Rectal prolapse is a profoundly disabling condition with a significant impact on quality of life. Despite that, the understanding of its nature and pathophysiology is poor, contributing to a limited ability to identify the optimal surgical approach for the individual patients. This is reflected in trials, systematic and Cochrane reviews that have not demonstrated superiority of one operation over another [1,2,3], and recurrence rates remain stubbornly high [1, 2].

As reflected in the PROSPER trial [2], the choice of procedure is mainly based on patient comorbidity, and surgeon preference and training, rather than features of the prolapse pathology itself [4], an approach not followed in other colorectal conditions such as cancer or inflammatory bowel disease. We hypothesise that the pathophysiology and biomechanical mechanisms may be different between patient subgroups and therefore require distinct surgical approaches.

Rectal prolapse: a disease of parous elderly women?

Traditionally, rectal prolapse has been considered to be a condition affecting parous elderly women, a similar demographic to utero-vaginal prolapse (commonly referred to as pelvic organ prolapse, or POP), but good epidemiological studies are lacking. In fact, there is some evidence that nulliparity rates in rectal prolapse are as high as 50% [5]. Also, while men make up a small minority of Western surgical prolapse cohorts (typically 5–10%), they are more frequent in non-Western populations (20–40% in Egyptian series) [6, 7] and actually predominate (> 50%) in studies from Indian [8, 9] and Iranian populations [10, 11]. Another small study of consecutive rectal prolapse patients from Turkey reported both 36% men as well as 22% nulliparas [12]. A feature of rectal prolapse in men and nulliparous women is their clinical presentation at a significantly younger age than parous women [13]. Switching focus to these two populations provides an extremely useful window on causation in rectal prolapse, because they demand postulation of an alternative causation besides parity and age.

Nulliparity and POP

Despite an assumption of similar causation (parity and age), there appear to be different causal pathways between POP and rectal prolapse. Nulliparity is surprisingly understudied in POP, and on the rare occasion it has been studied, nulliparity has been found to be very uncommon (< 2%) in patients undergoing surgery for POP [14]. One study using perineal ultrasound [15] showed an uncommon (2%) association of nulliparity and POP, and when it was present, it was usually (64%) posterior compartment (rectocoele) not middle and anterior compartment prolapse (uterine prolapse and cystocoele). A study of pudendal nerve function in POP and controls using single-fibre electromyography (EMG) showed an inverse correlation between prolapse plus perineal descent and rectocoele size [16].

Two pathological phenotypes: high and low take-off prolapse

There have been anecdotal mentions in the literature of “take-off” as a feature of rectal prolapse [17,18,19]. Take-off is believed to be the physical origin or lead point of a prolapse and to have a variable level in the rectum, with two broad phenotypes alluded to, high and low take-off. However, until recently there has been little published that provides a solid definition for these terms or that explores how take-off might relate more broadly to the aetiology and pathology of rectal prolapse [17,18,19,20,21], and to its treatment.

Recent proctographic work has shown that a high take-off prolapse might be better understood as a long intussusception (with the origin or lead point being the proximal rectal intussusceptum invaginating into the distal rectal intussuscipiens). A low take-off prolapse might be better understood either as a short intussusception or in some cases a minimal intussusception and more analogous to a “hernia” of the pelvic floor, with the protrusion at the anus of an effacing prolapse.

Defining and understanding the nature of the variation in the level of intussusceptum may shine some light onto the causation and pathology of rectal prolapse. It might help explain stubbornly high recurrence rates, and might generate prognostic data that influence decision-making, enabling surgeons to opt for a procedure that specifically targets a particular anatomical pathology that may ultimately reduce recurrence.

Two causal pathways: obstetric birth injury and connective tissue

Since causal explanation by parity and age does not account for the occurrence of rectal prolapse in men and nulliparous women, a separate, additional causation needs to be proposed. A small number of studies have pointed to an association of connective tissue disorders and either internal or external rectal prolapse. A high incidence of joint hypermobility and thus abnormal connective tissue was seen in a cohort with rectal evacuatory dysfunction [22]. In a series of patients undergoing surgery for internal and external rectal prolapse, a higher incidence of recurrence was noted in those with joint hypermobility as determined by Beighton criteria [23].

Basic scientific studies [24, 25] have demonstrated changes in the extracellular matrix and collagen types 1 and 3 of patients with rectal prolapse, in comparison to control. Alterations in the elastic fibres within the dermis of patients point towards connective tissue disorder as causative in rectal prolapse. The pelvic connective tissues were noted to have an increase in matrix metalloproteinase-1 (MMP-1), associated with a reduction in connective tissue supports surrounding the rectum. A reduction in the expression of transforming growth factor-β (TGFβ)—which may be involved in the above process—was found to be associated with the development of external prolapse. Moreover, a different response to prolapse was noted between male and female patients, with attenuated cellularity in men and increased cellularity in women, in some of whom the cells did not differentiate to the type normally identified in pelvic connective tissues. There are indications then, from clinical, genetic and biochemical work, that rectal prolapse may have a different causation in a subgroup of patients, going beyond obstetric birth injury.

Future research channels

Clearly, a deeper and better understanding of rectal prolapse is needed, one that has lagged well behind that which we have for cancer and inflammatory bowel disease, and requires further work at many levels. Firstly, large-scale international epidemiological studies of rectal prolapse (and POP in comparison) and analysis of big record-linked data sets (e.g. Clinical Practice Research Datalink and Hospital Episode Statistics in the UK) will shed more light on causation and causal pathways to prolapse. Secondly, basic science efforts including genetic studies (genome-wide association studies using UK biobanking, and whole genome sequencing of individuals with prolapse), as well as cellular and tissue work, will provide the fundamental mechanistic underpinning of the different phenotypic sub-expressions of rectal prolapse. Finally, more biomechanical and functional markers on defaecation proctography and anorectal/colonic physiology are waiting to be identified and collected, to build anatomical and physiological causation bridges between genetic mechanisms, pathological phenotypes and clinical phenotypes.

Selection and correction

Development of these research workstreams should generate epidemiological, clinical, anatomical and physiological prognostic markers. These can be clinically validated by prospective collection and correlation with PROMS in large registries. An immature field with large knowledge gaps is not the home of the randomised trial. Only then will we be able to better select patients for surgery, and choose the appropriate surgical intervention to best correct the phenotypic pathology to reduce recurrence and improve bowel function and chronic pain outcomes.

It is likely that with a fuller appreciation of the role of connective tissue in rectal prolapse, as well as the genetics of connective tissue abnormalities and cheaper whole genome sequencing, development of polygenic risk scoring will drive a move away from meshes and visceropexy towards ligamentous reconstruction [26] and regenerative medicine [27].