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Aromatase deficiency (ORPHA:91; OMIM: 613,546) is a rare, autosomal recessive disorder due to loss of function mutations in the CYP19A1 gene, described in both genders with an estimated incidence below 1/1000000. While in female the clinical manifestations generally occur at birth or in early infancy, and mainly involve sexual characteristics, in men clinical signs of aromatase deficiency mostly occur in puberty and especially in late puberty, so that diagnosis is generally established after the second decade due to tall stature, unfused epiphyses and reduced bone mass. Here we review the available information concerning the skeletal and extraskeletal phenotype and the clinical management of bone health in patients with aromatase CYP19A1 gene mutations. [ABSTRACT FROM AUTHOR]

Regular exercise has numerous health benefits, but the human population displays significant variability in exercise participation. Rodent models, such as voluntary wheel running (VWR) in rats, can provide insight into the underlying mechanisms of exercise behavior and its regulation. In this study, we focused on the role of estrogen on VWR in female rats. Female rats run more than males, and we aimed to determine to what extent running levels in females were regulated by estrogen signaling. The running behavior of rats (duration, speed, and total distance run) was measured under normal physiological conditions, ovariectomy (OVX), and estrogen replacement in an OVX background. Results show cyclic variations in running linked to the estrous cycle. Ovariectomy markedly reduced running and eliminated the cyclic pattern. Estrogen replacement through estradiol benzoate (EB) injections and osmotic minipumps reinstated running activity to pre-OVX levels and restored the cyclic pattern. Importantly, individual differences and ranking are preserved such that high versus low runners before OVX remain high and low runners after treatment. Further analysis revealed that individual variation in running distance was primarily caused by rats running different speeds, but rats also varied in running duration. However, it is noteworthy that this model also displays features distinct from estrogen-driven running behavior under physiological conditions, notably a delayed onset and a broader duration of running activity. Collectively, this estrogen causality VWR model presents a unique opportunity to investigate sex-specific mechanisms that control voluntary physical activity. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Cortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura and a headache trigger. Migraine is three times more prevalent in women than men, linked to circulating female hormones. High estrogen levels or estrogen withdrawal may be a migraine trigger for many women. We, therefore, aimed to examine whether sex, gonadectomy, and female hormone supplementation and withdrawal affect the susceptibility to CSD. Methods To determine CSD susceptibility, we recorded the frequency of CSDs triggered during 2-h topical KCl application in intact or gonadectomized female and male rats, without or with estradiol or progesterone supplementation via daily intraperitoneal injections. Estrogen or progesterone treatment followed by withdrawal was studied in a separate cohort. To take the first step towards identifying potential mechanisms, we studied glutamate and GABAA receptor binding using autoradiography. Results The CSD frequency in intact female rats was higher than intact male and ovariectomized rats. We did not detect a change in CSD frequency during different stages of the estrous cycle in intact females. Daily estrogen injections for three weeks did not change CSD frequency. However, one-week estrogen withdrawal after two weeks of treatment significantly increased CSD frequency compared with the vehicle group in gonadectomized females. The same protocol of estrogen treatment and withdrawal was ineffective in gonadectomized males. In contrast to estrogen, daily progesterone injections for three weeks elevated CSD susceptibility, and one-week withdrawal after two weeks of treatment partially normalized this effect. Autoradiography did not reveal significant changes in glutamate or GABAA receptor binding density after estrogen treatment and withdrawal. Conclusions These data suggest that females are more susceptible to CSD, and sexual dimorphism is abrogated by gonadectomy. Moreover, estrogen withdrawal after prolonged daily treatment enhances CSD susceptibility. These findings may have implications for estrogen-withdrawal migraine, although the latter tends to be without aura.

Background and aims: Cortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura and a headache trigger. Migraine is three times more prevalent in women than men, linked to circulating female hormones. High estrogen levels or estrogen withdrawal may be a migraine trigger for many women. We, therefore, aimed to examine whether sex, gonadectomy, and female hormone supplementation and withdrawal affect the susceptibility to CSD. Methods: To determine CSD susceptibility, we recorded the frequency of CSDs triggered during 2-h topical KCl application in intact or gonadectomized female and male rats, without or with estradiol or progesterone supplementation via daily intraperitoneal injections. Estrogen or progesterone treatment followed by withdrawal was studied in a separate cohort. To take the first step towards identifying potential mechanisms, we studied glutamate and GABAA receptor binding using autoradiography. Results: The CSD frequency in intact female rats was higher than intact male and ovariectomized rats. We did not detect a change in CSD frequency during different stages of the estrous cycle in intact females. Daily estrogen injections for three weeks did not change CSD frequency. However, one-week estrogen withdrawal after two weeks of treatment significantly increased CSD frequency compared with the vehicle group in gonadectomized females. The same protocol of estrogen treatment and withdrawal was ineffective in gonadectomized males. In contrast to estrogen, daily progesterone injections for three weeks elevated CSD susceptibility, and one-week withdrawal after two weeks of treatment partially normalized this effect. Autoradiography did not reveal significant changes in glutamate or GABAA receptor binding density after estrogen treatment and withdrawal. Conclusions: These data suggest that females are more susceptible to CSD, and sexual dimorphism is abrogated by gonadectomy. Moreover, estrogen withdrawal after prolonged daily treatment enhances CSD susceptibility. These findings may have implications for estrogen-withdrawal migraine, although the latter tends to be without aura. [ABSTRACT FROM AUTHOR]

In the present study, effects of ovariectomy (Ovx) and estradiol-17β (E2) replacement on the brain steroid levels were investigated in the resting and prespawning phases of the female catfish Heteropneustes fossilis. The study showed that Ovx resulted in significant decreases in plasma levels of estradiol-17β (E2) and its precursors, and the effect varied with the reproductive stage and duration. Our study showed that E2 supplementation reversed the effect of Ovx in 3-week Ovx fish group, either restored or increased according to the dose. In contrast, E2 levels increased in the brain after Ovx in the resting stage and produced a biphasic effect of significant decreases on week 1 and 2, and significant increases on week 3, 4 and 5 in the pre-spawning stage. The brain E2 levels significantly inhibited in E2 supplementation groups. The testosterone (T) levels showed biphasic effects, an initial decrease (up to 3 weeks Ovx) and an increase later (week 4, 5) in the resting stage. In the pre-spawning stage, the T levels increased significantly after Ovx. The E2 supplementation significantly inhibited the T levels, more severely in the low dose group in the resting and pre-spawning stages. Brain 17-hydroxyprogesterone(17-OHP4) levels increased (week 1, 2, 3) but decreased on week 4 and 5 of Ovx in the resting stage and increased throughout Ovx in the pre-spawning stage except in the 5th week (though compared to other steroids, level was very low; almost negligible). The E2 replacement significantly decreased the steroid levels further down compared to the Ovx control group. Brain progesterone (P4) and pregnenolone (P5) levels decreased initially (week 1 and 2 Ovx) and recovered later. The E2 replacement significantly decreased P4 levels in the Ovx fish in the pre-spawning stage and in the lower dose group in the resting stage. The P5 levels remained inhibited after the E2 supplementation in the resting stage but unchanged or increased it in the pre-spawning stage. Brain cortisol (F) levels were inhibited initially (1 and 2 weeks and later increased after OVX in the resting stage. In the pre-spawning stage, the F levels increased in the week 1, 2 and 3 of Ovx and decreased in the 4th and 5th weeks. The E2 supplementation inhibited the cortisol (F) levels in both phases. The results show that ovarian steroids influence neurosteroidogenesis in a reproductive stage-dependent manner.

