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Higher mammographic breast density in premenopausal and postmenopausal women is related to a higher breast cancer risk. In this review, we analyze the correlation between estrogen, progesterone, and mammographic density in postmenopausal women and clarify whether these findings are consistent across different types of mammographic breast density. We extracted data concerning mammographic density increases in the populations treated with estrogen-only hormone replacement therapy and those treated with estrogen and progestin hormone replacement therapy. Postmenopausal women treated with estrogen and progesterone regimens had a statistically significant lesser mammographic density increase than estrogen-only hormone replacement therapy regimens.

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Fibromyalgia syndrome (FMS) is a chronic pain syndrome, characterised by diffuse pain in musculoskeletal system and accompanied by stiffness, fatigue, tender points, sleep disturbances and cognitive and gastrointestinal symptoms. It affects middle-aged women (between 40 and 65) predominantly. Climacteric syndrome, which is characterised by vasomotor, somatic (headache, sleep disorders, myalgia and arthralgia) and psychical (mood changes) symptoms, results from the change in brain neurotransmitter concentrations due to gradual decline of ovarian hormone levels. Currently, studies focus on the similarities of FMS and climacteric syndrome in terms of age of occurrence, epidemiology, etiopathogenesis, symptomatology and treatment. Hormonal fluctuation during menopausal transition is likely the triggering factor for both syndromes. Therefore, hormone replacement therapy is a favourable approach in the treatment of FMS due to the antiallodynic, anti-inflammatory and neuroprotective effect of oestrogen. In this review, we emphasise the similarity of FMS and climacteric syndrome and suggested that FMS could be considered as a characteristic symptom of climacterium.

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INTRODUCTION: There is increasing evidence that vitamin D has widespread tissue effects. In addition to osteoporosis, vitamin D deficiency has been associated with cardiovascular disease, diabetes, cancer, infections and neurodegenerative disease. However, the effect of vitamin D supplementation on non-skeletal outcomes requires clarification, especially in postmenopausal women. AIM: This position statement provides an evidence-based overview of the role of vitamin D in the health of postmenopausal women based on observational and interventional studies. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Vitamin D status is determined by measuring serum 25-hydroxyvitamin D levels. Concentrations <20 ng/ml (<50 nmol/l) and <10 ng/ml (<25 nmol/l) are considered to constitute vitamin D deficiency and severe deficiency, respectively. Observational data suggest an association between vitamin D deficiency and adverse health outcomes in postmenopausal women, although they cannot establish causality. The evidence from randomized controlled trials concerning vitamin D supplementation is not robust, since many studies did not consider whether people were deficient at baseline. Moreover, high heterogeneity exists in terms of the population studied, vitamin D dosage, calcium co-administration and duration of intervention. Concerning skeletal health, vitamin D deficiency is associated with low bone mass and an increased risk of fractures. Vitamin D supplementation at maintenance doses of 800-2000 IU/day (20-50 µg/day), after repletion of vitamin D status with higher weekly or daily doses, may be of benefit only when co-administered with calcium (1000-1200 mg/day), especially in the elderly populations and those with severe vitamin D deficiency. Concerning cardiovascular disease, vitamin D deficiency is associated with an increased prevalence of cardiovascular risk factors, mainly metabolic syndrome, type 2 diabetes mellitus and dyslipidemia. Vitamin D deficiency, especially its severe form, is associated with an increased risk of cardiovascular events (coronary heart disease, stroke, mortality), independently of traditional risk factors. Vitamin D supplementation may have a modestly beneficial effect on lipid profile and glucose homeostasis, especially in obese individuals or those ≥60 years old and at doses of ≥2000 IU/day (≥50 µg/day). However, it has no effect on the incidence of cardiovascular events. Concerning cancer, vitamin D deficiency is associated with increased incidence of and mortality from several types of cancer, such as colorectal, lung and breast cancer. However, the data on other types of gynecological cancer are inconsistent. Vitamin D supplementation has no effect on cancer incidence, although a modest reduction in cancer-related mortality has been observed. Concerning infections, vitamin D deficiency has been associated with acute respiratory tract infections, including coronavirus disease 2019 (COVID-19). Vitamin D supplementation may decrease the risk of acute respiratory tract infections and the severity of COVID-19 (not the risk of infection). Concerning menopausal symptomatology, vitamin D deficiency may have a negative impact on some aspects, such as sleep disturbances, depression, sexual function and joint pains. However, vitamin D supplementation has no effect on these, except for vulvovaginal atrophy, at relatively high doses, i.e., 40,000-60,000 IU/week (1000-1500 IU/week) orally or 1000 IU/day (25 µg/day) as a vaginal suppository.

