Hormone Deprivation Research Articles

Potentiality of Postponing Menopause through Ovarian Auto-graft Transplantation

Menopause is a critical stage in the life of women in which the menses stop with loss of fertility. Deprivation of female hormones especially estrogen might be accompanied with some physical and psychological disorders. Therefore, this mini-review aimed to highlight the anatomy of the ovary at different age stages and to discuss the possibility of using technology of cryopreservation in postponing the menopause to alleviate its associated disorders and ensure healthy life for women. Ovarian tissue cryopreservation has been successfully used for rescuing the harvested ovary from destruction that could be caused by chem- or radiotherapy used in cases of cancer management. Then, slices of such tissues re-implanted into the patients give good results restoring the fertility and hormonal production. Therefore, it is suggested that trials to re-transplant ovarian auto-graft might be performed to postpone the menopause in volunteers in order to preserve endocrine function of ovary.

THE COMBINATION OF EXTERNAL RADIATION THERAPY WITH HIGH DOSE RATE BRAHYTERAPY BOOST FOR PROSTATE CANCER: A COMPARATIVE CHARACTERISTIC OF TWO FRACTION MODES

The purpose of the study was to analyze treatment outcomes in prostate cancer patients, who received external radiotherapy combined with high dose rate (HDR) 198 Ir brachytherapy boost of 10 Gy in 2 fractions or 15 Gy in 1 fraction. Material and methods. Between July 2012 and June 2017, 98 patients with prostate cancer received radiation therapy at N.N. Petrov National Medical Research Center of Oncology (St-Petersburg, Russia). Intensitymodulated radiation therapy (IMRT) at a total dose of 46–50 Gy was delivered to the prostate, seminal vesicles and regional lymph outflow areas (RTOG, 2009). The patients were then divided into 2 groups. Group I patients (81 patients, 82.7 %) received HDR brachytherpy boost of 10 Gy in 2 fractions, Group II patients (17 patients, 17.3 %) received HDR brachytherpy boost of 15 Gy in 1 fraction. Inclusion criteria were: high or extremely high risk of relapse according to NCCN (2010), no evidence of distant metastases and no evidence of pronounced urinary tract disorders (residual urine volume less than 50 ml, IPSS less than 17 points, maximum urination rate ≥10 ml / sec). Assessment of radiation-induced complications (toxicity) was carried out in accordance with generally accepted RTOG / EORTC (1995) criteria and taking into account the terminological recommendations of CTCAE v 4.0 (2009). Results. The median follow-up time was 39.2 [30.7; 48.7] (20.3–69.8) months in Group I and 37.0 [30.9; 47.9] (23.7–50.7) months in Group II. The 3-year disease-free survival rate in the study groups regardless of the boost was 77.1 % (75.9 % in Group I and 77.8 % in group II, p=0.7). The 3-year disease-free survival rates in patients with high and extremely high risk regardless of the radiotherapy regimen were 88.6 % and 70.8 %, respectively (р=0.04). Genitourinary early radiation toxicity and rectal intestinal early radiation toxicity of grade 3 were observed in 13.5% and 12.3 % of Group I patients and in 17.6 and 5.9 % of Group II patients. The most significant late complications were the formation of urethral stricture (1 patient of group I) and postradiation rectal stenosis (1 patient of group II). Evaluation of the level of erectile function in both groups showed a significant decrease in satisfaction with the quality of sexual life, which, apparently, can be explained not only by radiation damage to the structures responsible for hemodynamics of the penis, but also by castration syndrome due to prolonged hormonal deprivation in the vast majority of patients. Conclusion . The combination of external beam radiation therapy with HDR brachytherapy boost is an effective method of radical treatment of prostate cancer patients with high and extremely high risk of recurrence.

Endocrinotherapy resistance of prostate and breast cancer: Importance of the NF‑κB pathway (Review).

