Clinical use of hyaluronic acid in andrology: A review

Abstract Background Hyaluronic acid is a glycosaminoglycan widely used in the fields of orthopedics, ophthalmology, and aesthetic medicine due to its significant ability to reduce the synthesis of pro‐inflammatory proteins and its activity against oxidative stress, a feature of many degenerative illnesses. Objectives The objective of the present review is to provide a comprehensive narrative review of the most recent literature on the use of hyaluronic acid in andrology in order to facilitate the use of this therapeutic device in the common clinical practice of many physicians. Specific conditions covered in the review are Peyronie's disease, premature ejaculation, and penile enlargement. Materials and methods A broad and comprehensive literature search included Medline, EMBASE, and the Cochrane Libraries, with no time restriction up to December 2020 and restricted to English language publications. Unpublished studies were not included. The study was registered as “The role of hyaluronic acid in andrology: A systematic review and meta‐analysis” in PROSPERO with the ID CRD42021223416. Discussion and conclusion Hyaluronic acid is a valid choice for the treatment of Peyronie's disease in terms of the resolution of the acute phase of the disease and of contributing to stabilizing the disease as a bridge to potential surgery. Data, furthermore, suggest that hyaluronic acid is frequently associated with an overall clinical improvement, allowing the patient to resume normal sexual activity. With regard to premature ejaculation, data suggests hyaluronic acid‐based treatments were effective in prolonging intra‐vaginal ejaculation time. Furthermore, hyaluronic acid was found to be safe and well‐tolerated, with main adverse events limited to local discomfort, ecchymosis, papule formation, and glans numbness, all of which were reported to resolve spontaneously. Last, with regard to penile enlargement, the overall perception of experts is that hyaluronic acid may be an extremely well‐tolerated compound with potential for application in specific areas of male sexual health that are often neglected as compared to more common, and relatively simpler to treat, conditions.


INTRODUCTION
Hyaluronic acid (HA) is a glycosaminoglycan and a major component of the extra-cellular matrix of the mammalian. The wide use of HA in the fields of orthopedics, ophthalmology, aesthetic medicine, and more is mainly associated with its biological properties, including its significant anti-inflammatory and anti-oxidative stress properties, making it the ideal compound for the treatment of osteoarticular degenerative pathologies. 1 Indeed, free oxygen radicals (ROS), such as hydrogen peroxide (H 2 O 2 ), hypochlorite ion (ClO -), hydroxyl radical (UOH), and superoxide anion (O2 -), are involved in both intracellular signal transduction and cellular degenerative processes. 2,3 Several studies have shown that chondrocyte apoptosis and cartilage degradation be caused by high ROS production levels, hence contributing to the pathogenesis of osteoarthritis. [2][3][4][5][6][7] Numerous data show that HA reduces ROS levels at the synovial sites in cases of osteoarthritis, counteracting apoptosis and promoting cell survival. 1,8 In a physiological condition, the hyaluronate molecule is highly polar and water-soluble. In the connective tissue, HA maintains hydration, turgidity, plasticity, and viscosity, due to its specific steric conformation, which allows the storage of a considerable number of water molecules. Furthermore, HA possesses favorable biomechanical characteristics, thus acting like an anti-shock molecule and efficient lubricant (e.g., in the synovial fluid), preventing damage to cells by physical stress. 2,3 These characteristics, together with its hypoallergenic properties, make HA the ideal candidate for increasing soft tissue volume and to be used as a filler. Once injected, HA is gradually metabolized and then reabsorbed over varying time frames depending on the treated surface and the type of HA used.
Injective HA treatment in andrology is now widespread, but data is limited due to the lack of prospective randomized and controlled studies with large series and consistent follow-up assessments.
In this paper, we performed a comprehensive narrative review of the most recent literature on the use of HA in andrology. We first registered this study as "The role of HA in andrology:

MATERIALS AND METHODS
a systematic review and meta-analysis" in PROSPERO with the ID CRD42021223416. However, at the time of the systematic review, the inclusion criteria set out in the PROSPERO protocol were not applicable due to the lack of randomized clinical trials. Furthermore, many clinical trials did not include a control group and did not present common outcomes which could be analyzed with comparable parameters. It was therefore impossible to proceed with a meta-analysis model, and the panel opted for a narrative review method.
Three research teams were engaged in the literature search, each of which was constituted by two individuals each with specific clinical expertise. The groups independently focused on: i) PD, ii) PE, and iii) penile enlargement. After preliminary evaluation, if the research team was not in agreement on the article content, the article was reevaluated by an external reviewer (belonging to another of the three teams). The selected articles were then assessed in their full test and evaluated via the Risk Bias systems (Rob 2 tool). This further evaluation was then omitted due to difficulties in carrying out a true systematic review process. Tables 1-3 contain the selected papers in the three fields of interest.