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This care pathway from the European Menopause and Andropause Society (EMAS) provides an updated pathway for monitoring and guidance of women at midlife, focusing on those approaching the end of the reproductive life-cycle, going through the menopausal transition and beyond. The care pathway is written by professionals involved in women's health and provides a stepwise individualized approach, stratified according to needs, symptoms and reproductive stage. Furthermore, the pathway provides details on screening for chronic diseases related to menopause and ageing. Treatment options for climacteric symptoms range from menopausal hormone therapy to non-hormonal alternatives and lifestyle modifications. Therapy should be tailored to personal needs and wishes. The pathway aims to offer a holistic, balanced approach for monitoring middle-aged women, aiming to control health problems effectively and ensure healthy ageing.

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INTRODUCTION: The menopause, or the cessation of menstruation, is a stage of the life cycle which will occur in all women. Managing perimenopausal and postmenopausal health is a key issue for all areas of healthcare, not just gynecology. AIM: To provide recommendations for the curriculum of education programs for healthcare professionals worldwide, so that all can receive high quality training on menopause. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Training programs for healthcare professionals worldwide should include menopause and postmenopausal health in their curriculum. It should include assessment, diagnosis and evidence-based management strategies.

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INTRODUCTION: Worldwide, there are 657 million women aged 45-59 and around half contribute to the labor force during their menopausal years. There is a diversity of experience of menopause in the workplace. It is shaped not only by menopausal symptoms and context but also by the workplace environment. It affects quality of life, engagement, performance, motivation and relations with employers. AIM: To provide recommendations for employers, managers, healthcare professionals and women to make the workplace environment more menopause supportive, and to improve women's wellbeing and their ability to remain in work. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Workplace health and wellbeing frameworks and policies should incorporate menopausal health as part of the wider context of gender and age equality and reproductive and post-reproductive health. Workplaces should create an open, inclusive and supportive culture regarding menopause, involving, if available, occupational health professionals and human resource managers working together. Women should not be discriminated against, marginalized or dismissed because of menopausal symptoms. Health and allied health professionals should recognize that, for some women, menopausal symptoms can adversely affect the ability to work, which can lead to reduction of working hours, underemployment or unemployment, and consequently financial insecurity in later life.

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INTRODUCTION: Vulvovaginal atrophy (VVA) is a chronic condition caused by estrogen deficiency. It affects around 50% of postmenopausal women, reducing their general and sexual quality of life as well as the quality of their personal relationships. AIM: The aim of this clinical guide is to set out an individualized approach to the management of VVA with topical estrogens and non-hormonal preparations. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: An individualized approach is required for the management of VVA. Topical low-dose estrogens are effective and also alleviate urinary incontinence and prevent recurrent urinary tract infections. Women should not be denied long-term use of topical estrogens as long as they feel that this treatment is of benefit to them, because the safety data are reassuring. Non-hormonal preparations (lubricants and moisturizers) should be the first-line treatment for VVA in women taking adjuvant endocrine therapies for cancers considered to be hormone-dependent. They can be used over the long term.

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INTRODUCTION: The prevalence of urinary incontinence and of other lower urinary tract symptoms increases after the menopause and affects between 38 % and 55 % of women aged over 60 years. While urinary incontinence has a profound impact on quality of life, few affected women seek care. AIM: The aim of this clinical guide is to provide an evidence-based approach to the management of urinary incontinence in postmenopausal women. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Healthcare professionals should consider urinary incontinence a clinical priority and develop appropriate diagnostic skills. They should be able to identify and manage any relevant modifiable factors that could alleviate the condition. A wide range of treatment options is available. First-line management includes lifestyle and behavioral modification, pelvic floor exercises and bladder training. Estrogens and other pharmacological interventions are helpful in the treatment of urgency incontinence that does not respond to conservative measures. Third-line therapies (e.g. sacral neuromodulation, intravesical onabotulinum toxin-A injections and posterior tibial nerve stimulation) are useful in selected patients with refractory urge incontinence. Surgery should be considered in postmenopausal women with stress incontinence. Midurethral slings, including retropubic and transobturator approaches, are safe and effective and should be offered.

