Search

Background: Selective oestrogen receptor modulators and aromatase inhibitors stimulate endogenous gonadotrophins and testosterone in men with hypogonadism. There are no systematic reviews/meta‐analyses assessing the effects of selective oestrogen receptor modulators/aromatase inhibitors on semen parameters in men with secondary hypogonadism. Objectives: To assess the effect of monotherapy or a combination of selective oestrogen receptor modulators/aromatase inhibitors on sperm parameters and/or fertility in men with secondary hypogonadism. Materials and methods: A systematic search was conducted in PubMed, MEDLINE, Cochrane Library and ClinicalTrials.gov. Study selection and data extraction were performed by two reviewers independently. Randomised controlled trials and non‐randomised studies of interventions reporting effects of selective oestrogen receptor modulators and/or aromatase inhibitors on semen parameters or fertility in men with low testosterone with low/normal gonadotrophins were selected. The risk of bias was assessed using ROB‐2 and ROBINS‐I tools. The results of randomised controlled trials were summarised using vote counting while summarising effect estimates where available. Non‐randomised studies of intervention meta‐analysis were conducted using the random‐effect model. The certainty of evidence was assessed using GRADE. Results: Five non‐randomised studies of interventions (n = 105) of selective oestrogen receptor modulators showed an increase in sperm concentration (pooled mean difference 6.64 million/mL; 95% confidence interval 1.54, 11.74, I2 = 0%) and three non‐randomised studies of interventions (n = 83) of selective oestrogen receptor modulators showed an increase in total motile sperm count (pooled mean difference 10.52; 95% confidence interval 1.46–19.59, I2 = 0%), with very low certainty of evidence. The mean body mass index of participants was >30 kg/m2. Four randomised controlled trials (n = 591) comparing selective oestrogen receptor modulators to placebo showed a heterogeneous effect on sperm concentration. Three included men with overweight or obesity. The results were of very low certainty of evidence. Limited pregnancy or live birth data were available. No studies comparing aromatase inhibitors with placebo or testosterone were found. Discussion and conclusion: Current studies are of limited size and quality but suggest that selective oestrogen receptor modulators may improve semen parameters in those patients, particularly when associated with obesity. [ABSTRACT FROM AUTHOR]

Background: The beneficial effects of hormonal therapy in stimulating spermatogenesis in patients with non-obstructive azoospermia (NOA) and either normal gonadotrophins or hypergonadotropic hypogonadism prior to surgical sperm retrieval (SSR) is controversial. Although the European Association of Urology guidelines state that hormone stimulation is not recommended in routine clinical practice, a significant number of patients undergo empiric therapy prior to SSR. The success rate for SSR from microdissection testicular sperm extraction is only 40-60%, thus hormonal therapy could prove to be an effective adjunctive therapy to increase SSR rates.Objective and Rationale: The primary aim of this systematic review and meta-analysis was to compare the SSR rates in men with NOA (excluding those with hypogonadotropic hypogonadism) receiving hormone therapy compared to placebo or no treatment. The secondary objective was to compare the effects of hormonal therapy in normogonadotropic and hypergonadotropic NOA men.Search Methods: A literature search was performed using the Medline, Embase, Web of Science and Clinicaltrials.gov databases from 01 January 1946 to 17 September 2020. We included all studies where hormone status was confirmed. We excluded non-English language and animal studies. Heterogeneity was calculated using I2 statistics and risk of bias was assessed using Cochrane tools. We performed a meta-analysis on all the eligible controlled trials to determine whether hormone stimulation (irrespective of class) improved SSR rates and also whether this was affected by baseline hormone status (hypergonadotropic versus normogonadotropic NOA men). Sensitivity analyses were performed when indicated.Outcomes: A total of 3846 studies were screened and 22 studies were included with 1706 participants. A higher SSR rate in subjects pre-treated with hormonal therapy was observed (odds ratio (OR) 1.96, 95% CI: 1.08-3.56, P = 0.03) and this trend persisted when excluding a study containing only men with Klinefelter syndrome (OR 1.90, 95% CI: 1.03-3.51, P = 0.04). However, the subgroup analysis of baseline hormone status demonstrated a significant improvement only in normogonadotropic men (OR 2.13, 95% CI: 1.10-4.14, P = 0.02) and not in hypergonadotropic patients (OR 1.73, 95% CI: 0.44-6.77, P = 0.43). The literature was at moderate or severe risk of bias.Wider Implications: This meta-analysis demonstrates that hormone therapy is not associated with improved SSR rates in hypergonadotropic hypogonadism. While hormone therapy improved SSR rates in eugonadal men with NOA, the quality of evidence was low with a moderate to high risk of bias. Therefore, hormone therapy should not be routinely used in men with NOA prior to SSR and large scale, prospective randomized controlled trials are needed to validate the meta-analysis findings. [ABSTRACT FROM AUTHOR]

