Chronic Stress in Pregnancy Is Associated with Low Birth Weight: A Meta-Analysis.

BACKGROUND AND OBJECTIVES: Chronic activation of the stress system has cumulative effects on the body, and it places individuals at risk for adverse health outcomes. Chronic stress has been assessed by health questionnaires in pregnancy. During the perinatal period, mothers experience increased physical and emotional demands. Chronic stress interferes with hormonal functions in mothers and infants. This meta-analysis studies the effect of maternal chronic stress during pregnancy, as assessed by established stress questionnaires, on the birth weight of their full-term infants. DESIGN AND METHODS: According to our criteria and after research collection, we obtained 107 studies and we conducted two types of analyses: a logistic (N = 22,342) and linear regression analysis (N = 7431). RESULTS: Our results show that chronic stress is associated with a statistically significant risk of low birth weight (OR = 1.50, CI 95% = [1.13; 1.99], p ≤ 0.02). CONCLUSIONS: Increased maternal chronic stress, as assessed by questionnaires, in pregnancy is associated with a low-birth-weight baby. The above meta-analysis indicates that maternal high chronic stress questionnaire scores could be used as a clinical tool in order to assess low-birth-weight risk.

Reverse Onco-Cardiology: What Is the Evidence for Breast Cancer? A Systematic Review of the Literature.

Breast cancer and cardiovascular diseases (CVD) represent significant global health challenges, with CVD being the leading cause of mortality and breast cancer, showing a complex pattern of incidence and mortality. We explore the intricate interplay between these two seemingly distinct medical conditions, shedding light on their shared risk factors and potential pathophysiological connections. A specific connection between hypertension (HTN), atrial fibrillation (AF), myocardial infarction (MI), and breast cancer was evaluated. HTN is explored in detail, emphasizing the role of aging, menopause, insulin resistance, and obesity as common factors linking HTN and breast cancer. Moreover, an attempt is made to identify the potential impact of antihypertensive medications and highlight the increased risk of breast cancer among those women, with a focus on potential mechanisms. A summary of key findings underscores the need for a multisystem approach to understanding the relationship between CVD and breast cancer is also explored with a highlight for all the gaps in current research, such as the lack of clinical observational data on MI and breast cancer in humans and the need for studies specifically designed for breast cancer. This paper concludes that there should be a focus on potential clinical applications of further investigation in this field, including personalized prevention and screening strategies for women at risk. Overall, the authors attempt to provide a comprehensive overview of the intricate connections between breast cancer and cardiovascular diseases, emphasizing the importance of further research in this evolving field of cardio-oncology.

Breast Cancer and Fertility Preservation in Young Female Patients: A Systematic Review of the Literature.

INTRODUCTION: Breast cancer affects almost 1.5 million women worldwide below the age of 45 years each year. Many of these women will be advised to undergo adjuvant chemotherapy to minimize the risk of death or recurrence of the tumor. For these patients, chemotherapy is a known cause of infertility, as it can damage primordial follicles, which can lead to early menopause or premature ovarian insufficiency. This systematic review aims to synthesize the current evidence of the most suitable treatments for fertility preservation. METHODOLOGY: This review was performed following the PRISMA guidelines. The authors conducted an extensive search from the last 15 years. Relevant studies were pursued in PubMed, Embase, and the Cochrane Library up until 31 July 2023. A total of seven eligible studies were identified. RESULTS: From the reviewed literature, ovarian suppression with gonadotropin-releasing hormone agonists showed promising results in preserving fertility for breast cancer patients undergoing chemotherapy. Additionally, oocyte and embryo cryopreservation demonstrated successful outcomes, with embryo cryopreservation being the most effective option. Notably, the slow-freezing and vitrification methods were both effective in preserving embryos, with vitrification showing superior results in clinical-assisted reproductive technologies. Ovarian tissue cryopreservation emerged as a viable option for prepubertal girls and those unable to undergo conventional ovarian stimulation. The potential of in vitro maturation (IVM) as an alternative method presents a promising avenue for future fertility preservation research. DISCUSSION: The most suitable treatments for fertility preservation in young patients is the temporary suppression with luteinizing hormone-releasing analogs, while the patient undergoes chemotherapy and cryopreservation. For cryopreservation, the physicians might deem it necessary to either cryopreserve ovarian tissue taken from the patient before any treatment or cryopreserve embryos/oocytes. Cryopreservation of oocytes and/or embryos is the most effective solution for fertility preservation in women of reproductive age, who have a sufficient ovarian reserve and are diagnosed with breast cancer, regardless of the histological type of the tumor. Because approximately 50% of young breast cancer patients are interested in becoming pregnant right after completion of therapy, the evolution and development of fertility preservation techniques promise to be very exciting.