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INTRODUCTION: Globally, 985 million women are aged 50 and over, leading to increasing concerns about chronic conditions such as cardiovascular disease, osteoporosis, dementia, and cognitive decline, which can adversely affect quality of life and independent living. AIM: To evaluate the evidence from observational studies and randomized trials on the effects of the Mediterranean diet on short- and long-term menopausal health: estrogen deficiency symptoms, cardiovascular disease, osteoporosis, cognitive and mental health, breast cancer, and all-cause mortality. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: The Mediterranean diet is a non-restrictive dietary pattern common in the olive-growing areas of the Mediterranean basin. It may improve vasomotor symptoms, cardiovascular risk factors such as blood pressure, cholesterol and blood glucose levels, as well as mood and symptoms of depression. Long-term adherence may: improve cardiovascular risk and events, and death; improve bone mineral density; prevent cognitive decline; and reduce the risk of breast cancer and all-cause mortality.

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INTRODUCTION: Dyslipidemias are common and increase the risk of cardiovascular disease. The menopause transition is associated with an atherogenic lipid profile, with an increase in the concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein B (apoB) and potentially lipoprotein (a) [Lp(a)], and a decrease in the concentration of high-density lipoprotein cholesterol (HDL-C). AIM: The aim of this clinical guide is to provide an evidence-based approach to management of menopausal symptoms and dyslipidemia in postmenopausal women. The guide evaluates the effects on the lipid profile both of menopausal hormone therapy and of non-estrogen-based treatments for menopausal symptoms. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Initial management depends on whether the dyslipidemia is primary or secondary. An assessment of the 10-year risk of fatal cardiovascular disease, based on the Systematic Coronary Risk Estimation (SCORE) system, should be used to set the optimal LDL-C target. Dietary changes and pharmacological management of dyslipidemias should be tailored to the type of dyslipidemia, with statins constituting the mainstay of treatment. With regard to menopausal hormone therapy, systemic estrogens induce a dose-dependent reduction in TC, LDL-C and Lp(a), as well as an increase in HDL-C concentrations; these effects are more prominent with oral administration. Transdermal rather than oral estrogens should be used in women with hypertriglyceridemia. Micronized progesterone or dydrogesterone are the preferred progestogens due to their neutral effect on the lipid profile. Tibolone may decrease TC, LDL-C, TG and Lp(a), but also HDL-C concentrations. Low-dose vaginal estrogen and ospemifene exert a favorable effect on the lipid profile, but data are scant regarding dehydroepiandrosterone (DHEA). Non-estrogen-based therapies, such as fluoxetine and citalopram, exert a more favorable effect on the lipid profile than do sertraline, paroxetine and venlafaxine. Non-oral testosterone, used for the treatment of hypoactive sexual desire disorder/dysfunction, has little or no effect on the lipid profile.

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INTRODUCTION: Globally, the total number of people with depression exceeds 300 million, and the incidence rate is 70 % greater in women. The perimenopause is considered to be a time of increased risk for the development of depressive symptoms and major depressive episodes. AIM: The aim of this position statement is to provide a comprehensive model of care for the management of depressive symptoms in perimenopausal and early menopausal women, including diagnosis, treatment and follow-up. The model integrates the care provided by all those involved in the management of mild or moderate depression in midlife women. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Awareness of depressive symptoms, early detection, standardized diagnostic procedures, personalized treatment and a suitable follow-up schedule need to be integrated into healthcare systems worldwide. Recommended treatment comprises antidepressants, psychosocial therapies and lifestyle changes. Alternative and complementary therapies, although widely used, may help with depression, but a stronger evidence base is needed. Although not approved for this indication, menopausal hormone therapy may improve depressive symptoms in peri- but not in postmenopausal women, especially in those with vasomotor symptoms.

