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Benign Prostatic Enlargement Management of Nocturia in men with lower urinary tract symptoms PART 4 Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai Nocturia has been defined as the complaint of waking at night to void [1]. The ICS Standardisation Steering Committee has introduced the concept of main sleep period, defined as “the period from the time of falling asleep to the time of intending to rise for the next “day” [2]. Nocturia reflects the relationship between the amount of urine produced while asleep, and the ability of the bladder to store the urine received. Nocturia can occur as part of lower urinary tract dysfunction (LUTD), such as OAB and chronic pelvic pain syndrome. Nocturia can also occur in association with other forms of LUTD, such as BOO, but here it is debated whether the link is one of causation or simply the co-existence of two common conditions. Crucially, nocturia may have behavioural, sleep disturbance (primary or secondary) or systemic causes unrelated to LUTD (Table 2). Differing causes often co-exist and each has to be considered in all cases. Only where LUTD is contributory should nocturia be termed a LUTS. Table 1. Categories of nocturia The golden standard treatment for Nocturia based on the antidiuretic hormone arginine vasopressin (AVP) which plays a key role in body water homeostasis and control of urine production by binding to V2 receptors in the renal collecting ducts. Arginine vasopressin increases water re-absorption and urinary osmolality, so decreasing water excretion and total urine volume. Arginine vasopressin also has V1 receptor mediated vasoconstrictive/hypertensive effects and a very short serum halflife, which makes the hormone unsuitable for treating nocturia/nocturnal polyuria. Desmopressin is a synthetic analogue of AVP with high V2 receptor affinity and no relevant V1 receptor affinity. It has been investigated for treating nocturia [3], with specific doses, titrated dosing, differing formulations, and options for route of administration. Most studies have short follow-up. Global interpretation of existing studies is difficult due to the limitations, imprecision, heterogeneity and inconsistencies of the studies. A SR of randomised or quasi-randomised trials in men with nocturia found that desmopressin may decrease the number of nocturnal voids by -0.46 compared to placebo over short-term follow-up (up to three months); over intermediate-term follow-up (three to twelve months) there was a change of -0.85 in nocturnal voids in a substantial number of participants without increase in major adverse events [4]. Another SR of comparative trials of men with nocturia as the primary presentation and LUTS including nocturia or nocturnal polyuria found that antidiuretic therapy using dose titration was more effective than placebo in relation to nocturnal voiding frequency and duration of undisturbed sleep [5]. Adverse events include headache, hyponatremia, insomnia, dry mouth, hypertension, abdominal pain, peripheral edema, and nausea. Three studies evaluating titrated-dose desmopressin in which men were included, reported seven serious adverse events in 530 patients (1.3%), with one death. There were seventeen cases of hyponatraemia (3.2%) and seven of hypertension (1.3%). Headache was reported in 53 (10%) and nausea in fifteen (2.8%) [5]. Hyponatremia is the most important concern, especially in patients > 65 years of age, with potential lifethreatening consequences. Baseline values of sodium over 130 mmol/L have been used as inclusion criteria in some research protocols. Assessment of sodium levels must be undertaken at baseline, after initiation of treatment or dose titration and during treatment. Desmopressin is not recommended in high-risk groups [5]. Desmopressin oral disintegrating tablets (ODT) have been studied separately in the sex-specific pivotal trials CS41 and CS40 in patients with nocturia [6,7]. Almost 87% of included patients had nocturnal polyuria and approximately 48% of the patients were > 65 years. The co-primary endpoints in both trials were change in number of nocturia episodes per night from baseline and at least a 33% decrease in the mean number of nocturnal voids from baseline during three months of treatment. The mean change in nocturia episodes from baseline was greater with desmopressin ODT compared to placebo (difference: women = -0.3 [95% CI: -0.5 to -0.1]; men = -0.4 [95% CI: -0.6 to -0.2]). The 33% responder rate was also greater with desmopressin ODT compared to placebo (women: 78% vs. 62%; men: 67% vs. 50%). Analysis of three published placebo-controlled trials of desmopressin ODT for nocturia showed that clinically significant hyponatraemia was more frequent in patients aged > 65 years than in those aged < 65 years in all dosage groups, including those receiving the minimum effective dose for desmopressin (11% of men aged > 65 years vs. 0% of men aged < 65 years receiving 50 mcg; 4% of women > 65 aged years vs. 2% of women aged < 65 years receiving 25 mcg). Severe hyponatraemia, defined as < 125 mmol/L serum sodium, was rare, affecting 22/1,431 (2%) patients overall [8]. Low dose desmopressin ODT has been approved in Europe, Canada and Australia for the treatment of nocturia with > 2 episodes in gender-specific low doses 50 mcg for men and 25 mcg for women; however, it initially failed to receive FDA approval, with the FDA citing uncertain benefit relative to risks as the reason. Following resubmission to the FDA in June 2018 desmopressin acetate sublingual tablet, 50 mcg for men and 25 mcg for women, was approved for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least two times per night to void with a boxed warning for hyponatremia. Desmopressin acetate nasal spray is a new low-dose formulation of desmopressin and differs from other types of desmopressin formulation due to its bioavailability and route of administration. Desmopressin acetate nasal spray has been investigated in two RCTs including men and women with nocturia (over two episodes per night) and a mean age of 66 years. The average benefit of treatment relative to placebo was statistically significant but low, -0.3 and -0.2 for the 1.5 mcg and 0.75 mcg doses of desmopressin acetate, respectively. The number of patients with a reduction of more than 50% of nocturia episodes was 48.5% and

Benign Prostatic Enlargement Surgical Therapy PART 3 Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai The Surgical treatment is one of the cornerstones of LUTS/BPO management. Based on its ubiquitous availability, as well as its efficacy, Monopolar-TURP has long been considered as the reference technique for the surgical management of LUTS/BPO. However, in recent years various techniques have been developed with the aim of providing a safe and effective alternative to Monopolar-TURP. The transurethral resection of the prostate (TURP) is performed using two techniques: monopolar TURP (M-TURP) and bipolar TURP (B-TURP). Monopolar transurethral resection of the prostate removes tissue from the transition zone of the gland. Bipolar TURP addresses a major limitation of M-TURP by allowing performance in normal saline. Prostatic tissue removal is identical to M-TURP. Contrary to M-TURP, in B-TURP systems, the energy does not travel through the body to reach a skin pad. Bipolar circuitry is completed locally; energy is confined between an active (resection loop) and a passive pole situated on the resectoscope tip (“true” bipolar systems) or the sheath (“quasi” bipolar systems). The various bipolar devices available differ in the way in which current flow is delivered [1,2]. Monopolar-TURP is an effective treatment for moderate-to-severe LUTS secondary to BPO. The choice should be based primarily on prostate volume (30-80 mL suitable for M-TURP). No studies on the optimal cut-off value exist, but the complication rates increase with prostate size [3]. The upper limit for M-TURP is suggested as 80 mL (based on the European Association of Urology Guidelines 2022 consensus, under the assumption that this limit depends on the surgeon’s experience, choice of resectoscope size and resection speed), as surgical duration increases, there is a significant increase in the rate of complications and the procedure is safest when performed in under 90 minutes [4]. Bipolar TURP in patients with moderate-to-severe LUTS secondary to BPO, has similar efficacy with M-TURP, but lower peri-operative morbidity. The duration of improvements with B-TURP were documented in a number of RCTs with mid-term follow-up. Long-term results (up to five years) for B-TURP showed that safety and efficacy are comparable to M-TURP [5-13]. The choice of B-TURP should be based on equipment availability, surgeon’s experience, and patient’s preference. The holmium laser enucleation of the prostate does not play a role in contemporary treatment algorithms, because there were no relevant publications on holmium laser resection of the prostate (HoLRP) have been published since 2004, HoLRP of the prostate. The thulium-aluminum-garnet laser (Tm:YAG) vaporization of the prostate has wavelength between 1,940 and 2,013 nm and is emitted in continuous wave mode. The laser is primarily used in front-fire applications [14]. Different applications such as vaporesection (ThuVARP) have been published [15]. As a limited number of RCTs with mid- to long-term follow-up support the efficacy of ThuVARP, there is a need for ongoing investigation of the technique. The transurethral incision of the prostate (TUIP) involves incising the bladder outlet without tissue removal. Transurethral incision of the prostate is conventionally performed with Collins knife using monopolar electrocautery; however, alternative energy sources such as holmium laser may be used [16]. This technique may replace M-TURP in selected cases, especially in prostate sizes < 30 mL without a middle lobe. The transurethral incision of the prostate is an