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The combined incidence and the extended disease course of breast and prostate cancer is a major challenge for health care systems. The solution for society requires an economically viable treatment strategy to maintain individuals disease free and productive, so as to avoid the fracture of the family unit. Forty years ago, translational research using the antiestrogen tamoxifen was targeted to estrogen receptor (ER) positive micrometastatic tumor cells and established the long-term antihormone adjuvant treatment strategy used universally today. The antihormone strategy was the accepted structure of cancer biology. Sex steroid deprivation therapy remains the orthodox strategy for the treatment of both breast and prostate cancer. Despite major initial therapeutic success, the strategies of long term anti-hormone therapies with either tamoxifen or aromatase inhibitors (AI) or antiandrogens or abiraterone for breast and prostate cancer, respectively, eventually lead to a significant proportion of anti-hormone resistant or stimulated tumor growth. Remarkably, a general principle of anti-hormone resistance has emerged for both breast and prostate cancer based primarily on clinical and supportive laboratory data. Paradoxically, anti-hormone resistant cell populations emerge and grow but are vulnerable to the cytotoxicity of estrogen or androgen-induced apoptosis for both breast and prostate cancer, respectively. These consistent anticancer actions of sex steroids appear to recapitulate the more complex mechanism of bone remodeling in elderly men and women during sex steroid deprivation. Estrogen is the key hormone in both sexes because in men androgen is first converted to estrogen. Estrogen regulates and triggers apoptosis in osteoclasts that develop during estrogen deprivation and destroy bone to cause osteoporosis. Sex steroid deprived breast and prostate cancer has recruited a streamlined natural apoptotic program from the human genome, but this is suppressed in the majority of sex steroid deprived tumors. Targeted strategies to neutralize cell survival pathways are now required to amplify and enhance sex steroid induced apoptosis. Successful blockade of the critical pathways for cell survival will introduce an inexpensive targeted therapy to maintain breast and prostate cancer patients indefinitely. Rotating anti-hormonal and sex steroid targeted cocktails could maintain patients at a microscopic tumor burden to enhance the quality of life, enhance survival, and maintain the family as a self-supporting and economically productive unit within society.

The clinical usefulness of assessing the enzymatic activity of CYPD6 in patients taking tamoxifen had been longly debated. In favour of preemptive evaluation of phenotypic profile of patients is the strong pharmacologic rationale, being that the formation of endoxifen, the major and clinically most important metabolite of tamoxifen, is largely dependent on the activity of CYP2D6. This enzyme is highly polymorphic for which the activity is largely depending on genetics, but that can also be inhibited by a number of drugs, i.e. antidepressants, which are frequently used in patients with cancer. Unfortunately, the clinical trials that have been published in the last years are contradicting each other on the association between CYP2D6 and significant clinical endpoints, and for this reason CYP2D6 genotyping is at present not generally recommended. Despite this, the CYP2D6 genotyping test for tamoxifen is available in many laboratories and it may still be an appropriate test to use it in specific cases., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although long non-coding RNAs such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR (HOX antisense intergenic RNA) is upregulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or by tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the long non-coding RNA HOTAIR is directly repressed by ER and its upregulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.

Preclinical data indicate that omega-3 fatty acids (n-3FA) potentiate the chemopreventive effect of the antiestrogen (AE) tamoxifen against mammary carcinogenesis. The role of n-3FA in breast cancer prevention in humans is controversial. Preclinical and epidemiologic data suggest that n-3FA may be preferentially protective in obese subjects. To directly test the protective effect of n-3FA against breast cancer, we conducted a 2-year, open-label randomized clinical trial in 266 healthy postmenopausal women (50% normal weight, 30% overweight, 20% obese) with high breast density (BD; ≥25%) detected on their routine screening mammograms. Eligible women were randomized to one of the following five groups (i) no treatment, control; (ii) raloxifene 60 mg; (iii) raloxifene 30 mg; (iv) n-3FA lovaza 4 g; and (v) lovaza 4 g plus raloxifene 30 mg. The 2-year change in BD, a validated biomarker of breast cancer risk, was the primary endpoint of the study. In subset analysis, we tested the prespecified hypothesis that body mass index (BMI) influences the relationship between plasma n-3FA on BD. While none of the interventions affected BD in the intention-to-treat analysis, increase in plasma DHA was associated with a decrease in absolute breast density but only in participants with BMI >29. Our results suggest that obese women may preferentially experience breast cancer risk reduction from n-3FA administration., (©2015 American Association for Cancer Research.)

Background: Racial/ethnic disparities in preterm birth remain a major public health challenge in the United States. While 17-alpha hydroxyprogesterone caproate (17OHP-C) is recommended for preterm birth prevention in women with a prior preterm birth, non-Hispanic black women continue to experience higher rates of recurrent preterm birth than white women receiving the same treatment. Further investigation of disparities in 17OHP-C use and adherence is warranted., Objective: We sought to evaluate whether racial and ethnic disparities exist in the use of and adherence to 17OHP-C within a population of eligible women., Study Design: This was a retrospective cohort study of women with a prior spontaneous, singleton preterm birth who were eligible for 17OHP-C for preterm birth prevention and received care at a single institution from 2010 through 2014. Associations between self-identified race/ethnicity (non-Hispanic black vs women in all other racial/ethnic groups) and documented counseling about 17OHP-C, receipt of any 17OHP-C, and adherence to 17OHP-C administration were each estimated by bivariable analysis and multivariable logistic regression. Adherence to 17OHP-C was defined as not >1 missed dose, initiation <20 weeks' gestational age, and continuation until 37 weeks or delivery., Results: Of 472 women who were clinically eligible for 17OHP-C, 72% (N = 296) had documented 17OHP-C counseling and 48.9% (N = 229) received 17OHP-C. There were no differences in likelihood of 17OHP-C counseling or receipt of 17OHP-C based on race/ethnicity. While overall 83% (N = 176) of women were adherent to 17OHP-C, only 70% (N = 58) of non-Hispanic black women were adherent, compared to 91% (N = 118) of all other women (P < .001). Non-Hispanic black women had more missed doses (2.4 vs 0.4 doses, P < .001) and later initiation of care (12.0 vs 10.2 weeks, P < .001) than women in other racial/ethnic groups. After adjustment for potential confounders, non-Hispanic black women were significantly less likely to be adherent to 17OHP-C (adjusted odds ratio, 0.16; 95% confidence interval, 0.04-0.65). A significant interaction between non-Hispanic black race/ethnicity and public insurance was identified (adjusted odds ratio, 0.16; 95% confidence interval, 0.05-0.52)., Conclusion: In a diverse cohort of women eligible for preterm birth prevention, non-Hispanic black women are at an increased risk of nonadherence to 17OHP-C. Non-Hispanic black women with public insurance are at a particularly increased risk of nonadherence., (Copyright © 2016 Elsevier Inc. All rights reserved.)