Biological therapies for premature ovarian insufficiency: what is the evidence?

Premature Ovarian Insufficiency (POI) is a multi-factorial disorder that affects women of reproductive age. The condition is characterized by the loss of ovarian function before the age of 40 years and several factors have been identified to be implicated in its pathogenesis. Remarkably though, at least 50% of women have remaining follicles in their ovaries after the development of ovarian insufficiency. Population data show that approximately up to 3.7% of women worldwide suffer from POI and subsequent infertility. Currently, the treatment of POI-related infertility involves oocyte donation. However, many women with POI desire to conceive with their own ova. Therefore, experimental biological therapies, such as Platelet-Rich Plasma (PRP), Exosomes (exos) therapy, In vitro Activation (IVA), Stem Cell therapy, MicroRNAs and Mitochondrial Targeting Therapies are experimental treatment strategies that focus on activating oogenesis and folliculogenesis, by upregulating natural biochemical pathways (neo-folliculogenesis) and improving ovarian microenvironment. This mini-review aims at identifying the main advantages of these approaches and exploring whether they can underpin existing assisted reproductive technologies.

Fertility status in childhood cancer survivors of hematological malignancies: a systematic review.

Stunning advances in treatment modalities implemented in children with hematological malignancies have led to 5-year overall survival rates exceeding 85%. However, this growing population of long-term survivors has raised significant concerns about their fertility status throughout adulthood, while specific treatment- and non-treatment-related factors appear to possibly affect fertility through distinct mechanisms. We aimed to comprehensively review the published literature on the association between treatment-related factors and risk of impaired fertility in childhood hematological cancer survivors. We searched PubMed up to March 2021 to identify eligible studies published during the last two decades. A narrative synthesis of the results was performed, although no meta-analysis was feasible due to the small number of studies and the large heterogeneity of evidence. Five studies on 2020 survivors of childhood leukemia were deemed eligible. The qualitative data synthesis showed significant fertility deficits in survivors treated with cranial radiotherapy and chemotherapy for childhood leukemia. Two studies examined biochemical measures of reduced ovarian reserve, providing some evidence that the levels of anti-Müllerian hormone can be used as a proxy for diminished ovarian reserve. The current findings should facilitate the delivery of age- and gender-appropriate interventions to optimize reproductive outcomes in childhood hematological cancer survivors.

Effect of Aromatase Inhibitors on Serum Calprotectin Levels in an Animal Experimental Model: Trial.

BACKGROUND/AIM: Utilizing an experimental animal model, we investigated the correlation between aromatase inhibitors (AIs) (anastrozole and letrozole) and Calprotectin levels. AIs have demonstrated superior efficacy when used as adjuvant endocrine therapy or monotherapy for postmenopausal patients with hormone receptor (HR)-positive early-stage breast cancer, although various side effects have been recorded. MATERIALS AND METHODS: Fifty-five adult female Wistar rats were randomized and assigned into four groups. The control group received no intervention. The other three groups were subjected to ovariectomy, and serum Calprotectin levels were measured at baseline, 2, and 4 months. In addition, glucose, total cholesterol, very low-density lipoprotein- (VLDL-) cholesterol, low-density lipoprotein (LDL-) cholesterol, high-density lipoprotein- (HDL-) cholesterol, and triglyceride levels were measured. Histological analysis of liver tissue was carried out following rats' euthanasia. RESULTS: Aromatase inhibitors (anastrozole and letrozole) affect calprotectin levels in ovariectomized rats. Calprotectin, a marker of inflammation, was found to be affected by the use of the inhibitors. CONCLUSION: The potential of hepatotoxicity can be examined by assessing the elevation of inflammation markers such as Calprotectin, which is an indicator that should be strictly taken into consideration when administering aromatase inhibitors as treatment.

Soy Isoflavones and Breast Cancer Risk: A Meta-analysis.