Oesophageal cancer is the seventh most common cancer in the world and adenocarcinoma is the dominant subtype in Western industrialised nations. The global 5‐year relative survival rate for oesophageal adenocarcinoma is 12%. Chemotherapy is a standard treatment offered to patients with both resectable and unresectable disease. However, there are only a few established chemotherapeutic drug options and progress in this area is limited. Recent efforts have focused on targeted molecular therapies. Epidemiological evidence points towards hormonal influences on disease development, particularly sex hormones. Several research studies have demonstrated oestrogen receptor (ER) expression in oesophageal adenocarcinoma tissue, making them a possible option for targeting with ER modulating agents. ERs are also present in laboratory models of the disease and experiments in ER‐positive cell lines suggest that ER modulator therapy may be effective. A deeper understanding of the roles of ERα and ERβ in this disease would be valuable for future translation into clinical practice. In this review, we discuss the association between oestrogens and the development of oesophageal adenocarcinoma and the potential to modulate ER signalling networks for therapeutic benefit. [ABSTRACT FROM AUTHOR]

ObjectiveTo study whether long-term treatment with oestrogen (E(2) ), selective E(2) receptor modulators (SERMs), or growth hormone (GH) can prevent the development of abnormal voiding patterns during filling cystometry (CMG) in a postpartum, ovariectomized (Ovx) female rat.Materials and methodsImmediately after spontaneous delivery, 60 primiparous Sprague-Dawley rats were randomly divided into six equal groups. One group served as uninjured sham controls and five groups underwent intravaginal balloon dilatation. On day seven, previously dilated rats underwent bilateral Ovx and implantation of a subcutaneous hormone-delivery pump. The five treatment groups received normal saline (control), E(2) , raloxifene, levormeloxifene, or GH for 7 weeks. Conscious CMG was performed 7 weeks after Ovx. Urethral sphincter tissue was harvested for elastin immunohistochemistry and real-time polymerase chain reaction of α(1A) -adrenoceptor mRNA.ResultsNo abnormal voiding patterns were detected in the group treated with GH. The E(2) , raloxifene and levormeloxifene groups had greater detrusor overactivity and urethral relaxation incontinence than control rats. The raloxifene group had a significantly lower baseline bladder pressure and opening pressure. GH-treated rats had higher elastin content in the urethra. Urethral α(1A) -adrenoceptor mRNA concentration was significantly lower in the SERM-treated rats compared with controls.ConclusionsGH prevents the development of abnormal voiding patterns during filling CMG in a rat model of parturition-induced incontinence; E(2) and SERMs may worsen voiding patterns.

Glyceollins are phytoalexins produced by soy plants in response to stressful stimuli such as fungal infections, UV exposure or changes in temperature. Glyceollins have demonstrated anti-oestrogenic activity both in vitro in tumour cell lines and in animal models in vivo, suppressing oestrogen-responsive tumours through action at oestrogen receptors (ERs). More recent evidence suggests that glyceollins may also possess oestrogenic properties or may exhibit their effects through non ER-mediated mechanisms. In addition to antitumour effects, glyceollins possess antimicrobial and antioxidant activity, along with effects on glucose and lipid metabolism. This review also focuses on intestinal absorption, osteoinductive properties, and potential central nervous system effects of glyceollins. Further research is warranted to determine effective treatment doses, safety and possible side effects of long-term exposure to glyceollins in non-target tissues to realize the potential application of these compounds as dietary supplements or therapeutic agents.