There is a potential for reducing the incidence of breast cancer by modifying or changing the reversible risk factors like dietary modifications, modifications in the sedentary life habits, etc. One of such methods which has gained popularity now is chemoprevention. Many agents have been evaluated in the chemoprevention setting in females with increased risk of breast cancers. Metformin, NSAIDS, Bisphosphonates, and statins were evaluated by various investigators with variable results. One of the agents that have been proven to be beneficial in this setting is the anti-estrogens. A major disadvantage of chemoprevention is that unlike prophylactic mastectomy it can never reduce the risk to near zero although it reduces the risk significantly. Another issue is the compliance as chemoprevention with anti-estrogens will need to be continued for 5 years while surgery is a one-time procedure. Another disadvantage is the possible side effects peculiar to each drug used which may not be a significant concern in prophylactic mastectomy group. All these factors must also be kept in mind and properly explained to the patient before starting chemoprevention using anti-estrogens. Here in this review we intend to look into the large randomized controlled trials to quantify the present status of chemoprevention with anti-estrogens.

Background: Prematurity is the leading cause of neonatal morbidity and death among nonanomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17-alpha hydroxyprogesterone caproate is not always effective, and one-third of high-risk women will have a recurrent preterm birth, despite 17-alpha hydroxyprogesterone caproate therapy. The reasons for this variability in response are unknown. Previous investigators have examined the influence of a variety of factors on 17-alpha hydroxyprogesterone caproate response but have analyzed data that used a fixed outcome of term delivery to define progesterone response., Objective: We hypothesized that the demographics, history, and pregnancy course among women who deliver at a similar gestational age with 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention differs when compared with those women who deliver later with 17-alpha hydroxyprogesterone caproate and that these associations could be refined by the use of a contemporary definition of 17-alpha hydroxyprogesterone caproate "responder.", Study Design: This was a planned secondary analysis of a prospective, multicenter, longitudinal study of women with ≥1 previous documented singleton spontaneous preterm birth at <37 weeks gestation. Data were collected at 3 prespecified gestational age epochs during pregnancy. All women who were included in this analysis received 17-alpha hydroxyprogesterone caproate during the studied pregnancy. We classified women as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest spontaneous preterm birth. Responders were defined as those with pregnancy that extended ≥3 weeks later with 17-alpha hydroxyprogesterone caproate, compared with the delivery gestational age of their earliest previous spontaneous preterm birth. Data were analyzed with the use of chi-square test, t-test, and logistic regression., Results: One hundred fifty-five women met the inclusion criteria. The 118 responders delivered later on average (37.7 weeks gestation) than the 37 nonresponders (33.5 weeks gestation; P < .001). Among responders, 32% (38/118 women) had a recurrent spontaneous preterm birth. Demographics (age, race/ethnicity, education, and parity) were similar between groups. In the regression model, the gestational age of the previous spontaneous preterm birth (odds ratio, 0.68; 95% confidence interval, 0.56-0.82; P < .001), vaginal bleeding/abruption in the current pregnancy (odds ratio, 0.24; 95% confidence interval, 0.06-0.88; P = .031), and first-degree family history of spontaneous preterm birth (odds ratio, 0.37; 95% confidence interval, 0.15-0.88; P = .024) were associated with response to 17-alpha hydroxyprogesterone caproate. Because women with a penultimate preterm pregnancy were more likely to be 17-alpha hydroxyprogesterone caproate nonresponders, we performed an additional limited analysis examining only the 130 women whose penultimate pregnancy was preterm. In regression models, the results were similar to those in the main cohort., Conclusion: Several historic and current pregnancy characteristics define women who are at risk for recurrent preterm birth at a similar gestational age, despite 17-alpha hydroxyprogesterone caproate therapy. These data should be studied prospectively in larger cohorts and combined with genetic and environmental data to identify women who are most likely to benefit from this intervention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Worldwide, gastric cancer is one of the most common malignancies with high mortality. Various aspects of the development and progression of gastric cancer continue to be extensively investigated in order to further our understanding and provide more effective means for the prevention, diagnosis, and treatment of the disease. Estrogen receptors (ERs) are steroid hormone receptors that regulate cellular activities in many physiological and pathological processes in different tissues. There are two distinct forms of ERs, namely ERα and ERβ, with several alternative-splicing isoforms for each. They show distinct tissue distribution patterns and exert different biological functions. Dysregulation of ERs has been found to be associated closely with many diseases, including cancer. A number of studies have been conducted to investigate the role of ERs in gastric cancer, the possible mechanisms underlying these roles, and the clinical relevance of deregulated ERs in gastric cancer patients. To date, inconsistent associations of different ERs with gastric cancer have been reported. These inconsistencies may be caused by variations in in vitro cell models and clinical samples, including assay conditions and protocols with regard to different forms of ERs. Given the potential of the deregulated ERs as diagnostic/prognostic markers or therapeutic targets for gastric cancer, it will be important to identify/confirm the association of each ER isoform with gastric cancer, to determine the specific roles and interactions that these individual ER isoforms play under specific conditions in the development and/or progression of gastric cancer, and to elucidate precisely these mechanisms. In this review, we summarize the achievements from early ER studies in gastric cancer to the most up-to-date discoveries, with an effort to provide a comprehensive understanding of the role of ERs roles in gastric cancer and its possible mechanisms. Furthermore, we propose directions for future investigations.

Background: To investigate the impact of high circulating AMH on the outcome of CC ovulation induction in women with PCOS., Methods: This prospective cohort observational study included 81 anovulatory women with PCOS who underwent 213 cycles of CC ovarian stimulation. Serum AMH concentrations were measured on cycle day 3 before the commencement of CC in the first cycle, which were compared between responders and CC-resistant anovulation (CRA). Logistic regression analysis was applied to study the value of serum AMH for the prediction of ovarian responsiveness to CC stimulation. The receiver-operating characteristic (ROC) curve was used to evaluate the prognostic value of circulating AMH., Main Outcome Measures: Serum AMH levels., Results: Women who ovulated after CC therapy had a significantly lower AMH compared with the CRA (5.34 ± 1.97 vs.7.81 ± 3.49, P < 0.001). There was a significant gradient increase of serum AMH levels with the increasing dose of CC required to achieve ovulation (P < 0.05). In multivariate logistic regression analysis, AMH was an independent predictor of ovulation induction by CC in PCOS patients. ROC curve analysis showed AMH to be a useful predictor of ovulation induction by CC in PCOS patients, having 92 % specificity and 65 % sensitivity when the threshold AMH concentration was 7.77 ng/ml., Conclusion: Serum AMH may be clinically useful to predict which PCOS women are more likely to respond to CC treatment and thus to direct the selection of protocols of ovulation induction.