Prostate cancer (PCa) and breast cancer(BCa) are two common sex hormone‑related cancer types with high rates of morbidity, and are leading causes of cancer death globally in men and women, respectively. The biological function of androgen or estrogen is a key factor for PCa or BCa tumorigenesis, respectively. Nevertheless, after hormone deprivation therapy, the majority of patients ultimately develop hormone‑independent malignancies that are resistant to endocrinotherapy. It is widely recognized, therefore, that understanding of the mechanisms underlying the process from hormone dependence towards hormone independence is critical to discover molecular targets for the control of advanced PCa and BCa. This review aimed to dissect the important mechanisms involved in the therapeutic resistance of PCa and BCa. It was concluded that activation of the NF‑κB pathway is an important common mechanism for metastasis and therapeutic resistance of the two types of cancer; in particular, the RelB‑activated noncanonical NF‑κB pathway appears to be able to lengthen and strengthen NF‑κB activity, which has been a focus of recent investigations.

Why a Non-Metastatic Prostate Cancer Should Become a Castration Resistant Prostate Cancer?

The issue of resistance to the “hormonal deprivation control” in Prostate Cancer (PC), is one of the most common and problematic aspects of this disease...

Noninvasive treatment of organ-confined prostate cancer in elderly patients-results of the HAROW study

Noninvasive treatment options such as active surveillance (AS), watchful waiting (WW), and hormone deprivation therapy (HT) are particularly important in elderly patients with localized prostate cancer (PCa). We examine the use of these noninvasive treatment options in the everyday care in acohort of patients ≥70years old. In the HAROW study, the treatment of localized PCa under everyday conditions is investigated. The only inclusion criterion was newly diagnosed organ-confined PCa (≤cT2c). In AS, WW, and HT patients, we compared initial tumor and patient characteristics, follow-up examinations and changes of therapy. Of 457 patients ≥70years, 210 chose AS, 160 HT, and 87WW. Observation times were 6.3 years (AS), 7.5 years (HT), and 7.0 years (WW). AS patients (73.2 years) were younger than WW (76.0 years) and HT patients (76.9 years) and had ahigher proportion of low-risk tumors (80%) versus WW (31%) and HT (19%). Achange of therapy was observed in 47.1% of AS, 17.2% of WW and 13.1% of HT patients. Metastasis occurred in 1.0% of AS, 4.6% of WW, and 6.9% of HT patients. Overall survival was 94.3% for AS, 90.8% for WW and 81.9% for HT. Within the first 28.4months, the mean number of PSA determinations did not differ between AS and WW (6.1 vs. 5.2; p = 0.09); arebiopsy was performed in 37.6% of AS, 11.4% of WW, and 17% of HT patients. The allocation to curative and palliative strategies should be made according to patient and tumor characteristics by definition. Palliative procedures may represent concepts in older patients who initially chose acurative AS strategy.

Conjugated Linoleic Acid Supplemented Diet Influences Serum Markers in Orchidectomized Sprague‐Dawley Rats

