Prostaglandin E2 Reverses Prostate Enlargement in Rats, Rivaling Finasteride

In a surprise result that cuts against decades of prostaglandin biology, researchers report that dinoprostone—the naturally occurring prostaglandin E2—largely prevented prostate enlargement in rats treated with testosterone, performing nearly as well as finasteride, the standard drug for benign prostatic hyperplasia. The study, published in the journal Pharmacia, is a preliminary animal experiment, and its authors caution that the findings require validation before any human relevance can be considered. Even so, the outcome challenges the prevailing view that prostaglandin E2 signaling drives prostatic proliferation, and it opens an unexpected pharmacological avenue for a condition that affects a large share of aging men.

Benign prostatic hyperplasia is a non-malignant growth of glandular epithelial and stromal tissue within the transition and periurethral zones of the prostate. It is histologically distinct from simple benign prostatic enlargement, although it can ultimately produce bladder outlet obstruction and the cluster of problems known as lower urinary tract symptoms. Histological findings and clinical symptoms do not always align: a man can have tissue changes without obstruction, or symptoms without marked enlargement. Chronic localized inflammation, sometimes reflecting low-grade prostatitis or autoimmune processes, is commonly seen in the tissue and contributes to the overall pathology. Current drug therapy targets two components of the obstruction. Alpha-blockers relax adrenergically mediated prostatic smooth muscle, addressing the dynamic component, while 5-alpha reductase inhibitors such as finasteride shrink the gland by blocking the conversion of testosterone into dihydrotestosterone, the androgen that fuels the static component. Both classes carry side effects that undermine long-term adherence: 5-alpha reductase inhibitors can cause reduced libido, erectile dysfunction, decreased ejaculate volume and gynecomastia through endocrine interference, and survey instruments have linked chronic exposure to both drug classes with self-reported memory loss, confusion, depression and anxiety.

Dinoprostone acts through four G-protein-coupled receptors, EP1 through EP4, and influences processes ranging from inflammation to smooth muscle tone. Earlier in vitro work showed that prostaglandin E2 inhibits nerve-mediated contractile responses in isolated rat prostate tissue, an effect attributed to the EP2 subtype, suggesting a non-adrenergic route to prostatic smooth muscle relaxation. Yet the same signaling axis has well-documented pro-proliferative roles: EP2 and EP4 activation raises intracellular cyclic AMP and stimulates protein kinase A, a pathway generally associated with cell survival, and prostaglandin E2 is known to promote proliferation and tumorigenesis in many tissues, including prostate cancer models. The research team reasoned that context matters—receptor subtype engagement, tissue microenvironment and disease state can all flip the direction of the signal—and hypothesized that EP2-selective modulation might be therapeutic in benign hyperplasia rather than harmful.

To test the idea, the investigators used forty adult male Sprague-Dawley rats, two and a half to three months old and weighing 210 to 250 grams, randomly allocated into four groups of ten. Benign prostatic hyperplasia was induced by subcutaneous testosterone at 3 milligrams per kilogram per day for four consecutive weeks. A normal control group received phosphate-buffered saline only. A testosterone-only group served as the disease model, while two treatment groups received, in addition to testosterone, either oral finasteride at 5 milligrams per kilogram per day in 2.5 percent ethanol or oral dinoprostone at 7 milligrams per kilogram per day dissolved in a minimal ethanol and dimethyl sulfoxide vehicle, given one hour before the testosterone injection. The four-week treatment window was based on established timeframes for testosterone-driven hyperplasia in rats, and the dinoprostone dose was selected from prior rodent pharmacology studies showing biological activity without serious toxicity, with pilot observations supporting the choice.

The results were striking. Testosterone produced a highly significant enlargement of the prostate compared with normal controls, with p-values below 0.0001 for both absolute prostate weight and the prostatic index, which normalizes organ weight to body weight. Both finasteride and dinoprostone reversed this hypertrophy almost completely, returning weight and index to levels statistically indistinguishable from the normal baseline and from each other. Histological examination at 400-fold magnification showed the expected hyperplastic picture in the testosterone group—epithelial stratification, papillary infoldings into the gland lumina, and dense fibromuscular stromal expansion. Semi-quantitative histopathology scores rose sharply in the disease group and fell to comparable medians of roughly 1.5 in both treatment groups, with restored glandular architecture and reduced epithelial crowding. The dinoprostone group in particular showed a marked reduction in epithelial height and stratification, approaching normal morphology.

