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Immunohistological study of the density and distribution of human penile neural tissue: gradient hypothesis

International Journal of Impotence Research volume 35, pages 286–305 (2023)Cite this article

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Abstract

Immunohistological patterns of density and distribution of neural tissue in the human penis, including the prepuce, are not fully characterized, and effects of circumcision (partial or total removal of the penile prepuce) on penile sexual sensation are controversial. This study analyzed extra- and intracavernosal innervation patterns on the main penile axes using formalin-fixed, paraffin-embedded human adult and fetal penile tissues, single- and double-staining immunohistochemistry and a variety of neural and non-neural markers, with a special emphasis on the prepuce and potential sexual effects of circumcision. Immunohistochemical profiles of neural structures were determined and the most detailed immunohistological characterizations to date of preputial nerve supply are provided. The penile prepuce has a highly organized, dense, afferent innervation pattern that is manifest early in fetal development. Autonomically, it receives noradrenergic sympathetic and nitrergic parasympathetic innervation. Cholinergic nerves are also present. We observed cutaneous and subcutaneous neural density distribution biases across our specimens towards the ventral prepuce, including a region corresponding in the adult anatomical position (penis erect) to the distal third of the ventral penile aspect. We also describe a concept of innervation gradients across the longitudinal and transverse penile axes. Results are discussed in relation to the specialized literature. An argument is made that neuroanatomic substrates underlying unusual permanent penile sensory disturbances post-circumcision are related to heightened neural levels in the distal third of the ventral penile aspect, which could potentially be compromised by deep incisions during circumcision.

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Fig. 1: What is the prepuce?
Fig. 2: Ventral-dorsal innervation patterns in four sagittally sectioned human fetal penile specimens.
Fig. 3: Intra and extracavernosal innervation patterns in sagittal sections of two human fetal penile specimens.
Fig. 4: PGP9.5 and pan-TRK immunoreactive intraepithelial fibers in a mid-sagittally sectioned fetal human penis at 16 weeks fertilization age.
Fig. 5: Human adult preputial nerve bundles and their immunohistochemical profiles.
Fig. 6: Preputial smooth muscle and its dual autonomic innervation.
Fig. 7: Human adult preputial corpuscular receptors and their immunohistochemical profiles.
Fig. 8: Immunohistochemical profile of a serially sectioned human preputial Pacinian corpuscle located deep in the dorsal dartos layer of a 68-year-old man.
Fig. 9: Human adult preputial FNEs and their immunohistochemical profiles.

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Data availability

Data supporting results of this study are available from the corresponding author on reasonable request.

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We would like to thank the anonymous reviewers for providing detailed and valuable feedback.

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Authors and Affiliations

  1. Department of Morphological Sciences, School of Medicine and Dentistry, University of Santiago de Compostela, Santiago de Compostela, Spain

    Alfonso Cepeda-Emiliani, Marina Gándara-Cortés, Juan Suárez-Quintanilla, Tomás García-Caballero, Rosalía Gallego & Lucía García-Caballero

  2. Department of Pathology, University Clinical Hospital, Santiago de Compostela, Spain

    Marina Gándara-Cortés & Tomás García-Caballero

  3. Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain

    María Otero-Alén

  4. National Institute of Legal Medicine and Forensic Sciences of Colombia, Barranquilla, Colombia

    Heidy García

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Contributions

AC-E, TG-C, RG and LG-C designed the study, interpreted results, and wrote the manuscript. AC-E, MG-C, MO-A and JS-Q recruited material. AC-E, MG-C, MO-A, HG, TG-C, RG, JS-Q and LG-C performed histopathological and immunohistochemical analyses. All authors revised and approved the manuscript.

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Correspondence to Alfonso Cepeda-Emiliani.

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Cepeda-Emiliani, A., Gándara-Cortés, M., Otero-Alén, M. et al. Immunohistological study of the density and distribution of human penile neural tissue: gradient hypothesis. Int J Impot Res 35, 286–305 (2023). https://doi.org/10.1038/s41443-022-00561-9

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  • DOI: https://doi.org/10.1038/s41443-022-00561-9

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