Treatment of Urogenital Symptoms in Individuals With a History of Estrogen-dependent Breast Cancer: Clinical Consensus.

SUMMARY: With an estimated 3.8 million breast cancer survivors in the United States, obstetrician-gynecologists often are on the front lines of addressing survivorship issues, including the hypoestrogenic-related adverse effects of cancer therapies or early menopause in survivors (1). Although systemic and vaginal estrogen are used widely for symptomatic relief of genitourinary syndrome of menopause in the general population, among individuals with a history of hormone-sensitive cancer, there is uncertainty about the safety of hormone-based therapy, leading many individuals with bothersome symptoms to remain untreated, with potential negative consequences on quality of life (2). An effective management strategy requires familiarity with a range of both hormonal and nonhormonal treatment options, knowledge about the pharmaceutical mechanisms of action, and the ability to tailor treatment based on individual risk factors. This clinical consensus document was developed using an a priori protocol in conjunction with two authors specializing in urogynecology and gynecologic oncology. This document has been updated to review the safety and efficacy of newer hormonal treatment options as well as nonhormonal modalities.

Interstrain Variability of Human Vaginal Lactobacillus crispatus for Metabolism of Biogenic Amines and Antimicrobial Activity against Urogenital Pathogens.

Lactobacillus crispatus is the dominant species in the vagina of many women. With the potential for strains of this species to be used as a probiotic to help prevent and treat dysbiosis, we investigated isolates from vaginal swabs with Lactobacillus-dominated and a dysbiotic microbiota. A comparative genome analysis led to the identification of metabolic pathways for synthesis and degradation of three major biogenic amines in most strains. However, targeted metabolomic analysis of the production and degradation of biogenic amines showed that certain strains have either the ability to produce or to degrade these compounds. Notably, six strains produced cadaverine, one produced putrescine, and two produced tyramine. These biogenic amines are known to raise vaginal pH, cause malodour, and make the environment more favourable to vaginal pathogens. In vitro experiments confirmed that strains isolated from women with a dysbiotic vaginal microbiota have higher antimicrobial effects against the common urogenital pathogens Escherichia coli and Enterococcus faecium. The results indicate that not all L. crispatus vaginal strains appear suitable for probiotic application and the basis for selection should not be only the overall composition of the vaginal microbiota of the host from which they came, but specific biochemical and genetic traits.

Association between postmenopausal vulvovaginal discomfort, vaginal microbiota, and mucosal inflammation.

BACKGROUND: Half of all postmenopausal women report symptoms of vulvar, vaginal, or urinary discomfort with substantial impact on sexual function and quality of life; underlying mechanisms leading to symptoms are poorly understood. OBJECTIVE: To examine the possibility that the vaginal microbiota and/or mucosal immune response contributes to the severity of bothersome vaginal symptoms, we conducted a substudy of samples from a randomized trial of vaginal treatment for genitourinary syndrome of menopause to compare these features between women whose symptoms improved and women whose symptoms did not improve. STUDY DESIGN: This is a secondary analysis of samples collected in a 12-week randomized trial of treatment with vaginal estradiol or moisturizer vs placebo for moderate-severe postmenopausal symptoms of vaginal discomfort. We randomly selected 20 women in each arm with ≥2-point decrease in most bothersome symptom severity (responders) and 20 matched controls with ≤1-point decrease (nonresponders). At 0, 4, and 12 weeks, we characterized vaginal microbiota (16S ribosomal RNA gene sequencing), vaginal fluid metabolites (broad-based metabolomic profiling), vaginal fluid-soluble immune markers (Meso Scale Discovery), pH, and vaginal maturation index. We compared responders with nonresponders at baseline and across all visits using linear mixed models to evaluate associations with microbiota, metabolites, and immune markers, incorporating visit and participant-specific random effects while controlling for treatment arm. RESULTS: Here, the mean age of women was 61 years (n=120), and most women (92%) were White. At enrollment, no significant differences were observed between responders and nonresponders in age, most bothersome symptom type or severity, microbiota composition or diversity, Lactobacillus dominance, metabolome, or immune markers. There was a significant decrease in diversity of the vaginal microbiota in both responders and nonresponders (P<.001) over 12 weeks. Although this change did not differ by responder status, diversity was associated with treatment arm: more women in the estradiol arm (63%) had Lactobacillus-dominant, lower diversity bacterial communities than women in the moisturizer (35%) or dual placebo (23%) arms (P=.001) at 12 weeks. The metabolome, vaginal maturation index, and measured immune markers were not associated with responder status over the 12 weeks but varied by treatment arm. CONCLUSION: Postmenopausal vaginal symptom severity was not significantly associated with vaginal microbiota or mucosal inflammatory markers in this small study. Women receiving vaginal estradiol experienced greater abundance of lactobacilli and lower vaginal pH at end of treatment.