Purpose of Review: Patients with chronic kidney disease (CKD) have a greatly increased fracture risk compared with the general population. Gonadal hormones have an important influence on bone mineral density (BMD) and fracture risk, and hormone therapies can significantly improve these outcomes. Gonadal dysfunction is a frequent finding in patients with CKD; yet, little is known about the impact of gonadal hormones in the pathogenesis and treatment of bone health in patients with CKD. This systematic review and meta-analysis aimed to examine the effects of gonadal hormones and hormone therapies on bone outcomes in men and women with CKD.Methods: EMBASE, MEDLINE, SCOPUS, and clinical trial registries were systematically searched from inception to February 14, 2018 for studies that assessed gonadal hormones or hormone treatments with bone outcomes in patients with CKD stage 3-5D. Two independent reviewers screened the titles and abstracts of search results according to inclusion criteria and assessed study quality and risk of bias using validated assessment tools.Recent Findings: Thirteen studies met the inclusion criteria. Six moderate-to-high quality observational studies showed inconsistent association between any gonadal hormone and bone outcomes, limited by significant study heterogeneity. Five moderate-high risk of bias interventional studies examined treatment with selective oestrogen receptor modulators in post-menopausal women (four using raloxifene and one bazedoxifene) and demonstrated variable effects on BMD and fracture outcomes. Meta-analysis of raloxifene treatment in post-menopausal women demonstrated improvement in lumbar spine (SMD 3.30; 95% CI 3.21-3.38) and femoral neck (SMD 3.29; 95% CI 3.21-3.36) BMD compared with placebo. Transdermal oestradiol/norethisterone in pre-menopausal women receiving dialysis (n = 1 study), demonstrated BMD improvement over 12 months. Testosterone treatment for 6 months in dialysis-dependant men (n = 1 study) did not improve BMD.Summary: There is evidence that raloxifene treatment may be beneficial in improving BMD in post-menopausal women with CKD. There is insufficient evidence for other hormone treatments in men or women. Despite high fracture rates and frequent gonadal dysfunction in patients with CKD, significant evidence gaps exist, and well-designed studies are required to specifically assess the impact of gonadal status in the pathogenesis of CKD-related bone fragility and its treatment. [ABSTRACT FROM AUTHOR]

Neoadjuvant treatment discriminates responders, but pathologic complete response is uncommon in oestrogen receptor (ER)-positive/HER2-negative early breast cancer. We aimed to assess the prognostic value of Ki-67 index after neoadjuvant endocrine therapy (NET). We conducted a systematic literature search of PubMed, Embase, CENTRAL, and conference proceedings up to 22nd August 2023 to identify studies reporting the association of Ki-67 index after NET with recurrence-free survival (RFS) and/or overall survival (OS) in women with ER-positive/HER2-negative early breast cancer. We combined RFS and OS hazard ratios (HRs) with 95% confidence intervals (CIs). Twelve studies including 7897 patients were analysed. Most studies were clinical trials (n = 7547) including only postmenopausal women (n = 3953) treated with aromatase inhibitor (n = 3359). Three studies evaluated Ki-67 in a preplanned core biopsy at 2–4 weeks of NET (n = 3348), while nine evaluated Ki-67 in the surgical specimen (n = 4549) after 2–24 weeks of NET. Median follow-up ranged between 37 and 95 months for RFS and 62–84 months for OS. High Ki-67 index after NET was significantly associated with worse RFS (HR 2.48, 95% CI 1.86–3.30) and OS (HR 2.66, 95% CI 1.65–4.28). A sensitivity analysis including three studies that measured Ki-67 in a preplanned core biopsy showed similar association with RFS (HR 2.41, 95% CI 1.77–3.30). High Ki-67 after NET is associated with worse survival outcomes, even after a short course of NET, emphasising the prognostic value of this biomarker in women with ER-positive/HER2-negative early breast cancer. • Meta-analysis of Ki-67 prognostic value after neoadjuvant endocrine therapy. • Twelve studies reporting data from 7897 women with ER+/HER2− early breast cancer. • High Ki-67 was associated with worse recurrence-free survival and overall survival. • Ki-67 index after neoadjuvant endocrine therapy is a strong prognostic biomarker. • These findings will better inform clinical trials design and future clinical practice. [ABSTRACT FROM AUTHOR]

Glyceollins are phytoalexins produced by soy plants in response to stressful stimuli such as fungal infections, UV exposure or changes in temperature. Glyceollins have demonstrated anti-oestrogenic activity both in vitro in tumour cell lines and in animal models in vivo , suppressing oestrogen-responsive tumours through action at oestrogen receptors (ERs). More recent evidence suggests that glyceollins may also possess oestrogenic properties or may exhibit their effects through non ER-mediated mechanisms. In addition to antitumour effects, glyceollins possess antimicrobial and antioxidant activity, along with effects on glucose and lipid metabolism. This review also focuses on intestinal absorption, osteoinductive properties, and potential central nervous system effects of glyceollins. Further research is warranted to determine effective treatment doses, safety and possible side effects of long-term exposure to glyceollins in non-target tissues to realize the potential application of these compounds as dietary supplements or therapeutic agents. [ABSTRACT FROM AUTHOR]