Objective: To assess the impact of an estrogen replacement regimen on frozen embryo transfer (FET) cycle outcome. Methods: In the present retrospective cohort study, data of infertile women undergoing FET with good‐quality embryos were reviewed. The first group received 2 mg of estradiol hemihydrate (EH) once daily for 6 to 7 days, then twice daily for 4 to 5 days, and then three times a day until embryo transfer. The second group received EH twice daily for 7 to 8 days, then three times a day. The third group received EH three times a day constantly. The main outcome measure was live birth rate. Results: In total, 394 FET cycles were included. The fixed 6‐mg group required the highest estradiol hemihydrate dose. The duration of estrogen treatment was significantly longer in the first group. Maximal endometrial thickness was highest in the second group (10.2 ± 1.3 mm vs. 9.6 ± 1.4 mm vs. 8.6 ± 0.9 mm, respectively; P < 0.001). The clinical pregnancy rates in the groups were 41.1%, 55.2%, and 42.2%, respectively (P = 0.035). Live birth rates were 40.8%, 50.9%, and 48.1%, respectively (P = 0.320). Conclusion: In FET cycles with hormone replacement therapy, a step‐up 4‐mg regimen provides thicker endometrium with optimal‐dose estrogen in an adequate time frame. The tendency for increased clinical pregnancy and live birth rates is remarkable. Synopsis: In artificial frozen embryo transfer cycles, estrogen replacement starting from 4 mg provides thicker endometrium with optimal doses and shows a tendency for increased live birth rates compared with starting from 2 or 6 mg. [ABSTRACT FROM AUTHOR]

Turner syndrome is one of the most frequently reported sex chromosomal abnormalities, affecting approximately 40 in every 100 000 live female births. The underlying chromosomal alteration is the complete or partial loss of X chromosome or mosaicism. Because of primary ovarian insufficiency, the synthesis of estrogen hormones is compromised, and patients require hormone substitution. Apart from the phenotypical presentation (short stature, primary amenorrhea), the effects of ovarian insufficiency can affect diverse organ systems (such as cardiovascular, endocrine, and lymphatic systems). Hepatobiliary pathology can present on a broad spectrum: from mild asymptomatic hypertransaminasemia to marked architectural changes. Estrogen hormone replacement therapy in these patients can improve the perturbations of laboratory values and can attenuate the progression of hepatic structural changes. Moreover, providing sufficient estrogen replacement has numerous benefits for other conditions of the patients as well. Both the all-cause mortality and deaths from cardiovascular complications are greatly increased in Turner syndrome, and hormone replacement might contribute to the decreased incidence of these events. The diagnostics of Turner syndrome are outside the scope of our paper, and we briefly discuss the cardiovascular complications because many the liver involvement partially involves alterations of vascular origin. Though we sought to highlight the importance of proper hormone replacement therapy, we did not attempt to write a comprehensive recommendation for exact treatment protocols. We provided an overview of preferred therapeutic approaches, as the treatment should be tailored according to the individual patient's needs. [ABSTRACT FROM AUTHOR]

In the present study, effects of ovariectomy (Ovx) and estradiol-17β (E2) replacement on the brain steroid levels were investigated in the resting and prespawning phases of the female catfish Heteropneustes fossilis. The study showed that Ovx resulted in significant decreases in plasma levels of estradiol-17β (E2) and its precursors, and the effect varied with the reproductive stage and duration. Our study showed that E2 supplementation reversed the effect of Ovx in 3-week Ovx fish group, either restored or increased according to the dose. In contrast, E2 levels increased in the brain after Ovx in the resting stage and produced a biphasic effect of significant decreases on week 1 and 2, and significant increases on week 3, 4 and 5 in the pre-spawning stage. The brain E2 levels significantly inhibited in E2 supplementation groups. The testosterone (T) levels showed biphasic effects, an initial decrease (up to 3 weeks Ovx) and an increase later (week 4, 5) in the resting stage. In the pre-spawning stage, the T levels increased significantly after Ovx. The E2 supplementation significantly inhibited the T levels, more severely in the low dose group in the resting and pre-spawning stages. Brain 17-hydroxyprogesterone(17-OHP4) levels increased (week 1, 2, 3) but decreased on week 4 and 5 of Ovx in the resting stage and increased throughout Ovx in the pre-spawning stage except in the 5th week (though compared to other steroids, level was very low; almost negligible). The E2 replacement significantly decreased the steroid levels further down compared to the Ovx control group. Brain progesterone (P4) and pregnenolone (P5) levels decreased initially (week 1 and 2 Ovx) and recovered later. The E2 replacement significantly decreased P4 levels in the Ovx fish in the pre-spawning stage and in the lower dose group in the resting stage. The P5 levels remained inhibited after the E2 supplementation in the resting stage but unchanged or increased it in the pre-spawning stage. Brain cortisol (F) levels were inhibited initially (1 and 2 weeks and later increased after OVX in the resting stage. In the pre-spawning stage, the F levels increased in the week 1, 2 and 3 of Ovx and decreased in the 4th and 5th weeks. The E2 supplementation inhibited the cortisol (F) levels in both phases. The results show that ovarian steroids influence neurosteroidogenesis in a reproductive stage-dependent manner. [ABSTRACT FROM AUTHOR]

