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. Author manuscript; available in PMC: 2023 Jan 1.
Published in final edited form as: Neurourol Urodyn. 2021 Oct 4;41(1):35–41. doi: 10.1002/nau.24807

Advancing our understanding of the neural control of the female human urethra

Claire C Yang 1, James A Hokanson 2, Janet R Keast 3
PMCID: PMC8738110  NIHMSID: NIHMS1743939  PMID: 34605569

1. Introduction

Current treatment of lower urinary tract dysfunction (LUTD) related to the urethra focuses on its anatomic position (as the target for slings and other methods of suspension within the pelvis), its integrated role with the pelvic floor (as the target of physical therapy), and its tissue integrity (as the target for hormonal replacement and medications). But the urethra is not a passive conduit for urine to pass out of the bladder: it is a dynamic structure working in concert with the bladder to achieve urine storage and release. The function of the urethra and its sphincters is to maintain continence during bladder filling and appropriately allow unobstructed passage of urine during voiding. These functions are regulated by neural circuits of the brain, spinal cord, ganglia and nerves. Improving therapy for LUTD targeting the urethra will require growth of knowledge of the neuroanatomy and neurophysiology of circuits regulating the urethra and bladder, and integration of this knowledge with characterization of muscle biomechanics and fluid dynamics.

To evaluate existing knowledge on the urethra and stimulate new approaches to fill knowledge gaps, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a virtual seminar series entitled “Female Urethral Function and Failure: Advancing Basic and Translational Research for Genitourinary Conditions” (October 2020). One area of discussion was the neural control of the urethra -- both what is known, and what areas need more expansion, in order to advance our understanding of the field. Building on this initiative and as a result of the group effort of the meeting, here we propose several approaches that have the potential to fill major knowledge gaps in our understanding of neural contributors to urethra function and dysfunction. Our goal here is not to provide a detailed review of the literature, but largely to demonstrate what is needed to build our understanding of the reflexes that regulate human urethral function, since reflexes are the neurophysiological paradigm through which to understand autonomic/visceral function: peripheral afferent and efferent neural pathways, their visualization, and their integration into reflexes as deduced from physiology. Definition of these reflexes can be achieved with neuroanatomical and electrodiagnostic techniques and studies, which will be expanded upon here.

We hope that by providing several tractable exemplars, especially to demonstrate advances that can be made by applying or adapting currently available techniques, we will increase engagement of the research community with investigating the neuroanatomy and neurophysiology of the urethra, and stimulate new discussions and data collection directed to clinical outcomes. Our emphasis here is on the peripheral neural circuitry of the urethra, but it is equally important to functionally and structurally characterize brain and spinal cord circuitry relevant to urethra function and dysfunction, and understanding its integration with neural circuits regulating urethral vasculature and the pelvic floor.

2. Experimental Animal vs Human Research

Many of the fundamental concepts of lower urinary tract function and its neural regulation in humans were initially established in experimental animals that enable a wide scope for hypothesis testing, controlled perturbations and analyses, and extension from the behavioral to the molecular levels. While allowing for species differences (e.g., related to upright posture), the primary structural and functional elements of the neural ‘continence circuits’ are largely comparable across species. Much remains to be learned about experimental animal and human systems, but the primary question is now how to prioritize and synergize those studies to improve clinical outcomes.

We propose to enhance understanding of neural regulation of the human urethra by focusing on the similarities and synergies between experimental animal and clinical research, rather than allowing species differences to impede or detract from cross-disciplinary communication. While important to acknowledge species differences, much can be learned about continence regulation by understanding how different species have evolved and adapted to solve physiological challenges. To enhance the overall effort in this already under-studied area, we welcome a more effective and timely sharing of knowledge across fields, including candid discussion of the strengths and limitations of the primary assays and approaches utilized within each domain of expertise.

This emphasis on elements comparable across species does not reduce the importance of recognizing species differences, but instead directs those specific questions to a different range of approaches, e.g., by drawing upon the fields of comparative anatomy, physiology and behavior. Moreover, the capacity of animal experimental work to inform complex urological conditions in humans is under-explored. Specifically, there are ongoing opportunities to incorporate or adapt behavioral assays drawn from the stress, addiction and pain fields1–3; many of these studies apply the wide range of genetic tools available in rodents, including optogenetic perturbation of circuit function. Conversely, it is essential that ongoing clinical advances to define and stratify urological conditions are appreciated by animal experimentalists aiming to develop improved models of specific contributors to urological conditions.