AbstractConjugated isomers of linoleic acid have beneficial effects on human health, with demonstrated anticarcinogenic, antiatherogenic, antioxidant, and anti‐inflammatory properties. Previous studies have shown that the loss of sex hormones induced by orchidectomy affects vascular function and serum lipids. The objective of this work is to evaluate the effect of conjugated linoleic acid (CLA) on serum lipids, cardiac, renal, and hepatic markers in orchidectomized Sprague‐Dawley rats. Male sex hormone deprivation is induced by orchidectomy to 24‐week‐old rats. The rats are fed a diet containing 1.8% w/w CLA, or a control diet for 8 weeks. At the end of the treatment, serum markers are measured using commercially available kits. The concentrations found in the orchidectomized‐CLA (ORX‐CLA) group of total cholesterol, low‐density lipoproteins (LDL), as well as the atherogenic index, concentrations of creatine kinase, lactate dehydrogenase, C‐reactive protein, glucose, urea, uric acid, creatinine, albumin, calcium, total protein, and bilirubin are significantly lower compared to the orchidectomized‐control (ORX‐C) group. The concentrations of high‐density lipoproteins (HDL), calcium, total protein, albumin, total bilirubin, and indirect bilirubin are significantly higher in the ORX‐CLA group than in the ORX‐C group. The CLA‐supplemented diet exerts a beneficial effect on different biochemical parameters negatively affected by orchidectomy, which may result in vascular protection.Practical Applications: The relationship between testosterone deficiency and the alteration of serum lipids is demonstrated; however, it is demonstrated in this study that the markers of renal damage, cardiac damage, and oxidative stress are also negatively affected by the lack of this hormone. This information has enriched the understanding about the relationship between testosterone deficiency and the development of different diseases such as metabolic syndrome, type 2 diabetes, kidney failure, osteoporosis, cardiovascular diseases, and cancer. On the other hand, CLA has been studied mainly as a nutraceutical and sports supplement; the information in this study will help to expand the knowledge about the benefits of these isomers of linoleic acid, providing guidelines for its use as a protection against negative effects triggered by orchidectomy.

LncRNA LINP1 confers tamoxifen resistance and negatively regulated by ER signaling in breast cancer

Tamoxifen (TAM) is frequently used to treat patients with estrogen receptor-positive (ER+) breast cancer; however, the development of endocrine resistance represents a major impediment for successful treatment. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) may serve critical roles in regulating endocrine resistance in breast cancer. In the present study, it was determined that the expression of lncRNA in nonhomologous end joining pathway 1 (LINP1) was increased in tamoxifen-resistant breast cancer cells, and that LINP1 knockdown significantly attenuated the tamoxifen resistance and viability of tamoxifen-resistant breast cancer cells in vitro and in vivo. LINP1 knockdown increased apoptosis in cells following treatment with tamoxifen. Furthermore, LINP1 overexpression resulted in increased cell mobility by regulating the EMT process. Mechanistically, LINP1 is a direct target of ER-mediated transcriptional repression, and both tamoxifen treatment and hormone deprivation increased the expression of LINP1. LINP1 overexpression was associated with downregulation of the levels of ER protein and attenuated the estrogen response, which is a pivotal contributing factor to anti-estrogen resistance. Taken together, the present study highlights the pivotal role of LINP1 in tamoxifen resistance, which may serve as a potential target to improve the effectiveness and efficacy of tamoxifen treatment in breast cancer.

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators.

Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.

Loss of Lgals3 Protects Against Gonadectomy-Induced Cortical Bone Loss in Mice.

Sex hormone deprivation commonly occurs following menopause in women or after androgen-depletion during prostate cancer therapy in men, resulting in rapid bone turnover and loss of bone mass. There is a need to identify novel therapies to improve bone mass in these conditions. Previously, we identified age- and sex-dependent effects on bone mass in mice with deletion of the gene encoding the β-galactoside binding lectin, galectin-3 (Lgals3-KO). Due to the influence of sex on the phenotype, we tested the role of sex hormones, estrogen (β-estradiol; E2), and androgen (5α-dihydroxytestosterone; DHT) in Lgals3-KO mice. To address this, we subjected male and female wild-type and Lgals3-KO mice to gonadectomy ± E2 or DHT rescue and compared differential responses in bone mass and bone formation. Following gonadectomy, male and female Lgals3-KO mice had greater cortical bone expansion (increased total area; T.Ar) and reduced loss of bone area (B.Ar). While T.Ar and B.Ar were increased in response to DHT in wild-type mice, DHT did not alter these parameters in Lgals3-KO mice. E2 rescue more strongly increased B.Ar in Lgals3-KO compared to wild-type female mice due to a failure of E2 to repress the increase in T.Ar following gonadectomy. Lgals3-KO mice had more osteoblasts relative to bone surface when compared to wild-type animals in sham, gonadectomy, and E2 rescue groups. DHT suppressed this increase. This study revealed a mechanism for the sex-dependency of the Lgals3-KO aging bone phenotype and supports targeting galectin-3 to protect against bone loss associated with decreased sex hormone production.