Study Objective: To assess hormone replacement therapy (HRT) prescription pattern in patients undergoing premature surgical menopause on the basis of surgical indication.Design: Retrospective cohort study.Setting: Academic tertiary care center.Patients: Surgically menopausal patients aged ≤45 years who underwent a minimally invasive hysterectomy with salpingo-oophorectomy.Interventions: HRT prescription in the 6-week postoperative period.Measurements and Main Results: A total of 63 patients met inclusion criteria. Of these, 52% (n = 33) were prescribed HRT in the 6-week postoperative period. Indications for surgical menopause included pelvic pain or endometriosis (31.7%), gynecologic malignancy (20.6%), BRCA gene mutation (17.4%), breast cancer (9.5%), Lynch syndrome (4.8%), and other (15.8%). In total, 80% of patients with pelvic pain, 25% with gynecologic malignancies, 45% with BRCA gene mutations, 33.3% with breast cancer, and 66.6% with Lynch syndrome used HRT postoperatively. In patients who used HRT postoperatively, 76% were offered preoperative HRT counseling. This is in contrast with those patients who did not use HRT postoperatively, of whom only 33% were offered HRT counseling (p <.001). Perioperative complications were not predictive of HRT use postoperatively. In patients who did not use HRT postoperatively, 13.3% used alternative nonhormonal therapy.Conclusion: In patients who underwent premature surgical menopause, 52% used HRT postoperatively. Patients with pelvic pain and Lynch syndrome were more likely to use HRT, whereas those with gynecologic or breast malignancies and BRCA gene mutations were less likely to use HRT. Preoperative HRT counseling was associated with postoperative HRT use. [ABSTRACT FROM AUTHOR]

Menopause is often accompanied by visceral obesity. With the aim of exploring the consequences of ovarian failure on visceral fat, we evaluated the effects of ovariectomy and estrogen replacement on the proteome/phosphoproteome and on the fatty acid profile of the retroperitoneal adipose depot (RAT) of rats. Eighteen 3-mo-old female Wistar rats were either ovariectomized or sham operated and fed with standard chow for 3 mo. A subgroup of ovariectomized rats received estradiol replacement. RAT samples were analyzed with data-independent acquisitions LC-MS/MS, and pathway analysis was performed with the differentially expressed/phosphorylated proteins. RAT lipid profile was analyzed by gas chromatography. Ovariectomy induced high adiposity and insulin resistance and promoted alterations in protein expression and phosphorylation. Pathway analysis showed that five pathways were significantly affected by ovariectomy, namely, metabolism of lipids (including fatty acid metabolism and mitochondrial fatty acid β-oxidation), fatty acyl-CoA biosynthesis, innate immune system (including neutrophil degranulation), metabolism of vitamins and cofactors, and integration of energy metabolism (including ChREBP activates metabolic gene expression). Lipid profile analysis showed increased palmitic and palmitoleic acid content. The analysis of the data indicated that ovariectomy favored lipogenesis whereas it impaired fatty acid oxidation and induced a proinflammatory state in the visceral adipose tissue. These effects are consistent with the findings of high adiposity, hyperleptinemia, and impaired insulin sensitivity. The observed alterations were partially attenuated by estradiol replacement. The data point to a role of disrupted lipid metabolism in adipose tissue in the genesis of obesity after menopause. [ABSTRACT FROM AUTHOR]

Objectives: To assess compliance with the European Society for Human Reproduction and Embryology (ESHRE) guidelines on the investigation and management of women with premature ovarian insufficiency at the Leeds Teaching Hospitals NHS Trust (LTHT) and to determine whether this varies depending on the clinical setting in which the women present.Study design: A retrospective review of all females diagnosed with premature ovarian insufficiency between 1 July 2016 and 30 June 2017, presenting to one of the following clinics: reproductive medicine, specialist menopause, general gynaecology, oncology long-term follow-up, general endocrinology or paediatric endocrinology.Main outcome measures: Proportion of patients who had the necessary investigations performed and relevant treatment options discussed.Results: 103 women were included in the study. Overall, 40.6% had a karyotype. Screening for the Fragile-X pre-mutation, thyroid peroxidase and 21-hydroxylase antibodies occurred in 7.4%, 11.1% and 13.6% of women, respectively. Only 35.9% had their bone mineral density measured. There was significant variation in the performance of a karyotype (p < 0.001) and thyroid peroxidase antibodies (p < 0.01) between the different clinical settings. Overall, lifestyle advice was offered to 30.1%. Estrogen replacement, contraception, fertility options and bone protection were discussed with 76.0%, 38.4%, 59.0% and 75.0%, respectively. Psychological support was offered to 25.2%. There was significant variation for all apart from contraception.Conclusion: The investigation and treatment of women with premature ovarian insufficiency at the LTHT is not consistent with the ESHRE guidelines and requires improvement. Furthermore, there is significant variation in management depending on the department to which the patient initially presents. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation are a group of rare related disorders causing multisystem dysfunction, including ovarian failure in females that requires early estrogen replacement. Glycosylation defects also disrupt normal synthesis of several coagulation factors, increasing thrombotic risks and complicating hormone replacement. This series describes four females with different types of CDG who developed venous thromboses while on transdermal estrogen replacement. The authors highlight the knowledge gaps around anticoagulation for this population and propose further investigations. [ABSTRACT FROM AUTHOR]

Purpose of Review: After the publication of the Women's Health Initiative, there was a dramatic reduction in prescriptions for menopausal hormonal therapy (MHT). We performed a literature search and reviewed major society guidelines to discuss recommendations and practice since 2010 regarding MHT. Recent Findings: While not recommended for management and prevention of chronic diseases, MHT offers relief for bothersome menopausal symptoms. For vasomotor symptoms and vaginal atrophy, low-dose estrogen therapy (systemic and vaginally, respectively) provided effective relief of symptoms and improved quality of life. For cognitive and mood related effects, MHT had little benefit. Summary: Consideration of MHT for menopausal symptoms should be part of an overall strategy including lifestyle recommendations regarding diet, exercise, smoking cessation, and safe levels of alcohol consumption for maintaining the health of peri- and postmenopausal women. Future research should examine best practices for tapering therapy and monitoring for endometrial cancer risk. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to assess the efficacy of a minimal ovarian stimulation involving combined clomiphene citrate (CC) and estradiol (E2) administration for poor responders with diminished ovarian reserve (DOR). Material and Methods In this case-control study, we recruited 41 consecutive hypergonadotropic poor responders (69 cycles) who met Bologna-criteria and had experienced cancellation of oocyte retrieval. In 10 (20 cycles), 11 (21 cycles) and 20 patients (28 cycles) between 2012 and 2014, follicular development was induced using an E2 cycle, CC cycle and CC + E2 cycle, respectively. After confirmation of high follicle-stimulating hormone levels (15-40 mIU/ml) at menstrual day 3, DOR patients were treated with oral E2 of 1.0 mg/day, CC of 100 mg/day, or both CC and E2 continuously, until ovulation induction. Two days later, we transvaginally aspirated the follicles, performed in vitro fertilization, and cryopreserved the cleavage embryos. One warmed embryo was transferred into the uterus during the hormone replacement cycles. Results For the E2, CC, and CC + E2 cycles, the median patient age was 41 years in all groups, and the serum anti-Müllerian hormone levels were 0.2 ± 0.3, 0.4 ± 0.4, and 0.2 ± 0.3 ng/mL, respectively ( P = 0.258); follicular development failure rates were 50.0%, 19.0%, and 3.6%, respectively ( P < 0.001); numbers of retrieved oocytes (/cycle) were 0.5 ± 0.6, 0.8 ± 0.7, and 1.2 ± 1.1, respectively ( P = 0.033); and clinical pregnancy rates (/cycle) were 5.0%, 4.8%, and 10.7%, respectively ( P = 0.725). Conclusion CC + E2 administration for the patients with DOR was effective with a lower cancellation rate of oocyte retrieval and a higher number of retrieved oocytes. © 2015 Japan Society of Obstetrics and Gynecology [ABSTRACT FROM AUTHOR]