3. Neuroanatomy

The location and connections of neural pathways, and the specific elements comprising those pathways, are fundamental to the design and interpretation of neurophysiological and behavioral studies. Here we propose several strategies for enhancing neuroanatomical knowledge of the urethra, focusing on human systems and tissues. Our discussion below is directed to innervation of all tissues within the urethra, not only its muscular wall. Several aspects of bladder regulation and dysregulation have been transformed by expanding knowledge of the urothelium4, 5. A greater understanding of urethral epithelium, its embedded secretory cells and innervation, provides further opportunities6.

3.1. Data collection

Most of the published human neuroanatomical data relevant to the lower urinary tract has focused on qualitative appraisal of axons within bladder or urethra tissues, illustrated by representative images of those structures7. This provides valuable knowledge on neuronal structures within specific tissues. However, maximum benefit for the community would be obtained in future mapping studies by performing quantitative analyses of innervation patterns across lower urinary tract regions, tissues, and individuals. In addition, a greater sharing of data (publicly available, complete sets of original, raw images) would encourage other research groups to perform analyses of these data sets, in line with their own areas of image processing or statistical expertise, and specific research questions.

Samples of human tissues suitable for characterization of neural structures can be obtained from several sources, each with different limitations but each also providing excellent opportunities for growing the knowledge base for normal and abnormal innervation.

3.1.1. Neuroanatomical studies in samples from cadaveric dissection

Access to cadaveric tissues from institutional body donor programs has formed the foundation for macroscopic mapping of major neural tracts (e.g., the pudendal nerve) and ganglia relevant to lower urinary tract function (e.g., sacral dorsal root ganglia and the inferior hypogastric plexus). However, each of these more distant structures also contain neural pathways supplying other organs. Therefore, without additional strategies to identify specific neural classes or visualize organ-specific trajectories, pathways unique to urethral control cannot be discerned.

In most institutions, the method used for preservation (e.g., conventional embalming fluids) and unavoidable postmortem delays preclude application of most or all of the neural classification tools such as proteomic analysis and immunohistochemical labeling of neural markers. Nevertheless, new foundational knowledge underpinning pelvic organ innervation can be derived from these tissues. For example, conventional histology (H&E) has the capacity to identify bundles of axons and aggregates of neuronal cell bodies within cadaveric samples8, 9. Macroscopic and microscopic maps of trajectories and ganglionic tissue within complex structures such as the inferior hypogastric plexus or neural tracts as they enter the lower urinary tract can be obtained from this approach. The large size of these structures in adults would require considerable effort in generating such maps but would provide valuable insights into neural patterning and intra- and inter-individual variations.

3.1.2. Neuroanatomical studies in samples from biopsies and donor tissues

Urethra neuroanatomy studies have the capacity to greatly benefit from organ donor programs that include protocols to retrieve specific tissues for approved research purposes. Access to tissues that can be rapidly fixed to preserve neural antigens or processed for proteomic or transcriptomic analysis has the potential to greatly advance our knowledge. Tissues obtained from biopsies for other clinical purposes are also valuable, although usually more constrained by their limitations in sample size, availability of ‘control’ tissue and feasibility of obtaining tissue from specific, defined regions of organs or neural structures.

It is important to recognize that neural structures within the lower urinary tract will primarily be axons, not neuronal cell bodies. Therefore, most data collection will involve visualization and detailed analysis of these tortuous, branching neuronal processes as they innervate specific cells, tissues and regions within the lower urinary tract. A small number of isolated neuronal cell bodies or small aggregates (micro-ganglia) are located throughout the bladder and urethra or near their surfaces, but insufficient is known to predict their precise location, making them difficult to study.