effective treatment for moderate-to-severe LUTS secondary to BPO. The choice between M-TURP and TUIP should be based primarily on prostate volume (< 30 mL TUIP) [17]. The open prostatectomy is the oldest surgical treatment for moderate-to-severe LUTS secondary to BPO. Obstructive adenomas are enucleated using the index finger, approaching from within the bladder (Freyer procedure) or through the anterior prostatic capsule (Millin procedure). It is used for substantially enlarged glands (> 80-100 mL). The open prostatectomy is the most invasive surgical method, but it is an effective and durable procedure for the treatment of LUTS/BPO. In the absence of an endourological armamentarium including a holmium laser or a bipolar system and with appropriate patient consent, OP is a reasonable surgical treatment of choice for men with prostates > 80 mL. The bipolar transurethral enucleation of the prostate is a technology to enucleated the obstructive adenoma endoscopically by the transurethral approach. Bipolar-transurethral enucleation of the prostate (B-TUEP) evolved from plasma kinetic (PK) B-TURP and was introduced by Gyrus ACMI. The technique, also referred to as PK enucleation of the prostate (PKEP), utilises a bipolar high-frequency generator and a variety of detaching instruments, for this true bipolar system, including a point source in the form of a axipolar cystoscope electrode suitable for enucleation [18] or a resectoscope tip/resection loop [19, 20]. More recently, a novel form of B-TUEP has been described, bipolar plasma enucleation of the prostate (BPEP), stemming from B-TURP (TURis, Olympus Medical), that utilises a bipolar high frequency generator and a variety of detaching instruments including a mushroom- or button-like vapo-electrode [21,22] and a Plasmasect enucleation electrode [23] for this quasi-bipolar system. Bipolar transurethral enucleation of the prostate is followed by either morcellation [21,18] or resection [19-22, 24-26] of the enucleated adenoma. The holmium:yttrium-aluminium garnet (Ho:YAG) laser (wavelength 2,140 nm) is a pulsed solid-state laser that is absorbed by water and water-containing tissues. Tissue coagulation and necrosis are limited to 3-4 mm, which is enough to obtain adequate haemostasis [27]. Holmium laser enucleation of the prostate requires experience and relevant endoscopic skills. The experience of the surgeon is the most important factor affecting the overall occurrence of complications [28, 29]. Enucleation using the Tm:YAG laser includes ThuVEP (vapoenucleation i.e. excising technique) and ThuLEP (blunt enucleation). ThuLEP seems to offer similar efficacy and safety when compared to TURP, bipolar enucleation and HoLEP; whereas, ThuVEP is not supported by RCTs. Based on the limited number of RCTs there is a need for ongoing investigation of these techniques. The term minimal invasive simple prostatectomy (MISP) includes laparoscopic simple prostatectomy (LSP) and robot-assisted simple prostatectomy (RASP). The technique for LSP was first described in 2002 [30], while the first RASP was reported in 2008 [31]. Both LSP and RASP are

Benign Prostatic Enlargement Pharmacological treatment, plant Extracts-phytotherapy PART 2 Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai As conservative treatment, the watchful waiting strategy (WWS) is a viable option for benign prostatic enlargement disease management. Many men with LUTS are not troubled enough by their symptoms to need drug treatment or surgical intervention. All men with LUTS should be formally assessed prior to any allocation of treatment in order to establish symptom severity and to differentiate between men with uncomplicated (the majority) and complicated LUTS. Watchful waiting strategy (WWS) is a viable option for many men with non-bothersome LUTS as few will progress to AUR and complications (e.g. renal insufficiency or stones) [1,2], whilst others can remain stable for years [3]. In one study, approximately 85% of men with mild LUTS were stable on Watchful waiting strategy (WWS) at one year [4]. A study comparing Watchful waiting strategy (WWS) and transurethral resection of the prostate (TURP) in men with moderate LUTS showed the surgical group had improved bladder function (flow rates and PVR volumes), especially in those with high levels of bother; 36% of Watchful waiting strategy (WWS) patients crossed over to surgery within five years, leaving 64% doing well in the Watchful waiting strategy (WWS) group [5,6]. Increasing symptom bother and PVR volumes are the strongest predictors of Watchful waiting strategy (WWS) failure. Men with mild-to-moderate uncomplicated LUTS who are not too troubled by their symptoms are suitable for Watchful waiting strategy (WWS). The behavioral and dietary modification for benign prostatic enlargement disease management is customary for this type of management to include the following components: • education (about the patient’s condition); • reassurance (that cancer is not a cause