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Article

Impact of Major Pelvic Ganglion Denervation on Prostate Histology, Immune Response, and Serum Prolactin and Testosterone Levels in Rats

by
Pabeli Saraí Becerra-Romero
1,
Cynthia Fernández-Pomares
2,
Juan Carlos Rodríguez-Alba
3,
Jorge Manzo
4,
Gonzalo E. Aranda-Abreu
4,
Fausto Rojas-Durán
4,
Deissy Herrera-Covarrubias
4,
María Rebeca Toledo-Cárdenas
4,
Genaro Alfonso Coria-Ávila
4 and
Maria Elena Hernández-Aguilar
4,*
1
Doctorado en Investigaciones Cerebrales, Universidad Veracruzana, Xalapa 91190, Veracruz, Mexico
2
Laboratorio para el Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela de Medicina del Instituto Politécnico Nacional, Mexico City 11340, Mexico
3
Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa 91190, Veracruz, Mexico
4
Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa 91190, Veracruz, Mexico
*
Author to whom correspondence should be addressed.
Immuno 2025, 5(3), 33; https://doi.org/10.3390/immuno5030033
Submission received: 17 April 2025 / Revised: 1 July 2025 / Accepted: 19 July 2025 / Published: 6 August 2025
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Abstract

The prostate gland, a male accessory reproductive organ, is regulated by hormonal inputs and autonomic innervation from the major pelvic ganglion. This study examined the effects of major pelvic ganglion denervation on prostate histology, immune cell infiltration, and systemic levels of prolactin, testosterone, and cytokines in rats. Male Wistar rats (300–350 g) were divided into groups receiving bilateral axotomy of the hypogastric nerve, the pelvic nerve, or both, alongside with a sham-operated control. After 15 days, the animals were killed, and prostate tissue was dissociated in DMEM medium containing DNase I and collagenase. The dissociated cells were stained with fluorochrome-conjugated antibodies, and cell characterization was performed using a flow cytometer. Hematoxylin and eosin (H&E) staining was used to analyze histological characteristics, while testosterone, prolactin, and interleukin levels were measured via ELISA. Histological analysis revealed inflammatory atypical hypertrophy e hiperplasia. Immunological assessments demonstrated increased leukocytes, T lymphocytes (CD4+ and CD8+), B lymphocytes, and macrophages following double nerve axotomy. Serum analyses showed elevated pro-inflammatory cytokines IL-1β, IL-6, and IFN-γ, as well as anti-inflammatory IL-10, in denervated animals. Hormonal assessments revealed significant increases in serum prolactin and testosterone levels after double axotomy. Loss of neural control may promote pathological prostate changes via inflammation and hormonal dysregulation, offering insights into neuroimmune and neuroendocrine mechanisms underlying prostate pathologies.

1. Introduction

The prostate gland, a key male accessory reproductive organ, produces prostatic fluid essential for sperm motility and fertilization [1]. Its function and structural integrity are regulated by autonomic innervation from the major pelvic ganglion, which integrates sympathetic and parasympathetic fibers originating from the hypogastric and pelvic nerves, originating from the T13–L2 and L6–S1 spinal segments, respectively [2]. Disruption of this neural input significantly alters prostate physiology, leading to structural and functional changes [3,4].
Histologically, the prostate consists of secretory acini lined by pseudostratified epithelium, supported by connective tissue and smooth muscle. In male rats, the prostate includes ventral, dorsal, and lateral lobes with distinct features, the ventral lobe has small alveoli with abundant invaginations lined by columnar epithelial cells (~10–12 μm in height), whereas the dorsolateral lobes contain cuboidal epithelial cells with centrally or basally located nuclei [5,6,7,8]. Denervation of the hypogastric and pelvic nerves can induce epithelial atrophy, loss of nuclear polarity, and tissue disorganization, underscoring the essential role of autonomic innervation in prostate architecture maintenance [4].
Hormonal regulation is equally crucial for prostate development and function. Testosterone and prolactin are key regulators, promoting epithelial proliferation, prostatic fluid synthesis, and cellular growth [9,10,11,12]. Neural disruption can alter hormonal levels; denervation has been shown to suppress testosterone release and reduce androgen receptor expression, although prolactin receptor expression remains unchanged in the prostate and the major pelvic ganglion [13,14]. Such disruptions mimic age-related hormonal changes, including reduced testosterone and elevated prolactin levels, which are associated with conditions like benign prostatic hyperplasia (BPH) and prostate cancer [15,16,17].
The immune response can also contribute to prostate health and even participate in disease progression. Neural denervation can trigger inflammation, leading to increased infiltration of leukocytes, T lymphocytes, B lymphocytes, and macrophages into prostatic tissue [18,19,20]. This inflammatory response is associated with elevated pro-inflammatory and anti-inflammatory cytokines, such as IL-1β, IL-6, IFN-γ, and IL-10 [17,21,22,23,24,25]. Chronic inflammation disrupts the balance between cell proliferation and apoptosis, driving tissue remodeling and contributing to the development of BPH and prostate cancer [17,21,26]. Thus, a complex interplay exists between neural regulation, hormonal control, and immune responses within the prostate. We hypothesize that autonomic denervation of the major pelvic ganglion, or the absence of autonomic input, alters prostate histology, hormonal secretion, and modifies immune dynamics, fostering inflammation and pathological changes. This study aims to investigate the effects of major pelvic ganglion denervation on prostate histology, serum prolactin and testosterone levels, and immune responses, including cytokine profiles and immune cell infiltration. Understanding these mechanisms will provide insights into the neuroimmune and neuroendocrine regulation of prostate pathologies.

