Benign prostatic hyperplasia (BPH) is one of the most prevalent ailments of aging men, affecting nearly 50% and 100% of this population by the time they reach 50 and 80 years of age, respectively, with a detrimental impact on their quality of life (QoL) [1].The prostate grows at a rate of 2.5% per year in higher age groups and the age-related prostatic enlargement mainly affects the prostatic periurethral zone [2]. Subsequent prostatic urethral compression occurs with resultant urinary outflow obstruction, urinary bladder hypertrophy and reduction of the bladder volume reservoir [3, 4].
The lower urinary tract symptoms affect up to 74% of adults above 40 years, 42% of whom report a moderate degree of symptoms. In addition, an age-dependent lower urinary symptomatic progression occurs in 5-year increments with a resultant poor sexual life due to erectile and ejaculatory dysfunctions and side effects of antiandrogenic medications [5].
To further explore the underlying mechanisms of prostatic enlargement, Gat et al. [4, 6, 7] proposed that the blood flow mechanics of the anatomically connected prostatic and testicular veins follow Pascal’s [8] and Bernoulli’s [9] laws, which postulate that the fluid hydrostatic pressure equalizes across communicating vessels. The age-related valvular destruction of the spermatic veins establishes continuous blood columns with elevated hydrostatic pressures (27 and 32 mmHg for 35 and 40 cm columns heights on the right and left, respectively, compared to 6 mmHg for a normal intervalvular blood segment). In addition to collaterals development, the testicular venous elevated pressures establish a pressure gradient, which diverges free testosterone (dihydrotestosterone or DHT) from the testes to the prostate with subsequent prostatic congestion and androgen-dependent prostatic hyperplasia [7] (Fig. 1).
Gat et al. [4, 6, 7] referred to the testicular-prostatic venous backflow as ‘the backdoor phenomenon,’ which was used to explain the biologic paradox of testosterone-dependent BPH despite age-dependent serum testosterone decline. The Gat theory was confirmed during venography by the visualization of a prostatic capsular blush following the opacification of an impaired testicular vein while applying abdominal compression to simulate the elevated hydrostatic pressure (Fig. 2). Subsequently, Gat considered varicoceles sclerotherapy to be a super-selective intraprostatic androgen deprivation therapy because the occlusion of the refluxing spermatic veins and their vertical bypasses eliminates the testicular-prostatic pressure gradient with back-flow cessation and reversal of the prostatic hyperplasia [7].
Several studies agreed with the Gat theory while others rejected it. The supporting studies included the Strunk and Rauch study [10] that detected an improvement of the urinary symptoms upon sclerotherapy application in patients with prostatomegaly, the Ur Rehmen et al. study [11] that found the pressure in the incompetent left ISV to be 31 mmHg with Valsalva, and the Pejčić et al. study [12] that detected a fourfold rise in the dihydrotestosterone (DHT) quantity of the BPH specimens using mass spectrometry. Some studies observed a direct association between varicoceles and BPH with age [13, 14] while others found that orchiectomy and antiandrogenic medications aid the prostatic volume reduction [15, 16].
On the other hand, studies that rejected the Gat theory disputed the proposed causal relationship between varicoceles and BPH, and claimed that the prostatic enlargement is a multifactorial process caused by androstenedione-dependent DHT, aromatase-dependent estrogen stromal proliferation, androgen and estrogen receptors overexpression, chronic inflammation, and immune dysregulation [17,18,19,20]. In addition, two prospective studies published different results from those of the Gat studies [4, 6, 7]; Goana et al. study [21] uncovered no statistical significance in varicoceles percentage between patients with prostatic volumes ≥ 40 ml and < 40 ml and De Caestecker et al. study [22] detected high periprostatic plexus testosterone in only 2 out of 7 patients undergoing Millin prostatectomy for BPH.
The aim of our study is to test the Gat theory via occluding varicoceles and studying the subsequent effect on prostatic volumes and prostatic-related lower urinary tract symptoms in middle-aged and elderly men suffering from benign prostatic hyperplasia.
Patients
For 6 months from June 2021 till November 2021, our single-arm interventional pilot study enrolled 40 cases; 36 of whom were included and the remaining 4 were excluded.
The patients complaining of lower urinary tract symptoms with elevated PSA were referred by the urology clinics of our hospital and nearby centers for prostatic biopsies to exclude any underlying prostatic malignancies. Those patients received complementary scrotal sonographic assessments to detect the presence of refluxing varicoceles and to help determine if they fitted the inclusion criteria of our study.
The inclusion criteria were: males ≥ 40 years having sonographically-detected refluxing varicoceles with concomitant prostatic volumes > 30 cc due to benign prostatic enlargements. All of the enlarged prostatic glands included in the study were biopsied and were pathologically proven to be benign prostatic hyperplasia.
The inclusion criteria also specified patients with lower urinary tract complaints for over a year with little relief on antiandrogenic medications despite compliance for ≥ 6 months, suffering from antiandrogenic drugs side effects or refusing prostatic surgeries. The exclusion criteria comprised young adults complaining of varicoceles-induced infertility or having asymptomatic varicoceles without BPH or LUTS. Any patient with a known urological cancer, a history of urological surgeries, an ongoing infection, having stones, renal failure (creatinine clearance < 30 ml/min), or a bleeding tendency (INR > 2) was also excluded.
Clinical assessment
A comprehensive medical history was obtained from each patient regarding his relevant comorbidities as Diabetes Mellitus. Each patient was also asked about the intake of bladder irritants (tobacco and caffeine), drugs inciting lower urinary tract symptoms as diuretics, and antiandrogenic drugs namely alpha-blockers and 5-alpha-reductase inhibitors. The patients’ lower urinary complaints were divided into obstructive, post micturition and storage symptoms. The obstructive urinary symptoms included weak urine streams, straining, intermittency, and hesitancy. The post micturition symptoms included terminal and post micturition dribble while the storage urinary symptoms included frequency, urgency, nocturia, and incontinence.
Each patient was asked to fill an International Prostate Symptom Score (IPSS) and a Quality of Life (QOL) questionnaire (Fig. 3) to determine the severity of his urinary symptoms and was also asked to detail the impact of the urological problems on his sexual performance and satisfaction. Each patient underwent a testicular examination for palpable varicoceles, an abdominal examination for a palpable urinary bladder, and a digital rectal examination (DRE) to assess the prostatic size, mobility, and symmetry.
Preprocedural evaluation and preparation
The patients’ preprocedural evaluation included laboratory testing, imaging assessment and urodynamic studies. Each patient did a PSA level as a baseline for follow-up and was tested via a urine analysis to exclude infections, a serum creatinine test to rule out renal failure, and a coagulation profile to exclude any bleeding diathesis. As for imaging, each patient underwent a pelvic sonography to measure the prostatic volume and the post void residual volume, and a testicular Doppler to detect and grade subclinical varicoceles. The urodynamic studies confirmed the urine outflow tract obstruction by measuring the maximum urinary flow rate (Q max) and excluded concomitant detrusor over activity.
The preprocedural instructions mainly specified a 48-h stoppage of the intake of nephrotoxic medications including metformin, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. The rest of the instructions entailed preprocedural adequate hydration and bladders evacuation.