Objective We investigated the effect of ovariectomy (OVX) and 17β-estradiol (E2) replacement on both mitochondrial and myocardial function in cTnT-Q92 transgenic mice generated by cardiac-restricted expression of a human hypertrophic cardiomyopathy (HCM) mutation. Methods The cTnT-Q92 mice were ovariectomized at twenty weeks of age and were treated with either placebo (OVX group) or E2 (OVX + E2 group) for twelve weeks before being sacrificed. Wild-type and cTnT-Q92 female mice receiving sham operation were used as controls. Indices of diastolic function such as mitral early (E) and late (A) inflow as well as isovolumic relaxation time (IVRT) were measured by echocardiography. A Clark-type electrode was used to detect respiratory control, and ATP levels were determined at the mitochondrial level using HPLC. Key components related to mitochondrial energy metabolism, such as peroxisome proliferator-activated receptor α (PPARα), PPARγ coactivator 1α (PGC-1α) and nuclear respiratory factor-1 (NRF-1), were also analyzed using Western blot and RT–PCR. The levels of oxidative stress markers were determined by measuring malondialdehyde (MDA) using the thiobarbituric acid assay. Results The cTnT-Q92 mice had impaired diastolic function compared with wild-type mice (E/A ratio, 1.39 ± 0.04 vs. 1.21 ± 0.01, p < 0.001; IVRT, 19.17 ± 0.85 vs. 22.15 ± 1.43 ms, p = 0.028). In response to ovariectomy, cardiac function further decreased compared with that observed in cTnT-Q92 mice that received the sham operation (E/A ratio, 1.15 ± 0.04 vs. 1.21 ± 0.01, p < 0.001; IVRT, 28.31 ± 0.39 vs. 22.15 ± 1.43 ms, p = 0.002). Myocardial energy metabolism, as determined by ATP levels (3.49 ± 0.31 vs. 5.07 ± 0.47 μmol/g, p < 0.001), and the mitochondrial respiratory ratio (2.04 ± 0.10 vs. 2.63 ± 0.11, p = 0.01) also decreased significantly. By contrast, myocardial concentrations of MDA increased significantly in the OVX group, and PGC-1α, PPARα and NRF-1decreased significantly. E2 supplementation significantly elevated myocardial ATP levels (4.55 ± 0.21 vs. 3.49 ± 0.31 μmol/g, p = 0.003) and mitochondrial respiratory function (3.93 ± 0.05 vs. 2.63 ± 0.11, p = 0.001); however, it reduced the MDA level (0.21 ± 0.02 vs. 0.36 ± 0.03 nmol/g, p < 0.001), which subsequently improved diastolic function (E/A ratio, 1.35 ± 0.06 vs. 1.15 ± 0.04, p < 0.001; IVRT, 18.22 ± 1.16 vs. 28.31 ± 0.39 ms, p = 0.007). Conclusions Our study has shown that 17β-estradiol improved myocardial diastolic function, prevented myocardial energy dysregulation, and reduced myocardial oxidative stress in cTnT-Q92 mice. [ABSTRACT FROM AUTHOR]

Background: Most of the women suffer from vaginal atrophy and dryness, and therefore, effi cient and safe treatment is needed to improve vaginal lubrication. Vitamin D has several important functions which may be effective in proliferation and repair of the epithelial tissue. This study aimed to evaluate the effect of vitamin D vaginal suppositories on maturation index, pH, and dryness in postmenopausal women. Materials and Methods: Women were enrolled in this double-blind clinical trial, in whom menopause occurred at least one year ago. Those women who had an abnormal Papanicolaou smear, had undergone hormonal treatment, or have had vaginal infection in the previous year were excluded. Forty-four women who found eligible were randomized into two equal groups, the treatment and control groups, which received vitamin D and placebo vaginal suppository daily for 8 weeks, respectively. Vaginal pH and maturation value were measured at the beginning and end of the study. Pain, dryness, and paleness were assessed before treatment and at the end of the 2, 4, and 8 weeks of treatment. Results: In the treatment group, the number (Mean ± SD) of superfi cial cells increased (69.76 ± 12.4) and vaginal pH decreased (1.42 ± 0.67) signifi cantly compared to the control group after 56 days. The mean pain signifi cantly reduced after 8 weeks in the treatment group (1.23 ± 0.53) compared to the control group 1.95 ± 0.74 (P < 0.001). The mean of dryness and paleness reduced signifi cantly in the treatment group versus control at 56 days. Conclusions: Vitamin D is effective in improving the maturation index and decreased the pH and dryness of the vaginal atrophy due to menopause. [ABSTRACT FROM AUTHOR]

Menopause increases the risk of cardiometabolic diseases in women. This circumstance is usually attributed to a deficiency in circulating estrogen levels although the underlying mechanism remains elusive. Given the pivotal role of AMP-activated protein kinase (AMPK) in the regulation of energy metabolism and cardiac function, this study was designed to examine the role of AMPK in estrogen deficiency and replacement-exerted cardiomyocyte responses. Adult female WT and AMPK kinase dead (KD) mice were subjected to bilateral ovariectomy (OVX) or sham operation. A cohort of ovariectomized mice received 17β-estradiol (E2) (40 μg/kg/day, i.p.) for 6 weeks. Mechanical and intracellular Ca 2+ properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-90%-relengthening (TR 90 ), and maximal velocity of shortening/relengthening (±dL/dt). Levels of AMPK, Akt JNK, ACC, SERCA, membrane Glut4, AS160 and PGC-1α were assessed using Western blot. OVX significantly decreased PS, ±dL/dt and intracellular Ca 2+ rise in responsible to electric stimulus, prolonged TR 90 and intracellular Ca 2+ decay without affecting TPS and resting intracellular Ca 2+ , the effects of which were reconciled by E2 replacement. Western blot analysis depicted that OVX suppressed phosphorylation of Akt AMPK and ACC although it promoted JNK phosphorylation, the effects of which were mitigated or significantly attenuated by E2 treatment in WT but not KD mice. Moreover, OVX procedure downregulated SERCA2a and membrane Glut4 while inhibiting AS160 phosphorylation without affecting PGC-1α levels. In vitro study revealed that E2 corrected cardiomyocyte contractile dysfunction elicited by OVX in cardiomyocytes from WT but not the AMPK kinase dead mice. Taken together, these data suggest that E2 treatment ameliorates estrogen deficiency-induced changes in cardiac contractile function possibly through an AMPK-dependent mechanism. [ABSTRACT FROM AUTHOR]