An overview of dehydroepiandrosterone (EM-760) as a treatment option for genitourinary syndrome of menopause.

Introduction: Dyspareunia caused by vulvovaginal atrophy is a primary symptom of genitourinary syndrome of menopause (GSM), a chronic, progressive medical condition that results from estrogen and androgen deficiency at menopause. Dehydroepiandrosterone (DHEA, prasterone) is an endogenous precursor steroid hormone that is metabolized into both androgens and estrogens that has been recently been approved by the FDA for the treatment of moderate to severe dyspareunia caused by vulvovaginal atrophy secondary to menopause.Areas covered: This is a comprehensive drug evaluation describing the chemical composition, pharmacokinetics, metabolism, clinical efficacy and safety of dehydroepiandrosterone (prasterone) in the treatment of dyspareunia and VVA secondary to menopause. Preclinical and clinical data suggesting further potential uses, benefits, and contraindications in the genitourinary health of postmenopausal women are also considered.Expert opinion: Intravaginal dehydroepiandrosterone (prasterone) is effective for the management of dyspareunia secondary to menopause and may be effective in the treatment of other types of sexual dysfunction that are secondary to menopause. Further studies should explore additional dosing regimens and different indications.

Oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis.

The body of evidence from the past three decades demonstrates that oxidative stress can be involved in several diseases. This study aims to summarise the current state of knowledge on the association between oxidative stress and the pathogenesis of some characteristic to the biological systems diseases and aging process. This review also presents the effect of physical activity on redox homeostasis. There is strong evidence from studies for participation of reactive oxygen and nitrogen species in pathogenesis of acute and chronic diseases based on animal models and human studies. Elevated levels of pro-oxidants and various markers of the oxidative stress and cells and tissues damage linked with pathogenesis of cancer, atherosclerosis, neurodegenerative diseases hypertension, diabetes mellitus, cardiovascular disease, atherosclerosis, reproductive system diseases, and aging were reported. Evidence confirmed that inflammation contributes widely to multiple chronic diseases and is closely linked with oxidative stress. Regular moderate physical activity regulates oxidative stress enhancing cellular antioxidant defence mechanisms, whereas acute exercise not preceded by training can alter cellular redox homeostasis towards higher level of oxidative stress. Future studies are needed to clarify the multifaceted effects of reactive oxygen/nitrogen species on cells and tissues and to continue study on the biochemical roles of antioxidants and physical activity in prevention of oxidative stress-related tissue injury.

Genitourinary Changes with Aging.

Both chronologic aging and menopause affect the physical, physiologic, and microbiological characteristics of the genitourinary tract. The genitourinary syndrome of menopause, characterized by vulvovaginal and lower urinary tract signs and symptoms, is prevalent and has a significant negative impact on women's lives. In this article, the authors detail the genitourinary tract changes associated with menopause and/or aging. They also review the 2014 North American Menopause Society's definition of the genitourinary syndrome of menopause and present the epidemiology and impact of genitourinary aging in midlife and older women, namely, vulvovaginal, urinary, and sexual symptoms.

Therapeutic Roles of Statins in Gynecology and Obstetrics: The Current Evidence.

INTRODUCTION: Statins are a class of drugs, which act by inhibiting the rate-limiting enzyme of cholesterol biosynthesis (3-hydroxy-3-methyl-glutaryl-CoA reductase). The inhibition of mevalonate synthesis leads to subsequent inhibition of downstream products of this pathway, which explains the pleiotropic effects of these agents in addition to their well-known lipid-lowering effects. Accumulating evidence suggests that statins might be beneficial in various obstetric and gynecologic conditions. METHODS: Literature searches were performed in PubMed and EMBASE for articles with content related to statins in obstetrics and gynecology. The findings are hereby reviewed and discussed. RESULTS: Inhibition of mevalonate pathway leads to subsequent inhibition of downstream products such as geranyl pyrophosphate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. These products are required for proper intracellular localization of several proteins, which play important roles in signaling pathways by regulating membrane trafficking, motility, proliferation, differentiation, and cytoskeletal organization. The pleiotropic effects of statins can be summarized in 4 categories: antiproliferative, anti-invasive, anti-inflammatory, and antiangiogenic. The growing body of evidence is promising for these agents to be beneficial in endometriosis, polycystic ovary syndrome, adhesion prevention, ovarian cancer, preeclampsia, and antiphospholipid syndrome. Although in vivo studies showed varying degrees of benefit on fibroids and preterm birth, appropriately designed clinical trials are needed to make definitive conclusions. CONCLUSION: Statins might play a role in the treatment of endometriosis, polycystic ovary syndrome, adhesion prevention, ovarian cancer, preeclampsia, and antiphospholipid syndrome.