Androgen Receptor Signaling in the Development of Castration-Resistant Prostate Cancer.

Most prostate cancers are androgen-sensitive malignancies whose growths depend on the transcriptional activity of the androgen receptor (AR). In the 1940s, Charles Huggins demonstrated that the surgical removal of testes in men can result in a dramatic improvement in symptoms and can induce prostate cancer regression. Since then, androgen deprivation therapies have been the standard first-line treatment for advanced prostate cancer, including: surgical castration, medical castration, antiandrogens, and androgen biosynthesis inhibitors. These therapies relieve symptoms, reduce tumor burden, and prolong patient survival, while having relatively modest side effects. Unfortunately, hormone deprivation therapy rarely cures the cancer itself. Prostate cancer almost always recurs, resulting in deadly castration-resistant prostate cancer. The underlying escape mechanisms include androgen receptor gene/enhancer amplification, androgen receptor mutations, androgen receptor variants, coactivator overexpression, intratumoral de novo androgen synthesis, etc. Whereas, the majority of the castration-resistant prostate cancers continuously rely on the androgen axis, a subset of recurrent cancers have completely lost androgen receptor expression, undergone divergent clonal evolution or de-differentiation, and become truly androgen receptor-independent small-cell prostate cancers. There is an urgent need for the development of novel targeted and immune therapies for this subtype of prostate cancer, when more deadly small-cell prostate cancers are induced by thorough androgen deprivation and androgen receptor ablation.

Effects of Mechanical Vibration in Neuromuscular Junctions and Fiber Type of the Soleus Muscle of Oophorectomized Wistar Rats.

Objective To evaluate the neuromuscular junctions (NMJs) and the type of muscle fibers of the soleus muscle of oophorectomized Wistar rats submitted to a mechanical vibration protocol. Methods A total of 36 randomized rats were used in the pseudo-oophorectomy without and with treatment and oophorectomy without and with treatment groups. The treatment was performed with a vibratory platform, frequency of 60 Hz and duration of 10 minutes, 3 times a week, for 4 weeks. At the end of the intervention period, the animals were euthanized and the soleus muscles were collected and processed for analysis of the NMJs and fiber type. The data were analyzed for normality by the Shapiro-Wilk test and analysis of the 3-way variance using the post-hoc Tukey test, when necessary, and a significance level of 5% was adopted. Results In the analysis of the NMJs, the oophorectomy group presented a smaller area than the pseudo-oophorectomy group, but the oophorectomy with treatment group was equal to the pseudo-oophorectomy with treatment group. For the larger diameter of the joints, the oophorectomy group was also different from the others; however, the oophorectomy and treatment animals were larger than those of the pseudo-oophorectomy and treatment group. There was no distinction of the types of fibers, with the muscle presenting fibers of the oxidative type. Conclusion Hormonal deprivation reduced the area and diameter of the NMJs, with reversion of this process in the groups that underwent vibratory platform treatment for 4 weeks, and both surgery and treatment did not influence the type of soleus muscle fiber, composed of oxidative fibers.

Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer.

