Progesterone and Inflammatory Response in the Oviduct during Physiological and Pathological Conditions

Progesterone has been shown to be a potent suppressor of several inflammatory pathways. During pregnancy, progesterone levels increase, allowing for normal pregnancy establishment and maintenance. The dysregulation of progesterone, as well as inflammation, leads to poor pregnancy outcomes. However, it is unclear how progesterone imbalance could impact inflammatory responses in the oviduct and subsequently result in early pregnancy loss. Therefore, in this review, we describe the role of progesterone signaling in regulating the inflammatory response, with a focus on the oviduct and pathological conditions in the Fallopian tubes

Progesterone and Inflammatory Response in the Oviduct during Physiological and Pathological Conditions

Progesterone has been shown to be a potent suppressor of several inflammatory pathways. During pregnancy, progesterone levels increase, allowing for normal pregnancy establishment and maintenance. The dysregulation of progesterone, as well as inflammation, leads to poor pregnancy outcomes. However, it is unclear how progesterone imbalance could impact inflammatory responses in the oviduct and subsequently result in early pregnancy loss. Therefore, in this review, we describe the role of progesterone signaling in regulating the inflammatory response, with a focus on the oviduct and pathological conditions in the Fallopian tubes

Crucial role of estrogen for the mammalian female in regulating semen coagulation and liquefaction <i>in vivo</i>

<div><p>Semen liquefaction changes semen from a gel-like to watery consistency and is required for sperm to gain mobility and swim to the fertilization site in the Fallopian tubes. Kallikrein-related peptidases 3 (KLK3) and other kallikrein-related peptidases from male prostate glands are responsible for semen liquefaction by cleaving gel-forming proteins (semenogelin and collagen). In a physiological context, the liquefaction process occurs within the female reproductive tract. How seminal proteins interact with the female reproductive environment is still largely unexplored. We previously reported that conditional genetic ablation of <i>Esr1</i> (estrogen receptor α) in the epithelial cells of the female reproductive tract (<i>Wnt7a</i>^Cre/+;<i>Esr1</i>^f/f) causes female infertility, partly due to a drastic reduction in the number of motile sperm entering the oviduct. In this study, we found that post-ejaculated semen from fertile wild-type males was solidified and the sperm were entrapped in <i>Wnt7a</i>^Cre/+;<i>Esr1</i>^f/f uteri, compared to the watery semen (liquefied) found in <i>Esr1</i>^f/f controls. In addition, semenogelin and collagen were not degraded in <i>Wnt7a</i>^Cre/+;<i>Esr1</i>^f/f uteri. Amongst multiple gene families aberrantly expressed in the absence of epithelial ESR1, we have identified that a lack of <i>Klks</i> in the uterus is a potential cause for the liquefaction defect. Pharmacological inhibition of KLKs in the uterus replicated the phenotype observed in <i>Wnt7a</i>^Cre/+;<i>Esr1</i>^f/f uteri, suggesting that loss of uterine and seminal KLK function causes this liquefaction defect. In human cervical cell culture, expression of several <i>KLKs</i> and their inhibitors (<i>SPINKs</i>) was regulated by estrogen in an ESR1-dependent manner. Our study demonstrates that estrogen/ESR1 signaling in the female reproductive tract plays an indispensable role in normal semen liquefaction, providing fundamental evidence that exposure of post-ejaculated semen to the suboptimal microenvironment in the female reproductive tract leads to faulty liquefaction and subsequently causes a fertility defect.</p></div

Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses

Female fertility requires estrogen to specifically stimulate estrogen receptor α (ERα)-dependent growth of the uterine epithelium in adult mice, while immature females show proliferation in both stroma and epithelium. To address the relative roles of ERα in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ERα knockout (UtEpiαERKO) mouse line was generated by crossing Esr mice with Wnt7a -Cre mice. Expression of Wnt7a directed Cre activity generated selective deletion of ERα in uterine epithelium, and female UtEpiαERKO are infertile. Herein, we demonstrate that 17β-estradiol ( E 2 )-induced uterine epithelial proliferation was independent of uterine epithelial ERα because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpiαERKO uteri after E 2 treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wild-type (WT) and UtEpiαERKO and mimicked the E 2 stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ERα was necessary to induce lactoferrin, an E 2 -regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ERα did not alter the E 2 -dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpiαERKO had robust evidence of apoptosis after 3 d of E 2 treatment. Therefore, we surmise that estrogen induced uterine hyperplasia involves a dispensable role for uterine epithelial ERα in the proliferative response, but ERα is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ERα in uterine tissue and its contribution during pregnancy