of the urinary symptoms); • periodic monitoring; • lifestyle advice [3,4,7,8] such as: reduction of fluid intake at specific times aimed at reducing urinary frequency when most inconvenient (e.g., at night or when going out in public); avoidance/moderation of intake of caffeine or alcohol, which may have a diuretic and irritant effect, thereby increasing fluid output and enhancing frequency, urgency and nocturia; use of relaxed and double-voiding techniques; urethral milking to prevent post-micturition dribble; distraction techniques such as penile squeeze, breathing exercises, perineal pressure, and mental tricks to take the mind off the bladder and toilet, to help control OAB symptoms; bladder retraining that encourages men to hold on when they have urgency to increase their bladder capacity and the time between voids; reviewing the medication and optimising the time of administration or substituting drugs for others that have fewer urinary effects (these recommendations apply especially to diuretics); providing necessary assistance when there is impairment of dexterity, mobility, or mental state; treatment of constipation. Evidence exists that self-management as part of Watchful waiting strategy (WWS) reduces both symptoms and progression [7,8]. Men randomised to three self-care management sessions in addition to standard care had better symptom improvement and QoL than men treated with standard care only, for up to a year [7]. A SR and meta-analysis found reasonable certainty in estimates that self-management intervention significantly reduced symptom severity in terms of IPSS at six months compared with usual care [9]. The reduction in IPSS score with self-management was similar to that achieved with drug therapy at six to twelve weeks. Self-management had a smaller, additional benefit at six weeks when added to drug therapy [9]. The Plant Extracts- phytotherapy with herbal medicinal products and their drug preparations are made of roots, seeds, pollen, bark, or fruits. There are single plant preparations (mono-preparations) and preparations combining two or more plants in one pill (combination preparations) [10]. Possible relevant compounds include phytosterols, ß-sitosterol, fatty acids, and lectins [10]. In vitro, plant extracts can have anti-inflammatory, anti-androgenic and oestrogenic effects; decrease sexual hormone binding globulin; inhibit aromatase, lipoxygenase, growth factor-stimulated proliferation of prostatic cells, α-adrenoceptors, 5 α-reductase, muscarinic cholinoceptors, dihydropyridine receptors and vanilloid receptors; and neutralise free radicals [10-12]. The in vivo effects of these compounds are uncertain, and the precise mechanisms of plant extracts remain unclear. The extracts of the same plant produced by different companies do not necessarily have the same biological or clinical effects; therefore, the effects of one brand cannot be extrapolated to others [13]. In addition, batches from the same producer may contain different concentrations of active ingredients [14]. A review of recent extraction techniques and their impact on the composition/biological activity of available Serenoa repens based products showed that results from different clinical trials must be compared strictly according to the same validated extraction technique and/or content of active compounds [15], as the pharmacokinetic properties of the different preparations can vary significantly. Heterogeneity and a limited regulatory framework characterise the current status of phytotherapeutic agents. The European Medicines Agency (EMA) has developed the Committee on Herbal Medicinal Products (HMPC). European Union (EU) herbal monographs contain the HMPC’s scientific opinion on safety and efficacy data about herbal substances and their preparations intended for medicinal use. The HMPC evaluates all available information, including non-clinical and clinical data, whilst also documenting long-standing use and experience in the EU. European Union monographs are divided into two sections: a) Well established use (marketing authorisation): when an active ingredient of a medicine has been used for more than ten years and its efficacy and safety have been well established (including a review of the relevant literature); and b) Traditional use (simplified registration): for herbal medicinal products which do not fulfil the requirements for a marketing authorisation, but there is sufficient safety data and plausible efficacy on the basis of long-standing use and experience. Table 1 lists the available EU monographs for herbal medicinal products and the current calls for update. Table 1: European Union monographs for herbal medicinal products Only hexane extracted Serenoa repens (HESr) has been recommended for wellestablished use by the HMPC. Based on this a detailed scoping search covering the timeframe between the search cut-off date of the EU monograph and May 2021 was conducted for HESr. A large meta-analysis of 30 RCTs with 5,222 men