In the majority of women, breast cancer progresses through increased transcriptional activity due to over-expressed oestrogen receptors (ER). Therapeutic strategies include: (i) reduction of circulating ovarian oestrogens or of peripherally produced oestrogen (in postmenopausal women) with aromatase inhibitors and (ii) application of selective ER modulators for receptor blockade. The success of these interventions is limited by the variable but persistent onset of acquired resistance and by an intrinsic refractiveness which manifests despite adequate levels of ER in about 50% of patients with advanced metastatic disease. Loss of functional ER leads to endocrine insensitivity, loss of cellular adhesion and polarity, and increased migratory potential due to transdifferentiation of the epithelial cancer cells into a mesenchymal- like phenotype (epithelial-mesenchymal transition; EMT). Multiple mechanisms contributing to therapeutic failure have been proposed: (i) loss or modification of ER expression including epigenetic mechanisms, (ii) agonistic actions of selective ER modulators that may be enhanced through an increased expression of co-activators, (iii) attenuation of the tamoxifen metabolism through expression of genetic variants of P450 cytochromes which leads to more or less active metabolites and (iv) increased growth factor signalling particularly through epidermal growth factor receptor activation of pathways involving keratinocyte growth factor, platelet-derived growth factor, and nuclear factor κB. In addition, the small non-coding microRNAs, recently recognized as critical gene regulators, exhibit differential expression in tamoxifen-sensitive versus resistant cell lines. Several studies suggest the potential of using these either as targets or as therapeutic agents to modulate EMT regulators as a means of reversing the aggressive metastatic phenotype by reversal of the EMT, with the added benefit of re-sensitization to anti-oestrogens. [ABSTRACT FROM AUTHOR]

Objective. RA predominantly affects post-menopausal women and is strongly associated with development of generalised osteoporosis. To find treatments that target both joint manifestations and osteoporosis in RA is desirable. The third generation of selective oestrogen receptor modulators (SERMs) [lasofoxifene (LAS) and bazedoxifene (BZA)] are new treatment options for post-menopausal osteoporosis. The aim of this study was to investigate the effects of LAS and BZA on arthritic disease and inflammationassociated bone loss using CIA in mice. Methods. Female DBA/1 mice were ovariectomised and subjected to CIA as a model of post-menopausal RA. Mice received treatment with LAS, BZA, 17b-estradiol (E2) as reference or vehicle. Arthritis development was assessed and BMD was determined by peripheral quantitative CT of the femurs. Serologic markers of inflammation and cartilage destruction were analysed. Immune cells in lymph nodes were studied by flow cytometry. Results. LAS and BZA reduced the clinical severity of arthritis as well as the grade of histologic synovitis and erosions on cartilage and bone. Moreover, SERMs protected against generalised bone loss in CIA by increasing trabecular BMD. Both SERMs decreased serum marker of cartilage destruction and LAS reduced serum IL-6 levels. SERMs did not alter Th17 cells in lymph nodes as E2 did. Conclusion. The anti-osteoporotic drugs LAS and BZA were found to be potent inhibitors of joint inflammation and bone destruction in experimental arthritis. This study provides new important knowledge regarding the treatment regimen of post-menopausal women with RA who suffer from increased risk for osteoporosis. [ABSTRACT FROM AUTHOR]

Infertility affects 15% of couples worldwide and in approximately 50% of cases the cause is secondary to an abnormality of the sperm. However, treatment options for male infertility are limited and empirical use of hormone stimulation has been utilised. We review the contemporary data regarding the application of hormone stimulation to treat male infertility. There is strong evidence supporting the use of hormone stimulation in hypogonadotropic hypogonadism but there is inadequate evidence for all other indications. • GnRH and Gonadotropins are an effective treatment for hypogonadotropic hypogonadism. • Evidence for use of hormone therapy in hypergonadotropism and eugonadism is poor. • Doctors should consider the risks of adverse events when using empirical therapies. • Randomised trials and protocol standardisation are needed to improve data quality. [ABSTRACT FROM AUTHOR]