Prostate cancer is the most commonly diagnosed cancer affecting men in the United States. The prostate is a hormone-dependent gland in which androgen hormones testosterone and dihydrotestosterone bind to and activate the androgen receptor, initiating nuclear translocation of androgen receptor and a subsequent signaling cascade. Due to the androgen dependency of the prostate, androgen deprivation therapies have emerged as first line treatment for aggressive prostate cancer. Such therapies are effective until the point at which prostate cancer, through a variety of mechanisms including but not limited to generation of ligand-independent androgen receptor splice variants, or intratumoral androgen production, overcome hormone deprivation. These cancers are androgen ablation resistant, clinically termed castration resistant prostate cancer (CRPC) and remain incurable. First-generation antiandrogens established androgen receptor blockade as a therapeutic strategy, but these therapies do not completely block androgen receptor activity. Efficacy and potency have been improved by the development of second-generation antiandrogen therapies, which remain the standard of care for patients with CRPC. Four second-generation anti-androgens are currently approved by the Food and Drug Administration (FDA); abiraterone acetate, enzalutamide, and recently approved apalutamide and darolutamide. This review is intended to provide a thorough overview of FDA approved second-generation antiandrogen discovery, treatment application, strategies for combination therapy to overcome resistance, and an insight for the potential future approaches for therapeutic inhibition of androgen receptor.

Addressing Vulvovaginal Atrophy (VVA)/Genitourinary Syndrome of Menopause (GSM) for Healthy Aging in Women.

Vaginal health is an essential component of active and healthy aging in women at midlife and beyond. As a consequence of hormonal deprivation and senescence, the anatomy and function of urogenital tissues are significantly affected and vulvovaginal atrophy (VVA) may occur. In a high proportion of postmenopausal women, progressive and chronic VVA symptoms have a strong impact on sexual function and quality of life. The new definition of genitourinary syndrome of menopause (GSM) comprises genital symptoms (dryness, burning, itching, irritation, bleeding), sexual symptoms (dyspareunia and other sexual dysfunctions) and urinary symptoms (dysuria, frequency, urgency, recurrent urinary infections). Many variables (age, sexual activity and partnership status) influence the clinical impact VVA/GSM symptoms and attitudes of elderly women to consult for receiving effective treatments. Psychosocial factors play a critical role in sexual functioning, but the integrity of the urogenital system is as well important affecting many domains of postmenopausal women's health, including sexual function. Several international surveys have extensively documented the need to improve VVA/GSM management because of the strong impact on women's daily life and on couple's intimacy. Health care providers (HCPs) need to be proactive in the early recognition of VVA/GSM in order to preserve urogenital and sexual longevity, by using hormonal and non-hormonal strategies. The clinical diagnosis is based on genital examination to identify objective signs and on the use of subjective scales to rate most bothersome symptoms (MBS), especially vaginal dryness. Recent studies point to the importance of addressing VVA/GSM as a potential early marker of poor general health in analogy with vasomotor symptoms. Therefore, a standard of VVA/GSM care in elderly women is desirable to enhance physical, emotional and mental well-being.

Abstract 266: Sex Differences in Anthracycline-Induced Cardiotoxicity in Young Mice

Introduction: The role of sex as a risk factor for Anthracycline-Induced Cardiotoxicity (AIC) is not well defined. In pediatric cancer patients, most studies report that female sex is a significant risk factor for AIC. Conversely, in adult preclinical rodent studies, there is clear evidence that female sex is protective against AIC, with a possible protective role of female sex hormones and/or a detrimental role of male sex hormones. However, sex differences in AIC have not been reported in young experimental animals. Therefore, the current work aims to characterize sex differences in AIC in young male and female mice. Methods: Five-week old male and female C57Bl/6 mice were injected with doxorubicin (DOX) 4 mg/kg/week IP for 3 to 6 weeks. After a 5-week recovery period, a cohort of control and DOX-treated mice were administered daily IP injections of isoproterenol (10 mg/kg) for 14 days to determine the effect of catecholamine stress on cardiac function and morphometry in DOX-exposed mice. Another cohort of gonadectomized and sham-operated male and female mice were injected with DOX 4 mg/kg/week for 5 weeks. Cardiac function and morphometry were measured by trans-thoracic echocardiography 5 weeks after the last DOX injection and after 14 days of isoproterenol injections. Results: In male mice only, DOX 4 mg/kg/week for 3 to 5 weeks caused cardiac atrophy without decline in cardiac function, whereas DOX administration for 6 weeks caused cardiac atrophy and dysfunction. Female mice were protected from both cardiac atrophy and dysfunction at the 3-6 weeks regimens. Isoproterenol caused cardiac dysfunction in male and female control and DOX-treated mice. Male, but not female, DOX-exposed mice failed to develop cardiac hypertrophy when challenged by isoproterenol. Intriguingly, castration of male mice exacerbated DOX-induced cardiac atrophy, while ovariectomy had no significant effect. Conclusion: In contrast to most clinical studies, young female mice are protected against DOX-induced cardiac atrophy and dysfunction. Juvenile exposure to DOX modulated the cardiac response to isoproterenol in a sex-dependent manner. Deprivation of sex hormones by gonadectomy did not reverse this sexual dimorphism, suggesting that other mechanisms are implicated.