CYP2D6 is primarily responsible for the metabolism of clomiphene citrate (CC). The purpose of the present study was to investigate the relationship between CYP2D6 genotypes, concentrations of CC and its major metabolites and drug response in infertility patients. We studied 42 patients with ovulatory dysfunction treated with only CC. Patients received a dose of 100 mg/day CC on days 3-7 of the menstrual cycle. CYP2D6 genotyping and measurement of CC and the major metabolite concentrations were performed. Patients were categorized into CC responders or non-responders according to one cycle response for the ovulation. Thirty-two patients were CC responders and 10 patients were non-responders with 1 cycle treatment. The CC concentrations were highly variable within the same group, but non-responders revealed significantly lower (E)-clomiphene concentration and a trend of decreased concentrations of active metabolites compared to the responders. Nine patients with intermediate metabolizer phenotype were all responders. We confirmed that the CC and the metabolite concentrations were different according to the ovulation status. However, our results do not provide evidence for the contribution of CYP2D6 polymorphism to either drug response or CC concentrations.

The present opinion paper, explores the possibility that optimal hormone treatment and judicious nutraceutical food supplement can help ageing men to gain quality-adjusted life years. Testosterone treatment of patients with late-onset hypogonadism is given via the transdermal route or by intramuscular injections. There is overwhelming evidence that testosterone replacement therapy (TRT) has many beneficial effects and increases longevity by approximately 2% per year. On the basis of knowledge of physiology, animal and human experimental data, we explain why TRT reduces the risk of cardiovascular disease and of prostate cancer. However, the total testosterone load supplied per day should remain within the physiological range, and new galenical formulations should be developed, mimicking normal day-night variations., (© 2015 Blackwell Verlag GmbH.)

In the treatment of women with abnormal uterine bleeding, once a thorough history, physical examination, and indicated imaging studies are performed and all significant structural causes are excluded, medical management is the first-line approach. Determining the acuity of the bleeding, the patient's medical history, assessing risk factors, and establishing a diagnosis will individualize their medical regimen. In acute abnormal uterine bleeding with a normal uterus, parenteral estrogen, a multidose combined oral contraceptive regimen, a multidose progestin-only regimen, and tranexamic acid are all viable options, given the appropriate clinical scenario. Heavy menstrual bleeding can be treated with a levonorgestrel-releasing intrauterine system, combined oral contraceptives, continuous oral progestins, and tranexamic acid with high efficacy. Nonsteroidal antiinflammatory drugs may be utilized with hormonal methods and tranexamic acid to decrease menstrual bleeding. Gonadotropin-releasing hormone agonists are indicated in patients with leiomyoma and abnormal uterine bleeding in preparation for surgical interventions. In women with inherited bleeding disorders all hormonal methods as well as tranexamic acid can be used to treat abnormal uterine bleeding. Women on anticoagulation therapy should consider using progestin-only methods as well as a gonadotropin-releasing hormone agonist to treat their heavy menstrual bleeding. Given these myriad options for medical treatment of abnormal uterine bleeding, many patients may avoid surgical intervention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Endocrine therapy is a compulsory step in the adjuvant management of early breast cancer expressing the estrogen receptor, by reducing as much as possible serum and tissue levels of estrogens. Tamoxifen is the standard therapy for non-menopausal women. Ovarian function suppression, in addition to exemestane or tamoxifen, could be an alternative option for young women at high risk of recurrence and non menopausal after adjuvant or neo-adjuvant chemotherapy. Recent studies show a trend for improvement of overall survival and disease-free-survival with aromatase inhibitors among postmenopausal women. However, safety of aromatase inhibitors is controversial and adverse events may lead to switch for tamoxifen with no loss of efficacy. Extension therapy by tamoxifen or aromatase inhibitor after five years of tamoxifen and for a total duration of ten years significantly improves overall survival. There is to date no data supporting the extension therapy after five years of aromatase inhibitor., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Two types of prognostic signatures for predicting recurrent risk of ER+ breast cancer patients have been developed: one type for patients accepting surgery only and another type for patients receiving post-operative tamoxifen therapy. However, the first type of signature cannot distinguish high-risk patients who cannot benefit from tamoxifen therapy, while the second type of signature cannot identify patients who will be at low risk of recurrence even if they accept surgery only. In this study, we proposed to develop two coupled signatures to solve these problems based on within-sample relative expression orderings (REOs) of gene pairs. Firstly, we identified a prognostic signature of post-operative recurrent risk using 544 samples of ER+ breast cancer patients accepting surgery only. Then, applying this drug-free signature to 840 samples of patients receiving post-operative tamoxifen therapy, we recognized 553 samples of patients who would have been at high risk of recurrence if they had accepted surgery only and used these samples to develop a tamoxifen therapy benefit predictive signature. The two coupled signatures were validated in independent data. The signatures developed in this study are robust against experimental batch effects and applicable at the individual levels, which can facilitate the clinical decision of tamoxifen therapy.

Disparities in the prognosis and incidence of melanoma between male and female patients have led clinicians to explore the influence of steroid hormones on the development and progression of this malignancy. A better understanding of the disparities of melanoma behavior between sexes and ages could lead to improved prevention and treatment options. There are multiple themes in the literature that unify the physiologic functions of estrogen and androgen receptors; herein we discuss and map their pathways. Overall, it is important to understand that the differences in melanoma behavior between the sexes are multifactorial and likely involve interactions between the immune system, endocrine system, and environment, namely UV-radiation. Melanoma deserves a spot among hormone-sensitive tumors, and if tamoxifen is re-introduced for future therapy, tissue ratios of estrogen receptors should be obtained beforehand to assess their therapeutic predictive value. Because androgens, estrogens, and their receptors are involved in signaling of commonly mutated melanoma pathways, potential synergistic properties of the recently developed molecular kinase inhibitors that target those pathways may exist., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Individuals with Dyskeratosis Congenita (DC) are at increased risk for complications in variety of systems including pulmonary fibrosis. Idiopathic and DC-associated pulmonary fibrosis are progressive and fatal disorders without known treatment. Here we describe, for the first time, marked improvement in the clinical and laboratory parameters of the pulmonary disease of a child who suffered from TINF2-associated DC and severe pulmonary fibrosis after initiation of therapy with Danazol. We recommend that the clinical efficacy of Danazol in slowing down the progression of pulmonary fibrosis in patients with telomere-related disorders is evaluated in prospective studies., (© 2015 Wiley Periodicals, Inc.)

Estrogen and progesterone receptors (ERs and PRs) are known for their prognostic as well as treatment predictive value in breast cancer. Although these receptors are differentially expressed in some other malignancies, and likely participate in the biology of those cancer types, the relevance to outcome and therapy is not well established. The use of ER as a highly effective therapeutic target in oncology was pioneered in breast cancer, and the lessons learned from its success could potentially benefit patients with several other malignancies in which hormone receptors are highly expressed. Indeed, there are several potent drugs available that target hormone receptors. These agents show incontrovertible evidence of benefit in patients with hormone receptor-positive breast cancer. It is conceivable that these drugs may have salutary effects in a variety of cancers other than those originating in the breast, based on the overexpression of hormone receptors in some patients, and the preclinical and clinical reports showing responses to these drugs in diverse cancers, albeit in small series or anecdotally. We therefore undertook a literature review in order to summarize the current data regarding the biologic and clinical implications of expression of estrogen and progesterone receptors in various malignancies and the possibilities for deployment of hormone manipulation beyond breast cancer.