Copyright of Der Gynäkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: The aim of this work was to evaluate the feasibility of delivering transdermally a series of highly lipophilic compounds (log P ~4–7), comprising several selective oestrogen receptor modulators and a modified testosterone (danazol). The maximum fluxes of the drugs were predicted theoretically using the modified Potts & Guy algorithm (to determine the permeability coefficient (kp ) from water) and the calculated aqueous solubilities. The correction provided by Cleek & Bunge took into account the contribution of the viable epidermal barrier to the skin permeation of highly lipophilic compounds. Experimental measurements of drug fluxes from saturated hydroalcoholic solutions were determined in vitro through excised pig skin. Overall, the predicted fluxes were in good general agreement (within a factor of 10) with the experimental results. Most of the experimental fluxes were greater than those predicted theoretically suggesting that the 70:30v/v ethanol–water vehicle employed may have had a modest skin penetration enhancement effect. This investigation shows that the transdermal fluxes of highly lipophilic compounds can be reasonably predicted from first principles provided that the viable epidermis, underlying the stratum corneum, is included as a potentially important contributor to the skin's overall barrier function. Furthermore, the absolute values of the measured fluxes, when considered in parallel with previous clinical studies, indicate that it might be feasible to topically deliver a therapeutically useful amount of some of the compounds considered to treat cancerous breast tissue. [Copyright &y& Elsevier]

The use of selective oestrogen receptor modulators has been prohibited since 2005 by the World Anti-Doping Agency regulations. As they are extensively cleared by hepatic and intestinal metabolism via oxidative and conjugating enzymes, a complete investigation of their biotransformation pathways and kinetics of excretion is essential for the anti-doping laboratories to select the right marker(s) of misuse. This work was designed to characterize the chemical reactions and the metabolizing enzymes involved in the metabolic routes of clomiphene, tamoxifen and toremifene. To determine the biotransformation pathways of the substrates under investigation, urine samples were collected from six subjects (three females and three males) after oral administration of 50 mg of clomiphene citrate or 40 mg of tamoxifen or 60 mg of toremifene, whereas the metabolizing enzymes were characterized in vitro, using expressed cytochrome P450s and uridine diphosphoglucuronosyltransferases. The separation, identification and determination of the compounds formed in the in vivo and in vitro experiments were carried out by liquid chromatography coupled with mass spectrometry techniques using different acquisition modes. Clomiphene, tamoxifen and toremifene were biotransformed to 22, 23 and 18 metabolites respectively, these phase I reactions being catalyzed mainly by CYP3A4 and CYP2D6 isoforms and, to a lesser degree, by CYP3A5, CYP2B6, CYP2C9, CYP2C19 isoforms. The phase I metabolic reactions include hydroxylation in different positions, N-oxidation, dehalogenation, carboxylation, hydrogenation, methoxylation, N-dealkylation and combinations of them. In turn, most of the phase I metabolites underwent conjugation reaction to form the corresponding glucuro-conjugated mainly by UGT1A1, UGT1A3, UGT1A4, UGT2B7, UGT2B15 and UGT2B17 isoenzymes. [ABSTRACT FROM AUTHOR]

Trials with tamoxifen have clearly shown that the risk of developing oestrogen receptor-positive breast cancer can be reduced by at least 50 % with prophylactic agents. The current challenge is to find new agents which achieve this or better efficacy, but with fewer side effects. Recent results indicate that the selective estrogen-receptor modulator (SERM) raloxifene has fewer endometrial cancers, gynaecologic symptoms, and thromboembolic side effects, but is also slightly less efficacious. Results for contralateral tumours in adjuvant trials suggest that aromatase inhibitors may be able to prevent up to 70-80 % of ER-positive breast cancers, and the MAP3 trial has shown to reduce all invasive breast cancer by 65 % in the preventive setting. The IBIS-II trial is currently investigating anastrozole in healthy postmenopausal women. New agents are needed for receptor negative breast cancer and premenopausal women, and several possibilities are currently under investigation. [ABSTRACT FROM AUTHOR]

Abstract: The present study was performed to investigate the influence of the intake of selective oestrogen receptor modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5α-androstan-3α,17β-diol, 5β-androstan-3α,17β-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography–mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80mg for 2days) or toremifene (120mg for 2days) or clomiphene (100mg for 2days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3h, for 3days prior to the treatment; whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen receptor modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5α-androstan-3α,17β-diol and 5β-androstan-3α,17β-diol urinary levels and on testosterone/epitestosterone, 5α-androstan-3α,17β-diol/5β-androstan-3α,17β-diol and androsterone/etiocholanolone ratios. [Copyright &y& Elsevier]

Abstract: Breast stem cells are long-lived cells and so are exposed to carcinogenic influences for much longer than normal differentiated breast ductal cells. It is hypothesized that these stem cells are the major site of carcinogenesis within the breast. Epidemiological studies have suggested that early life events and early first pregnancy profoundly affect breast cancer risk in adult life. It seems likely that these observations may be, at least partially explained, through changes in stem cell number and function. After menopause, despite very low systemic oestradiol levels, intra-breast oestradiol concentrations remain high due to increased biosynthesis of oestrogens in breast fat and stromal tissue. Stem cells are usually tightly regulated within a niche. The malignant process seems to involve changes in not only the cancer stem cell but also its microenvironment. The likely impact of hormone replacement and SERMs on stem cell function is discussed. [ABSTRACT FROM AUTHOR]