2. Materials and Methods

2.1. Subjects

Twenty-six male Wistar rats (300–350 g) were housed in a large Plexiglas cage and maintained on a 12:12 reverse light/dark cycle (light off for 8 h). Food and water were provided ad libitum. All experimental procedures were approved by the Veracruzana University Committee on Laboratory Animals with registration number 2021-016-a and the Official Mexican Norm (NOM.062-ZOO-1999).

2.2. Experimental Groups and Surgical Procedures

Rats were randomly assigned to one of the four groups: sham-operated (n = 6): pelvic (Pv) and hypogastric (Hg) nerves were exposed but not transected; Pv lesion (n = 6): bilateral transection of the pelvic nerves; Hg lesion (n = 6): the bilateral transection of the hypogastric nerves: Pv + Hg lesion (n = 6): the bilateral transection of both the pelvic and hypogastric nerves.
Under deep anesthesia (sodium pentobarbital, 50 mg/kg, i.p.), the major pelvic ganglion was exposed near the prostate, and the Pv and/or Hg nerves were carefully tracked and transected as per group assignments. In the sham group, the nerves were exposed but not cut. Given that Pv lesions impair micturition, the bladder was manually expressed twice daily post-surgery to maintain animal health. Muscle and skin were sutured using Catgut 3-0, and animals received a single intramuscular dose of antibiotic (0.1 mL Pengesod, 1,000,000 U, Lakeside Mexico). At the study’s conclusion, nerve regeneration was ruled out upon re-examination, and animals were kept under those conditions for 15 days.

2.3. Histological Analysis

Formaldehyde (10%) fixed prostate tissues were dehydrated through graded alcohols, embedded using paraffin, and sectioned at 5 μm thickness in a microtome (RM 2125RT Leica, Wetzlar, Germany). Sections were mounted on gelatinized slides and stained with hematoxylin and eosin (H&E) following standard protocols: deparaffinization: twice in xylene (5 min each); rehydration: graded alcohols (100% and 96%) and water; staining: hematoxylin (6 min), rinse in water (30 s), acid alcohol differentiation (quick immersion), rinse in water (10 s), lithium carbonate bluing (30 s), rinse in water (10 s), and eosin (4 min); dehydration and clearing: ethanol (96% and 100%; 3 min each), ethanol/xylene (1:1; 5 min), and xylene (5 min). Then, slides were coverslipped with Permount, air-dried, and examined under a light microscope (Optisum Mic 990, Desego, México) and an OPTISUM camera coupled with TopView software for photo and video capture (Velab. Com). Photomicrographs were captured at 40× magnification. We evaluated histological characteristics following the criteria reported by Skolnik et al. 1994 [27].

2.4. Tissue Collection

Rats were killed using an intraperitoneal overdose of sodium pentobarbital (120 mg/kg, i.p.). Blood was collected via cardiac puncture for serum analysis. The prostate lobes (ventral and dorsolateral) were excised; the right lobes used for immune cell analysis and the left lobes fixed in 10% formaldehyde for histological examination.
For immune analysis, tissues were washed with phosphate-buffered saline (PBS; pH 7.4; Sigma-Aldrich P3813) and twice with Hanks’ solution (without calcium chloride, magnesium sulfate, or sodium bicarbonate; Sigma-Aldrich H2387) to remove debris. The tissues were then placed in Dulbecco’s Modified Eagle Medium (DMEM; Gibco 12100-038) with 20% fetal bovine serum (FBS; Sigma-Aldrich F2442) for dissociation.

2.5. Dissociation of Prostate Tissue

Prostate tissues were minced in a Petri dish into 2–3 mm3 pieces, then were immersed in conical tubes and incubated in 5 mL of DMEM with 20% FBS. Then, collagenase type IV (1 mg/mL per 100 mg tissue; Sigma-Aldrich C5138; ≥125 CDU/mg) was added at 37 °C for 2 h with gentle agitation every 10 min.
Following incubation, DNase I (0.12 mg/mL; Roche 11284932001) was added to enhance dissociation, and samples were pipetted gently for one minute. The cell suspension was filtered through a 100 μm cell strainer, centrifuged (1500 rpm, 5 min), and erythrocytes were lysed using 3 mL of 0.85% ammonium chloride for 3 min at room temperature. After stopping the reaction with 5 mL of cold Hank’s solution, cells were centrifuged again, and the pellet resuspended in 1 mL of DMEM with 20% FBS. Viability was assessed using the trypan blue exclusion method, stained at a 1:1 ratio and counted using a Neubauer chamber under 40× microscope magnification.

2.6. Quantification of Serum Interleukins, Prolactin, and Testosterone

Blood samples were collected via cardiac puncture, allowed to clot, centrifuged (3500 rpm, 10 min) at room temperature, and serum was separated and stored at −20 °C. Testosterone, prolactin, and interleukin levels (IL-1β, IL-6, IFN-γ, and IL-10) were quantified using ELISA as per the manufacturer’s instructions.