Objectives Aromatase deficiency is a rare disorder resulting in estrogen insufficiency in humans. It has been reported in remarkably few men with loss-of-function mutations in the CYP19A1 gene encoding the aromatase, a cytochrome P450 enzyme that plays a crucial role in the biosynthesis of estrogens from androgens. We investigated a non-consanguineous family including an adult man with clinical features of aromatase deficiency, and studied the effects of estrogen replacement in the man. Methods We investigated the clinical and biochemical phenotype, performed CYP19A1 mutational analysis in the family and 50 unrelated persons, studied the effects of CYP19A1 mutations on aromatase protein structure, functionally characterized the mutations by cell-based aromatase activity assays, and studied the effects of estrogen replacement on the bone, lipid, liver and glucose metabolism. Results The man with clinical features of aromatase deficiency had novel compound heterozygous CYP19A1 mutations (Y81C and L451P) that were not found in 50 unrelated persons. Three-dimensional modeling predicted that Y81C and L451P mutants disrupted protein structure. Functional studies on the basis of in vitro expression showed that Y81C and L45P mutants significantly decreased the aromatase activity and catalytic efficiency. Estrogen replacement in the man increased bone mineral density, accelerated bone maturation, improved lipid profile and liver steatosis, and improved glucose levels but not insulin resistance. Conclusions We have identified two novel CYP19A1 missense mutations in an aromatase-deficient man. Estrogen replacement in the man shows great impact on recovering the impairments in the bone, lipid, liver and glucose metabolism, but fails to improve insulin resistance. [ABSTRACT FROM AUTHOR]

ABSTRACT Concerned about the safety of conventional estrogen replacement therapy, women are using botanical dietary supplements as alternatives for the management of menopausal symptoms such as hot flashes. Before botanical dietary supplements can be evaluated clinically for safety and efficacy, botanically authenticated and standardized forms are required. To address the demand for a standardized, estrogenic botanical dietary supplement, an extract of hops ( Humulus lupulus L.) was developed. Although valued in the brewing of beer, hop extracts are used as anxiolytics and hypnotics and have well-established estrogenic constituents. Starting with a hop cultivar used in the brewing industry, spent hops (the residue remaining after extraction of bitter acids) were formulated into a botanical dietary supplement that was then chemically and biologically standardized. Biological standardization utilized the estrogen-dependent induction of alkaline phosphatase in the Ishikawa cell line. Chemical standardization was based on the prenylated phenols in hops that included estrogenic 8-prenylnaringenin, its isomer 6-prenylnaringenin, and pro-estrogenic isoxanthohumol and its isomeric chalcone xanthohumol, all of which were measured using high-performance liquid chromatography-tandem mass spectrometry. The product of this process was a reproducible botanical extract suitable for subsequent investigations of safety and efficacy. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Increased visceral fat is strongly associated with a series of metabolic complications. Postmenopausal women have an increased risk of visceral fat accumulation, metabolic disorders, and a high incidence of cardiovascular events. However, the effect of estrogen replacement therapy on visceral adipose tissue among postmenopausal women of different ages remains controversial, and the underlying mechanism remains unclear. Hence, it is important to understand when estrogen replacement therapy affects the function of visceral adipose tissue (VAT). Therefore, we collected VAT from pre- and post-menopausal females and we observed increased pro-inflammatory cytokines and insulin resistance-inducing factors, decreased insulin-sensitizing factors, and thermogenic factors in VAT of postmenopausal women. The analysis of adipocytes isolated from the VAT of females of different ages indicated that adiponectin and browning signature genes were significantly decreased with estrogen treatment in postmenopausal women, but were not altered in the young group. Estrogen supplementation in aged female mice (22 m) significantly prevented visceral fat accumulation. However, it deteriorated VAT function by inducing pro-inflammatory cytokines and insulin resistance-inducing factors and decreasing insulin-sensitizing and thermogenic factors. Mechanistically, estrogen induced the expression of long non-coding RNA Gas5 via binding ERα in premenopausal women, which therefore suppressed IGF2BP1 to maintain VAT function. After menopause, with the reversal of ERα/ERβ ratio in VAT, estrogen supplementation mainly worked through ERβ, which led to low expression levels of Gas5 and eventually caused VAT dysfunction. Our study demonstrated the adverse effects of estrogen supplementation on VAT function in aged postmenopausal population and further elucidated the involved mechanism. • VAT dysfunction steadily worsened in postmenopausal women compared with premenopausal women. • Estrogen in postmenopausal subjects prevented VAT accumulation but deteriorated its function. • Estrogen maintained VAT function via ERα-Gas5-IGF2BP1 axis in premenopausal female subjects. • ERβ became the major receptor of estrogen in postmenopausal subjects, leading to VAT dysfunction. [ABSTRACT FROM AUTHOR]

Purpose: A thin endometrium is one of the most difficult problems encountered in assisted reproduction every day practice. Whether a daily dose of 150 IU HCG for 7 days concomitant with estrogen administration in estrogen replacement cycles can increase the endometrial thickness and improve pregnancy outcome, was the objective of the current study. Methods: Seventeen infertile patients with successive implantation failures and resisting thin endometrium, being recipients of fresh donor or frozen embryos were recruited. This was a prospective cohort, proof of concept study, NCT01768247. On day-8 or 9 of the estrogen administration, and continuing 8 mg estrogen per day, subcutaneous injections of 150 IU HCG were initiated daily for 7 days. After a week on HCG priming, (day-14 or 15) endometrial thickness was controlled with ultrasound, and progesterone was initiated. Results: Mean endometrial thickness was increased from 5.2 mm to 6 mm ( p = 0.008). 35.3 % of the patients had more than 20 % improvement of their endometrial thickness after HCG priming. 17 % achieved an endometrial thickness more than 7 mm, and 29.4 % did not improve their thickness at all. Interestingly, from the later two became pregnant. Overall, 41 % of them (7/17) finally delivered. Conclusions: One hundred fifty IU HCG endometrial priming for 7 days in the proliferative phase of estrogen substituted cycles for frozen embryos is highly promising, as not only the thickness of the endometrium improves but also eventually the receptivity appears normalized. [ABSTRACT FROM AUTHOR]

