Reversible female contraceptives: historical, current, and future perspectives†.

Contraception is a practice with extensive and complicated social and scientific histories. From cycle tracking, to the very first prescription contraceptive pill, to now having over-the-counter contraceptives on demand, family planning is an aspect of healthcare that has undergone and will continue to undergo several transformations through time. This review provides a comprehensive overview of current reversible hormonal and non-hormonal birth control methods as well as their mechanism of action, safety, and effectiveness specifically for individuals who can become pregnant. Additionally, we discuss the latest Food and Drug Administration (FDA)-approved hormonal method containing estetrol and drospirenone that has not yet been used worldwide as well as the first FDA-approved hormonal over-the-counter progestin-only pills. We also review available data on novel hormonal delivery through microchip, microneedle, and the latest FDA-approved non-hormonal methods such as vaginal pH regulators. Finally, this review will assist in advancing female contraceptive method development by underlining constructive directions for future pursuits. Information was gathered from the NCBI and Google Scholars databases using English and included publications from 1900 to present. Search terms included contraceptive names as well as efficacy, safety, and mechanism of action. In summary, we suggest that investigators consider the side effects and acceptability together with the efficacy of contraceptive candidate towards their development.

Cell-type specific analysis of physiological action of estrogen in mouse oviducts.

One of the endogenous estrogens, 17ß-estradiol (E2 ) is a female steroid hormone secreted from the ovary. It is well established that E2 causes biochemical and histological changes in the uterus. However, it is not completely understood how E2 regulates the oviductal environment in vivo. In this study, we assessed the effect of E2 on each oviductal cell type, using an ovariectomized-hormone-replacement mouse model, single-cell RNA-sequencing (scRNA-seq), in situ hybridization, and cell-type-specific deletion in mice. We found that each cell type in the oviduct responded to E2 distinctively, especially ciliated and secretory epithelial cells. The treatment of exogenous E2 did not drastically alter the transcriptomic profile from that of endogenous E2 produced during estrus. Moreover, we have identified and validated genes of interest in our datasets that may be used as cell- and region-specific markers in the oviduct. Insulin-like growth factor 1 (Igf1) was characterized as an E2 -target gene in the mouse oviduct and was also expressed in human fallopian tubes. Deletion of Igf1 in progesterone receptor (Pgr)-expressing cells resulted in female subfertility, partially due to an embryo developmental defect and embryo retention within the oviduct. In summary, we have shown that oviductal cell types, including epithelial, stromal, and muscle cells, are differentially regulated by E2 and support gene expression changes, such as growth factors that are required for normal embryo development and transport in mouse models. Furthermore, we have identified cell-specific and region-specific gene markers for targeted studies and functional analysis in vivo.

Extracellular Vesicles and the Oviduct Function.

In mammals, the oviduct (or the Fallopian tube in humans) can be divided into the infundibulum (responsible for oocyte pick-up), ampulla (site of fertilization), isthmus (where preimplantation embryos develop), and uterotubal junction (where embryos transit to the uterus). The oviductal fluid, as well as extracellular vesicles produced from the oviduct epithelial cells, referred to as oEVs, have been shown to improve the fertilization process, prevent polyspermy, and aid in embryo development. oEVs contain molecular cargos (such as miRNAs, mRNAs, proteins, and lipids) that can be delivered and fuse to recipient cells. oEVs produced from the ampulla appear to be functionally distinct from those produced from the isthmus. In multiple species including mice, cats, dogs, pigs, and cows, oEVs can be incorporated into the oocytes, sperm, and embryos. In this review, we show the positive impact of oEVs on gamete function as well as blastocyst development and how they may improve embryo quality in in vitro conditions in an assisted reproductive technology setting for rodents, domestic animals, farm animals, and humans.

Generation of Oviductal Glycoprotein 1 Cre Mouse Model for the Study of Secretory Epithelial Cells of the Oviduct.

The epithelial cell lining of the oviduct plays an important role in oocyte pickup, sperm migration, preimplantation embryo development, and embryo transport. The oviduct epithelial cell layer comprises ciliated and nonciliated secretory cells. The ciliary function has been shown to support gamete and embryo movement in the oviduct, yet secretory cell function has not been well characterized. Therefore, our goal was to generate a secretory cell-specific Cre recombinase mouse model to study the role of the oviductal secretory cells. A knock-in mouse model, Ovgp1Cre:eGFP, was created by expressing Cre from the endogenous Ovgp1 (oviductal glycoprotein 1) locus, with enhanced green fluorescent protein (eGFP) as a reporter. EGFP signals were strongly detected in the secretory epithelial cells of the oviducts at estrus in adult Ovgp1Cre:eGFP mice. Signals were also detected in the ovarian stroma, uterine stroma, vaginal epithelial cells, epididymal epithelial cells, and elongated spermatids. To validate recombinase activity, progesterone receptor (PGR) expression was ablated using the Ovgp1Cre:eGFP; Pgrf/f mouse model. Surprisingly, the deletion was restricted to the epithelial cells of the uterotubal junction (UTJ) region of Ovgp1Cre:eGFP; Pgrf/f oviducts. Deletion of Pgr in the epithelial cells of the UTJ region had no effect on female fecundity. In summary, we found that eGFP signals were likely specific to secretory epithelial cells in all regions of the oviduct. However, due to a potential target-specific Cre activity, validation of appropriate recombination and expression of the gene(s) of interest is absolutely required to confirm efficient deletion when generating conditional knockout mice using the Ovgp1Cre:eGFP line.

Classical Estrogen Signaling in Ciliated Epithelial Cells of the Oviduct Is Nonessential for Fertility in Female Mice.

Ciliary action performs a critical role in the oviduct (Fallopian tube) during pregnancy establishment through sperm and egg transport. The disruption of normal ciliary function in the oviduct affects oocyte pick-up and is a contributing factor to female infertility. Estrogen is an important regulator of ciliary action in the oviduct and promotes ciliogenesis in several species. Global loss of estrogen receptor α (ESR1) leads to infertility. We have previously shown that ESR1 in the oviductal epithelial cell layer is required for female fertility. Here, we assessed the role of estrogen on transcriptional regulation of ciliated epithelial cells of the oviduct using single-cell RNA-sequencing analysis. We observed minor variations in ciliated cell genes in the proximal region (isthmus and uterotubal junction) of the oviduct. However, 17ß-estradiol treatment had little impact on the gene expression profile of ciliated epithelial cells. We also conditionally ablated Esr1 from ciliated epithelial cells of the oviduct (called ciliated Esr1d/d mice). Our studies showed that ciliated Esr1d/d females had fertility rates comparable to control females, did not display any disruptions in preimplantation embryo development or embryo transport to the uterus, and had comparable cilia formation to control females. However, we observed some incomplete deletion of Esr1 in the ciliated epithelial cells, especially in the ampulla region. Nevertheless, our data suggest that ESR1 expression in ciliated cells of the oviduct is dispensable for ciliogenesis and nonessential for female fertility in mice.