[THE CHARACTER OF EXPRESSION AND THE ROLE OF APOPTOSIS MARKERS IN THE DEVELOPMENT OF PLACENTAL DYSFUNCTION IN PREGNANT WITH UROGENITAL INFECTIONS].

The aim of the current study was to examine the expression level and possibilities of apoptotic markers in realization of placental insufficiency in pregnant women with urogenital infections. The study was conducted on 250 pregnant women with urogenital infections (1-st group - 50 pregnant women with bacterial infections (Chlamydia, ureaplasma, mycoplasma), 2-nd group - 50 pregnant women with viral infections (CMV and herpes simplex virus), 3-rd group - 150 patients with mixed viral and bacterial infections) and 50 pregnant women with normal pregnancy. The content of apoptosis inducers: sFasL and TNF-α in blood serum of pregnant women was determined; the level of caspase-3 in placental sample was analyzed; sonographic examination of the placenta was performed. Maximal indices of apoptosis inducers were observed in the 3-rd group (with mixed viral and bacterial infections). Changes in the placenta according to ultrasound data were determined in all pregnant women with urogenital infections. It was suggested that increased placental cell death in apoptosis might be one of the key points, triggering the development of placental dysfunction.

Effect of cytokine level variations in individuals on the progression and outcome of bacterial urogenital infections--a meta-analysis.

Bacterial urogenital infections such as chlamydia, gonorrhoea and syphilis are widespread inflammatory diseases, which may be accompanied by severe complications. These complications can range from basic inflammation to tubal pathology, infertility and neurological dysfunction, though infections go unnoticed in the majority of cases. Cytokines in the host play a vital role in both the initial and long-term immune response and inflammation. However, levels of cytokine expression vary between individuals. A meta-analysis was performed to evaluate the effect of cytokine expression differences on severity of infections with these pathogens. Studies comparing expression of cytokines in humans with inflammation or inflammation-based complications were identified using NCBI, Google Scholar and Cochrane databases. Only studies into human cytokine expressions were included, and three articles per subject were required to be suitably analysed during meta-analysis. A total of 52 articles were included for meta-analysis. It was shown that differences in IL-1, IL-6, IL-8, IL-10, TNFα and IFNγ affect the clinical outcome of Chlamydia trachomatis infection significantly. Similarly, IL-1 and IL-8 expression during Neisseria gonorrhoeae infection significantly affects the outcome of the disease. For Treponema pallidum infection, it was shown that IFNγ variation in hosts could be linked to severity of disease. However, a lack of studies to use in the meta-analysis and fluctuation in the resulting data depending on the adjustments makes adequate evaluation difficult.

Adecuación de la solicitud de urocultivos e impacto de sus resultados en el tratamiento de la infección urinaria en Atención Primaria / Adequacy of requesting urine cultures and their impact on urinary tract infection treatment in primary care

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Molecular imaging of urogenital diseases.

There is an expanding and exciting repertoire of PET imaging radiotracers for urogenital diseases, particularly in prostate cancer, renal cell cancer, and renal function. Prostate cancer is the most commonly diagnosed cancer in men. With growing therapeutic options for the treatment of metastatic and advanced prostate cancer, improved functional imaging of prostate cancer beyond the limitations of conventional CT and bone scan is becoming increasingly important for both clinical management and drug development. PET radiotracers, apart from ¹8F-FDG, for prostate cancer are ¹8F-sodium fluoride, ¹¹C-choline, and ¹8F-fluorocholine, and (¹¹C-acetate. Other emerging and promising PET radiotracers include a synthetic l-leucine amino acid analogue (anti-¹8F-fluorocyclobutane-1-carboxylic acid), dihydrotestosterone analogue (¹8F-fluoro-5α-dihydrotestosterone), and prostate-specific membrane antigen-based PET radiotracers (eg, N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-¹8F-fluorobenzyl-l-cysteine, 89Zr-DFO-J591, and 68Ga [HBED-CC]). Larger prospective and comparison trials of these PET radiotracers are needed to establish the role of PET/CT in prostate cancer. Although renal cell cancer imaging with FDG-PET/CT is available, it can be limited, especially for detection of the primary tumor. Improved renal cell cancer detection with carbonic anhydrase IX (CAIX)-based antibody (¹²4I-girentuximab) and radioimmunotherapy targeting with ¹77Lu-cG250 appear promising. Evaluation of renal injury by imaging renal perfusion and function with novel PET radiotracers include p-¹8F-fluorohippurate, hippurate m-cyano-p-¹8F-fluorohippurate, and rubidium-82 chloride (typically used for myocardial perfusion imaging). Renal receptor imaging of the renal renin-angiotensin system with a variety of selective PET radioligands is also becoming available for clinical translation.

