An Overview of the Current Known and Unknown Roles of Vitamin D3 in the Female Reproductive System: Lessons from Farm Animals, Birds, and Fish.

Recent studies have clearly shown that vitamin D3 is a crucial regulator of the female reproductive process in humans and animals. Knowledge of the expression of vitamin D3 receptors and related molecules in the female reproductive organs such as ovaries, uterus, oviduct, or placenta under physiological and pathological conditions highlights its contribution to the proper function of the reproductive system in females. Furthermore, vitamin D3 deficiency leads to serious reproductive disturbances and pathologies including ovarian cysts. Although the influence of vitamin D3 on the reproductive processes of humans and rodents has been extensively described, the association between vitamin D3 and female reproductive function in farm animals, birds, and fish has rarely been summarized. In this review, we provide an overview of the role of vitamin D3 in the reproductive system of those animals, with special attention paid to the expression of vitamin D3 receptors and its metabolic molecules. This updated information could be essential for better understanding animal physiology and overcoming the incidence of infertility, which is crucial for optimizing reproductive outcomes in female livestock.

Combinational exposure to Bisphenol A and a high-fat diet causes trans-generational Malfunction of the female reproductive system in mice.

Bisphenol A (BPA) is a common endocrine disruptor and a high-fat diet (HFD) also affects fertility. However, little is known about the long-term consequences of simultaneous exposure to BPA and a HFD on reproductive health. Herein, we assessed the effects of maternal exposure to BPA in combination with a HFD on reproductive function in subsequent generations of female mice and evaluated its effects on the hypothalamic-pituitary-gonadal axis. We found that the combination of maternal exposure to BPA and a HFD led to increased urine BPA levels, precocious puberty, altered estrous cyclicity, decreased follicle numbers, and altered hypothalamic Kiss1 methylation status in F1 and F2 mice. Therefore, we demonstrated that maternal exposure to BPA in combination with a HFD exerts a trans-generational effect on female reproduction.

Comparison of Female Genital Tract Cytokine and Microbiota Signatures Induced by Initiation of Intramuscular DMPA and NET-EN Hormonal Contraceptives - a Prospective Cohort Analysis.

Background: Cervicovaginal inflammation, bacterial microbiota and hormonal contraceptives all influence sexual and reproductive health. To date, the effects of intramuscular depo-medroxyprogesterone acetate (DMPA-IM) versus injectable norethisterone enanthate (NET-EN) on vaginal microbiota or cytokines have not been compared back-to-back, although in-vitro data suggest that DMPA-IM and NET-EN have different pharmacokinetic and biologic activities. This study aimed at comparing the effects of DMPA-IM versus NET-EN initiation on cervicovaginal cytokines and microbiota in women at high risk for sexually transmitted infections (STIs) assigned to the respective contraceptives. Methods: We collected socio-demographic characteristics and vaginal samples from women initiating DMPA-IM (ECHO Trial; n = 53) and NET-EN (UChoose Trial; n = 44) at baseline and after two consecutive injections to assess cytokine concentrations by Luminex, vaginal microbiota by 16S rRNA gene sequencing, STIs, bacterial vaginosis (BV) and candidiasis. Results: Cytokine concentrations did not change significantly after initiating DMPA-IM or NET-EN, although NET-EN versus DMPA-IM-associated profiles were distinct. While the abundance of bacterial taxa associated with optimal and non-optimal microbiota fluctuated with DMPA-IM use, overall community composition did not significantly change with either contraceptive. HSV-2 serology, chlamydial infection, gonorrhoea and candidiasis did not influence the associations between contraceptive type and cervicovaginal cytokines or microbiota. Conclusions: Both DMPA-IM and NET-EN use did not lead to broad inflammatory or microbiota changes in the female genital tract of sub-Saharan African women. This suggests that NET-EN is likely a viable option for contraception in African women at high risk of BV and STIs.

Potential effets of ginkgo (Ginkgo biloba, L.) on female reproduction.