Breast cancer represents one of the most important problems of clinical and experimental oncology. Excluding cancers of the skin, breast cancer is the most frequent neoplasm in women, forming approximately 30 % of all tumours. The knowledge on the possibility and suitability of the prevention of breast cancer rose sharply in last years. The strategy of chemoprevention seems to be promising for reducing cancer incidence both in well-defined high-risk individuals and also in the general population. Several clinical studies have shown that in high-risk women for breast cancer, the drugs such as non-steroidal inflammatory drugs, selective oestrogen receptor modulators and retinoids, may reduce this risk. Chemopreventive studies carried out on model laboratory animals have an important role in new drugs efficacy evaluation in pre-clinical tests. Our group tested several groups of chemopreventive substances in female rat mammary carcinogenesis. [ABSTRACT FROM AUTHOR]

Copyright of Der Kardiologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Selective oestrogen receptor modulators (SERMs) may offer improved alternatives to oestrogen as neuroprotectants in experimental stroke. The present study investigated the role of a novel SERM, LY362321, in a rat model of transient middle cerebral artery occlusion (MCAO). Female Sprague-Dawley rats were ovariectomised and began receiving daily s.c. injections of either 1 mg/kg (n = 13), 10 mg/kg (n = 14) of LY362321, or vehicle (n = 13). The left MCA was temporarily occluded (90 min), with cortical blood flow monitoring, at 12 days post ovariectomy. Sensorimotor function was assessed using a neurological score prior to the MCAO and daily for 3 days following the MCAO. Tissue was processed for infarct volume assessment using 2,3,5-triphenyltetra-zolium chloride staining. The results indicated that there were no significant differences amongst groups in cortical blood flow during the MCAO. Furthermore, there was no significant difference in infarct size amongst vehicle, 1, and 10 mg/kg treated animals: 22.9 ± 5.0, 16.7 ± 4.2, and 21.1 ± 4.1, respectively, one-wayanova [F(2,32) = 0.542, P = 0.587]. The MCAO induced a significant decline in neurological score in the vehicle group (from 14 to 7 at 24 h post-MCAO) but this was not significantly affected by LY362321 at either dose. In conclusion, pretreatment with a low or high dose of the novel SERM LY362321 did not significantly influence cerebral blood flow, infarct volume, or sensorimotor function in rats exposed to transient MCAO. [ABSTRACT FROM AUTHOR]

In this review we summarize available data regarding linear growth in oestrogen receptor alpha (ERα)- and oestrogen receptor beta (ERβ)-deficient mice. We discuss these findings in relation to known oestrogenic effects in humans and the possibility of applying this knowledge for the therapeutic modulation of longitudinal bone growth employing selective oestrogen receptor modulators (SERMs). We conclude that SERMs potentially could offer new possibilities to modulate bone growth by specifically targeting different oestrogen receptors within the growth plate. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy of toremifene in the treatment of premenstrual mastalgia. Design Double-blind, placebo-controlled crossover study. Setting Three Finnish general practices from the districts of Satakunta Central Hospital and Tampere University Hospital. Population A total of 62 women aged 25–45 years with premenstrual mastalgia during at least three previous menstrual cycles. Methods Women were randomised to receive toremifene 20 mg daily or placebo from day 15 of the menstrual cycle until menstruation for three consecutive cycles. After a wash-out cycle, the women were crossed over to receive placebo or toremifene for three additional cycles. Main outcome measures Cyclic breast pain relief assessed by visual analogue scale (VAS) score. Quality-of-life scores assessed by a modified 36-item Finnish Depression Scale, with a score ranging from 0 to 108. Acceptability of treatment. Results About 32 women were randomised to receive toremifene first and 30 to receive placebo first. Twenty-nine and 27 participants in the groups treated with toremifene first or placebo first completed the treatment, respectively. There were significant reductions in VAS scores in both groups after three treatment cycles. This was significantly greater in the toremifene-treated group (VAS: 1.8 in the toremifene group and 3.7 in the placebo group, P= 0.004). Treatment effect between treatment cycles was significant ( P= 0.001). Quality of life was similar during the toremifene and placebo cycles. Conclusion This study demonstrates that the antiestrogenic compound, toremifene, is able to relieve premenstrual breast pain without major adverse effects. There was a 64% reduction in median pain scores in the toremifene-treated cycles compared with a 26% reduction in placebo-treated cycles. [ABSTRACT FROM AUTHOR]