Development of detailed, quantitative maps of axon classes within specific tissues and regions of the normal human urethra would provide a powerful resource for the research community. Such maps could be produced for specific classes of axons defined by their molecular properties, for which the function can be inferred from prior animal experimental studies that have characterized function associated with those properties (e.g., specific sensory modalities10). The primary experimental tool for such studies continues to be immunohistochemistry, with many antibodies now available that have been validated in human tissue. While some species differences in neural marker expression are known or still being defined (see 3.1.3), there are also many features common across species (e.g., cholinergic innervation of the muscle wall, noradrenergic innervation of arterioles). We propose that similar quantitative mapping approaches be applied to characterize the innervation of the bladder neck. This potential ‘transition zone’ between the bladder and urethra has a potentially unique role in LUTD that remains to be explored.

3.1.3. Extending neuroanatomical studies using neural transcriptomes

Our understanding of the peripheral nervous system is rapidly advancing with transcriptome (RNA) analyses of peripheral ganglia and spinal cord, especially characterization at the single cell level. These complex datasets of gene expression, largely derived from rodent tissues, are revealing new molecular subclasses of nociceptors, mechanoreceptors, autonomic ganglion neurons and motor neurons11–15. Very few of the sensory ganglion transcriptome studies performed in rodents have been designed to characterize visceral pathways and, to our knowledge, none have yet aimed to specifically characterize urethral sensory or motor neurons. Likewise, the transcriptome of the pelvic ganglion (the rodent homolog of the inferior hypogastric plexus) has not yet been defined for adult systems or urethra-specific neurons.

Until recently, high throughput approaches for transcriptome analysis could only be performed on neuronal cell bodies (the primary location of RNA), as they were not sufficiently sensitive to quantify the much lower levels of RNA present in axons16. Therefore most neural transcriptome analyses to date have been obtained from experimental animals, where ganglia and spinal cord are easily obtained and can be quickly dissected postmortem. However, similarly rich datasets are just starting to emerge from human dorsal root ganglia17, 18. Ideally, a human visceral transcriptome would be generated from freshly dissected samples containing neuronal cell bodies relevant to the urethra (e.g., sacral dorsal root ganglia, inferior hypogastric plexus), but there are limited opportunities to obtain such tissues. Nevertheless, because many markers of neuronal classes characterized first in rodents are similarly expressed in humans (e.g.19), we can exploit the new knowledge of gene expression patterns and neural subclasses arising from rodent transcriptome studies. This relies on availability of specific antibodies suitable to map these neural classes within human tissues. Together this provides an exciting opportunity to understand the normal distribution of a newly defined axon subclasses within the urethra, and to understand the impact of challenge on these neurons (e.g., after injury or infection).

3.2. Data aggregation and integration

Fundamental to new data collection on neural tissues relevant to urethral function will be a framework for maximizing its aggregation and integration across laboratories. The most powerful datasets will integrate across scale - from macroscopic to microscopic - with each research team collecting data according to their specific type of anatomical and microscopy expertise. A significant limitation to data collection on urethra innervation and its aggregation across studies is the lack of clarity in several areas of terminology relating to the anatomy of the lower urinary tract organs and regions. Specific regions within the urethra have been named inconsistently and there is no broadly agreed definition of the bladder-urethra boundary, at the bladder neck. As exemplified by refinements in nomenclature in other organ systems20, a solution would best combine knowledge from topographic and surgical anatomy, with knowledge available from intramural patterning of tissues and cells. Together, these would provide a strong foundation upon which to design and communicate analyses of axonal patterning within samples of human urethra and bladder neck.

4. Electrodiagnostic testing and other biomarkers of neural function

From the foundation of neuroanatomy can follow a better understanding of the reflex control of the urethra. Although there remain many unknowns in this area, there is precedence on how to tackle this puzzle of lower urinary tract neurophysiology. The example of other organ systems, such as with cardiac and skeletal muscle, is to develop clinical electrodiagnostic tests to measure electrical signals from the end-organ, and to interrogate the neural pathways to and from the end-organ. Electrodiagnosis is a method of obtaining information about tissues either through passive recording of electrical activity from parts of the body, or by measuring tissue responses to external electrical stimuli. Electrodiagnostic testing came into being after the recognition that muscles and nerves were sources of electrical energy. Examples of such tests in humans include recording of electrical signals of the heart (electrocardiograms or ECGs), recording of brain activity from the surface of the scalp (electroencephalograms or EEGs), and recording of non-cardiac muscle tissue (electromyograms or EMGs). These tests provide valuable information on the health and innervation of the respective organs and identify possible causes of dysfunction. These tests may record naturally occurring activity or the response to external stimuli (sometimes referred to as evoked potentials). All such techniques provide information on the integrity of the neural and muscular tissue in question, as well as the signal pathways that mediate the end-organ function.