BACKGROUND/AIM: Soy contains genistein and daidzein isoflavones. Isoflavones are phytoestrogens, with a similarity in structure to human 17-ß estradiol hormone. They imitate the action of estrogen on organs by binding and activating estrogen receptors. Numerous studies have examined the relationship between soy consumption and breast cancer but not the amount of consumption itself. We performed a systematic review of the literature in order to determine whether the amount of soy and isoflavones consumed has a positive effect in pre- and post-menopausal women. MATERIALS AND METHODS: Data gathering was performed following PRISMA guidelines. Narrowing down the result set for all relevant data was performed via title, abstract, full-text evaluation and the snowball procedure. The selected articles had all relevant data extracted. Analysis of the data was performed using Cochrane's Review Manager statistical analysis tool in order to draw conclusions regarding the positive effect for the amount of soy and isoflavones consumed. RESULTS: Significant results were found when statistically analyzing data from prospective studies which compared soy isoflavones consumption, breast cancer risk and occurrence. The data were indicative of a clear inverse correlation between the amount of isoflavones consumed and breast cancer occurrence in pre- and post-menopausal women. CONCLUSION: The consumption of soy isoflavones can reduce the risk of breast cancer in pre-menopausal and post-menopausal women.

The expression of Galectin-3 in endometrial cancer: a systematic review of the literature.

BACKGROUND: Galectin-3 is part of a protein group called lectins and acts as a multifunctional glycoprotein due to its expression location. Galectin-3 is expressed by different human tissues. It plays a significant role in carcinogenesis and the selection of tumor-related physiological and pathological activities. Galectin-3 has been utilized through the years as a diagnostic and prognostic marker for various types of cancers. METHODS AND RESULTS: This review describes the outcomes of some studies on the matter that were selected appropriately through a review of the existing literature. These studies examined the levels of Galectin-3 expression in endometrial carcinomas, the outcomes, and the prognosis of these carcinomas. Two of the studies concluded that high expression of Galectin-3 is associated with a tumor's histological grade, type and depth. This enhanced nuclear Galectin-3 expression might assist in progression to atypia and neoplasia. The other three on the contrary concluded that malignant tumors had a decreased expression of Galectin-3 and that Galectin-3 played a suppressive role in tumor growth. CONCLUSIONS: The part Galectin-3 might potentially have in metastasis of cancers and the offering of a better prognosis for patients is of high importance. To date, there is minimal literature regarding the effects of Galectin-3 and more research is required.

Demographic, clinical and hormonal characteristics of patients with premature ovarian insufficiency and those of early menopause: data from two tertiary premature ovarian insufficiency centers in Greece.

The aim of the study was to compare demographic, hormonal and clinical parameters in patients with premature ovarian insufficiency (POI) and women with early menopause in Greece. One hundred thirty-nine women of Greek origin, aged 14-45 years, referring for oligomenorrhea and having elevated FSH concentrations were divided into three groups regarding the age of menstrual disturbances onset [POI1:

Intrauterine CRH-treated PBMC in repeated implantation failure.

BACKGROUND: The intrauterine administration of activated autologous peripheral blood monocytes (PBMC) prior to embryo transfer seems to improve reproductive outcomes in women with repeated implantation failure (RIF). We have previously shown that the intrauterine administration of PBMC treated with corticotropin-releasing hormone (CRH) prior to blastocyst transfer (day 5) improves significantly the clinical pregnancy rate of women with RIF. In the present crossover pilot study, we have investigated whether CRH-PBMC treatment could be of benefit in case of fresh early cleavage stage embryo transfer (day 3) in women with RIF. METHODS: Twenty-six (n = 26) women with at least three previous failed IVF attempts and no history of clinical pregnancy in the past were recruited in this study. Ovarian stimulation was performed following either the long or the short protocol. PBMC were collected during the oocyte retrieval, were treated with CRH, and transferred in the uterine cavity 2 days later. Good quality cleavage stage embryos were transferred at day 3, following oocyte retrieval. RESULTS: Following the intrauterine administration of CRH-treated autologous PBMC, 15/26 clinical pregnancies occurred (57.69%). Compared to the null result of the same women prior to recruitment, this observation was considered significant (P < 10-2 ). CONCLUSION: Our findings further support the role of the intrauterine administration of CRH-treated PBMC as an effective approach when transferring cleavage stage embryos in women with RIF. Prospective randomized studies are needed to clarify whether such intervention could be of benefit in clinical practice.

Endometrial CRH and implantation: from bench to bedside.

Endometrial corticotropin-releasing hormone (CRH) has been described as a mediator of decidualisation and as a contributor of maternal-fetal immunotolerance. Deregulation of the CRH expression pattern has been associated with unfavourable reproductive outcomes as well as chronic endometrium-derived inflammatory disorders, such as endometriosis and adenomyosis. The current review summarises the evidence produced regarding the role of CRH in endometrial physiology and pathophysiology and highlights recent clinical data regarding the role of CRH in improving clinical pregnancy rates in women with repeated implantation failures following in vitro fertilisation and embryo transfer.

CRH Receptors in Human Reproduction.