At the molecular level, testosterone elevated intraprostatic dihydrotestosterone, 5-alpha reductase type 2, the proliferation marker PCNA, the Wnt signaling effector beta-catenin, and estrogen receptor beta gene expression, the last nearly eight-fold above controls. Both drugs significantly suppressed all of these, generally restoring values toward normal. Finasteride, as expected from its mechanism, suppressed dihydrotestosterone slightly more than dinoprostone, a difference that reached significance at p below 0.05, and it also produced modestly stronger reductions in beta-catenin and estrogen receptor beta. The suppression of 5-alpha reductase activity itself, however, was statistically equivalent between the two treatments—an intriguing observation, since dinoprostone is structurally and mechanistically unrelated to 5-alpha reductase inhibitors, implying an indirect action on the androgen metabolic axis.

Inflammatory and remodeling mediators told a similar story with some nuance. Testosterone sharply raised the pro-inflammatory cytokine interleukin-6, prostaglandin E2 itself, the regulatory cytokine interleukin-27, the fibrotic factor transforming growth factor beta, and the angiogenic factor vascular endothelial growth factor, while suppressing the anti-inflammatory nuclear receptor PPAR-gamma. Both treatments corrected all of these deviations. Finasteride achieved slightly greater reductions in interleukin-6, prostaglandin E2 and interleukin-27, but the two drugs were statistically indistinguishable in suppressing transforming growth factor beta and vascular endothelial growth factor and in restoring PPAR-gamma. The authors interpret the fibrotic and angiogenic effects as downstream of reduced dihydrotestosterone, since DHT strongly induces vascular endothelial growth factor transcription, and possibly of EP2/cyclic AMP signaling, which in other models inhibits TGF-beta-driven collagen synthesis through phosphorylation of Smad proteins.

One result complicates simple narratives in both directions. The anti-apoptotic protein BCL2, elevated by testosterone, rose further under both treatments—significantly so with finasteride compared with both normal and disease controls, and with dinoprostone compared with normal controls but not significantly beyond the disease group. Combined with the drop in PCNA, the authors read this as a shift toward cytostasis rather than apoptosis: cells stop proliferating but remain viable. They argue this cytostatic equilibrium could theoretically spare tissue from apoptotic loss, though they acknowledge that BCL2 overexpression is also associated with tumor survival, making the long-term implications uncertain. The discussion frames the whole outcome as a resolution of the so-called prostaglandin E2 paradox: in malignant settings the EP2/cyclic AMP axis stabilizes beta-catenin and promotes growth, whereas in this non-malignant hyperplastic context the same signal appears to act oppositely, perhaps by inducing cell cycle arrest through regulatory kinases.

The limitations are substantial and the authors state them plainly. Only a single dinoprostone dose was tested, so no dose-response relationship exists. The design lacked a vehicle-only control group, meaning the solvents used to dissolve dinoprostone cannot be fully excluded as confounders. The work is a short-term rodent model of chemically induced hyperplasia, offering no long-term safety or efficacy data and no evidence about human disease. The abstract itself describes the findings as preliminary and warranting further investigation. What the study does establish is a reproducible signal in a controlled animal system: exogenous prostaglandin E2, at one dose, matched finasteride on anti-hypertrophic, anti-inflammatory and anti-angiogenic endpoints while falling slightly short on androgen suppression. If future work with multiple dosing regimens, dedicated vehicle controls and longer treatment periods confirms the mechanism, selective EP2 modulators could become candidates for a disease area where existing drugs trade symptom control for side effects that many patients cannot tolerate. For now, the result stands as an intriguing, context-dependent contradiction of prostaglandin dogma—confined to rats, and awaiting the studies that would tell whether it means anything for people.

Subject of Research: An animal study testing whether prostaglandin E2 (dinoprostone) prevents testosterone-induced benign prostatic hyperplasia in rats compared with finasteride.

Article Title: Preventive effect of Dinoprostone (Prostaglandin E2) on testosterone-induced prostatic hyperplasia in a rat model

Article References: Aldhalmi, A. K., Abdul-Hussein, B. A., Mashloosh, I. K. M., & Ridha-Salman, H. (2026). Preventive effect of Dinoprostone (Prostaglandin E2) on testosterone-induced prostatic hyperplasia in a rat model. Pharmacia, 73, Article e184820. https://doi.org/10.3897/pharmacia.73.e184820

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e184820

Keywords: benign prostatic hyperplasia, dinoprostone, prostaglandin E2, finasteride, testosterone, EP2 receptor, dihydrotestosterone, 5-alpha reductase, PCNA, rat model, prostate, preclinical study