Dual-action intranasal oxytocin enhances both male sexual performance and fertility in rats

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Oxytocin plays essential roles in both central and peripheral reproductive functions; however, its therapeutic potential for male sexual dysfunction remains largely unexplored. Currently available treatments often focus on either central or peripheral mechanisms, with few options addressing both simultaneously. For example, phosphodiesterase type 5 inhibitors primarily target peripheral erectile mechanisms but do not address central aspects of sexual desire or motivation. Conversely, dopaminergic agents may enhance central sexual motivation but have limited peripheral effects on reproductive organs. A comprehensive approach targeting both central and peripheral mechanisms could potentially offer more complete therapeutic benefits for male sexual dysfunction. Oxytocin has traditionally been recognized primarily as a female hormone due to its established roles in uterine contractions during parturition and milk ejection during lactation. However, emerging evidence suggests significant oxytocin involvement in male sexual function, as demonstrated by elevated blood oxytocin levels following ejaculation in men. In male rats, parvocellular paraventricular nucleus (PVN) oxytocin neurons project to the spinal cord and facilitate male sexual function by activating the spinal ejaculation generator located in the lumbar spinal cord.1 Furthermore, intraperitoneal oxytocin administration in male rats reduces the latency to sexual behavior, suggesting that exogenous oxytocin may enhance male sexual activity through central mechanisms.1 Beyond its central effects, oxytocin also plays an essential role in peripheral androgen synthesis and metabolism. In men, chronic reduction in circulating androgen levels leads to erectile dysfunction and depressive symptoms associated with male climacteric syndrome, also known as late-onset hypogonadism. Although androgen replacement therapy effectively alleviates these symptoms, prolonged steroid administration is associated with serious adverse effects, including prostatic hyperplasia and cancer, highlighting the need for androgen-independent strategies to improve sexual function. When rat or goat testicular tissue fragments are exposed to oxytocin, testosterone concentrations decrease while concentrations of 5α-dihydrotestosterone (DHT), a more potent androgen metabolite with higher affinity for androgen receptors, increase. Furthermore, in the rat testis and prostate, and in the human prostate, oxytocin promotes the expression and enzymatic activity of 5α-reductase, which converts testosterone to DHT.2 These findings suggest that oxytocin plays a part in the regulation of reproductive function by enhancing DHT synthesis through increased 5α-reductase activity. Recently, intranasal administration has gained attention as a minimally invasive method for effective drug delivery to the brain.3 This approach offers advantages over traditional systemic administration by potentially allowing direct nose-to-brain transport while also achieving systemic distribution, making it ideally suited for testing dual central and peripheral effects. The present study aimed to investigate whether intranasal oxytocin administration can simultaneously improve central and peripheral reproductive functions in male rats through dual-targeting mechanisms. Wistar rats (Jackson Laboratory, Japan) were used in this study. Sexually mature males (8-16 weeks of age, n = 44) and females (8-16 weeks of age, n = 12) were used. All experimental procedures were conducted in accordance with protocols approved by the Animal Experiment Committees of Okayama University, Japan. Adult male Wistar rats received oxytocin by intranasal administration. To investigate central effects, we analyzed hypothalamic neuronal activation using phosphorylated ERK (pERK)-immunoreactivity, which offers more rapid expression kinetics than traditional c-Fos, allowing better detection of direct central effects while minimizing secondary effects through peripheral feedback pathways. A total of 40 min after intranasal administration of either saline (control), 1 mM, or 10 mM oxytocin (n = 4 per group), brain sections were processed for pERK immunohistochemistry. The 10 mM oxytocin-treated group exhibited pronounced pERK-immunoreactivity in the PVN compared with other brain nuclei. Quantitative analysis revealed significantly enhanced pERK staining intensity in the PVN of 10 mM oxytocin-treated males compared to controls (P < 0.05), demonstrating that intranasal oxytocin effectively activates hypothalamic neurons (Figure S1). To evaluate effects on sexual behavior, we identified sexually inactive males that failed to ejaculate during a 4-week training period with estrus females. These males received either saline (n = 6) or 10 mM oxytocin (n = 6) 40 min before weekly behavioral observations for an additional 4 weeks. In sexually inactive male rats, oxytocin treatment markedly improved sexual activity. By week 7 of treatment, oxytocin-treated males showed significantly decreased mount and intromission latencies (P < 0.01) with a trend toward reduced ejaculation latency (P = 0.09) (Figure S2A). The oxytocin-treated group also showed increased frequencies of mounts, intromissions, and ejaculations compared to controls (mount frequency: P < 0.01; intromission frequency: P = 0.026; ejaculation frequency: P < 0.01), as evidenced by increased rates of ejaculatory and intromission behaviors (Figure S2B). Analysis of cumulative incidences of sexual behaviors revealed that the oxytocin-treated group showed a trend toward a higher proportion of animals displaying ejaculation (P = 0.075) (Figure S2C). To investigate effects on peripheral reproductive function, a separate cohort of male rats received daily intranasal administration of either saline (control) (n = 10) or 10 mM oxytocin (n = 10) for 1 week. Chronic intranasal oxytocin administration significantly enhanced sperm parameters as assessed by computer-assisted sperm analysis (CASA) system (HT CASA-Ceros II; Hamilton Thorne, MA, USA) as previously described.4 The oxytocin-treated group exhibited significantly higher sperm motility rate, progressive motility rate, and sperm count compared to the control group (all P < 0.001) (Figure S3). Additionally, oxytocin treatment significantly increased epididymal, seminal vesicle, and prostate weights (epididymis: P = 0.030; seminal vesicles: P = 0.018; prostate: P < 0.01), all of which suggest improved reproductive function (Figure S4). In contrast, both body weight and testis weight remained unchanged between groups, indicating that oxytocin may enhance epididymal epithelial cell function and accessory gland activity rather than directly affecting testicular sperm production (Figure S4). Our findings on sexual behavior are particularly notable because we used males that remained ejaculation-naïve despite extended training. The improvement observed in these sexually inactive males suggests that oxytocin may overcome fundamental deficits in sexual motivation or performance, potentially through both direct central actions and enhanced androgen signaling.1 The increased epididymal sperm counts without changes in testis weight suggests that oxytocin enhances epididymal function, promoting sperm maturation and storage rather than directly increasing sperm production.2 Since decreased androgen signaling attenuates male sexual activity, sexually inactive males may have insufficient androgen synthesis. Intranasal oxytocin may therefore enhance sexual activity by promoting androgen synthesis to optimal levels. This dual-action mechanism may be relevant to understanding age-related reproductive decline, as both testosterone levels and oxytocin signaling decline with age, potentially contributing to sexual dysfunction.2 This study demonstrates dual effects of intranasal oxytocin on both central and peripheral reproductive functions in a rat model. Our findings provide preclinical evidence of oxytocin’s dual mechani

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