2.7. Characterization of Immune Cells

Prostate-derived single-cell suspensions (1 × 105 cells/mL) were stained with fluorochrome-conjugated antibodies (BD Biosciences, San Diego, CA, USA): Anti-CD45 BV421, Anti-CD3 BV605, Anti-CD4 PE, Anti-CD8a APC, Anti-CD19 APC Cy7, and Anti-CD11b PerCP Cy5.5. After a 15-minute dark incubation at room temperature, cells were washed with PBS, centrifuged (1500 rpm for 5 min), fixed in FixFacs solution (1% paraformaldehyde in PBS), protected from light, and stored at 4 °C. Flow cytometry was performed using a BD LSRFortessa flow cytometer (Becton Dickinson, San Jose, CA, USA), and data were analyzed using FlowJo software (Tree Star Inc., Ashland, OR, USA).

2.8. Statistical Analysis

Data are presented as mean ± standard error of the mean (SEM). Group comparisons of immune cell populations and serum hormone levels were analyzed using One-way ANOVA, followed by Tukey’s post hoc test. Interleukin levels were analyzed using unpaired t-tests. Statistical significance was set at p < 0.05, and analyses were performed using GraphPad Prism software (v10.3.1).

3. Results

Previous work from our laboratory demonstrated that axotomy of the Pv and Hg nerves induces significant alterations in prostate cytoarchitecture, accompanied by increased immune cell infiltration (27). Building on these findings, the current study provides a detailed analysis of histological, immune, and hormonal changes associated with major pelvic ganglion denervation.

3.1. Histological Description of the Ventral and Dorsolateral Prostate

In normal ventral prostate histology, the acini are lined by columnar epithelium with basally located round nuclei and a prominent supranuclear clear zone corresponding to the Golgi apparatus. The epithelial cells form a regular monolayer supported by a thin basal membrane, and the lumen contains homogeneous acidophilic material. Each alveolus is surrounded by dense stromal tissue composed of smooth muscle fibers, nerves, and fibroblasts (A). Following hypogastric nerve axotomy, the epithelium exhibited cuboidal to columnar cells, mild cellular crowding, loss of nuclear-cytoplasmic polarity, and periglandular inflammatory infiltration, suggesting atrophic inflammatory hyperplasia (B). Pelvic nerve axotomy resulted in irregularly shaped acini of varying sizes projecting into the lumen. The epithelial cells displayed increased height, loss of polarity, and small piling-up formations, along with interstitial leukocytic infiltration, indicating inflammatory atypical hypertrophy (C). Combined pelvic and hypogastric nerve axotomy led to crowded, rounded epithelial cells with absent supranuclear zones. Notably, abundant interstitial and luminal leukocytic infiltration was observed, consistent with inflammatory atypical hyperplasia (D).
The dorsolateral prostate displays comparable histological features to the ventral lobe, with the exception of a cuboidal epithelial lining. The dorsolateral prostate displays comparable histological features to the ventral lobe, with the exception of a cuboidal epithelial lining (E). Following hypogastric nerve axotomy, the cells retained the histological features of this lobe; however, there was abundant leukocytic infiltration in both the stroma and the lumen, reflecting an inflammatory process (F). Comparable changes also occurred in the dorsolateral lobe, with pelvic nerve axotomy inducing irregular acini projecting into the lumen, epithelial elongation, loss of polarity, small piling-up formations, and interstitial leukocytic infiltration, consistent with inflammatory atypical hypertrophy (G). Following axotomy of both nerves, the epithelial cells exhibited a morphological change from cuboidal to rounded, with budding into the lumen. Accompanying this, there was notable leukocytic infiltration within the lumen. These features are consistent with inflammatory atypical hyperplasia (H) (Figure 1).

3.2. Immune Cell Infiltration in the Ventral and Dorsolateral Prostate

Preganglionic axotomy significantly increased immune cell infiltration in the prostate. In the ventral prostate (Figure 2), axotomy led to a substantial increase in CD45+ cells. Leukocytes increased by ~50% following Hg or Pv axotomy and by over 60% with double axotomy. Similarly, in the dorsolateral prostate, leukocyte infiltration increased by ~45% with Hg axotomy, ~50% with Pv axotomy, and ~70% with double axotomy. These findings highlight the exacerbated immune response induced by dual nerve denervation.
Total T lymphocyte (CD3+) levels (Figure 3) increased in both prostate lobes following axotomy. In the ventral lobe, CD3+ cells rose by ~50% after Pv axotomy and double axotomy. In the dorsolateral lobe, increases were ~35% with Hg axotomy, ~45% with Pv axotomy, and ~60% with double axotomy. Interestingly, a slight decrease in T lymphocytes was observed in the sham group, indicating a baseline regulatory state in the absence of nerve injury.
Helper T lymphocytes (CD4+) showed substantial increases in response to axotomy (Figure 4). In the ventral prostate, CD4+ cells increased by ~38% with Hg axotomy and by ~55% with Pv and double axotomy. In the dorsolateral lobe, increases were ~35% and ~40% with Hg and Pv axotomy, respectively, and ~63% with double axotomy, underscoring the amplified inflammatory response in dual nerve denervation.
Cytotoxic T lymphocytes (CD8+) (Figure 5) were also elevated across both lobes. In the ventral prostate, increases of ~56% with Hg axotomy, ~42% with Pv axotomy, and ~68% with double axotomy were observed. Similar trends were noted in the dorsolateral lobe, indicating a consistent cytotoxic T cell response to nerve injury.
B lymphocyte (CD19+) infiltration increased significantly in both lobes (Figure 6). Following Hg axotomy, CD19+ cells increased by 15–25%, while Pv axotomy resulted in ~40% increases. Double axotomy triggered the highest increases, ranging from ~50% to ~60%, suggesting a strong humoral immune response induced by nerve denervation.
Macrophages (CD11b+), key mediators of phagocytosis and immune modulation, displayed progressive increases in the ventral prostate (Figure 7). Following Hg axotomy, macrophages increased by ~18%, Pv axotomy resulted in a ~35% increase, and double axotomy led to a ~38% rise. In the dorsolateral lobe, macrophage increases were ~10% with Hg and Pv axotomy, escalating to ~20% with double axotomy.