Fluorescent molecular imaging: technical progress and current preclinical and clinical applications in urogynecologic diseases.

Many molecular imaging probes have been developed in recent years that hold great promise for both diagnostic and therapeutic functions in urogynecologic disease. Historically, optical probe designs were based on either endogenous or exogenous fluorophores. More recently, organic fluorophore probes have been engineered to target specific tissues and emit fluorescence only upon binding to targets. Several different photochemical mechanisms of activation exist. This review presents a discussion of the history and development of molecular imaging probe designs and provides an overview of successful preclinical and clinical models employing molecular probes for in vivo imaging of urogynecologic cancers.

Germinated brown rice and its bioactives modulate the activity of uterine cells in oophorectomised rats as evidenced by gross cytohistological and immunohistochemical changes.

BACKGROUND: Germinated brown rice (GBR) is gaining momentum in the area of biomedical research due to its increased use as a nutraceutical for the management of diseases. The effect of GBR on the reproductive organs of oophorectomised rats was studied using the gross, cytological, histological and immunohistochemical changes, with the aim of reducing atrophy and dryness of the genital organs in menopause. METHODS: Experimental rats were divided into eight groups of six rats per group. Groups 1, 2 and 3 (sham-operated (SH), oophorectomised without treatment (OVX) and oophorectomised treated with 0.2 mg/kg oestrogen, respectively) served as the controls. The groups 4,5,6,7 and 8 were treated with 20 mg/kg Remifemin, 200 mg/kg of GBR, ASG, oryzanol and GABA, respectively. All treatments were administered orally, once daily for 8 weeks. Vaginal smear cytology was done at the 7th week on all the rats. The weight and dimensions of the uterus and vagina were determined after sacrifice of the rats. Uterine and vaginal tissues were taken for histology and Immunohistochemical examinations. RESULTS: GBR and its bioactives treated groups significantly increased the weight and length of both the uterus and the vagina when compared to Oophorectomised non-treated group (OVX-non-treated) (p < 0.05). Significant changes were observed in the ratio of cornified epithelial cells and number of leucocytes in the vaginal cytology between the oophorectomised non-treated and treated groups. There was also an increase in the luminal and glandular epithelial cells activity in the treated compared with the untreated groups histologically. Immunohistochemical staining showed specific proliferating cell nuclear antigen (PCNA) in the luminal and glandular epithelium of the treated groups, which was absent in the OVX-non-treated group. GBR improved the length and weight of the uterus and also increased the number of glandular and luminal cells epithelia of the vagina. CONCLUSION: GBR and its bioactives could be a potential alternative in improving reproductive system atrophy, dryness and discomfort during menopause.

Estrogens and the lower urinary tract.

The urogenital tract is sensitive to the effect of oestrogen and progesterone throughout adult life. Epidemiological studies have implicated oestrogen deficiency in the aetiology of lower urinary tract symptoms occurring following the menopause. Although to date the role of oestrogen replacement therapy in the management of postmenopausal urinary incontinence remains controversial its use in the management of women complaining of urogenital atrophy is now well established. This aim of this paper is to review the recent evidence regarding the urogenital effects of hormone therapy with a particular emphasis on the management of postmenopausal urinary incontinence, overactive bladder, recurrent lower urinary tract infections and urogenital atrophy. In addition to a review of the available evidence suggestions are also made regarding priorities for further research in the field.

Ghrelin and reproductive disorders.