Regarding electrodiagnostic testing, we believe an area where progress can currently be made is to clarify afferent and efferent components of reflexes relevant to urethral function. Reflexes are the neurophysiological paradigm through which to understand autonomic/visceral function. Many urethral reflexes have been demonstrated in animals21. Such reflexes include urethro-urethral and vesico-urethral reflexes to maintain continence (“guarding” reflexes), and a urethro-vesical reflex, that promotes bladder emptying. Defining and/or clarifying these reflexes in humans will allow for a deeper understanding of the neural interactions necessary for healthy function. Although our focus here is nominally on the urethra, it should be emphasized that evaluating the urethra in isolation, particularly in its dynamic functions, will not be as fruitful as studying it in concert with the innervation and function of the bladder; the function of both structures is intricately linked.

Progress can be made in this area simply by working to establish group consensus on currently defined reflexes and methodologies. There are multiple methodological variables to consider when characterizing reflexes. For example, precise sites of stimulation and recording need to be identified. An electrode positioned 2 cm from the balloon of a Foley catheter (used for convenience to position an electrode at a consistent urethral location) may not be at the same functional place along the urethra in different women. Electrodes at multiple stimulation sites along the urethra, stimulated simultaneously, may be activating different urethral reflex pathways22. The anal sphincter is often used as a proxy (during recording) for the striated urethral sphincter, despite evidence of independent activation, both endogenously23, 24, as well as in response to external stimulation25. Stimulus and recording parameters should be standardized for each segment of the lower urinary tract26, 27, and normative ranges established, accounting for age27. Since the urethra is a midline organ, and is bilaterally innervated, there may be differential responsivity to reflex testing, such that unilateral testing may not be a valid portrayal of function28. The merits or need for mechanical (e.g., fluid flow, balloon dilation) versus electrical stimulation need to be clarified and understood. Stimulation parameters need to be standardized, an issue noticeably absent in discussions of mechanical stimuli (e.g., balloon dilation rate). The state of the organ, notably of the bladder (e.g., empty, close to volume threshold, contracting), also needs to be explicitly documented, as reflexes are modulated by state.

Once a technique for establishing a reflex has been well defined, it will be necessary to test this reflex in a variety of different patient types. This will allow demonstration of healthy and pathologic signals, to define whether dysfunction is due to a disruption in neural transmission, myogenic failure, both, or neither. The difference between healthy and pathological is likely a continuum with no clearly defined threshold that can be used to distinguish healthy from pathological. The absence of such a threshold does not necessarily invalidate the test, but rather highlights that most urological dysfunction, including incontinence, is multifactorial with some subjects only showing symptoms due to multiple issues that tip the scales from asymptomatic to symptomatic. Discriminating causes of dysfunction will allow for better therapeutic decision-making.

5. Barriers to recording electrical signals from the urethra and lower urinary tract, what needs to be done

Although some progress can be made by simply working to establish group consensus on existing reflexes and refining existing methodologies, there are some barriers to defining urethral reflexes. These include an incomplete understanding of the peripheral innervation of the urethra and bladder, especially with regard to the autonomic innervation.

There are many challenges to recording from autonomic nerves and smooth muscle. The small diameter, slow conduction velocity, less temporally coordinated signaling, and in many cases lack of organized nerve bundles in favor of diffuse plexus arrangements make direct recordings from small unmyelinated autonomic nerve fibers difficult. Electrical stimulation of autonomic nerves is impeded by small nerve diameter and other factors, making traditional nerve conduction studies (as performed on somatic nerves) difficult.