This minireview will briefly outline the basic knowledge concerning the provenance, biological active constituents of ginkgo (Ginkgo biloba, L.) and its general health effects. Ginkgo has been shown to affect female reproductive functions: it can affect ovarian folliculo- and oogenesis, embryogenesis, promote ovarian granulosa cell apoptosis, reduce their proliferation and the release of ovarian hormones. Usually, ginkgo extract mainly suppresses, but its constituents like amifostine, leuprorelin, quercetin and kaempherol can promote ovarian functions. This may indicate the existence of anti-reproductive ginkgo constituent(s), such as ginkgolide B and allopregnenolone which, like ginkgo extract, can promote ovarian cell apoptosis and suppress ovarian follicullogenesis and oogenesis. Ginkgo effects could be mediated by an action on brain functions, ovarian steroidogenesis, oxidative processes, intracellular regulators of ovarian cell proliferation and apoptosis and GABA receptors. Ginkgo and its molecules, ginkgolide B and allopregnenolone can be useful for prevention and treatment of reproduction-related disorders like ovarian cancer, ovarian ischemia and menopausal syndrome. On the other hand, its constituents amifostine, leuprorelin, quercetin and kaempherol could be potentially applicable as biostimulators of female reproductive processes in human and veterinary medicine and animal production. Nevertheless, application of ginkgo is still limited by insufficient or contradictory knowledge concerning its active constituents, characters, targets and mediators of its action and their functional interrelationships. Impact of ginkgo action on reproductive organs other than ovaries remains largely unknown. Addressing these issues with proper animal and clinical studies could help to understand the distinct efficacy and consequences of medical application of ginkgo.

Inflammatory repercussions in female steroid responsive glands after perinatal exposure to bisphenol A and 17-ß estradiol.

The mammary gland (MG) and female prostate are plastic reproductive organs which are highly responsive to hormones. Thus, endocrine disruptors, such as bisphenol A (BPA) and exogenous estrogens, negatively affect glandular homeostasis. In addition to previously described alterations, changes in inflammatory markers expression also trigger the development of a microenvironment that contributes to tumor progression. The current work aimed to evaluate the inflammatory responses of the MG and prostate gland to BPA (50 µg/kg) and 17-ß estradiol (35 µg/kg) exposure during the perinatal window of susceptibility. The results showed that at 6 months of age there was an increase in the number of phospho-STAT3 (P-STAT3) positive cells in the female prostate from animals perinatally exposed to 50 µg/kg BPA daily. In addition, the number of macrophages increased in these animals in comparison with nonexposed animals, as shown by the F4/80 marker. Despite an increase in the incidence of lobuloalveolar and intraductal hyperplasia, the MG did not show any difference in the expression of the four inflammatory markers evaluated: tumor necrosis factor-α, COX-2, P-STAT3, and F4/80. Analysis of both glands from the same animal led to the conclusion that exposure to endocrine disruptors during the perinatal window of susceptibility leads to different inflammatory responses in different reproductive organs. As the prostate is more susceptible to these inflammatory mechanisms, it is reasonable to affirm that possible neoplastic alterations in this organ are related to changes in the inflammatory pattern of the stroma, a characteristic that is not evident in the MG.

Circulating immunity protects the female reproductive tract from Chlamydia infection.

Anatomical positioning of memory lymphocytes within barrier tissues accelerates secondary immune responses and is thought to be essential for protection at mucosal surfaces. However, it remains unclear whether resident memory in the female reproductive tract (FRT) is required for Chlamydial immunity. Here, we describe efficient generation of tissue-resident memory CD4 T cells and memory lymphocyte clusters within the FRT after vaginal infection with Chlamydia Despite robust establishment of localized memory lymphocytes within the FRT, naïve mice surgically joined to immune mice, or mice with only circulating immunity following intranasal immunization, were fully capable of resisting Chlamydia infection via the vaginal route. Blocking the rapid mobilization of circulating memory CD4 T cells to the FRT inhibited this protective response. These data demonstrate that secondary protection in the FRT can occur in the complete absence of tissue-resident immune cells. The ability to confer robust protection to barrier tissues via circulating immune memory provides an unexpected opportunity for vaccine development against infections of the FRT.

Melatonin and its mechanism of action in the female reproductive system and related malignancies.