Danazol has been used in the treatment of endometriosis and heavy menstrual bleeding for more than 40 years. This medication has both central antigonadotropic actions and direct atrophic effects on endometriotic tissue. Although it demonstrates a high-efficacy profile, the associated side effects have resulted in limited usage. Vaginal administration of the drug may prove favourable specifically in rectovaginal endometriosis. This targeted mode of delivery is associated with a significant reduction in both pain symptoms and nodule size. The relative persistence of these therapeutic benefits is likely related to the direct tissue effects after absorption through the vaginal mucosa. Vaginal administration would also limit systemic propagation of danazol and thus should minimize androgenic side effects. Use of vaginal danazol also improves heavy menstrual bleeding and may even restore fertility in some patients. In this review we provide a critical analysis of the existing literature on the use of vaginal danazol.

Women with breast cancer receive support from their partners to deal with the side effects of therapies over the cancer trajectory. Hormonal therapy (HT) is usually given after completing other treatments, and women receiving HT reclaim their normal life. This may lead to changes in support from their partners. Therefore, we explored women's perceptions of the support provided by their male partners in managing the side effects of adjuvant HT. We conducted semi-structured interviews with 10 women who received HT and recognized their partners as a main source of support. An interview guide was used to explore their experiences of treatment side effects, the contents of support received from their partners, their need for support, and their overall relationship with their partners. Interviews were analysed by content analysis. A theme on how participants perceived support from their partners was formulated as "Support not corresponding to transition to a new treatment" with the following categories: "Shrinking support," "Primacy of partner," and "Solitary new treatment." Participants felt lack of support from their partners because their partners did not understand their experience of the side effects induced by HT. Unlike the side effects of past treatments such as surgery and chemotherapy, side effects of HT cannot be observed and are highly subjective. Their partners often failed to notice these symptoms and provided little support. Nevertheless, participants aimed to accept the existing support without asking for more. They were left alone in the continuing trajectory of breast cancer. After starting HT, women entered a new treatment phase in which less understanding and support was provided by partners. Educational support for couples may enable sharing of subjective symptoms that are not obvious to partners and improve outcomes by facilitating partner engagement and support.

Objective: To assess the effect of treatment with a combination of the antiestrogen Tamoxifen citrate and Folate on semen quality of the infertile male with semen abnormality., Design: Prospective randomized controlled trial study., Material and Method: Between May 2013 and October 2014, 68 infertile male with semen abnormality were asked to join the present study. Informed consents were signed; all patients were divided into four groups, given placebo (control), Tamoxifen citrate 20 mg/day, Folate 5 mg/day, and Tamoxifen citrate plus Folate for continuous three months. The result of treatments i.e., semen parameters, hyaluronan binding assay, hypo-osmotic swelling test, and DNA damage test were evaluated at baseline, at the end of drugs treatment (3-month), and at 3-month after discontinuation of treatment (6-month)., Results: Tamoxifen alone caused a significant increase in sperm concentration, while Tamoxifen plus Folate significantly increased both sperm concentration and sperm motility at 3-month after treatment. Folate alone and Tamoxifen plus Folate significantly decreased DNA tail length at 3-month and at 3- and 6-month after treatment, whereas Tamoxifen alone caused no significant change in DNA tail length. Sperm DNA integrity was improved as seen by decrease in the length ofDNA tail., Conclusion: Our study indicated that Folate in combination with Tamoxifen citrate could improve sperm quality including semen parameters and sperm DNA integrity.

Chronic liver diseases, including liver cirrhosis, are caused by various pathogenesis, such as viral hepatitis, primary biliary cirrhosis, autoimmune hepatitis and steatohepatitis. There have not been enough clinical evidence about the treatment of hepatic osteodystrophy at the present time. Several reports suggested that bisphosphonates, such as alendronate, are effective for an increase in bone mineral density in patients with chronic liver disease. Vitamin D treatment might be useful for the frequent prevalence of vitamin D deficiency in the pathogenesis of hepatic oseodystrophy. The use of estrogens will be limited for the risk of liver dysfunction and hepatocellular carcinoma.

Purpose: Our aim was to study the role of AK000953 silencing for the killing effect of danazol on uterine fibroids., Methods: Quantitative PCR was applied to identify differential expression of AK000953 in uterine fibroid tissue and normal uterine tissue. Then we isolated and cultured uterine fibroid cells, designed the siRNA of AK000953 to silence its expression in uterine fibroid cells, and detected the treatment effect of danazol and AK000953 siRNA on cell proliferation, cell apoptosis, and cell invasion. Finally, guinea pig model of uterine fibroids was constructed to verify the effect of AK000953 silencing on uterine fibroid treatment with danazol in vivo., Results: Quantitative PCR showed that the AK000953 gene was highly expressed in uterine fibroid tissue compared with normal uterine tissue (2.1 ± 0.15 vs. 0.8 ± 0.05, p < 0.01). After AK000953 silencing in uterine fibroid cells, we discovered that the inhibition rate in danazol-siRNA group was 56 ± 5 %, the cell apoptosis rate of danazol-siRNA group was 43 ± 2.3 %, and the invasion rate of uterine fibroid cells was 12 ± 1 %, which all showed significant differences with the control group or danazol group. Guinea pig model confirmed that the treatment of danazol and AK000953 siRNA effectively inhibited the development of fibroids in vivo., Conclusion: AK000953 silencing could effectively enhance the killing effect of danazol on uterine fibroid cells.

Background: Decision-making experts emphasize that understanding and using probabilistic information are important for making informed decisions about medical treatments involving complex risk-benefit tradeoffs. Yet empirical research demonstrates that individuals may not use probabilities when making decisions., Objectives: To explore decision making and the use of probabilities for decision making from the perspective of women who were risk-eligible to enroll in the Study of Tamoxifen and Raloxifene (STAR)., Methods: We conducted narrative interviews with 20 women who agreed to participate in STAR and 20 women who declined. The project was based on a narrative approach. Analysis included the development of summaries of each narrative, and thematic analysis with developing a coding scheme inductively to code all transcripts to identify emerging themes., Results: Interviewees explained and embedded their STAR decisions within experiences encountered throughout their lives. Such lived experiences included but were not limited to breast cancer family history, a personal history of breast biopsies, and experiences or assumptions about taking tamoxifen or medicines more generally., Conclusions: Women's explanations of their decisions about participating in a breast cancer chemoprevention trial were more complex than decision strategies that rely solely on a quantitative risk-benefit analysis of probabilities derived from populations In addition to precise risk information, clinicians and risk communicators should recognize the importance and legitimacy of lived experience in individual decision making., (© The Author(s) 2015.)

