine absolute, neroli, rose otto, ylang ylang, orange and roman chamomile, which are thought to relieve perimenopasal symptoms. RESULTS: The results have shown increase of salivary estrogen concentration induced by exposure to geranium and rose otto compared to control odor. CONCLUSION: Together with the previous studies, the present study may give support to the notion that olfactory exposure to some essential oils can influence salivary concentration of estrogen.

Effect of Chaihushugan San on expression of the Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase pathway in the hippocampi of perimenopausal rats induced by immobilization stress.

OBJECTIVE: We wished to study the impact of Chaihushugan San (CSS) on the behavior of perimenopausal rats with liver-Qi stagnation (LQS) and to investigate the effect of CSS on signal transduction of the Raf/mitogen-activated protein kinase (MEK)/ extracellular signal-regulated kinase (ERK) cascade in the hippocampi of rats induced by immobilization. METHODS: Twenty 52-week-old female rats were divided into two groups by the random number table method: model control group (MCG) and CSS group (CSSG), with 10 rats in each group. Ten-week-old female rats were used as the normal control group (NCG). CSS effects were assessed using rats exposed to immobilization stress by measuring body weight and sucrose consumption, serum hormone levels, and observing performance in the open field test (OFT). Molecular mechanisms were examined by measuring the effect of CSS on expression of Raf1, MEK1/2 and ERK1/2 mRNA in hippocampi using quantitative real-time polymerase chain reaction and by measuring levels of these proteins and related phospho-proteins using Western blotting. RESULTS: Perimenopausal rats with LQS had decreased locomotor activity; reduced sucrose consumption; and increased serum levels of corticotropin releasing hormone (CRH) and corticosterone (CORT). Activation of hippocampal Raf/MEK/ERK cascade was suppressed significantly in the MCG, and activation was increased after 21 days of CSS treatment. CONCLUSION: CSS has significant effects upon relief of the symptoms of LQS in immobilization-induced rats. The mechanism underlying this action might (at least in part) be mediated by reversal of disruption of the Raf/MEK/ERK pathway.