BACKGROUND: Corticotropin releasing hormone (CRH), the main peptide-mediator of stress, has been found in the female reproductive system. OBJECTIVE: Herein, the role of CRH receptors in the female reproductive system is presented. RESULTS: It is clear that CRH receptors are involved in the regulation of the hypothalamic-pituitaryovarian axis, while locally are associated with decidualization, embryonic implantation, early fetal development and triggering of parturition. CONCLUSION: Abnormal CRH signaling may contribute to obstetrical pathophysiology, such as preeclampsia, abnormal placenta invasion, endometrial growth retardation and preterm delivery.

The Role of HCG in Implantation: A Mini-Review of Molecular and Clinical Evidence.

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes.

Repeated implantation failure: a new potential treatment option.

BACKGROUND: Previous studies have shown that the intrauterine administration of peripheral blood mononuclear cells (PBMC) may improve pregnancy outcome of women with repeated implantation failure (RIF). We have demonstrated that, during implantation, corticotropin-releasing hormone (CRH) plays a key role in facilitating endometrial decidualization and maternal-foetal immunotolerance. In the present preliminary study, we investigated whether the intrauterine administration of autologous CRH-treated PBMC can improve clinical pregnancy rates of women with RIF. METHODS: Forty-five (n = 45) women with at least three failed in vitro fertilization (IVF) attempts and no previously reported clinical pregnancy were included in this crossover study. All women underwent controlled ovarian stimulation using the long GnRH agonist protocol. PBMC were isolated at day of oocyte retrieval, treated with CRH and administered in the uterine cavity at day 2, following oocyte retrieval. Blastocyst transfer was performed on day 5. RESULTS: Following the CRH-PBMC intrauterine administration, a significant increase was observed in the clinical pregnancy rate of this cohort of women with RIF (20/45 women had a clinical pregnancy; 44.44%, P < 10(-3)) compared to the previous null clinical pregnancy rate prior to the intervention. CONCLUSION: The current findings support a possible role for the intrauterine administration of autologous CRH-treated PBMC in treating women with RIF. Further randomized controlled trials are needed to investigate the efficacy of this intervention.

Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement.

CONTEXT: Women with primary ovarian insufficiency have significantly lower serum estradiol and T levels compared with regularly menstruating women. They also have significantly reduced bone mineral density (BMD). OBJECTIVE: The objective of the study was to evaluate the efficacy of hormone replacement in maintaining BMD in these young women. DESIGN AND SETTING: This was a randomized, double-blind, single-center, placebo-controlled clinical trial at the National Institutes of Health clinical center (Bethesda, Maryland). PARTICIPANTS: Young women with primary ovarian insufficiency participated in the study. INTERVENTIONS: We compared the effect of estradiol and progestin replacement (n = 72) vs estradiol, progestin, and T replacement (n = 73) on BMD. We also compared findings with a contemporaneous control group of normal women (n = 70). All patients received transdermal estradiol (100 µg/d) plus oral medroxyprogesterone acetate 10 mg/d (12 d/mo) for a 3-month run-in period before being randomized in a double-blinded fashion to the addition of transdermal T (150 µg/d) or placebo. MAIN OUTCOME MEASURE: Change in BMD at the femoral neck was measured by dual-energy x-ray absorptiometry. RESULTS: At screening, patients had significantly lower femoral neck BMD compared with control women (0.77 vs 0.81 g/cm(2), P = .001) and did not differ in body mass index, age at menarche, or education level. Normal control women lost femoral neck BMD over the study period, whereas patients on estradiol and progestin therapy gained BMD; and at the end of the study period, femoral neck BMD of patients on estradiol and progestin therapy did not differ from that of control women (0.80 g/cm(2) in both groups, P = .9). The addition of T showed no further benefit (percentage change in BMD 3.9 vs 2.4, respectively, P = .9). Nonetheless, using a repeated-measures model, the T group achieved a mean BMD in the femoral neck 0.015 g/cm(2) higher than the placebo group at 3 years (95% confidence interval -0.005 to 0.034, P = .13). Similar findings were observed in the lumbar spine BMD as well. CONCLUSION: Long-term physiological transdermal estradiol replacement in combination with oral medroxyprogesterone acetate restores mean femoral neck BMD to normal in young women with spontaneous 46,XX primary ovarian insufficiency. However, the addition of physiological transdermal T replacement did not provide additional benefit.

Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency.

OBJECTIVE: Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI. METHODS: One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests. RESULTS: No differences in baseline characteristics, including serum hormone levels (P > 0.05), were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively (P = 0.35). After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo (P < 0.001). Baseline testosterone levels were not associated with either adverse or beneficial clinical effects. CONCLUSIONS: A 150-µg testosterone patch achieves physiologic hormone levels in women with POI. Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder.