Concepts of disease risk and its management are central to processes of medicalisation and pharmaceuticalisation. Through a narrative perspective, this paper aims to understand how such macro-level developments may (or may not) be experienced individually, and how an algorithm that is used for recruitment into a clinical trial may structure individual notions of being 'at risk' and 'in need of treatment'. We interviewed 31 women participating in the Study of Tamoxifen and Raloxifene (STAR), a chemoprevention trial conducted in the US between 1999 and 2006. Interviews were thematically analysed. Women in the study had experienced the threat of breast cancer and felt vulnerable to developing the disease prior to STAR participation. The diagnosis of 'being at risk' for cancer through an algorithm that determined risk-eligibility for STAR, opened up the possibility for the women to heal. The trial became a means to recognise and collectivise the women's experiences of vulnerability. Through medication intake, being cared for by study coordinators, and the sense of community with other STAR participants, trial participation worked to transform women's lives. Such transformative experiences may nevertheless have been temporary, enduring only as long as the close links to the medical institution through trial participation lasted., (© 2015 Foundation for the Sociology of Health & Illness.)

The use of the antiestrogen tamoxifen in melanoma therapy is controversial due to the unsuccessful outcomes and a still rather unclarified mechanism of action. It seemed that the days of tamoxifen in malignant melanoma therapy were close to an end, but new evidence may challenge this fate. On one hand, it is now believed that metabolism is a major determinant of tamoxifen clinical outcomes in breast cancer patients, which is a variable that has yet to be tested in melanoma patients, since the tamoxifen active metabolite endoxifen demonstrated superior cytostatic activity over the parent drug in melanoma cells; on the other hand, new evidence has emerged regarding estrogen-mediated signaling in melanoma cells, including the methylation of the estrogen receptor-α gene promoter and the expression of the G protein coupled estrogen receptor. The expression of estrogen receptor-α and G protein coupled estrogen receptor, as well as the cytochrome P450 (CYP) 2D6 genotype, may be used as predictive biomarkers to select the patients that may respond to antiestrogens based on specific traits of their tumors. This review focused on these new evidences and how they may contribute to shed new light on this long-lasting controversy, as well as their possible implications for future investigations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: There have been reports of transient psychosis in women medicated for gynecologic conditions., Objective: The aim of this paper was to explore this literature., Method: The PubMed and Google Scholar databases were searched for relevant case reports Results: The following reports were found: psychosis induced by gonadotropin-releasing hormone in the treatment of endometriosis, by clomiphene treatment for infertility, by bromocriptine treatment for milk suppression and by the withdrawal of domperidone prescribed as a galactologue as well as by the withdrawal of estrogen replacement therapy., Conclusion: In susceptible women, psychotic symptoms can result from treatments that reduce estrogen levels, such as leuprolide acetate or clomiphene, or treatments that increase dopamine levels (bromocriptine). Psychosis can also be caused indirectly when estrogen treatment is discontinued or dopamine antagonism (e.g. domperidone) withdrawn. Estrogen-reducing and dopamine-increasing treatments used in gynecology need to be carefully monitored.

Therapies targeting estrogen receptor alpha (ERα), including selective ER modulators such as tamoxifen, selective ER downregulators such as fulvestrant (ICI 182 780), and aromatase inhibitors such as letrozole, are successfully used in treating breast cancer patients whose initial tumor expresses ERα. Unfortunately, the effectiveness of endocrine therapies is limited by acquired resistance. The role of microRNAs (miRNAs) in the progression of endocrine-resistant breast cancer is of keen interest in developing biomarkers and therapies to counter metastatic disease. This review focuses on miRNAs implicated as disruptors of antiestrogen therapies, their bona fide gene targets and associated pathways promoting endocrine resistance., (© 2015 Society for Endocrinology.)

The most common cause of male infertility is idiopathic oligoasthenozoospermia. Empirical medical treatment for idiopathic male infertility is still a controversial issue. The aim of this study was to evaluate any possible effects of combining vitamin E as antioxidant and clomiphene citrate as antiestrogen on spermatozoa concentration and motility in comparison to give either of medications alone in patients with idiopathic oligoasthenozoospermia. This is a comparative prospective randomized study. Ninety patients with idiopathic oligoasthenozoospermia were randomized into equally three groups: Group A: received vitamin E (400 mg/day) for 6 months. Group B: received clomiphene citrate (25 mg daily) for 6 months. Group C: received combination of both drugs in the same doses for 6 months. All patients were subjected to the following: history taking, general and genital examination, semen analysis, serum FSH, total testosterone, and scrotal duplex. Semen examination was performed according to the guidelines of (WHO, 2010), at the start of treatment and was repeated after 3 months and after 6 months of treatment. Regarding vitamin E group, there was insignificant increase in mean sperm concentration after 6 months of treatment in comparison to baseline. On the other hand, there was a significant improvement of mean sperm concentration in the other two groups after 6 months of treatment, with more significance in combination therapy group (p = 0.001). The mean total sperm motility has improved in all patients groups, in comparison to baseline, with more significance in combination therapy group. In vitamin E group, it was 28.07 ± 9.65% (p = 0.000). For those in clomiphene citrate group, was 33.33 ± 14.10% (p = 0.003) and 40.50 ± 17.54% (p = 0.000) in combination therapy group. Combining antioxidant and anti-estrogen therapy is a valid option for the treatment of a selected group of men with unexplained isolated oligoasthenozoospermia., (© 2015 American Society of Andrology and European Academy of Andrology.)

In breast reconstructive procedures, adipose-derived stem cells (ASCs) that are present in clinical fat grafting isolates are considered to play the main role in improving wound healing. In patients following chemotherapy for breast cancer, poor soft tissue wound healing is a major problem. However, it is unclear if tamoxifen (TAM) as the most widely used hormonal therapeutic agent for breast cancer treatment, affects the ASCs and ultimately wound healing. This study evaluated whether TAM exposure to in vitro human ASCs modulate cellular functions. Human ASCs were isolated and treated with TAM at various concentrations. The effects of TAM on cell cycle, cell viability and proliferation rates of ASCs were examined by growth curves, MTT assay and BrdU incorporation, respectively. Annexin V and JC-1 Mitochondrial Membrane Potential assays were used to analyze ASC apoptosis rates. ASCs were cultured in derivative-specific differentiation media with or without TAM (5 uM) for 3 weeks. Adipogenic and osteogenic differentiation levels were measured by quantitative RT-PCR and histological staining. TAM has cytotoxic effects on human ASCs through apoptosis and inhibition of proliferation in dose- and time-dependent manners. TAM treatment significantly down-regulates the capacity of ASCs for adipogenic and osteogenic differentiation (p<0.05 vs. control), and inhibit the ability of the ASCs to subsequently formed cords in Matrigel. This study is the first findings to our knowledge that demonstrated that TAM inhibited ASC proliferation and multi-lineage ASC differentiation rates. These results may provide insight into the role of TAM with associated poor soft tissue wound healing and decreased fat graft survival in cancer patients receiving TAM., (© 2015 by the Wound Healing Society.)