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AIM: To determine the impact on osteopenia/osteoporosis of serum follicle-stimulating hormone (FSH), estradiol levels and time since menopause in a group of Turkish postmenopausal women. METHODS: Four hundred and thirty-three healthy postmenopausal women seen at the Marmara University Menopause Outpatient Clinic were enrolled for this prospective cohort study. The women were allocated to one of three groups according to the bone mineral density (BMD) of the lumbar vertebrae and total hip, as measured by dual energy X-ray absorptiometry (DEXA). Serum FSH, estradiol levels, age and time since menopause were compared between the groups. RESULTS: The mean serum FSH, LH, estradiol and testosterone levels for women with normal, osteopenic and osteoporotic BMD at lumbar vertrebra L1-L4 and total hip were comparable. Time since menopause had a stronger predictive value for low BMD (osteopenia or osteoporosis) in the lumbar and hip areas than did serum FSH or estradiol levels. CONCLUSIONS: Our study showed that neither FSH nor E2 has a strong impact on postmenopausal BMD. However it appears that time since menopause has a weak non-significant association with postmenopausal osteopenia and osteoporosis.

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OBJECTIVE: To determine if follicular dominance on the fifth day of controlled ovarian stimulation (COS) predicts implantation rates in down-regulated intracytoplasmic sperm injection (ICSI) cycles. STUDY DESIGN: One hundred and sixty-two consecutive women undergoing ICSI treatment with long down-regulation and recombinant follicle-stimulating hormone injections were included in a prospective cohort analysis. The clinical pregnancy and implantation rates per transfer were compared between two groups, one with and the other without follicular dominance detected by ultrasound on the fifth day of COS. RESULTS: There was no significant difference between the groups regarding the number of good quality embryos transferred, but clinical pregnancy and implantation rate per transfer were higher in group with follicular synchrony. CONCLUSIONS: Follicular dominance on COS day 5 results in reduced implantation rates after ICSI.

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OBJECTIVE: Menopause is associated with accelerated bone loss, a decrease in lean mass, an increase and redistribution of fat mass in the trunk region. Trunk obesity has been considered as a risk factor for endometrial cancer. We aimed to determine if body composition and fat distribution are determinants of femoral neck bone mineral density (BMD) and endometrial thickness in healthy postmenopausal women. STUDY DESIGN: Subjects were 40 healthy postmenopausal women with biopsy proven atrophic endometrium. Anthropometrical variables (total fat mass, trunk and leg fat masses, lean body mass and femoral neck BMD) were measured by dual energy X-ray absorptiometry. RESULTS: Femoral neck BMD was positively correlated with body mass index, total fat mass, trunk fat mass, leg fat mass and endometrial thickness, and negatively correlated with age, years since menopause and FSH levels. Trunk fat and age remained significant determinants of femoral neck BMD (R(2) = 32.9 %, p < 0.001) and endometrial thickness was significantly associated with femoral neck BMD and oestradiol levels (R(2) = 46.5%, p < 0.0001) on regression analysis. CONCLUSION: Truncal adiposity rather than overall adiposity or lean mass are more closely associated with femoral neck BMD and there is no relationship between subcutaneous fat mass and endometrial thickness in postmenopausal women.

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The beneficial effects of estrogen on vasculature are partially explained by an estrogen-induced increase in nitric oxide (NO) synthesis. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase. In the present study, the effect of 17beta-estradiol (E2) on ADMA and NO synthesis was investigated both in vivo and in vitro. Plasma NO and ADMA levels were measured in healthy women at a low menstrual estrogenic stage (E2 < 100 pg/ml) and in women who were undergoing ovarian hyperstimulation (E2 > 2000 pg/ml) before in vitro fertilization embryo transfer. Primary human umbilical vein endothelial cell (HUVEC) cultures were incubated with and without 100 nM E2 for 24 hours and the NO and ADMA levels of the media were measured. A nitric oxide analyzer was used for the detection of NO metabolites. ADMA and L-arginine were measured by high-performance liquid chromatography after precolumn derivatization with o-phthaldialdehyde. The IVF patients with high plasma E2 concentrations had significantly lower (48%, n = 12) plasma ADMA and higher (56%, n = 14) NO levels than the women at a low estrogenic stage. The incubation of HUVEC cultures with estradiol resulted in a significant decrease (47%, n = 10) in ADMA and an increase (46%, n = 10) in NO concentration in the culture media. Estradiol, by reducing ADMA, may therefore facilitate NO synthesis in endothelial cells. The protective effects of estradiol on vasculature may partly be related to a reduction in ADMA levels.