Metformin reduces the expression of corticotropin-releasing hormone and urocortin in the endometrium of healthy women.

OBJECTIVE: To investigate the effect of metformin administration on the expression of endometrial corticotrophin-releasing hormone (CRH) and urocortin (UCN) in the midluteal phase of the cycle. DESIGN: Experimental study, performed in 2010-2011. SETTING: University hospital. PATIENT(S): Eight healthy, normally cycling and parous women volunteered for the study. INTERVENTION(S): All women were investigated in two nonconsecutive cycles (control cycle, untreated and after one cycle break; trial cycle, oral administration of metformin [850 mg × 2]). Endometrial pipelle biopsies were obtained on day LH+7. MAIN OUTCOME MEASURE(S): The endometrial biopsies were immunohistochemically assessed for CRH and UCN expression. Evaluation of positivity was performed by applying the immunoreactive score. RESULT(S): Compared with samples from control cycles, CRH and UCN were significantly reduced in endometrial samples obtained during metformin treatment. This down-regulation was significant both in the endometrial cells and in the endometrial stroma. CONCLUSION(S): This is the first study showing that during the midluteal phase of the cycle, metformin may decrease the production of CRH and UCN in the endometrium. Metformin interference to decidualization could happen by CRH/UCN modification.

Increased vascular inflammation in early menopausal women is associated with hot flush severity.

CONTEXT: Menopause has been related to an increased atherosclerotic risk. Presence and severity of hot flushes in menopausal women have been associated with impaired endothelial function and advanced subclinical atherosclerosis. OBJECTIVE: The objective of the study was to evaluate the effect of menopausal transition on vascular inflammation indices and investigate the association of hot flush severity with these indices in early menopausal women. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women (controls). MAIN OUTCOMES: Serum high-sensitivity C-reactive protein, P-selectin, and soluble CD40 ligand (sCD40L) levels were measured. RESULTS: P-selectin and sCD40L were increased in early menopausal compared with control women (P = 0.006 and P = 0.02 respectively), whereas high-sensitivity C-reactive protein levels did not differ (P = 0.4) between the groups. Hot flush severity was the most important independent predictor of P-selectin levels (P = 0.011) in early menopausal women. Women with moderate/severe/very severe hot flushes had increased P-selectin compared with women with no/mild hot flushes or controls (P < 0.05 for both). The sCD40L levels were also higher in menopausal women with moderate/severe/very severe hot flushes compared with controls (P = 0.03) but did not differ significantly compared with women with no/mild hot flushes (P = 0.2). CONCLUSIONS: Increased indices of vascular inflammation in early menopausal compared with age-matched premenopausal women may indicate a higher atherosclerotic risk. Increased severity of hot flushes was associated with adverse changes in vascular inflammation, further supporting the emerging role of hot flushes in cardiovascular prognosis in these women.

Short-term hormone therapy improves sCD40L and endothelial function in early menopausal women: potential role of estrogen receptor polymorphisms.

OBJECTIVE: Hormone therapy (HT) has been suggested to improve vascular function and inflammation in menopausal women, although not consistently. We aimed to investigate the effects of HT on endothelial function and inflammation, especially sCD40L, in early menopausal women, and the effect of common estrogen receptor (ER) polymorphisms on vascular responses to HT. STUDY DESIGN: Eighty-four early menopausal women (<3 years in menopause) with menopausal complaints eligible for HT. Forty women received transdermal 17ß-estradiol plus cyclical micronized progesterone for 3 months while 44 did not (controls). MAIN OUTCOME MEASURES: Brachial artery flow-mediated dilation (FMD) and vascular inflammation markers (sICAM, sP-Selectin and sCD40L). Genetic polymorphisms of ERα (PvuII 454-397T>C and XbaI 454-351A>G) and ERß (AluI 1730A>G) were also assessed. RESULTS: The two groups did not differ at baseline. Following HT, vasomotor complaints' severity, blood pressure, LDL, sCD40L, sICAM and sP-Selectin decreased and FMD increased compared to controls (P<0.05 for all). ERß AluI A allele presence was the most important independent predictor of HT-induced increase in FMD while ERα XbaI A allele was the only independent predictor of decrease in sCD40L. CONCLUSIONS: Short-term HT in early menopausal women improved endothelial function and inflammation. Specific ER polymorphisms that were found to be main determinants of HT-induced effects on endothelium could identify subgroups of women who may benefit the most from HT.