Traditional menopausal hormone therapy containing estrogens/progestin has been associated with an increased risk of breast cancer, and estrogen exposure is known to promote growth and proliferation of a majority of breast cancers. Therefore, it is important for clinicians to consider the breast safety profile of any hormone-based therapy used in postmenopausal women. This review provides an overview of the breast safety and tolerability profiles of currently marketed selective estrogen receptor modulators, antiestrogens, and the first tissue selective estrogen complex combining conjugated estrogens with the selective estrogen receptor modulator bazedoxifene in postmenopausal women. Selective estrogen receptor modulators and antiestrogens act as estrogen receptor antagonists in the breast. Tamoxifen, toremifene, and the selective estrogen receptor degrader fulvestrant are used to treat breast cancer, and tamoxifen and raloxifene protect against breast cancer in high-risk women. Postmenopausal women using selective estrogen receptor modulators for prevention or treatment of osteoporosis (raloxifene, bazedoxifene) can be reassured that these hormonal treatments do not adversely affect their risk of breast cancer and may, in the case of raloxifene, even be protective. There are limited data on breast cancer in women who use ospemifene for dyspareunia. Conjugated estrogens/bazedoxifene use for up to two years did not increase mammographic breast density or breast pain/tenderness, and there was no evidence of an increased risk of breast cancer, suggesting that conjugated estrogens/bazedoxifene has an improved breast safety profile compared with traditional menopausal hormone therapies. Future research will continue to focus on development of selective estrogen receptor modulators and selective estrogen receptor modulator combinations capable of achieving the ideal balance of estrogen receptor agonist and antagonist effects., (© The Author(s) 2015.)

Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology and affect the majority of men at some time during their lives. The development of BPH/LUTS is associated with an increased ratio of estrogen to androgen levels, and this ratio, when mimicked in a variety of animals, induces BPH and lower urinary tract dysfunction (LUTD). While the precise molecular etiology remains unclear, estrogens have been implicated in the development and maintenance of BPH. Numerous endogenous and exogenous estrogens exist in humans. These estrogens act via multiple estrogen receptors to promote or inhibit prostatic hyperplasia and other BPH-associated processes. The prostate is an estrogen target tissue, and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of estrogen action directly affecting prostate growth and differentiation in the context of BPH is an understudied area and remains to be elucidated. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation illustrating their potential roles in the development of BPH as therapy. More work will be required to identify estrogen signaling pathways associated with LUTD in order to develop more efficacious drugs for BPH treatment and prevention.

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease, occurs in women, usually premenopausal, caused by the proliferation of neoplastic smooth muscle-derived cells. Mutations in the tuberous sclerosis complex genes, lead to the activation of mammalian target of rapamycin kinase (mTOR), results in proliferation of LAM cells, its increasing motility, and survival. Polycystic lung destruction, extensive involvement of lymphatic channels, chylothorax, chyloperitoneum, and renal angiomyolipomas can develop in LAM patients. The new, promising treatment strategies have been recently introduced due to discovery of the genetic and molecular mechanisms of LAM. Comprehension of the disease pathogenesis has resulted in the implementation of other therapeutic agents such as mTOR inhibitors, VEGF-D inhibitors, statins, interferon, chloroquine analogs, cyclin-dependent kinase inhibitors, matrix metalloproteinase inhibitors, aromatase inhibitors, and their combinations. The mTOR inhibitors appear to be the most important, and the efficacy of sirolimus in LAM treatment has been proved. The article discussed the new control studies with mTOR inhibitors, doxycycline, simvastatin, and combination of them in LAM patients.

Endocrine therapy is a key component of adjuvant treatment for premenopausal patients with endocrine-responsive tumors. It is commonly well tolerated, although side effects are a main concern in the selection of treatment options. Tamoxifen is still considered an adequate endocrine therapy in a large group of premenopausal patients (e.g. lower-risk patient, presence of co-morbidities, patient preference). Results of the SOFT and TEXT trials addressing new adjuvant endocrine treatment options in premenopausal patients were recently presented. Overall, in the SOFT study the premenopausal population did not benefit from the addition of ovarian function suppression (OFS). Nevertheless, for women at sufficient risk of recurrence to receive adjuvant chemotherapy and who maintained premenopausal estradiol, the addition of OFS to tamoxifen reduced the risk of recurrence. The magnitude of the effect was larger in younger patients. Moreover, in the SOFT and TEXT trials, adjuvant treatment with exemestane plus OFS, as compared with tamoxifen plus OFS, significantly improved disease-free survival, breast cancer-free interval and distant disease-free survival. However, premenopausal patients include heterogeneous subsets of women and tumors where costs and benefits of adjuvant endocrine therapy should be properly weighted. Issues specific for premenopausal patients, related to desire for pregnancy, family planning, safety, quality of life and subjective side effects, should be a priority in the therapeutic algorithm. Therefore, selecting the best-tolerated agent can enhance adherence to therapies and reduce the impact on quality of life and health status for these younger patients.

Prerequisites: Pathogenesis and pathophysiology of endometriosis, pharmacodynamics of oral contraceptives, progestagens, antiprogestagens, danazol, GnRh agonist and non-steroidal antiinflammatory., Purpose of Review: The aim of this paper is to systematically review the literature evidence of medical treatments for endometriosis and to summarize recently published recommendations., Methods: Literature and recently published recommendations review via bibliographic research using Pubmed/Medline, Google scholar and Cochrane database., Results: Endometriosis is an estrogen-dependent gynecological disease. Medical treatement of endometriosis induce an estrogen deprivation situation. The Oral contraceptives reduce the rate of postoperative endometrioma recurrence and should be considered an essential part of long-term therapeutic strategies.New agents promise a distinct perspective in endometriosis treatment., Conclusions: The effectiveness of medical treatmentis well established in the management pelvic pain and infertility associated with endometriosis and constitutes an important alternative or complement to surgery.

Livedoid vasculopathy (LV) is a thrombo occlusive disorder presenting with recurrent painful ulcers of lower extremities. Association of LV with increased level of lipoprotein (a) (LP(a)), a risk factor for cardiovascular disease, has been reported. Danazol has been used with success in the management of LV, but none of the previous studies looked at the correlation between response to the treatment and level of LP(a). The aim of this study was to demonstrate the efficacy of low-dose danazol in the treatment of LV and its effects on LP(a). We present four cases with LV who were successfully treated with low-dose danazol, assessing the clinical characteristics and laboratory tests including the level of LP(a). The average age of the patients was 45 years and the mean duration of the disease was 19 years. The treatment regime of danazol 200 mg daily led to complete healing of ulcers and reduction in pain and a 70% (ranging from 52 to 87%) reduction in the level of LP(a). The limitation of this study is "small sample size." In our patients with LV, low-dose danazol led to clinical improvement along with significant reduction in the level of LP(a)., (© 2015 Wiley Periodicals, Inc.)