3.3. Systemic Levels of Interleukins

Circulating levels of pro-inflammatory cytokines, including IL-1β, IL-6, and IFN-γ, as well as the anti-inflammatory cytokine IL-10, were significantly elevated in animals subjected to double denervation compared to the sham-operated group (Figure 8).

3.4. Systemic Levels of Prolactin and Testosterone

The effects of axotomy on serum prolactin and testosterone levels varied depending on the specific nerves targeted. Prolactin: axotomy of Hg nerve led to a decrease in serum prolactin levels, while axotomy of Pv nerve had no significant effect. Notably, double axotomy (Hg + Pv) induced a significant increase in systemic prolactin levels compared to all other groups. Testosterone: serum testosterone levels were unaffected by Hg axotomy compared to the sham-operated group. However, Pv axotomy resulted in a significant increase in testosterone levels, an effect that was further amplified following double axotomy (Hg + Pv) (Figure 9).

4. Discussion

This study examined the effects of major pelvic ganglion denervation on prostate histology, immune cell infiltration, and systemic levels of interleukins, prolactin, and testosterone in rats. The findings demonstrate that the loss of autonomic innervation profoundly disrupts prostate homeostasis, resulting in structural, immune, and hormonal changes. These results underscore the critical role of autonomic input in maintaining prostate integrity and reveal the intricate interplay between neural regulation, hormonal control, and immune responses.

4.1. Impact of Denervation on Prostate Histology

The prostate gland relies on autonomic innervation for maintaining its structural integrity and normal function. In this study, denervation of the pelvic and hypogastric nerves induced significant histological changes in both the ventral and dorsolateral lobes of the prostate (n = 6). These changes included loss of nuclear polarity, cellular disorganization, generating atypical hypertrophy and hyperplasia. These findings highlight the essential role of neural inputs in preserving the cytoarchitecture of the prostate epithelium, aligning with previous studies that have demonstrated the impact of autonomic control on glandular structure and function [3,28,29,30,31].
The observed histological changes are likely attributed to the loss of trophic support provided by neurotransmitters such as acetylcholine and norepinephrine, which are secreted by parasympathetic and sympathetic fibers, respectively. These neurotransmitters are known to regulate epithelial cell proliferation, differentiation, and secretory activity [32,33]. Despite the established importance of autonomic signaling, the precise molecular mechanisms driving these histological changes remain incompletely understood. One plausible explanation involves alterations to the cytoskeleton, a network of proteins critical for cellular stability and organization [34].
Denervation may disrupt adrenergic and cholinergic signaling, triggering adaptive changes in the cytoskeleton that destabilize cellular shape and cohesion within the prostate alveoli. Notably, increased expression of nerve growth factor (NGF) and its receptor TrkA has been implicated in promoting cellular atrophy and destabilizing actin filaments, which may contribute to the histological changes observed in this study [31,35]. This suggests that the loss of neural input may upregulate NGF-TrkA signaling, a hypothesis that warrants further investigation.
Another potential factor is vimentin, an intermediate filament protein involved in cellular integrity and adaptability to microenvironmental changes [36]. Vimentin interacts with actin and tubulin, supporting cytoskeletal stability under physiological conditions. Hormones such as prolactin, testosterone, and adrenaline have been shown to regulate vimentin expression in stromal cells and prostate fibroblasts [37,38,39]. However, overexpression of vimentin under pathological conditions has been associated with epithelial-mesenchymal transition (EMT), a process linked to structural remodeling and disease progression [40]. The histological changes observed in the denervated prostate may result from vimentin overexpression driving EMT [39,41,42]. Future studies should assess vimentin expression to determine whether these changes are directly attributable to disrupted neurotransmission or are secondary to elevated prolactin or testosterone levels observed in this study.
In summary, denervation-induced disruption of signaling molecules may destabilize the cytoskeleton, impairing cellular cohesion and structure. Alternatively, vimentin overexpression may promote EMT, further contributing to the observed histological changes in the prostate [43,44]. Investigating these mechanisms will provide valuable insights into how autonomic inputs regulate prostate integrity and how their loss contributes to disease pathogenesis.