1. Accumulated clinical evidence suggests that selective oestrogen receptor modulators (SERM), such as raloxifene, may be neuroprotective. Oxidative stress is a likely molecular mechanism in the neurotoxicity of kainic acid (KA), an excitotoxic substance. The expression levels of the apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) gene seem to correlate with cellular sensitivity to reactive oxygen species (ROS) and a reduction in the expression of APE/Ref-1 may cause oxidative DNA damage. 2. The aim of the present study was to assess the effects of KA and raloxifene on the level of APE/Ref-1 mRNA in the hippocampus of ovariectomized rats. The expression of the APE/Ref-1 gene was quantified using reverse transcription followed by real-time polymerase chain reaction. 3. The results show that the level of APE/Ref-1 mRNA increased significantly in raloxifene-treated rats. However, raloxifene treatment did not affect the seizure severity induced by KA. We also observed that raloxifene treatment against simultaneous KA injection maintained the increased level of APE/Ref-1 mRNA in the hippocampus. 4. Therefore, the results of the present study seem to support previous data suggesting the potential significance of raloxifene in neuroprotection. Key words: APE/ Ref-1, hippocampus, kainic acid, ovariectomy, raloxifene, real-time polymerase chain reaction, selective oestrogen receptor modulators. [ABSTRACT FROM AUTHOR]

Publication of the preliminary findings from the combination (oestrogen and progestogen) hormone therapy (HT) arm of the Women's Health Initiative (WHI) on the heels of the Heart and Estrogen/progestin Replacement Study (HERS) sent the field of menopausal medicine into turmoil. It is now considered that oestrogen therapy (ET)/HT should be used only to treat the shortterm climacteric conditions associated with menopause and that its use to treat conditions associated with long-term oestrogen deprivation (ie, cardiovascular disease, osteoporosis and delay of the onset of dementia and Alzheimer's disease) is no longer appropriate. As a result, there has been a dramatic decrease in the number of patients using ET/HT. With few new therapeutic options on the horizon to treat either the short or long-term consequences of oestrogen deprivation, it seems that progress in the treatment of the menopausal patient has taken a large step backwards. This review considers how the direction of research in the field of menopausal medicine has been shaped by the WHI and outlines what the future might hold. [ABSTRACT FROM AUTHOR]

Antioestrogens are among the most widely used agents in the treatment of breast cancer. There has been a recent surge of interest in these compounds because of their potential breast cancer chemopreventive properties. The newer generation of antioestrogens, with increased selectivity and better toxicity profiles, have the potential to increase the effectiveness of hormonal treatment of breast cancer. The selective oestrogen receptor modulators (SERMs) hold the promise of revolutionising the care of healthy postmenopausal women with their beneficial effects on bone and lipids in addition to the chemoprevention of breast cancer. [ABSTRACT FROM AUTHOR]

Hormonal replacement therapy (HRT) is generally regarded as first choice for pharmacological prevention of osteoporosis in women. We reviewed recent studies of HRT regimens and selective oestrogen receptor modulators (SERMs), including controlled trials of at least one-year duration published since 1995 until February 2000 providing data on bone mineral density (BMD) or fractures. Natural and synthetic oestrogens exert a continuum of positive effects on BMD in a dose-dependent, though non-proportional, fashion independent of age and mode of administration. Bone loss may be largely prevented by 25μg transdermal patch oestradiol, 0.3 mg conjugated equine or 0.3 mg esterified oestrogens. Progestogens neither attenuate nor augment the effect of oestrogens; sole use of tibolone prevents bone loss. Both the SERMs, tamoxifen and raloxifene, slightly increase BMD. There are no adequately powered fracture trials for any HRT regimen. Raloxifene 60 mg daily decreases the relative risk of vertebral fractures by at least 30%, as demonstrated by one 3-year fracture study of osteoporotic women. In conclusion, the recommendation to use oestrogen for postmenopausal osteoporosis, given both the lack of fracture trials and the rare trials on long-term use of HRT in (late) postmenopausal women, is not well supported. Fracture trials could overcome shortcomings of the current level of evidence. [ABSTRACT FROM PUBLISHER]