Fulvestrant is a novel endocrine therapy for breast cancer that exerts both anti-estrogenic and down-regulatory effects by binding to and degrading estrogen receptors (ERs). In the present study, the safety and effectiveness of 500 mg fulvestrant in 69 patients with advanced, recurrent, ER-positive postmenopausal breast cancer were investigated retrospectively. Outcomes were favorable for fulvestrant. The objective response rate was 24.6%, the clinical benefit rate was 49.2%, the median progression-free survival (PFS) was 203 days, and the median overall survival was 794 days. PFS tended to be longer in patients without a history of previous treatment or visceral metastasis. The main adverse events included injection site reactions and hot flushes; however, the majority of these events were mild to moderate. The present findings suggest that, among Japanese patients with advanced, recurrent, ER-positive postmenopausal breast cancer, 500 mg fulvestrant is effective and safe in those without metastasis and a minimal history of receipt of previous treatment regimens.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Introduction: Selective estrogen receptor (ER) modulators (SERMs) are a class of nonsteroidal compounds that interact with ERs, each with a distinct tissue-specific profile. Depending upon the degree of ER agonism/antagonism at the target tissue, SERMs show efficacy for various indications including osteoporosis, dyspareunia, and breast cancer, and are associated with safety risks., Areas Covered: This review describes the safety profile of SERMs (tamoxifen, raloxifene, toremifene, bazedoxifene, lasofoxifene, and ospemifene) and fulvestrant (a pure ER antagonist) from Phase III trials, long-term extension studies, and active comparator studies. Tamoxifen, a first-generation SERM, is indicated for breast cancer prevention and treatment but is associated with serious safety concerns including endometrial cancer, venous thromboembolic events (VTE), and stroke. Toremifene, raloxifene, bazedoxifene, lasofoxifene, and ospemifene present generally improved, though distinctly different, safety profiles compared with tamoxifen, especially with endometrial cancer and stroke. However, the risk of VTE remains a concern for most SERMs., Expert Opinion: Each SERM presents a unique risk/benefit profile based on varying indications and tissue-specific ER agonist and antagonist effects, making careful patient selection and ongoing patient monitoring crucial aspects of treatment. Future research may focus on identifying new SERMs for endocrine-resistant and endocrine-responsive cancers and post-menopausal symptoms.

Objective: To investigate the follicular size at spontaneous rupture on pregnancy rate in patients with polycystic ovary syndrome (PCOS) undergoing clomiphene citrate (CC) ovulation., Design: Cross-sectional study., Patients and Methods: One hundred and four women with ovulatory cycles after use of CC followed by ultrasound to determine the follicle size at the time of rupture, which was subsequently correlated with the occurrence of pregnancy or not in coit cycles., Results: In the group of follicular rupture at a mean diameter ≤25 mm (n = 54), pregnancy rate was 35.1% and when follicular rupture occurred at a mean diameter >25 mm (n = 50), it was 34% (p > 0.05). When different diameters at follicular rupture were randomly correlated with the pregnancy rate, there was no significant difference., Conclusion: Our data suggest that the occurrence of pregnancy after ovulation induction with CC in women with PCOS is not associated with follicle size at the time of rupture.

Purpose: We analyzed the significance of age together with other classic prognostic parameters on the course of breast cancer in postmenopausal patients., Methods: Our study included 151 postmenopausal patients with primary breast cancer, of which 55% received adjuvant tamoxifen therapy and 45% did not receive any kind of therapy. Probabilities of disease-free interval (DFI) were estimated using the Kaplan-Meier method and were compared by the log-rank test. A p value<0.05 was considered as statistically significant., Results: In the tamoxifen-treated subgroup, patients with estrogen receptor (ER) or progesterone receptor (PR) concentration≥5 fmol/mg had favorable course of disease (p<0.01, p<0.04), respectively. Patients≥66 years of age had a worse disease course compared to those<66 years. Also, patients≥66 years with pT1 tumors had a worse disease course compared to those<66 years and pT1 tumors. This result was repeated in other groups as well. In pT2 (≥2 cm), ER-positive, PR-positive and invasive ductal carcinoma (IDC) subgroups, patients≥66 years always had a worse disease course compared to patients<66 years. In the untreated subgroup, patients with ER≥52 fmol/mg (p<0.01), tumors≥2 cm (p<0.01), IDC (p<0.01) type or ≥56 years (p<0.04) had statistically more recurrences. Among patients≥56 years, those with ER-positive or pT2 tumors had shorter DFI compared to ER-negative or pT1. Positive correlation between ER, PR and age of patients was also shown in this subgroup (p<0.03, p<0.02)., Conclusion: Age of patients, ER and PR are significant prognostic factors in the tamoxifen-treated subgroup. In the untreated subgroup relevant prognostic parameters are age, tumor size, histological type and ER. The above prognostic factors retained their value in the long-term follow up in both the investigated subgroups of patients.

Skeletal muscle loss during menopause is associated with a higher risk of developing diabetes type II and the general development of the metabolic syndrome. Therefore, strategies combining nutritional and training interventions to prevent muscle loss are necessary. Danshen Si Wu is a traditional Chinese medicine used for menopausal complains. One of the main compounds of Danshen Si Wu is tanshinone IIA. Physiological effects of tanshinone IIA have been described as being mediated via the estrogen receptor. Therefore, it was the aim of this study to determine its tissue specific ERα- and ERβ-mediated estrogenic activity, to investigate its antiestrogenic properties, and, particularly, to study estrogen receptor-mediated biological responses to tanshinone IIA on skeletal muscle cells. The purity of tanshinone IIA was analyzed by LC-DAD-MS/MS analysis. ERα/ERβ-mediated activity was dose-dependently analyzed in HEK 239 cells transfected with ERα or ERβ expression vectors and respective reporter genes. Androgenic, antiandrogenic, and antiestrogenic properties of tanshinone IIA were analyzed in a yeast reporter gene assay. The effects of tanshinone IIA on proliferation and cell cycle distribution were investigated in ERα positive T47D breast cancer cells. The ability of tanshinone IIA to stimulate estrogen receptor-mediated myotube hypertrophy was studied in C2C12 myoblastoma cells. Our data show that tanshinone IIA is quite potent at stimulating ERα and ERβ reporter genes with comparable efficacy. Tanshinone IIA displayed antiestrogenic and also antiandrogenic properties in a yeast reporter gene assay. It inhibited the growth of T47D breast cancer cells by suppressing proliferation and arresting the cells in G0/G1. Tanshinone IIA also stimulated the hypertrophy of C2C12 myotubes via an estrogen receptor-mediated mechanism. Summarizing our results, tanshinone IIA can be characterized as an estrogen receptor partial agonist with antiandrogenic properties. It seems to inhibit ERα-mediated cell proliferation but induces ERβ-related biological responses like hypertrophy of myotubes. These findings are interesting with respect to the treatment of a variety of complains of postmenopausal females, including muscle wasting., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Mammographic breast density is one of the strongest independent risk factors for developing breast cancer. We examined the effect of exemestane and tamoxifen on breast density in Dutch postmenopausal early breast cancer patients participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial., Material and Methods: Analogue mammograms of selected TEAM participants before start, and after one and two (and if available after three) years of adjuvant endocrine therapy were collected centrally and reviewed. Study endpoints were change in breast density over time, and correlations between breast density and locoregional recurrence (LRR), distance recurrence (DR), and contralateral breast cancer (CBC)., Results: Mammograms of 378 patients (181 tamoxifen, 197 exemestane) were included in the current per protocol analyses. Baseline breast density was low (breast density score<50% in 75% of patients) and not different between patients randomised to exemestane or tamoxifen (coefficient 0.16, standard error 0.17). Breast density did not change during treatment in exemestane (p=0.25) or tamoxifen users (p=0.59). No relation was observed between breast density and the occurrence of a LRR [hazards ratio (HR) 0.87, 95% CI 0.45-1.68, p=0.67], a DR (HR 1.02, 95% CI 0.77-1.35, p=0.90), or CBC (HR 1.31, 95% CI 0.63-2.72, p=0.48)., Conclusion: The in general low breast density score in early postmenopausal breast cancer patients did not substantially change over time, and this pattern was not different between tamoxifen and exemestane users. Breast density was not a predictive marker for efficacy of adjuvant endocrine therapy.