4.2. Enhanced Immune Cell Infiltration and Inflammatory Response

One of the most striking observations in this study was the increased presence of leukocytes in prostate tissue following denervation. Leukocyte infiltration in the prostate of rats has been previously reported, with a notable presence of CD4+, CD8+, and NK lymphocytes playing key roles in maintaining tissue homeostasis, but denervation significantly amplified immune cell infiltration [16,20,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59].
This observation aligns with the concept that the nervous system plays a critical role in modulating immune function, and disruption of this regulation can lead to inflammation [50]. Autonomic nerves regulate immune responses through the production of anti-inflammatory cytokines and modulation of endothelial adhesion molecule expression, which governs leukocyte extravasation [51]. So, the absence of autonomic input may disrupt these mechanisms, allowing increased immune cell recruitment into the prostate.
One potential mechanism underlying this infiltration involves the upregulation of chemokines, such as IL-8, by epithelial cells following denervation [52]. IL-8 is a potent chemoattractant for immune cells, primarily neutrophils, but it also plays a role in recruiting other immune populations, including T cells and macrophages [53,54]. This chemokine-driven recruitment may be further amplified through interaction between immune cells and prostate epithelial cells via CD40-CD40L signaling. Prostate epithelial cells in both rats and humans express the CD40 receptor [55], while the CD40L ligand is expressed on B cells, macrophages, and activated T lymphocytes [56,57,58,59,60].
Denervation may increase CD40 expression in damaged epithelial cells, perpetuating inflammation and promoting the development of prostate pathologies [61]. The persistence of this inflammatory state suggests a shift in the local immune environment, potentially contributing to long-term tissue remodeling and dysfunction. Future studies should investigate whether blocking IL-8 signaling or inhibiting CD40-CD40L interactions can mitigate inflammation and preserve prostate homeostasis. Understanding the molecular pathways driving immune cell infiltration could offer new therapeutic targets for managing prostate diseases associated with chronic inflammation.

4.3. Elevated Systemic Cytokine Levels

This study identified significant increases in systemic levels of the pro-inflammatory cytokines IL-1β, IL-6, and IFN-γ, along with the anti-inflammatory cytokine IL-10, in animals subjected to denervation. These cytokines play pivotal roles in both the initiation and maintenance of inflammatory responses. IL-1β and IL-6 are critical for the activation and differentiation of immune cells, while IFN-γ is essential for macrophage activation and antigen presentation [62]. The elevation of IL-10 likely represents a compensatory mechanism aimed at limiting excessive inflammation. IL-10 is well-known for its ability to inhibit the synthesis of pro-inflammatory cytokines and mitigate immune-mediated tissue damage [63,64].
The simultaneous elevation of both pro- and anti-inflammatory cytokines reflects a complex regulatory response to denervation-induced tissue injury. The origin of this systemic response it is not known, although it is likely that the spleen is secreting these interleukins into the bloodstream to regulate the function of the immune cells recruited in the affected tissue [54,65,66,67,68].
In the context, the increase in pro-inflammatory cytokines such as IL-1β, IL-6, and IFN-γ indicates chronic inflammation driven by tissue injury. It is plausible to hypothesize that the spleen responds to IL-8 secreted by prostate epithelial cells, since the spleen contains receptors for this chemokine [54]. Testing this hypothesis in future studies could clarify the role of the spleen and other immune organs in denervation-induced inflammation.

4.4. Alterations in Serum Prolactin and Testosterone Levels

Denervation resulted in significant increases in serum levels of prolactin and testosterone, particularly pronounced when both the pelvic and hypogastric nerves were transected. Prolactin, beyond its role as a hormone, also functions as a cytokine, influencing immune responses and promoting inflammation [69]. Elevated prolactin levels may enhance the recruitment and activation of immune cells within the prostate, contributing to the inflammatory environment observed in denervated tissue. The increase in testosterone levels following denervation is particularly intriguing, given its established role in prostate growth and function, because it is generally considered to have anti-inflammatory effects within the prostate, and its elevation may reflect a compensatory mechanism to reduce the inflammation [70].
Disrupted neural input likely affects the hypothalamic-pituitary-gonadal (HPG) axis, leading to altered hormonal secretion. Both prolactin and testosterone are regulated by the hypothalamus: dopamine, produced in the arcuate nucleus inhibits prolactin release, while gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone (LH) release, promoting testosterone synthesis in the testes. Denervation-induced changes in neural signaling may reduce dopamine-mediated inhibition of prolactin and increase GnRH secretion, thereby elevating both hormones. Additionally, evidence suggests a connection between the prostate, the hypothalamus, the preoptic area, and the arcuate nucleus [71,72,73]. The loss of autonomic control from the prostate may disrupt this communication, triggering hormonal changes. Reduced dopamine levels in the portal circulation and elevated thyrotropin-releasing hormone (TRH) levels have been observed under similar conditions, which could contribute to the increased prolactin and testosterone levels seen in this study [74].

4.5. Interplay Between Neural Regulation, Hormones, and Immune Responses

This study highlights the intricate relationship between neural inputs, hormonal regulation, and immune responses in maintaining prostate homeostasis. Autonomic nerves not only regulate the physiological functions of the prostate, such as secretion and structural integrity, but also play a critical role in modulating local immune surveillance and systemic hormone levels. The loss of autonomic control may leave prostate tissue vulnerable to heightened immune activity, creating a pro-inflammatory environment that facilitates tissue remodeling and dysfunction. This inflammatory milieu, combined with hormonal imbalances, could contribute to the development of pathological conditions such as inflammatory atypical hypertrophy and hyperplasia (BPH), or even prostate cancer [15,16,75].