Sex Hormones and Anticancer Immunity.

The impact of sex hormones on anticancer immunity deserves attention due to the importance of the immune system in cancer therapy and the recognition of sex differences in immunity. Cancer is ultimately the result of failed immune surveillance, and the diverging effects of male and female sex hormones on anticancer immunity could contribute to the higher cancer incidence and poorer outcome in men. Estrogens and androgens affect the number and function of immune cells, an effect that depends on cell type, tumor microenvironment, and the age and reproductive status of the individual. Despite the recent progress in immuno-oncology, our current understanding of the interplay between sex hormones and anticancer immune responses is in its infancy. In this review, we will focus on the impact of sex hormones on anticancer immunity and immunotherapy. We will discuss the potential role of the changing hormone levels in anticancer immunity during aging and in the context of menopausal hormone therapies and oral contraception. We will review emerging data on sex differences in PD-L1 expression and potential biomarkers predictive for the efficacy of immune checkpoint inhibitors such as the microbiome and consider ongoing clinical trials evaluating the potential impact of hormone deprivation therapies to increase response to immune checkpoint inhibitors in breast and prostate cancer. Finally, we will point to areas of future research.

Loss of Notch1 Activity Inhibits Prostate Cancer Growth and Metastasis and Sensitizes Prostate Cancer Cells to Antiandrogen Therapies.

Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading to resistance to identify new therapies for aggressive prostate cancer. This study identifies Notch1 as a therapeutic target in prostate cancer. Loss of NOTCH1 in aggressive prostate cancer cells decreases proliferation, invasion, and tumorsphere formation. Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Loss of NOTCH1 and treatment of immunocompromised mice bearing prostate cancer xenografts with RO4929097 display significantly impaired tumor growth. Loss of NOTCH1 additionally decreased metastatic potential of prostate cancer cells in invasion assays in vitro as well as in vivo experiments. Moreover, treatment with gamma secretase inhibitors or NOTCH1 gene deletion synergized with antiandrogen therapies, enzalutamide or abiraterone, to decrease the growth of prostate cancer cells. Combination of gamma secretase inhibitors with abiraterone significantly inhibited cell migration and invasion, while combination with enzalutamide reversed enzalutamide-induced migration and invasion. These collective findings suggest loss of NOTCH1 delays growth of CRPC and inhibits metastasis, and inhibition of Notch1 activation in conjunction with second-generation antiandrogen therapies could delay growth and progression of prostate cancer.

Laser Therapy in the Treatment of Female Urinary Incontinence and Genitourinary Syndrome of Menopause: An Update.