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BACKGROUND: Reproducibility is an important issue when using tests for estimating ovarian reserve and counseling patients. However, little is known about the intercycle variabilities of basal antral follicle count and ovarian volume. In this prospective study, we analysed the intercycle variabilities of the antral follicle count and ovarian volume, and compared them with those of other basal ovarian reserve tests in subfertile patients. METHOD: Fifty-two ovulatory and infertile women were followed for two consecutive spontaneous cycles. The antral follicle count, ovarian volume, serum follicle stimulating hormone and estradiol levels were determined on day 3 of both cycles. Limits of agreement between two measurements were determined. RESULTS: Limits of agreement were -6.9 and 6.5 for the antral follicle count, and -8.3 and 8.6 for the ovarian volume. These degrees of variation corresponded to a range of 1.30 and 1.45 times their means for the ovarian volume and antral follicle count, respectively. The variability in the antral follicle count was greater in women who were younger than 24.5 years than in those who were older. CONCLUSIONS: Intercycle variabilities of the antral follicle count and ovarian volume were clinically significant. More variation was observed in the antral follicle count of young infertile patients. Therefore, a low antral follicle count in young, infertile, but ovulatory women should be cautiously interpreted. This may not reflect a low ovarian reserve, and these women may have a high antral follicle count in the next cycle.

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BACKGROUND/AIM: To investigate the expression and value for diagnosis of the genes, p53 and pTEN, the protein, Ki-67, and the receptors, estrogen and progesterone, in differentiating smooth muscle tumors of the uterus. MATERIAL AND METHOD: Seventeen samples of leiomyosarcoma, 2 smooth muscle tumors with uncertain malignant potential (STUMP), 9 atypical myomas and 15 leiomyomas were stained immunohistochemically. The chi(2) test was used for the statistical analysis of the data. RESULTS: The malignant side of the spectrum was strongly stained for Ki-67 and p53 while uniformly decreasing toward the benign tumors. The results were found to be statistically significant (p < 0.0001). The staining for progesterone receptor was also statistically significant, but the tumors that were considered benign, such as leiomyoma and atypical myoma, were the ones strongly stained (p = 0.005). The expression of estrogen receptor was significant in these tumors, but the p value was very close to the cut-off value (p = 0.07). As the degree of differentiation of the tumor increased, the trend showed stronger staining for estrogen receptor. However, no difference was detected in the staining properties of the tumors for pTEN (p = 0.2457). CONCLUSION: The expression of Ki-67, p53 and progesterone receptors is promising in immunodifferentiation of smooth muscle tumors of the uterus with malignant potential.

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OBJECTIVE: To analyze the predictive value of cycle day 7 follicle count (CD7-FC) for poor ovarian response during IVF in women down-regulated with a luteal start of GnRH analogue (long protocol). DESIGN: A retrospective analysis. SETTING: University hospital. PATIENT(S): Ninety-one consecutive IVF cycles of 82 subjects. INTERVENTION(S): Basal levels of FSH and E2 were determined in the spontaneous cycle before the IVF cycle. During the IVF cycle, the number of basal and CD7 follicles and CD7 endometrial thickness were determined by ultrasound, and CD7 serum E2 levels were measured. MAIN OUTCOME MEASURE(S): Ovarian response determined according to the number of mature oocytes retrieved. RESULT(S): On receiver operating characteristic analysis, CD7-FC had the highest combination of sensitivity and specificity to detect women with poor ovarian response when compared with the basal ovarian reserve tests. When a combined basal antral FC and CD7-FC evaluation was used with the optimum cutoff values of 6.5 and 7.5, respectively, sensitivity and specificity improved to 85% and 90%, respectively. CONCLUSION(S): Cycle day 7 follicle count during a long IVF protocol is helpful in predicting ovarian response in combination with the antral FC. This combination has high positive and negative predictive values. This may help clinicians and women to cancel cycles earlier and decrease the psychological, financial, and medical burden of a later cancellation.

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