Melatonin (N-acetyl-5-methoxytryptamine), the main product of pineal gland in vertebrates, is well known for its multifunctional role which has great influences on the reproductive system. Recent studies documented that melatonin is a powerful free radical scavenger that affects the reproductive system function and female infertility by MT1 and MT2 receptors. Furthermore, cancer researches indicate the influence of melatonin on the modulation of tumor cell signaling pathways resulting in growth inhibitor of the both in vivo/in vitro models. Cancer adjuvant therapy can also benefit from melatonin through therapeutic impact and decreasing the side effects of radiation and chemotherapy. This article reviews the scientific evidence about the influence of melatonin and its mechanism of action on the fertility potential, physiological alteration, and anticancer efficacy, during experimental and clinical studies.

Organ-on-a-chip technology for the study of the female reproductive system.

Over the past decade, organs-on-a-chip and microphysiological systems have emerged as a disruptive in vitro technology for biopharmaceutical applications. By enabling new capabilities to engineer physiological living tissues and organ units in the precisely controlled environment of microfabricated devices, these systems offer great promise to advance the frontiers of basic and translational research in biomedical sciences. Here, we review an emerging body of interdisciplinary work directed towards harnessing the power of organ-on-a-chip technology for reproductive biology and medicine. The focus of this topical review is to provide an overview of recent progress in the development of microengineered female reproductive organ models with relevance to drug delivery and discovery. We introduce the engineering design of these advanced in vitro systems and examine their applications in the study of pregnancy, infertility, and reproductive diseases. We also present two case studies that use organ-on-a-chip design principles to model placental drug transport and hormonally regulated crosstalk between multiple female reproductive organs. Finally, we discuss challenges and opportunities for the advancement of reproductive organ-on-a-chip technology.

Maternal Reproductive Toxicity of Some Essential Oils and Their Constituents.

Even though several plants can improve the female reproductive function, the use of herbs, herbal preparations, or essential oils during pregnancy is questionable. This review is focused on the effects of some essential oils and their constituents on the female reproductive system during pregnancy and on the development of the fetus. The major concerns include causing abortion, reproductive hormone modulation, maternal toxicity, teratogenicity, and embryo-fetotoxicity. This work summarizes the important studies on the reproductive effects of essential oil constituents anethole, apiole, citral, camphor, thymoquinone, trans-sabinyl acetate, methyl salicylate, thujone, pulegone, ß-elemene, ß-eudesmol, and costus lactone, among others.

Tribulus terrestris and female reproductive system health: A comprehensive review.

BACKGROUND: Tribulus terrestris L. (T. terrestris) positive performance on the male sexual system has been confirmed, but little is known about its effects on the female reproductive system. PURPOSE: This review discussed in detail the beneficial impact of T. terrestris and its secondary metabolites on the female reproductive system. STUDY DESIGN AND METHODS: In this review, the scientific Databases of Science direct, Pubmed, Web of Science, Google, Google Scholar, Researchgate, EMBASE, Scientific Information (SID), and Elsevier were searched profoundly. Studies about the pharmacological activities of T. terrestris on the female reproductive system in each aspect of investigations: human, in vivo, and in vitro studies, in the period from 1998 to 2020 were admitted. Our study was not limited by the language of publications. RESULTS: 23 articles about the effects of T. terrestris on the female reproductive system were found. These studies approved the T. terrestris efficacy on improvements in histological features of the ovary and uterus of polycystic ovary syndrome patients as well as the well-working of normal ovaries, enhancements in the sexual desire of postmenopausal syndrome, improve ovarian and breast cancers. CONCLUSION: These studies showed that the positive effect of T. terrestris on the female reproductive system was due to the presence of a secondary metabolite called protodioscin; a steroidal saponin compound, as the dominant active component of this plant.

Effects of experimental exposure to zearalenone on reproductive system morphometry, plasma oestrogen levels, and oocyte quality of beef heifer.