Vaginal birth trauma is the leading cause of stress urinary incontinence (SUI) in women. Also, the process of ageing and hormonal deprivation in postmenopause alters the metabolism of connective tissues and decreases collagen production leading to pelvic floor dysfunction. Noninvasive treatment is recommended as first-line management of urinary incontinence (UI) in women. Surgical procedures are more likely to be implemented to cure UI but are associated with more adverse events. Sex hormone deficiency affects changes also in the lower urinary tract where estrogens are the main regulators of physiological functions of the vagina. In the last decade, laser treatment of SUI and of the genitourinary syndrome of menopause (GSM) has been shown a promising treatment method in peer-reviewed literature. This review's aim is to present the evidence-based medical data and laser treatment of SUI and GSM in an outpatient setting to be a good treatment option, regarding short-term as well as long-term follow-ups. Long-term follow-up studies are needed to confirm that laser treatment is a good, painless outpatient procedure with no side effects in postmenopausal women.

Early Ovarian Hormone Deprivation Increases Cardiac Contractility In Old Female Rats - Role Of Physical Training

Physiological menopause occurs around 51 years of age. However, in some cases, menopause can happen early, that is, before the age of 40. Of the main consequences of early ovarian hormones deprivation or early menopause, one of the most alarming is the increased risk of cardiovascular diseases, contributing to an increase in the morbidity and mortality rate in these women. Our hypothesis is that early deprivation of ovarian hormones, when associated with the aging process, promotes more adverse cardiac remodeling and greater damage to cardiac function related to physiological ovarian failure. Thus, aerobic physical training is fundamental to attenuate these deleterious effects. PURPOSE: The objective of the present study was to investigate the effects of early deprivation of ovarian hormones on cardiac morphological and functional parameters in 82 week-old female rats subjected to ovariectomy at 10 weeks of age, as well as to evaluate the application of aerobic training as a non-pharmacological therapeutic tool. METHODS: Female Wistar rats (N = 48) were divided into two groups, at 10 weeks of life: early ovarian hormones deprivation by ovariectomy (OVX; N=24) and sham (SHAM; N=24).Between weeks 62 and 82, 12 animals of each group underwent aerobic training (OVX-T and SHAM-T, N=12). At the end of week 82, all were evaluated by echocardiography, cardiac function (Langendorff technique) and cardiac β-adrenergic receptor expression quantification. RESULTS: Echocardiography showed slight changes in morphology between OVX and SHAM. OVX (Δ= 101 ± 4.7 mmHg) showed higher values for maximal left intraventricular pressure in response to dobutamine, when compared to SHAM (Δ= 55 ± 11.8 mmHg).Both OVX-T (Δ= 70 ± 4.0 mmHg) and SHAM-T (Δ= 22 ± 6.6 mmHg) showed a reduction in this response. While, β-adrenergic receptor expression was not different between the sedentary groups, SHAM-T (0.23 ± 0.02AU) and OVX-T (0.29 ± 0.01AU) showed decreased expression of these receptors when compared to their respectively sedentary groups. CONCLUSIONS: Early ovarian hormones deprivation associated with aging, promotes discrete changes in cardiac morphology, increasing cardiac contractility. Aerobic training decreases β-adrenergic receptors expression, influencing the cardiac contractility. Supported by FAPESP Grant 01937-9

Humanin, a Mitochondrial-Derived Peptide Released by Astrocytes, Prevents Synapse Loss in Hippocampal Neurons.