4.6. Implications for Prostate Diseases and Future Directions

Chronic inflammation is a well-established contributor to the pathogenesis of prostate diseases. So, the denervation-induced inflammatory response observed in this study provides a potential mechanistic link between neural dysfunction and prostate pathology. Understanding how autonomic nerves regulate immune cell behavior and cytokine production could reveal novel therapeutic targets for managing prostate conditions driven by inflammation.
Additionally, the hormonal alterations following denervation underscore the importance of considering neuroendocrine factors in prostate disease development. The interplay between elevated prolactin and testosterone levels and their effects on prostate tissue and immune responses warrants further investigation. The exact molecular pathways through which denervation leads to increased cytokine production and immune cell infiltration remain to be fully elucidated. Future studies should focus on identifying these mechanisms, including the roles of neurotrophic factors, neurotransmitter receptors on immune cells, and the hypothalamic-pituitary axis in mediating these effects.
Moreover, investigating the long-term consequences of denervation on prostate health and determining whether these changes are reversible will have important clinical implications. Exploring pharmacological interventions targeting autonomic inputs, cytokine signaling, or hormonal regulation may provide effective strategies to mitigate inflammation, restore homeostasis, and prevent disease progression. By addressing these knowledge gaps, future research could pave the way for innovative approaches to the prevention and treatment of prostate diseases associated with autonomic dysfunction.

5. Conclusions

In conclusion, loss of hypogastric nerve control primarily induces inflammatory atypical hyperplasia when both nerves are simultaneously denervated in both lobes. In contrast, loss of pelvic nerve control primarily leads to inflammatory hypertrophy in both lobes. These findings suggest that the pelvic nerve regulates epithelial architecture and promotes glandular differentiation, while the hypogastric nerve modulates the inflammatory microenvironment. The combined loss of neural control favors a strong inflammatory response and atypical epithelial proliferation, supporting a complementary role of both nerves in maintaining prostatic homeostasis.
Together, these findings suggest that neural dysfunction may contribute to prostate disease pathogenesis by creating a microenvironment characterized by chronic inflammation and hormonal dysregulation, conditions known to drive diseases in the prostate. By elucidating the interplay between neural inputs, immune activity, and hormonal control, this study offers a foundation for future research aimed at developing therapeutic strategies targeting neuroimmune and neuroendocrine pathways. Such approaches could help mitigate inflammation, restore hormonal balance, and preserve prostate function in the face of autonomic dysfunction.

Author Contributions

Conceptualization, M.E.H.-A. and C.F.-P.; methodology, J.C.R.-A.; formal analysis, J.M. and G.A.C.-Á.; investigation, P.S.B.-R.; resources, M.E.H.-A. and J.C.R.-A.; data curation M.E.H.-A. and P.S.B.-R.; writing—original draft preparation, P.S.B.-R. and M.E.H.-A.; writing—review and editing, G.E.A.-A. and F.R.-D.; visualization, D.H.-C.; supervision, J.C.R.-A. and M.R.T.-C.; project administration, C.F.-P.; funding acquisition, M.E.H.-A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by a scholarship from SECIHTI (Grant Number. PSBR/960407), by the Academic Corps of Neurochemistry (Grant Number. UV-CA304) and UV-SIREI project (Grant. Number 10480202266) of Universidad Veracruzana.

Institutional Review Board Statement

The animal study protocol was approved by the Institutional Review Board, the Internal Committee for the Use and Care of Laboratory Animals (CICUAL) of the Brain Research Institute at Universidad Veracruzana (registration no. 2021-016-a), following the Mexican Official Standard NOM-062-ZOO-1999.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data are in this manuscript; there is no additional data.

Acknowledgments

The authors would like to thank Miriam Barradas Moctezuma, Eloy Gasca-Pérez, and Marilú Domínguez-Pantoja for their technical assistance.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

BPHBening Prostatic Hyperplasia
CDCluster of Differentiation
CICUALComité Interno para el Uso y Cuidado de Animales de Laboratorio
DMEMDulbecco’s Modified Eagle Medium
ELISAEnzyme-Linked Immunoabsorbent Assay
FBSFetal Bovine Serum
HgHypogastric Nerve
MPGMayor Pelvic Ganglion
PvPelvic Nerve
INF-γInterferon Gamma
ILInterleukin