Selective oestrogen receptor modulators (SERMs) are compounds which act like oestrogens in some target tissues but which antagonise their effects in others. The first example of a SERM (referred to as a first-generation compound) was tamoxifen, for which oestrogen-like agonist activity on bone was seen to occur simultaneously with oestrogen antagonist activity on the breast. An unwanted effect of tamoxifen was its oestrogen-like action on the endometrium. Second-generation compounds have since been developed, most notably alewife, which has oestrogen-like actions on bone, lipids and the coagulation system, and oestrogen antagonist effects on the breast and uterus. Raloxifene has undergone very extensive, prospective, placebo-controlled, randomised trial evaluation, in which anti-fracture efficacy (to date only for vertebral fracture) has been accompanied by a major reduction in the incidence of new breast cancer. The compound is similar to placebo in its uterine effects, and similar to oestrogen in causing a two- to threefold increase in the risk of venous thromboembolism. Its lipid effects are similar to those of oestrogen, except for a relatively small effect on high-density lipoprotein cholesterol, and no significant effect on triglycerides. Data on cardiovascular event rates are not yet available; data on cognitive function are preliminary and, to date, reassuring. The mechanisms by which the same compound can exert oestrogen agonist effects on one target and antagonist effects on another are still being clarified. Important aspects include the fact that the oestrogen receptor undergoes different conformational changes according to the ligand. Thus the crystal structure of oestradiol bound to the oestrogen receptor differs from that of raloxifene bound to the same receptor. The existence of two oestrogen receptor subtypes may also be relevant. Mechanisms include differing interactions with various domains of the oestrogen receptor, and tissue-specific... [ABSTRACT FROM AUTHOR]

This paper explores the concept that endometrial breakthrough bleeding results from the stimulatory effects of oestrogen in the endometrium. Though ‘progestin-only’ contraceptive regimens have long been associatedwith user dissatisfaction because of unpredictable vaginal bleeding, it is likely that the substantial contribution of endogenous ovarian oestradiol during such treatments predisposes the bleeding problems. Oestrogen causes endometrial proliferation, hyperplasia and neoplasia if unopposed. Oestrogenallows production of growth factors supporting angiogenesis which results in an abundance of dilated or fragile endothelial surface blood vessels, predisposing this tissue to bleeding when these vessels lose competence. [ABSTRACT FROM PUBLISHER]

Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg kg‐1 streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (intraluminal thread technique, 60 minutes) and assigned to one of three groups treated with either: vehicle, BZA (3 mg kg‐1 day‐1, i.p.) or 17β‐oestradiol (E2) (100 μg kg‐1 day‐1, i.p.). At 24 hours post‐ischaemia‐reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of oestrogen receptors (ER)α, ERβ and G protein‐coupled oestrogen receptor), and activity of the mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK)1/2 and phosphoinositide 3‐kinase/Akt pathways were analysed. At 24 hours after the ischaemic insult, both BZA‐ and E2‐treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size and decreased apoptotic cell death. Ischaemia‐reperfusion induced a significant decrease in ERα and ERβ expression without affecting that of G protein‐coupled oestrogen receptor, whereas BZA and E2 reversed such a decrease. The ischaemic insult up‐regulated the activity of both the MAPK/ERK1/2 and phosphoinositide 3‐kinase/Akt pathways; BZA and E2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The results of the present study lend further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E2 with respect to improving diabetic ischaemic stroke outcome after successful reperfusion. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness., (© 2015 The authors.)

Summary: Aims: To outline the progress being made in the understanding of acquired resistance to long term therapy with the selective oestrogen receptor modulators (SERMs, tamoxifen and raloxifene) and aromatase inhibitors. The question to be addressed is how we can amplify the new biology of oestrogen-induced apoptosis to create more complete responses in exhaustively antihormone treated metastatic breast cancer. Methods and Results: Three questions are posed and addressed. (1) Do we know how oestrogen works? (2) Can we improve adjuvant antihormonal therapy? (3) Can we enhance oestrogen-induced apoptosis? The new player in oestrogen action is GPR30 and there are new drugs specific for this target to trigger apoptosis. Similarly, anti-angiogenic drugs can be integrated into adjuvant antihormone therapy or to enhance oestrogen-induced apoptosis in Phase II antihormone resistant breast cancer. The goal is to reduce the development of acquired antihormone resistance or undermine the resistance of breast cancer cells to undergo apoptosis with oestrogen respectively. Finally, drugs to reduce the synthesis of glutathione, a subcellular molecule compound associated with drug resistance, can enhance oestradiol-induced apoptosis. Conclusions: We propose an integrated approach for the rapid testing of agents to blunt survival pathways and amplify oestrogen-induced apoptosis and tumour regression in Phase II resistant metastatic breast cancer. This Pharma platform will provide rapid clinical results to predict efficacy in large scale clinical trials. [Copyright &y& Elsevier]