The aim of the present study was to evaluate the effects of zearalenone (ZEA) on the reproductive system morphometry, oestrogen (E2) levels and oocyte quality of beef heifers. Twenty non-pregnant purebred Nellore (Bos indicus) heifers [age, ≥18 months; initial body weight, 348 ± 30 kg (mean ± standard deviation)] were used. The animals were randomly divided into experimental group and a control group of 10 animals each. Group experimental was administered 300 ppb ZEA per os for 98 days, and the control group was administered placebo per os for 98 days. The administration of ZEA was carried out daily by adding mycotoxin to the diet. All heifers were evaluated weekly via rectal ultrasound examinations (12 weeks). Diameters of the right and left uterine horns, right and left ovaries, largest antral follicle and corpus luteum were measured. Vulva size was also measured. Blood samples were collected to estimate E2 levels. At the end of 12 weeks, the heifers were slaughtered, and the ovaries were sent to the laboratory for in vitro embryo production. A completely randomized design was adopted, and repeated measures analysis of variance (p < .05) was performed (except for oocyte quality). Vulva size (p = .0985); diameters of uterine horns (p = .0522), ovaries (p = .6955), antral follicles (p = .6355) and corpus luteum (p = .3808); and E2 levels (p = .3379) were not affected by the treatments. ZEA-contaminated diet significantly reduced (p = .05) the proportion of viable oocytes (49.4%, n = 207) compared with the control diet (59.9%, n = 222); however, the blastocyst rate did not differ between the groups (p = .9418). The results indicate that contamination of beef heifer's diet with 300 ppb ZEA affected neither morphometric parameters nor plasma oestrogen levels; however, ZEA contamination was detrimental to oocyte quality.

Evaluation of possible effects of Persea americana seeds on female reproductive hormonal and toxicity profile.

ETHNOPHARMACOLOGICAL RELEVANCE: The seed of Avocado (Persea americana, Lauraceae), non-edible part of the fruit is used as health product. It has been reported as traditional female contraceptive and sterilizer in Peru and some Asian countries and in Nigeria as cardio-protective agent. The present study focused on the effect of hydro-methanolic seed extract of Persea americana on female hormones and toxicity profile using animal models. MATERIALS AND METHODS: The serum follicle stimulating hormone (FSH) and progesterone (PROG) concentrations in mature non-pregnant female rats were assayed using hormonal kits. The toxicity profile was assessed using Lorke's acute toxicity model, haemato-biochemical evaluation and histopathological studies of reproductive related organs. Parameters were measured on day-30, 60 and 90. Presence of biomarker flavonoid compounds were confirmed using High Performance Liquid Chromatography. RESULTS: The extract at 20, 100 and 500 mg kg -1 altered FSH and PROG hormone profile of the treated groups. The extract initially, dose-dependently decreased FSH level in day-30 (6.95, 3.97, 2.08 IU/L respectively) compared to untreated group before a significant increase was observed for day 60 and 90. Progesterone increased dose-dependently in the treated groups throughout the 90-day treatment duration. This may be Indicating cumulative effect on the hormone. No deleterious or toxicity effect was noticed. CONCLUSIONS: The extract of Persea americana seed affects female hormone activity. This may find application in various hormonal management procedures, maternal and reproductive health and fertility control/help health facilities. However, it should be used with caution in women intending to conceive.

Augmentation of the Female Reproductive System Using Honey: A Mini Systematic Review.

Phytochemical contents of honey are presumed to be beneficial to the female reproductive system (FRS). However, the biological effects of honey supplementation (HS) in vivo on the FRS remain unclear. This review aims to investigate the current literature on the effects of HS on the FRS, particularly on the sex hormone profile and reproductive organs (uterus and vagina). A systematic literature search using Scopus, MEDLINE via Ovid and Cochrane Library databases was conducted. Records were screened and identified for preclinical and clinical studies addressing the effects of HS on the FRS. Data on populations, interventions, outcomes and methodological quality were extracted. Studies were synthesised using tables and written summaries. Of the 198 identified records, six fulfilled the inclusion criteria. All six records were used for data extraction: two experimental studies using rats as the model organism and four human clinical studies of honey on female reproductive health. HS elevated the progesterone levels, restrained body weight increase, prevented uterine and vaginal atrophies in ovariectomised rats, attenuated symptoms of candidiasis and improved oxidative status in patients. Current evidence shows that short-term HS following surgical or physiological menopause exerts an oestrogenic, antioxidant and anti-inflammatory effect on the FRS. However, insufficient long-term studies preclude any definitive conclusions.

Prenatal smoke exposure is associated with increased anogenital distance in female infants: a prospective case-control study.