Peyronie's disease
The etiology of PD is still largely unknown. Likewise, its complex pathogenetic mechanisms are not yet completely understood. However, in accordance with the different theories proposed by some authors, a single traumatic event or multiple and repeated micro-traumas during sexual activity could provoke a prolonged inflammatory reaction to the fibers of the tunica albuginea, thus causing an autoimmune response. 9,10 This complex reaction includes several mechanisms such as micro-vascular damage, accumulation of inflammatory cells and fibrin, over-expression of cytokines, and growth factors that stimulate matrix protein production, mainly collagen, which is partially responsible for the formation of the plaques. [11][12][13][14][15][16] Disease progression may eventually lead to calcification or ossification of the plaque in 15%-25% of patients. 17,18 The commonly used pharmacological treatments depend on the stage of the disease, with the aim of reversing, interrupting, or attenuating the course of the disease, reducing deformity, and improving sexual function. 19,20 The latest updated AUA and EAU guidelines 21,22 confirm that no drugs have been approved for the treatment of Peyronie's disease, except for potassium para-aminobenzoate (Potaba), considered "probably effective" by the FDA, and collagenase clostridium histolyticum, which is no longer available in the European market.   self-controlled, and interventional study. 25 The study showed encouraging results in terms of reduction in the size of the fibrotic plaque, penile recurvatum, and an improvement in terms of patients' overall sexual satisfaction. The study was mainly limited by the lack of a control group and the short follow-up (namely 3 months). 25 Similarly, Gennaro et al. 26  In conclusion, HA is emerging as a valid choice for the treatment of PD in terms of resolution of the acute phase of the disease, and it is plausible to posit that the use of HA may contribute to the stabilization of the disease, an indispensable requirement for the subsequent choice of a possible surgical strategy. Even more clinically relevant, the observed findings suggested that HA was associated with an overall improvement of the clinical picture which, in most cases, allowed the patient to resume an almost normal sexual activity.

Premature ejaculation
PE is defined by the International Society of Sexual Medicines as an ejaculation that always or nearly always occurs before or within about 1 min of vaginal penetration from the first sexual experience (lifelong PE), or a clinically significant reduction in latency time, often to about 3 min or less (acquired PE). 30 Moreover, PE is usually considered to be associated with emotional distress and bother. 31 Population-based studies have shown a prevalence of PE ranging from 8% to 30% of the male population. 32 The pathophysiology of PE has been associated with an underlying neurobiological functional disturbance characterized by an alteration of the 5-hydroxytryptamine neurotransmission leading to a lower ejaculatory threshold. 33 Moreover, both psychological and organic factors including urinary tract infections and metabolic alteration could play a role. 33 To date, numerous treatment modalities have been implemented for PE, including topical anesthetic agents, ondemand, on label, and continuous off-label selective serotonin reuptake inhibitors, and tramadol. 34 Notwithstanding, all these treatments have shown to be variably effective, and discontinuation rates are still high. 35,36 The injection of HA as a bulking agent within the glans has been suggested as a potential local treatment for PE, with the goal to act as a barrier inhibiting the tactic stimuli to access the receptor, thus delaying the ejaculatory reflex. 36 To date, three prospective single-arm studies, 36-38 one randomized non-controlled trial, 39 and one randomized controlled trial 40 have investigated the efficacy and safety of HA glans injection in men with PE ( Overall, data suggested that HA treatment for PE was effective in improving IELT (Figure 2), safe and well-tolerated, with reported side effects ranging from 0% to 30% across all studies. The main adverse events were local discomfort, ecchymosis, papule formation, and glans numbness, all resolving reported to resolve spontaneously.

Penile augmentation
The size of the penis has kept its subjective and popular importance over time, with adequate dimensions corresponding to the idea of advantages both from an aesthetic and a sexual standpoint.
A variety of surgical and physiotherapy techniques have been proposed throughout times to achieve lengthening and increasing the girth of the penis (i.e., penile girth enhancement) and the glans (i.e., glans penis augmentation). Such techniques have been characterized by wide limitations, mainly related to methodological biases of the proposed studies, frequent complications, not always satisfactory aesthetic outcomes, as well as the often unrealistic expectations of the patient. 41,42 In this context, while the use of various fillers has gained wide popularity with the aim of increasing the size of soft tissues in dermatology and aesthetic medicine, 43 the application of fillers intended for penile girth enhancement and glans penis augmentation posed particular problems in consideration of the specific anatomy of the penile shaft and, to date, it has not yet been established which should be the ideal filler dedicated to the purpose (Table 3).
By virtue of its molecular characteristics, HA is a potential candidate to be considered in the cosmetic and reconstructive andrological area, not only in hard penis plastics but also for penile "cosmetic" techniques. In fact, HA is a ubiquitous component of connective tissue and in the intercellular matrix of the dermis, thus presenting a high biocompatibility profile that limits its antigenic properties and foreign body reactions. 44 Historically, the first attempts of enlargement phalloplasty con- and substances to be infiltrated. However, the overall feeling is that HA may represent an extremely well-tolerated compound with scope for effective application in specific areas of male sexual health that are often neglected as compared with more common, and relatively simpler to treat, conditions.