Background: Aromatase deficiency is a rare autosomal recessive disorder caused by mutations in the CYP19A1 gene and characterized by lack of conversion of androgens to estrogens. It presents with virilization of pregnant mothers during the antenatal period, and virilization of female fetuses at birth. Affected subjects of either gender later manifest with features of estrogen deficiency and androgen excess. Patient and methods: We describe the clinical course of an Indian girl with aromatase deficiency from birth to 16 years of age. Estrogen replacement was begun at age 13.5 years. The child's growth, hormonal, radiological, and metabolic parameters were monitored throughout the course of treatment. Results: The child presented with obesity, tall stature, delayed bone age, osteoporosis, hyperinsulinemia with acanthosis nigricans, and hypergonadotropic hypogonadism with cystic ovaries. Estrogen replacement resulted in a plateauing of height, improvement of bone maturation, and pubertal progression with the disappearance of ovarian cysts. However, hyperinsulinemia and acanthosis nigricans persisted despite estrogen replacement and metformin. Genetic analysis revealed a homozygous arginine to cysteine substitution at codon 435 in exon 10 of CYP19A1. Conclusions: This is the first case of aromatase deficiency reported from India. This case highlights the role of estrogen in skeletal maturation and mineralization and the effect of estrogen deficiency and androgen excess over glucose metabolism in adolescent females. [ABSTRACT FROM AUTHOR]

Objective. To assess the psychological impact (Hospital Anxiety and Depression Scale) of an investigational ovarian stimulation protocol in women with premature ovarian failure (POF). Design. Prospective longitudinal study. Population. Ten women with POF. Methods. Women with idiopathic POF were placed on three consecutive treatment cycles consisting of gonadotropin ovarian stimulation after estrogen priming, gonadotropin-releasing hormone agonist pituitary desensitization, and corticosteroid immune suppression. Results. Median anxiety and depression scores increased significantly from baseline following three consecutive treatment cycles from 4.0 (range 2.0-8.0) to 11.0 (range 10.0-14.0) ( p-value 0.041) and from 1.5 (range 0-6.0) to 9.0 (range 7.0-10.0) ( p-value 0.039), respectively. There were nine 'probable' anxiety (90%) and three 'probable' depression (30%) cases on the final treatment cycle compared with none (0%) on baseline ( p-value 0.004 and 0.250, respectively). Conclusions. The use of investigational ovarian stimulation protocols in women with idiopathic POF was associated with excessive psychological strain. Women with POF should be cautioned against the potentially harmful aspect of similar treatments of unproven benefit. [ABSTRACT FROM AUTHOR]

We evaluated the effects of a standardized Labisia pumila var. alata (LPva) extract on body weight change, hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1) expressions and corticosterone (CORT) level in ovariectomized (OVX) rats. The decoction of LPva has been used for generations among Malay women in Malaysia to maintain a healthy reproductive system.Thirty-six Sprague-Dawley OVX rats were treated orally with LPva extract (10, 20 or 50 mg/kg/day) or estrogen replacement (ERT) for 30 days. Sham operated rats were used as controls. Compared to untreated OVX rats, LPva-treated rats showed less weight gain and had significantly down-regulated HSD11B1 mRNA in liver tissues. HSD11B1 mRNA in adipose tissues increased by 55% ( p < 0.05) in OVX rats but normalized in rats treated with LPva. Similarly, there was significant down-regulation ( p < 0.05) of protein levels of HSD11B1 in both liver and adipose tissue of LPva and ERT groups, and CORT levels were significantly reduced in both groups of rats. This is the first study ever conducted to evaluate the beneficial effects of LPva in relation to weight gain caused by estrogen insufficiency. Results implied that the bioactive components in LPva extract affect not only HSD11B1 expressions in both adipose and liver tissues but also decrease circulating CORT. The extract should be explored for its potential use as a natural remedy for weight management. [ABSTRACT FROM AUTHOR]

Objective. To determine the histopathological effect of estrogen deficiency and hormone replacement treatment on laryngeal tissue in ovariectomized rats.Study Design. Animal study.Setting. The study was conducted at the animal experiment laboratory of Marmara University School of Medicine, Istanbul, Turkey.Subjects and Methods. Six-month-old female Wistar albino rats were divided into the following 3 groups (n = 8 per group): sham-operated control, ovariectomized, and ovariectomized with estrogen replacement. Rats in the ovariectomized with estrogen replacement group received 17 β-estradiol valerate (200 µg/kg, subcutaneously) once a week. Animals were killed after 8 weeks of intervention.Results. Significant changes were observed in the ovariectomized group when edema in lamina propria, inflammation in squamous, respiratory epithelia and lamina propria, pseudostratification, and cilia loss were assessed. Except cilia loss, there were no significant differences in the assessments between the sham-operated control and ovariectomized with estrogen replacement groups.Conclusions. On the basis of histopathological evaluations, it was shown that estrogen replacement helped to improve laryngeal changes due to experimentally induced menopause. [ABSTRACT FROM PUBLISHER]

Background: To investigate whether estrogen may attenuate neointima formation in hyperhomocysteinemic rat carotid endarterectomy. Methods: Rats were divided into 6 groups: ovariectomized estradiol-treated homocysteine or chow; ovariectomized placebo-treated homocysteine or chow; intact placebo-treated homocysteine or chow. Chow served as controls while homocysteine served as exaggerated intimal hyperplasia. Prior to endarterectomy, rats were implanted with estradiol mini-pump or placebo, diets given 2 weeks before and after surgery. Homocysteine, estrogen, and neointimal hyperplasia were determined. Results: Homocysteine was elevated in homocysteine groups versus controls except in estradiol-treated group. Intimal hyperplasia increased in placebo-treated ovariectomized homocysteine versus intact group. Exaggerated intimal hyperplasia in placebo-treated ovariectomized homocysteine was reduced by estrogen and so was homocysteine. Estrogen replacement in ovariectomized homocysteine group reduced intimal hyperplasia to that of intact or ovariectomized controls. Conclusion: Estradiol treatment in this ovariectomized hyperhomocysteinemia carotid endarterectomy and resultant attenuation of homocysteine and neointima may have relevance to the beneficial effects of estrogen on hyperplastic response. [ABSTRACT FROM PUBLISHER]

Endothelium-dependent, nitric oxide (NO)-mediated vasodilation can be impaired by reactive oxygen species (ROS), and this deleterious effect of ROS on NO availability may increase with aging. Endothelial function declines rapidly after menopause, possibly because of loss of circulating estrogen and its antioxidant effects. The purpose of the current study was to determine the role of O2- and H2O2 in regulating flow-induced dilation in coronary arterioles of young (6-mo) and aged (24-mo) intact, ovariectomized (OVX), or OVX + estrogen-treated (OVE) female Fischer 344 rats. Both aging and OVX reduced flow-induced NO production, whereas flow-induced H2O2 production was not altered by age or estrogen status. Flow-induced vasodilation was evaluated before and after treatment with the superoxide dismutase (SOD) mimetic Tempol (100 μM) or the H2O2 scavenger catalase (100 U/ml). Removal of H2O2 with catalase reduced flow-induced dilation in all groups, whereas Tempol diminished vasodilation in intact and OVE, but not OVX, rats. Immunoblot analysis revealed elevated nitrotyrosine with aging and OVX. In young rats, OVX reduced SOD protein while OVE increased SOD in aged rats; catalase protein did not differ in any group. Collectively, these studies suggest that O2- and H2O2 are critical components of flow-induced vasodilation in coronary arterioles from female rats; however, a chronic deficiency of O2- buffering by SOD contributes to impaired flow-induced dilation with aging and loss of estrogen. Furthermore, these data indicate that estrogen replacement restores O2- homeostasis and flow-induced dilation of coronary arterioles, even at an advanced age. [ABSTRACT FROM AUTHOR]