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Figure 1. Microphotograph of the ventral prostate (VP) from a rat, stained with Hematoxylin-Eosin. (A) Normal ventral prostate. Acini are lined by columnar epithelial cells (arrow) with visible nuclei (N), a prominent Golgi apparatus (GA), lumen (Lu), stroma (S), and a blood vessel (Bv). (B) Atrophic inflammatory hyperplasia corresponding to hypogastric nerve axotomy. Acinar architecture is preserved, but epithelial cells are cuboidal, the blood vessel is enlarged, mild cellular crowding, and the stroma shows periglandular inflammatory infiltration (Lk). (C) Inflammatory atypical glandular hypertrophy following pelvic nerve axotomy. Epithelial cells exhibit increased height, the Golgi apparatus is not clearly visible, mild cellular crowding, and the stroma is enlarged with evident leukocytic infiltration. (D) Inflammatory atypical hyperplasia corresponding to combined hypogastric and pelvic nerve axotomy (HgN + PvN). Epithelial cells are rounded, and the epithelium appears disorganized with lukocytes in both the stroma and the lumen. (E) Normal dorsolateral prostate. Normal epithelium is composed of cuboidal epithelial cells (EC) with well-defined nuclei (N), a prominent Golgi apparatus (GA), lumen (Lu), stroma (S), and a blood vessel (BV). (F) Inflammatory process corresponding to hypogastric nerve axotomy. Acinar architecture is preserved, with leukocytes (Lk) present in both the stroma and the lumen. (G) Inflammatory atypical hypertrophy following pelvic nerve axotomy. Epithelial cells exhibit increased height, with the Golgi apparatus still visible, and are infiltrated by leukocytes, the stroma. (H) Inflammatory atypical hyperplasia corresponding to combined hypogastric and pelvic nerve axotomy (HgN + PvN). Epithelial cells are rounded, the epithelium appears disorganized, and leukocytes are present within the stroma and lumen. Scale bar = 50 µm (40× magnification). n = 6.
Figure 1. Microphotograph of the ventral prostate (VP) from a rat, stained with Hematoxylin-Eosin. (A) Normal ventral prostate. Acini are lined by columnar epithelial cells (arrow) with visible nuclei (N), a prominent Golgi apparatus (GA), lumen (Lu), stroma (S), and a blood vessel (Bv). (B) Atrophic inflammatory hyperplasia corresponding to hypogastric nerve axotomy. Acinar architecture is preserved, but epithelial cells are cuboidal, the blood vessel is enlarged, mild cellular crowding, and the stroma shows periglandular inflammatory infiltration (Lk). (C) Inflammatory atypical glandular hypertrophy following pelvic nerve axotomy. Epithelial cells exhibit increased height, the Golgi apparatus is not clearly visible, mild cellular crowding, and the stroma is enlarged with evident leukocytic infiltration. (D) Inflammatory atypical hyperplasia corresponding to combined hypogastric and pelvic nerve axotomy (HgN + PvN). Epithelial cells are rounded, and the epithelium appears disorganized with lukocytes in both the stroma and the lumen. (E) Normal dorsolateral prostate. Normal epithelium is composed of cuboidal epithelial cells (EC) with well-defined nuclei (N), a prominent Golgi apparatus (GA), lumen (Lu), stroma (S), and a blood vessel (BV). (F) Inflammatory process corresponding to hypogastric nerve axotomy. Acinar architecture is preserved, with leukocytes (Lk) present in both the stroma and the lumen. (G) Inflammatory atypical hypertrophy following pelvic nerve axotomy. Epithelial cells exhibit increased height, with the Golgi apparatus still visible, and are infiltrated by leukocytes, the stroma. (H) Inflammatory atypical hyperplasia corresponding to combined hypogastric and pelvic nerve axotomy (HgN + PvN). Epithelial cells are rounded, the epithelium appears disorganized, and leukocytes are present within the stroma and lumen. Scale bar = 50 µm (40× magnification). n = 6.
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Figure 2. Percentage of total leukocytes (CD45+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic axotomy of the pelvic and/or hypogastric nerves significantly increases the number of leukocytes (CD45+) in both prostate lobes, with the effect being more pronounced in the combined denervation of both nerves. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (** p < 0.001). n = 6.
Figure 2. Percentage of total leukocytes (CD45+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic axotomy of the pelvic and/or hypogastric nerves significantly increases the number of leukocytes (CD45+) in both prostate lobes, with the effect being more pronounced in the combined denervation of both nerves. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (** p < 0.001). n = 6.
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Figure 3. Percentage of total lymphocytes T (CD3+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. In the ventral prostate, preganglionic axotomy of the pelvic nerve and denervation of both nerves significantly increased the percentage of lymphocytes T (CD3+). In the dorsolateral prostate, all preganglionic denervations significantly increased the percentage of total lymphocytes T (CD3+), while the sham surgery induced a decrease in this percentage. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (* p < 0.05, ** p < 0.001). n = 6.
Figure 3. Percentage of total lymphocytes T (CD3+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. In the ventral prostate, preganglionic axotomy of the pelvic nerve and denervation of both nerves significantly increased the percentage of lymphocytes T (CD3+). In the dorsolateral prostate, all preganglionic denervations significantly increased the percentage of total lymphocytes T (CD3+), while the sham surgery induced a decrease in this percentage. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (* p < 0.05, ** p < 0.001). n = 6.
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Figure 4. Percentage of total T cytotoxic lymphocytes (CD8+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic injury to the pelvic and/or hypogastric nerves significantly increases the number of T cytotoxic lymphocytes (CD8+) in both prostate lobes, with the effect being less pronounced with the pelvic nerve. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (p < 0.001 **). n = 6.
Figure 4. Percentage of total T cytotoxic lymphocytes (CD8+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic injury to the pelvic and/or hypogastric nerves significantly increases the number of T cytotoxic lymphocytes (CD8+) in both prostate lobes, with the effect being less pronounced with the pelvic nerve. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (p < 0.001 **). n = 6.
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Figure 5. Percentage of T helper lymphocytes (CD4+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic injury to the pelvic and/or hypogastric nerves significantly increases the percentage of T helper lymphocytes (CD4+) in both prostate lobes, with a cumulative effect observed in the dorsolateral prostate when both nerves are denervated. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (p < 0.001 **). n = 6.
Figure 5. Percentage of T helper lymphocytes (CD4+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic injury to the pelvic and/or hypogastric nerves significantly increases the percentage of T helper lymphocytes (CD4+) in both prostate lobes, with a cumulative effect observed in the dorsolateral prostate when both nerves are denervated. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (p < 0.001 **). n = 6.
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Figure 6. Percentage of lymphocytes B (CD19+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic injury to the pelvic and/or hypogastric nerves significantly increases the percentage of lymphocytes B (CD19+) in both prostate lobes, with a cumulative effect observed in the ventral prostate when both nerves are denervated. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (p < 0.001 **). n = 6.
Figure 6. Percentage of lymphocytes B (CD19+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic injury to the pelvic and/or hypogastric nerves significantly increases the percentage of lymphocytes B (CD19+) in both prostate lobes, with a cumulative effect observed in the ventral prostate when both nerves are denervated. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (p < 0.001 **). n = 6.
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Figure 7. Percentage of macrophages (CD11b+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic injury to the pelvic and/or hypogastric nerves significantly increases the percentage of macrophages (C11b+) in both prostate lobes when both nerves are denervated. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (p < 0.001 **). n = 6.
Figure 7. Percentage of macrophages (CD11b+) in the ventral and dorsolateral lobes of the prostate from intact and denervated rats. Preganglionic injury to the pelvic and/or hypogastric nerves significantly increases the percentage of macrophages (C11b+) in both prostate lobes when both nerves are denervated. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Significant differences are shown in comparison to the intact group (p < 0.001 **). n = 6.
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Figure 8. Serum levels of interleukins in intact and denervated rats. The figure shows that preganglionic double denervation significantly increases the blood levels of all analyzed interleukins. Significant differences are shown in comparison to the control group (p < 0.001 **). n = 6.
Figure 8. Serum levels of interleukins in intact and denervated rats. The figure shows that preganglionic double denervation significantly increases the blood levels of all analyzed interleukins. Significant differences are shown in comparison to the control group (p < 0.001 **). n = 6.
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Figure 9. Serum levels of prolactin and testosterone in intact and denervated rats. Preganglionic denervation of the hypogastric nerve significantly decreased serum prolactin levels, whereas denervation of both nerves resulted in increased prolactin levels. In contrast, preganglionic denervation of pelvic nerve significantly increased serum testosterone levels, and this effect was further potentiated when both nerves were denervated. Significant differences are shown in comparison to the control group (** p < 0.001). n = 6.
Figure 9. Serum levels of prolactin and testosterone in intact and denervated rats. Preganglionic denervation of the hypogastric nerve significantly decreased serum prolactin levels, whereas denervation of both nerves resulted in increased prolactin levels. In contrast, preganglionic denervation of pelvic nerve significantly increased serum testosterone levels, and this effect was further potentiated when both nerves were denervated. Significant differences are shown in comparison to the control group (** p < 0.001). n = 6.
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Becerra-Romero, P.S.; Fernández-Pomares, C.; Rodríguez-Alba, J.C.; Manzo, J.; Aranda-Abreu, G.E.; Rojas-Durán, F.; Herrera-Covarrubias, D.; Toledo-Cárdenas, M.R.; Coria-Ávila, G.A.; Hernández-Aguilar, M.E. Impact of Major Pelvic Ganglion Denervation on Prostate Histology, Immune Response, and Serum Prolactin and Testosterone Levels in Rats. Immuno 2025, 5, 33. https://doi.org/10.3390/immuno5030033