EMG studies are widely used in skeletal muscles throughout the body. Techniques to measure electrical activity from smooth muscle can also be useful, to determine both the health of the muscle, as well as the nerves innervating the muscle. Smooth muscle electrophysiology differs from that of skeletal muscle in many ways29. The slower time course for contraction and different arrangement of muscle fibers among other factors makes recording electrical potentials from smooth muscle challenging compared to somatic counterparts. Given that the detrusor is exclusively smooth muscle, as is the majority of the urethra except for the striated urinary sphincter, novel approaches are required to overcome these challenges posed by smooth muscle electrophysiology.

A related issue is the difference between autonomic electrophysiology vs. somatic electrophysiology. Autonomic and somatic signals differ in a number of ways: compared to somatic potentials, autonomic signals from the urogenital organs can be difficult to selectively record, with a low signal to noise ratio; autonomic potentials are more likely to be autonomously firing in the resting state, compared to somatic potentials which typically fire with stimulation or provocation; and smooth muscle movement artefact easily compromises signal interpretation in autonomic electrodiagnosis. Recording electrical potentials from the bladder and urethra requires techniques to measure from autonomic nerves and smooth muscle. Further complicating electrodiagnostic study of the urinary tract is the need to combine somatic and autonomic measurements for interpretation – the lower urinary tract is one of the very few places in the body where somatic (striated urinary sphincter) and autonomic (detrusor and urethral smooth muscle) functions interact together so intimately.

Lastly, although the female urethra is accessible for clinical testing, it resides in an area of the body with significant emotional overlay, precluding easy manipulation, especially with existing electrodiagnostic electrodes. Transvaginal or transurethral electrodes will need to be developed to minimize the discomfort of genitourinary electrodiagnostic testing, in order to obtain electrical signals representative of actual function or dysfunction. Transabdominal capture of electrical signals from the urethra is likely to be unfruitful because of the low signal-to-noise ratio. Even though electrodiagnostic techniques are routinely used for skeletal muscle and somatic nerves outside of the pelvis, due to the difficulty in accessing the skeletal muscle striated urinary sphincter and its associated somatic nerves, electrodiagnosis is currently not part of the armamentarium to evaluate the urethra.

Thus, developments to advance LUT electrophysiology and electrodiagnosis are needed and necessary; but in humans, this area is still in its infancy. The potentially broad applicability of any developments in this field may stimulate the interest needed to push the field forward. Techniques to measure electrical signals in the urethra will likely be applicable to the bladder and vice versa, leveraging similar tissue and innervation characteristics. Also, potentials measured from the urethra are likely similar to those arising from other pelvic viscera, in that they are autonomic and arising from similar or adjacent spinal segments, traveling in adjacent spinal and peripheral pathways, and will have shared electrical characteristics. It is not unreasonable to consider that the techniques for LUT function will be broadly applicable to genital neurophysiology, and possibly gut neurophysiology.

In addition to the development of electrodiagnostic techniques, other physiologic measurements can be used alongside electrodiagnosis to measure and define reflex activity. Examples include manometry of the urethra (and bladder) and mechanical stimulation of urethral receptors (e.g., balloon dilation). These types of physiological measures, which already exist, should be modified as needed and integrated into the study of the neural control of the urethra and LUT.

6. Construction of interdisciplinary teams

LUT clinicians need to “think outside of the box”, by expanding their consideration of LUT clinical conditions well beyond static structural problems (e.g., anatomical displacement of pelvic structures), to the organs’ dynamic state and its regulation by a complex system of somatic and autonomic signaling – that is, to consider “how the wiring affects the plumbing”. In order to bridge the gap in knowledge, LUT clinicians and experts in neurology, neurophysiology, biomedical engineering, and other disciplines have to come together to solve this puzzle. But a special responsibility falls to LUT clinicians, who need to engage their patients in the research to develop electrodiagnostic techniques.

7. Conclusion

Neural control of the urethra is critical for proper lower urinary tract function, yet neural anatomy and function, and associated electrodiagnostics of the lower urinary tract, are poorly characterized and thus largely absent in clinical care decisions. Here we have provided several examples of ‘first steps’ that could be taken to address the large knowledge gaps in this area. We see this as an area with exciting potential for growth and innovation that will greatly benefit from establishing new interdisciplinary teams.

Grants:

K01 DK 121866 to James Hokanson

Footnotes

Competing interest: the authors have no competing interests

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