Ghrelin is an important factor involved in most of the metabolic and hormonal signals which adapt the reproductive functions in conditions of altered energy balance. Moreover, the coordinated role of leptin and ghrelin appears in fact to have a specific role in the regulation of puberty. Systemic action of ghrelin on the reproductive axis involves the control of the hypothalamic-pituitary-gondal axis. In addition, it has been shown that ghrelin may directly act at a gonadal level in both females and males. Available data also demonstrate that sex steroid hormones and gonadotropins may in turn regulate the gonadal effect of ghrelin, as documented by studies performed in females with the polycystic ovary syndrome and in hypogonadal men. Notably, recent studies also confirm a potentially important role for ghrelin in fetal and neonatal energy balance, and specifically in allowing fetal adaptation to an adverse intrauterine environment.

Vaginal estriol to overcome side-effects of aromatase inhibitors in breast cancer patients.

OBJECTIVE: Aromatase inhibitors are essential as endocrine treatment for hormone receptor-positive postmenopausal breast cancer patients. Menopausal symptoms are often aggravated during endocrine treatment. We investigated whether vaginal estriol is a safe therapeutic option to overcome the urogenital side-effects of aromatase inhibitors. Serum hormone levels were used as the surrogate parameter for safety. METHODS: Fasting serum hormone levels of ten postmenopausal breast cancer patients receiving aromatase inhibitors were prospectively measured by electro-chemiluminescence immunoassays and gas chromatography/mass spectrometry before and 2 weeks after daily application of 0.5 mg vaginal estriol (Ovestin® ovula), respectively. RESULTS: Two weeks of daily vaginal estriol treatment did not change serum estradiol or estriol levels. However, significant decreases in levels of serum follicle stimulating hormone (p = 0.01) and luteinizing hormone (p = 0.02) were observed. Five out of six breast cancer patients noticed an improvement in vaginal dryness and/or dyspareunia. CONCLUSIONS: The significant decline in gonadotropin levels, indicating systemic effects, has to be kept in mind when offering vaginal estriol to breast cancer patients receiving an aromatase inhibitor.

[State of antioxidant defense and L-arginin-nitrogen oxide system in blood of patients with urogenital chlamydiosis].

The system L-arginine-nitrogen oxide plays a significant role in maintenance of the anti-infectious protection of an organism. A condition of the given system and activity of a enzymatic part of antiradical protection in the blood of patients with chlamydiosis has been studied. Obtained data specify an intensification of processes of an oxidizing way of recycling of arginine in an organism of patients. Substantial increase of NO-synthase activity and insignificant activity of arginase in the blood is revealed. The level of nitrite-anion in blood cells of patients authentically increases: 1.7 times in erythrocytes, and 1.4 times in lymphocytes. It is shown, that in patients with chlamydiosis glutathione system is intensified, that is evidenced by an increase glutathione-peroxidase activity and authentic increase of glutathione level. It is assummed that the established features of nitrogen oxide exchange play a significant role in formation of a pathological condition at urogenital chlamydia infections.

[Role of Toll-like receptors and defensins in antimicrobial protection of urogenital tract in females].

Levels of expression of hBD-1 gene (beta-defensin 1) and Toll-like receptors (TLR1, TLR2, TLR6) in cells of cervical mucosa in healthy nonpregnant and healthy pregnant women as well as in pregnant women with urogenital infection was measured by developed RT-PCR systems. During normal pregnancy compared with nonpregnant women, increase of TLRs genes expression which was correlated with increase of hBD-1 gene expression was observed. During urogenital infection in pregnant women compared with healthy pregnant, 10- fold and 50-fold increase of TLR1 and TLR2 genes expression respectively was associated with 2.5-fold decrease of hBD-1 gene expression in cervical mucosa. In group of women with untrauterine infection more marked increase of TLRs genes expression was observed. Thus significant changes (TLRs, antimicrobial peptides, cytokines etc.) in cells of cervical mucosa can be used as prognostic criteria for development of intrauterine infection.

Getting rid of caveolins: phenotypes of caveolin-deficient animals.

The elucidation of the role of caveolae has been the topic of many investigations which were greatly enhanced after the discovery of caveolin, the protein marker of these flask-shaped plasma membrane invaginations. The generation of mice deficient in the various caveolin genes (cav-1, cav-2 and cav-3) has provided physiological models to unravel the role of caveolins or caveolae at the whole organism level. Remarkably, despite the essential role of caveolins in caveolae biogenesis, all knockout mice are viable and fertile. However, lack of caveolae or caveolins leads to a wide range of phenotypes including muscle, pulmonary or lipid disorders, suggesting their implication in many cellular processes. The aim of this review is to give a broad overview of the phenotypes described for the caveolin-deficient mice and to link them to the numerous functions so far assigned to caveolins/caveolae.