AMA Style

Becerra-Romero PS, Fernández-Pomares C, Rodríguez-Alba JC, Manzo J, Aranda-Abreu GE, Rojas-Durán F, Herrera-Covarrubias D, Toledo-Cárdenas MR, Coria-Ávila GA, Hernández-Aguilar ME. Impact of Major Pelvic Ganglion Denervation on Prostate Histology, Immune Response, and Serum Prolactin and Testosterone Levels in Rats. Immuno. 2025; 5(3):33. https://doi.org/10.3390/immuno5030033

Chicago/Turabian Style

Becerra-Romero, Pabeli Saraí, Cynthia Fernández-Pomares, Juan Carlos Rodríguez-Alba, Jorge Manzo, Gonzalo E. Aranda-Abreu, Fausto Rojas-Durán, Deissy Herrera-Covarrubias, María Rebeca Toledo-Cárdenas, Genaro Alfonso Coria-Ávila, and Maria Elena Hernández-Aguilar. 2025. "Impact of Major Pelvic Ganglion Denervation on Prostate Histology, Immune Response, and Serum Prolactin and Testosterone Levels in Rats" Immuno 5, no. 3: 33. https://doi.org/10.3390/immuno5030033

APA Style

Becerra-Romero, P. S., Fernández-Pomares, C., Rodríguez-Alba, J. C., Manzo, J., Aranda-Abreu, G. E., Rojas-Durán, F., Herrera-Covarrubias, D., Toledo-Cárdenas, M. R., Coria-Ávila, G. A., & Hernández-Aguilar, M. E. (2025). Impact of Major Pelvic Ganglion Denervation on Prostate Histology, Immune Response, and Serum Prolactin and Testosterone Levels in Rats. Immuno, 5(3), 33. https://doi.org/10.3390/immuno5030033

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