OBJECTIVES: To investigate the effects of maternal smoking during pregnancy on newborn infants' anogenital distance (AGD). METHODS: Fifty-six female and sixty-four male newborn infants from mothers who smoked during pregnancy were included in this study. A control group for each sex was selected from infants whose mothers had no active or passive (in either the household or the workplace) smoke exposure before or during pregnancy. Questionnaire data on maternal demographic characteristics and information about cigarette use were collected. We assessed genital anthropometry which included AGD for both male and female neonates, and stretched penile length (SPL), penile girth for males within the first 48 h after birth. AGD measurements were also normalized according to birth weight (AGD/weight in grams), length (AGD/height in millimeters), and ponderal index [AGD/(weight in grams/height in cubic centimeters)]. Anogenital index (AGI) was calculated by dividing the AGD by cube root of birth weight. RESULTS: In female infants, prenatal smoke exposure was associated with significantly increased weight-adjusted AGD (p=0.03). There was also a significant correlation between mothers' daily smoking rates and weight-adjusted AGD (r=0.27/p=0.03). In male infants, fetal smoke exposure was not associated with any AGD measurements, SPL and penile girth. CONCLUSIONS: A significant increase in weight-adjusted AGD in female infants exposed to maternal smoking may be an indicator of antenatal androgen exposure and may pose a risk for short and long-term endocrine, metabolic and behavioral problems.

Are glyphosate and glyphosate-based herbicides endocrine disruptors that alter female fertility?

Numerous evidences have alerted on the toxic effects of the exposure to glyphosate on living organisms. Glyphosate is the herbicide most used in crops such as maize and soybean worldwide, which implies that several non-target species are at a high risk of exposure. Although the Environmental Protection Agency (EPA-USA) has reaffirmed that glyphosate is safe for users, there are controversial studies that question this statement. Some of the reported effects are due to exposure to high doses; however, recent evidences have shown that exposure to low doses could also alter the development of the female reproductive tract, with consequences on fertility. Different animal models of exposure to glyphosate or glyphosate-based herbicides (GBHs) have shown that the effects on the female reproductive tract may be related to the potential and/or mechanisms of actions of an endocrine-disrupting compound. Studies have also demonstrated that the exposure to GBHs alters the development and differentiation of ovarian follicles and uterus, affecting fertility when animals are exposed before puberty. In addition, exposure to GBHs during gestation could alter the development of the offspring (F1 and F2). The main mechanism described associated with the endocrine-disrupting effect of GBHs is the modulation of estrogen receptors and molecules involved in the estrogenic pathways. This review summarizes the endocrine-disrupting effects of exposure to glyphosate and GBHs at low or "environmentally relevant" doses in the female reproductive tissues. Data suggesting that, at low doses, GBHs may have adverse effects on the female reproductive tract fertility are discussed.

The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers.

Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host-tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers.

Recombinant protein subunit vaccine reduces puerperal metritis incidence and modulates the genital tract microbiome.

The objective of this study was to evaluate the efficacy of 3 vaccine formulations containing proteins (FimH, leukotoxin, and pyolysin), inactivated whole cells (Escherichia coli, Fusobacterium necrophorum, and Trueperella pyogenes), or both, in the prevention of postpartum uterine diseases. A randomized clinical trial was conducted at a commercial dairy farm; 800 heifers were assigned into 1 of 4 different treatment groups: control, vaccine 1 (bacterin and subunit proteins), vaccine 2 (bacterin), and vaccine 3 (recombinant subunit proteins), and each heifer received a subcutaneous injection of its respective treatment at 240 ± 3 and 270 ± 3 d of gestation. Vaccination significantly reduced the incidence of puerperal metritis when compared with control (9.1% vs. 14.9%, respectively; odds ratio 0.51). Additionally, vaccine 3 was found to reduce the incidence of puerperal metritis when compared with the control (8.0% vs. 14.9%, respectively; odds ratio 0.46). Reproduction was improved for metritic cows that were vaccinated, and the effect was stronger for cows that were treated with vaccine 3. In general, vaccination decreased the total vaginal bacterial load and decreased the vaginal load of F. necrophorum by 9 d in milk. Vaccination reduced the prevalence of puerperal metritis in the first lactation of dairy cows, leading to less metritic disease and improved reproduction.