To explore the mechanism(s) of exercise training on ovariectomized (OVX)-induced liver lipid disorder, we observed effects of treadmill training on liver fat accumulation and ER alpha expression in intact and ovariectomized rats. Sixty female rats were randomly assigned to six groups: Sham sedentary (S-S), Sham exercised (S-EX), ovariectomized sedentary (O-S), ovariectomized exercised (O-EX), ovariectomized injected subcutaneously with 17beta-estradiol (E(2)) (O-E(2)), and ovariectomized treated with E(2) and exercise (O-E(2)-EX). Twelve weeks after intervention, OVX resulted in significantly higher body weight gain, intra-abdominal fat mass, serum levels of total cholesterol (TC), and liver triacylglycerol (TAG) concentrations and ER alpha expression than S-S group, while the relative uterus and liver mass, serum levels of E(2), TAG, and the ratio of high density lipoprotein (HDL) to TC were markedly lower in O-S group. All of these changes were decreased in O-S rats after treatment with E(2) alone with the exception of serum TC and HDL-C levels and liver ER alpha expression. Exercise alone significantly reversed the effect of OVX on serum E(2), the ratio of HDL-C to TC and the liver and intra-abdominal fat accumulation in OVX rats. The addition of E(2) to exercise induced the same uterus and lipid profile as E(2) alone. Moreover, an additive effect of exercise and E(2) was observed on liver ER alpha expression in Sham or OVX rats. In conclusion, treadmill training alone could prevent liver fat accumulation in OVX rats and the regulation of exercise on liver ER alpha expression in both OVX and Sham rats needs the presence of physical estrogen levels. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 112, 870–881. Declining levels of estrogen in women result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by hormone replacement therapy. However, the role of post-menopausal gonadotropin increases on cognition has not been evaluated. Here, we demonstrate that the down-regulation of ovariectomy-driven LH elevations using the gonadotropin releasing hormone super-analogue, leuprolide acetate, improves cognitive function in the Morris water maze and Y-maze tests in the absence of E2. Furthermore, our data suggest that these effects are independent of the modulation of estrogen receptors α and β, or activation of CYP19 and StAR, associated with the production of endogenous E2. Importantly, pathways associated with improved cognition such as CaMKII and GluR1-Ser831 are up-regulated by leuprolide treatment but not by chronic long-term E2 replacement suggesting independent cognition-modulating properties. Our findings suggest that down-regulation of gonadotropins is as effective as E2 in modulating cognition but likely acts through different molecular mechanisms. These findings provide a potential novel protective strategy to treat menopause/age-related cognitive decline and/or prevent the development of AD. [ABSTRACT FROM AUTHOR]

Introduction: cP450aromatase deficiency provides clues for the understanding of the role of aromatase in prepubertal and pubertal human health and disease. Placental aromatization of androgens protects the female fetus against the virilizing action of fetal androgens. After birth, the dual effect of aromatase deficiency, excessive androgens, and insufficient estrogens is responsible for a variable clinical picture. Nineteen cases of aromatase gene (CYP19) deficiency have been reported. Phenotype: Phenotype is dependent on sex and age. In newborns, aromatase deficiency should be considered in the etiology of 46,XX DSD, after ruling out congenital adrenal hyperplasia. In prepubertal aromatase deficient girls, high levels of ovarian androgens and gonadotropins facilitate the formation of ovarian cysts. Bone mineralization can be affected and bone aging is delayed. In pubertal girls, there is poor sexual development and abnormal virilization. The phenotype may be variable according to enzyme activity level. Insulin sensitivity may be abnormal in both men and women. Finally, aromatase might also play a role in the regulation of testicular cell mass in the newborn testis. Conclusion: Adequate interpretation of clinical data should lead to the analysis of the CYP19 gene for diagnostic confirmation and implementation of appropriate management. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR), abnormal lipid profile, and other features of the metabolic syndrome have been described in CYP19 gene knockout mice and in aromatase-deficient adult men but not in prepubertal affected girls. Aims: To study insulin sensitivity, as well as the effects of estrogen, metformin and GnRHa treatment on glucose homeostasis, in an aromatase-deficient girl. Methods: Clinical, metabolic and hormonal follow-up data, from 8 to 12 years of age, is presented. Results: At 9 years of age, IR (HOMA 5.6) and glucose intolerance was detected, along with high serum testosterone (2.28 nmol/l), androstenedione (4.92 nmol/l) and FSH (13.4 mIU/ml) levels. Estrogen replacement was ineffective to suppress gonadotropin and androgen levels, as well as IR. Under metformin therapy, she developed type 2 diabetes and acanthosis nigricans. GnRHa administration for 1 year resulted in marked decreases in gonadotropin and serum androgens, but severe IR persisted. Conclusion: Postnatal estrogen replacement and a marked decrease of endogenous androgens failed to improve IR and glucose tolerance. We propose that, in females, the increment of androgens and/or lack of estrogens during fetal life might alter the mechanism of fetal programming of insulin sensitivity. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

BACKGROUND: The aromatase inhibitor, letrozole, exerts embryo toxic effects in rats, causing increased embryo lethality and anomalies of the axial skeleton at pharmacologically relevant doses. Letrozole acts by inhibiting estrogen biosynthesis. It may thus be feasible that estrogen deprivation is a crucial determinant of the elicited developmental toxic effects. In order to gain insight on this hypothesis, the present study tested the capacity of estrogen replacement in preventing letrozole-mediated embryopathy. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: We investigated the effects of a standardized water extract of Labisia pumila var. alata (LPva), and compared to estrogen replacement (ERT), on body weight gain, uterus weight, adipose tissue mRNA and protein levels of adipokines in ovariectomized (OVX) rats. Methods: Eight-week-old OVX Sprague-Dawley rats were administered orally with either 10mg/kg/day (LPva10), 20mg/kg/day (LPva20) or 50mg/kg/day (LPva50) of LPva for 30 days. Sham-operated (Sham) and estrogen-treated OVX rats (ERT, 0.625mg/kg/day) served as controls. Plasma adipokines were measured, and mRNA expressions of the adipokines were determined in the adipose tissues. Results: ERT- and LPva50-treated OVX rats showed significantly less (p <0.05) weight gain compared to untreated OVX rats. Ovariectomy caused plasma leptin levels to decrease significantly (p <0.05), but when treated with LPva or ERT, plasma leptin increased significantly to levels higher or comparable to that seen in the Sham group. The mRNA expression of leptin was higher in the LPva-treated animals than in all other groups. In contrast, the elevated plasma resistin concentrations in OVX rats were significantly reduced in rats given ERT (p <0.05) and LPva extracts (p <0.05). There was no difference in adiponectin levels in all groups. The uterus to body weight ratio of untreated OVX rats was significantly low compared to Sham (p <0.05), but showed dose-dependent increase upon treatment with LPva. Conclusion: The present study provides first evidence that LPva exerts uterotrophic effect and regulates body weight gain by modulating secretion of leptin and resistin, and expression of the adipokines in adipose tissues. [Copyright &y& Elsevier]