Introduction: Several agents have been tried in the management of mastalgia. Centchroman (Ormeloxifene), a novel non-steroidal selective estrogen receptor modulator (SERM), has also been recently used in the management of mastalgia., Methods: Eligible patients, who had mastalgia for more than 3 months, were randomized into two groups - Group A received centchroman 30 mg daily and Group B received tamoxifen 10 mg daily. Treatment was continued for a total of 12 weeks; thereafter, patients were followed for another 12 weeks without medication to assess the continuum of relief. Pain severity was measured with VAS score. Patients were considered to have complete pain relief if their VAS score decreased to 3 or less., Results: Patients, in both the groups, showed gradual improvement in mastalgia with passage of time up to 12 weeks. Following cessation of treatment at 12 weeks, partial relapse of pain was observed at 24 weeks. There was no significant difference between Group A and Group B in terms of mean VAS Score and proportion of women reporting pain relief at 4, 8, 12, and 24 weeks. Fifteen patients in Group A had side effects namely dizziness, menstrual irregularities and development of ovarian cysts. There was no side effect noted in group B., Conclusion: Centchroman and tamoxifen were found to be of similar effectiveness in providing pain relief in mastalgia. High frequency of side effects, particularly development of ovarian cyst, in patients receiving centchroman is a matter of concern., (Copyright © 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: This study aimed to determine the progression-free interval (PFI) for patients with platinum-resistant ovarian cancer on antiestrogen therapy (AET), and to correlate PFI with tumor estrogen receptor (ER) expression status., Materials and Methods: This single-institution retrospective cohort study investigated platinum-resistant epithelial ovarian, fallopian tube, and primary peritoneal cancers treated with tamoxifen or an aromatase inhibitor from January 1999 to January 2012. Median PFI was calculated and a 95% confidence interval was constructed by bootstrapping. Relationships of PFI with disease characteristics were examined using 1-way analysis of variance or Pearson correlation. Estrogen receptor status of tumor specimens was assessed by immunohistochemistry. Progression-free interval was compared between ER groups with the Mann-Whitney test. Kaplan-Meier estimate was used to determine overall survival., Results: Ninety-nine patients met inclusion criteria: 77 (78%) received tamoxifen and 22 (22%) an aromatase inhibitor. Patients had a mean of 4 prior chemotherapy regimens (range, 1-14). Median PFI for any AET was 4.0 months (range, 1-49; 95% confidence interval, 3.0-5.0). Progression-free interval was independent of the number of prior treatments and type of AET, but longer with earlier stage at diagnosis. Estrogen receptor status was obtained for 63 patients, 44 were positive and 19 were negative. Progression-free interval was not statistically significant between ER-positive (median, 4.0 months) and ER-negative (median, 2.0 months) tumor status (P = 0.36)., Conclusions: This is the largest study to date investigating AET in heavily pretreated, platinum-resistant ovarian cancer patients. The median PFI of 4.0 months is comparable to standard cytotoxic therapies, and some patients with PFI greater than this median interval had ER-negative tumors. Given the limited adverse effects of AET, as well as low cost including oral administration, this treatment should be considered in all patients with platinum-resistant ovarian cancer.

The aim of the present study was to evaluate the effect of sunitinib on endometriotic implants and adhesions in a rat endometriosis model. An experimental endometriosis model was created in 21 rats. These rats were randomly divided into three groups: Group 1 (control group, 7 rats) was given no medication; Group 2 (sunitinib group, 7 rats) was given 3 mg/kg per day of oral sunitinib; and Group 3 (danazol group, 7 rats) was given 7.2 mg/kg per day of oral danazol. The volume of endometriotic implants was calculated. The extent and severity of adhesions were evaluated. The groups were compared by the Student's t-test, analysis of variance (ANOVA) and the Mann-Whitney U test. There was no statistically significant difference in the mean volume of endometriotic implants before medication between three groups. The volume of implants and extent, severity, total score of adhesions were significantly decreased after medication in Group 2 and Group 3. We noted that the volume of the endometriotic implants and adhesion formation were decreased both after sunitinib and danazol treatment. As a result, sunitinib seems to be effective for endometriotic peritoneal lesions. The effects of sunitinib in rat models give hope for improving the treatment of human endometriosis and prevention of pain symptoms.

Patients often respond differently to a treatment because of individual heterogeneity. Failures of clinical trials can be substantially reduced if, prior to an investigational treatment, patients are stratified into responders and nonresponders based on biological or demographic characteristics. These characteristics are captured by a predictive signature. In this paper, we propose a procedure to search for predictive signatures based on the approach of patient rule induction method. Specifically, we discuss selection of a proper objective function for the search, present its algorithm, and describe a resampling scheme that can enhance search performance. Through simulations, we characterize conditions under which the procedure works well. To demonstrate practical uses of the procedure, we apply it to two real-world data sets. We also compare the results with those obtained from a recent regression-based approach, Adaptive Index Models, and discuss their respective advantages. In this study, we focus on oncology applications with survival responses., (© 2014 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Anti-Mullerian-hormone (AMH) does not seem to fluctuate significantly during the menstrual cycle in healthy women. However, little is known about cycle fluctuations of AMH levels in patients with polycystic ovarian syndrome (PCOS). The purpose of this study was to examine AMH fluctuations during the follicular phase in PCOS patients receiving antiestrogens or recombinant follicle-stimulating hormone (FSH). About 40 PCOS patients diagnosed according to Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2003 and 19 controls were prospectively enrolled. PCOS patients received either antiestrogens or recombinant FSH for monoovulation induction and controls received antiestrogens. AMH levels were determined (1) between the 2nd and the 5th day of follicular phase and (2) when a single large dominant follicle ≥18 mm had appeared. Our study shows that AMH levels do not change during follicular development in controls as well as in PCOS patients with AMH levels < 5 ng/ml, irrespective of antiestrogen or FSH therapy. However, in PCOS patients with AMH levels ≥5 ng/ml, AMH declines significantly during follicular development (p < 0.01). We conclude that AMH levels should be determined in the early follicular phase in PCOS patients without the influence of antiestrogens or exogenous FSH, because these interventions may lower AMH values in patients with high levels.