Astroglial cells are crucial for central nervous system (CNS) homeostasis. They undergo complex morpho-functional changes during aging and in response to hormonal milieu. Ovarian hormones positively affect different astroglia parameters, including regulation of cell morphology and release of neurotrophic and neuroprotective factors. Thus, ovarian hormone loss during menopause has profound impact in astroglial pathophysilogy and has been widely associated to the process of brain aging. Humanin (HN) is a secreted mitochondrial-encoded peptide with neuroprotective effects. It is localized in several tissues with high metabolic rate and its expression decreases with age. In the brain, humanin has been found in glial cells in physiological conditions. We previously reported that surgical menopause induces hippocampal mitochondrial dysfunction that mimics an aging phenotype. However, the effect of ovarian hormone deprivation on humanin expression in this area has not been studied. Also, whether astrocytes express and release humanin and the regulation of such processes by ovarian hormones remain elusive. Although humanin has also proven to be beneficial in ameliorating cognitive impairment induced by different insults, its putative actions on structural synaptic plasticity have not been fully addressed. In a model of surgical menopause in rats, we studied hippocampal humanin expression and localization by real-time quantitative polymerase chain reaction (RT-qPCR) and double immunohistochemistry, respectively. Humanin production and release and ovarian hormone regulation of such processes were studied in cultured astrocytes by flow cytometry and ELISA, respectively. Humanin effects on glutamate-induced structural synaptic alterations were determined in primary cultures of hippocampal neurons by immunocytochemistry. Humanin expression was lower in the hippocampus of ovariectomized rats and its immunoreactivity colocalized with astroglial markers. Chronic ovariectomy also promoted the presence of less complex astrocytes in this area. Ovarian hormones increased humanin intracellular content and release by cultured astrocytes. Humanin prevented glutamate-induced dendritic atrophy and reduction in puncta number and total puncta area for pre-synaptic marker synaptophysin in cultured hippocampal neurons. In conclusion, astroglial functional and morphological alterations induced by chronic ovariectomy resemble an aging phenotype and could affect astroglial support to neuronal function by altering synaptic connectivity and functionality. Reduced astroglial-derived humanin may represent an underlying mechanism for synaptic dysfunction and cognitive decline after menopause.

Impact of germline DNA-repair gene BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-naïve prostate cancer: A single center analysis.

5056 Background: Germline mutations in DNA repair genes are common in patients with andvanced and metastatic prostate cancer (mPCa). Although BRCA mutation carriers have worse outcomes than noncarriers when conventionally treated for local or locally advanced PCa, recent studies reported conflicting results regarding their aggressiveness in patients with advanced disease. This study aimed to examine the impact of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with mPCa, receiving hormonal androgen deprivation therapy (ADT). Methods: A total of 76 patients with hormone-naive mPCa treated with first line ADT by luteinizing hormone-releasing hormone analogue (LHRHa) between 2014 and 2017 were recruited. Median follow-up was 34,8 mo. We focused on age, volume of metastatic spread, histologic grade, family history. All patients were genotyped for germline mutations in the BRCA1, BRCA2 and CHEK2 genes by polymerase chain reaction real-time and the Sanger sequencing. We used the standard definition of castration-resistance PCa (CRPC). Median time to CRPC were estimated using the Kaplan-Meier method, generated curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA1/2 and CHEK2 mutations. Results: Pathogenic and likely pathogenic germline mutations in the BRCA2 and CHEK2 gene were identified in 19 (25 %) patients. No cases of BRCA1 mutations were detected. Median time to CRPC was significantly shorter in BRCA2 and CHEK2 mutation carriers (7.9 mo, 95 % confidence interval (CI) 2.6 – 13.3), than in non-carriers (48.7 mo, 95 % CI 31.1 – 68.3, p < 0,001). There was no significant difference in median time to CRPC in BRCA2 (7.9 mo, 95 % CI 0.0 - 16.3) and CHEK2 mutation carriers (6.1 mo, 95 CI 5.0 - 7.2, p = 0,448) meanwhile both were shorter than in non-carriers (p = 0.002 and < 0,001). Multivariate analysis confirmed both BRCA2 (hazard ratio [HR]: 2.63; 95 CI 1.32-5.26, p = 0.006) and CHEK2 (HR 6.66, 95 CI 2.35-18.89, p < 0.001) mutations as an independent prognostic factor for time to CRPC, particularly in mPCa with low-volume metastatis spread (HR 3.09, 95 % CI 1.36–7.05, р = 0.007 and HR 14.1, 95 % CI 3.65-54.4, p < 0.001). Conclusions: BRCA2 and CHEK2 carriers had worse outcomes (shortened time to CRPC) than noncarriers when conventionally treated for metastatic PCa by standard first-line hormone treatment with LHRHa.