Abstract: The osteoinduction potential of human demineralized bone matrix (DBM) in females with low estrogen (E2) is unknown. Moreover, the osteoinductivity of commercial human DBM is tested in male athymic rats and mice, but DBM performance in these animals may not reflect performance in female animals or provide information on E2''s role in the process. To gain insight, human DBM was implanted bilaterally in the gastrocnemius of twenty-four athymic female mice (10 mg/implant) and twenty-four athymic female rats (15 mg/implant). Eight animals in each group were sham-operated (SHAM), ovariectomized (OVX), or ovariectomized with E2-replacement (OVX+E2) via subcutaneous slow release capsules of 17β-estradiol. OVX and OVX+E2 animals were pair-fed to SHAM animals. Four animals from each group were euthanized at 35 days and four at 56 days. Animal weight, uterine weight, and blood estrogen levels confirmed that pair feeding, ovariectomy, and E2 replacement were successful. Histological sections of implanted tissues were evaluated qualitatively for absence or presence of DBM, ossicle formation, and new bone or cartilage using a previously developed qualitative scoring system (QS) and by histomorphometry to obtain a quantitative assessment of osteoinduction. OVX mice had a small but significant QS decrease at 35 days compared to SHAM mice, confirmed by quantitative measurement of ossicle, marrow space, and new bone areas. The QS in rats was not affected by OVX but histomorphometry showed decreased new bone in OVX rats, which was restored by E2. The QS indicated that the number of new bone sites was not reduced by OVX in rats or mice at 56 days, but the relative amount of new bone v. marrow space was affected and differed with animal species. Residual DBM was less in OVX animals, indicating that DBM resorption was affected. Cartilage was present in rats but not in mice, suggesting that endochondral ossification was slower and indicating that bone graft studies in these species are not necessarily comparable. These results show the importance of E2 in human DBM-induced bone formation and suggest that E2 may be needed for clinical effectiveness in post-menopausal women. [Copyright &y& Elsevier]

Abstract: The present study was designed to determine whether estrogen modulates the angiotensin processing enzymes in membrane homogenates obtained from uterus and kidney cortex and medulla of Sprague–Dawley (SD) and heterozygous (mRen2)27-transgenic hypertensive (Tg(+)) female rats treated with or without 17β-estradiol (E2). We evaluated estrogen''s influence on neprilysin (NEP), an endopeptidase that forms angiotensin-(1–7) [Ang-(1–7)] and on aminopeptidase (AMP), which degrades Ang-(1–7). Renal tissue from normotensive and hypertensive male rats was also evaluated. E2 up-regulated NEP mRNA in the uterus of both SD and Tg(+) and this was associated with increased NEP activity in the uterus of SD (0.31±0.03nmol/min/mg versus 0.18±0.04nmol/min/mg of protein, p <0.05) and Tg(+) (0.26±0.04nmol/min/mg versus 0.13±0.02nmol/min/mg of protein, p <0.05) female). E2 had no significant effect on NEP activity in cortex and medulla of hypertensive and normotensive female. In female animals, cortical NEP activity is two-fold higher than medullary; in males there is a four-fold higher cortical NEP activity as compared to medulla. In male animals, medullary NEP was significantly lower than females with or without E2 treatment; no gender specific effect was found in cortex. E2 treatment also caused a two-fold increase in AMP activity in the uterus and 1.6-fold decrease in kidney cortex of SD and Tg(+) female (p <0.05). Our studies indicate that NEP may be a primary candidate for increased Ang-(1–7) processing in the uterus with estrogen treatment; kidney NEP, on the other hand, showed no modulation by estrogen, suggesting that down regulation of other processing enzymes, like AMP and ACE, may come into play in the kidney with estrogen replacement. In addition, these studies showed that there is tissue-specific regulation of NEP with estrogen treatment that is strain independent. [Copyright &y& Elsevier]

The authors examined the effect of menopausal status on several aspects of cognition in 4 groups of women (young premenopausal women, middle-aged pre- menopausal women, naturally postmenopausal women not using hormone therapy, and postmenopausal women using hormone replacement therapy). Participants (N = 48) completed questionnaires designed to assess psychological and physical health. The authors administered a test battery consisting of 10 neuropsychological tests to assess cognitive functioning. Using multivariate analyses of covariance with age as the covariate, the authors found a significant main effect of menopausal status on attention and complex processing abilities. Postmenopausal women using hormone replacement therapy significantly outperformed postmenopausal women not using hormone therapy on the Trail Making Test, Part B of the Halstead-Reitan (R. M. Reitan, 1958). This effect was significant even when the authors controlled for the effects of age, vocabulary levels, and education. Results are consistent with previous findings and may provide further evidence for an ameliorative effect of estrogen replacement therapy on specific cognitive functions. [ABSTRACT FROM AUTHOR]

Abstract: Estrogen has been shown to play a role in modulating social recognition memory. However, the literature regarding the influence of estrogen on social memory is sparse and only covers two experimental manipulations: acute injections and receptor knockout. Long-term effects of estrogen replacement on social investigation and social recognition are unknown. Furthermore, existing social recognition protocols focus on memory of very short durations (&#60;2 h). In the present study, we examined long-term effects of estrogen replacement on both short- (&#60;30 min) and long-term (24 h) social recognition in ovariectomized female C57BL/6 mice by implanting 60-day time-release pellets containing physiological doses of estradiol (0, 0.18, or 0.72 mg of 17β-estradiol). After 55 days of treatment, evidence of social recognition memory, measured by 24-h habituation, was found only in mice receiving the 0.72-mg pellet. This result is remarkable as previous reports indicate that individually-housed untreated rats and mice do not show habituation beyond 2 h. Our study further revealed that estrogen also increased frequencies of baseline social investigation without affecting general activity levels and decreased delayed post-swim-stress serum corticosterone concentration. Thus, these results suggest that long-term estrogen replacement increased the interest in social interaction as well as decreased stress responses. It is likely that the 24-h habituation observed in the estrogen replacement group is mediated jointly by the non-mnemonic effects of estrogen on the behavior displayed during the stage of memory encoding as well as mnemonic effects during the stage of memory consolidation. [Copyright &y& Elsevier]