Pregnenolone as a potential candidate for hormone therapy for female reproductive disorders targeting ERβ

Many steroid hormones such as estrogen (E2) bind to their receptors for the regulation of biological processes. Pregnenolone (P5) is the precursor form of almost all steroid hormones and is often used to treat skin disorders and neurological complications. However, the mechanism and physiological function of P5 in reproductive organs are not well established. In this study, we investigated the effects of P5 on activation and expression of E2 receptor (ER) in the uteri and ovaries. To study the mechanism of P5 directly, Ishikawa cells were transfected with E2 response element (ERE)-luciferase plasmid and isoforms of ER. ERE-luciferase activity induced by P5 was similar to that induced by E2, and P5 showed high activity for ERβ without any relevance to P5-metabolizing hormones such as progesterone (P4) and E2. In an animal study, immature female rats treated with P5 showed upregulation of ERα and downregulation of ERβ in the uteri, which is the main organ expressing ERα. In ERβ-expressing organ ovaries, estrogen receptor 1, estrogen receptor 2, and P4 receptor were all downregulated by P5 and E2. Also, a decrease of ovarian cell proliferation and viability was observed in response to P5 relative to the control, suggesting that P5 may be a candidate for antiproliferative hormone of ovarian cancer. These findings suggest that P5 stimulates ERE promoter by ERβ-mediated signaling in the uteri and ovaries. Activation of ERβ by P5 may help in understanding the mechanism of ER-related female reproductive diseases such as endometriosis and ovarian cancer.