Key words
abdomen - prostate - blood vessels - genital/reproductive
Introduction
Although testosterone promotes cell proliferation in the prostate [1], a low serum testosterone level is seen in patients with benign prostate hyperplasia
(BPH) [2]. Interestingly, it was nonetheless able to be shown that the administration of antiandrogenic
medications can have a reductive effect on BPH [3].
Based on this paradox, Gat et al. 2008 formulated the hypothesis that venous valve
insufficiency of the spermatic veins may be responsible for the development of BPH
[4]: On the one hand, the valve insufficiency results in reflux via venous collaterals
into the prostatic plexus which can cause an increase in the volume of the organ.
On the other hand, the backed-up blood contains significant quantities of free, unbound,
i. e., active, testosterone. This hormone load causes accelerated cell proliferation
and can ultimately lead to prostate hyperplasia.
Occlusion of the insufficient spermatic veins is intended to eliminate the pathological
hydrostatic pressure thus correcting the reflux and volume load. As a result of the
changed flow conditions, the testosterone-rich blood flows via the vesical veins to
the systemic circulation without impacting the prostate. This is intended to reverse
the hyperplasia.
The goal of our study was to use the vein occlusion treatment concept used by Gat
et al. in the clinical routine and to report initial results.
Patients and Methods
The following evaluation was based on 30 consecutive patients treated by intervention
for benign prostate hyperplasia (BPH) at our clinic by February 2014. Follow-up data
from at least 6 months was available for 16 of these patients by the cut-off date.
The inclusion criteria were an age of > 40 years, confirmed BPH, no obstructive uropathy,
no acute urinary retention, failure of treatment with medication for at least 6 months
or rejection of treatment with medication as well as rejection of surgery by the patient.
The exclusion criteria were acute urinary retention, obstructive uropathy, confirmed
prostate carcinoma and contraindications for intervention, such as coagulation defect,
renal insufficiency.
All patients contacted the clinic on their own because they had heard or read about
the vein occlusion treatment concept used by Gat et al. [4].
All patients were informed of possible complications, such as contrast medium reactions,
infections, bleeding and other vascular complications, orchitis, epididymitis, and
possible treatment failure, prior to intervention ([Table 1]).
Table 1
Reported complications after varicocele occlusion.
|
complications
|
frequency
|
|
large hematoma (after accidental arterial puncture)
|
< 0.4 % [6]
|
|
aneurysmal hematoma (after accidental arterial puncture)
|
< 0.4 % [6]
|
|
arteriovenous fistula
|
< 0.1 % [7]
|
|
contrast agent intolerance with severe anaphylactic reaction
|
0.04 % [8]
|
|
thrombosis and/or thrombophlebitis of the pampiniform plexus
|
0.5 % [9]
|
|
orchitis and/or epididymitis
|
0 – 4 % [6]
|
Patients were also informed of other available BPH treatment options during the preoperation
discussion. At this time
-
The patient history including prior treatments, interventions, secondary diagnoses,
and medication history were recorded.
-
Ultrasound of both kidneys, the bladder (before and after urination), the prostate
(transabdominal), and both testicles (to sonographically detect a varicocele) was
performed and documented. The prostate volume was calculated with the ellipsoid formula.
-
Patients were asked to complete a standardized questionnaire regarding quality of
life [QOL]) and another questionnaire (International Prostate Symptom Score [IPSS]),
which were used to classify the severity of the voiding disorder and the associated
level of suffering [5] ([Table 2], [3]).
-
The following laboratory values were determined: PSA, peripheral total testosterone,
creatinine, TSH, clotting.
Table 2
International prostate symptom score (IPSS).
|
questionnaire regarding urination
|
never
|
less frequently than in 1 of 5 cases
|
less frequently than in half of all cases
|
approximately in half
of all cases
|
in more than half of all cases
|
almost always
|
|
How often in the last month have you had the feeling that your bladder was not completely
empty after urination?
|
0
|
1
|
2
|
3
|
4
|
5
|
|
How often in the last month have you had to urinate a second time in less than two
hours?
|
0
|
1
|
2
|
3
|
4
|
5
|
|
How often in the last month have you had to stop and start again during urination?
|
0
|
1
|
2
|
3
|
4
|
5
|
|
How often in the last month have you had difficulty delaying urination?
|
0
|
1
|
2
|
3
|
4
|
5
|
|
How often in the last month have you had a weak stream during urination?
|
0
|
1
|
2
|
3
|
4
|
5
|
|
How often in the last month have you had to push or strain to start urinating?
|
0
|
1
|
2
|
3
|
4
|
5
|
|
On average, how often in the last month have you had to get up in the night to urinate?
The time between going to bed at night and getting up in the morning is decisive.
|
0
|
1
|
2
|
3
|
4
|
5
|
|
Total
|
0 – 7 points: mild symptoms
8 – 19 points: moderate symptoms
20 – 35 points: severe symptoms
|
Table 3
Quality of life score.
|
quality of life index
|
excellent
|
satisfied
|
largely satisfied
|
mixed, partly satisfied, partly unsatisfied
|
largely unsatisfied
|
unhappy
|
very unhappy
|
|
How would you feel if you could not change your current symptoms during urination
for the rest of your life?
|
0
|
1
|
2
|
3
|
4
|
5
|
6
|
The intervention was performed in 26/30 patients completely via a right cubital vein
access (cephalic vein or basilic vein, 5F introducer) and in 1/30 patients via the
right femoral vein (5F introducer) due to the lack of a suitable cubital puncture
point. The left spermatic vein was probed most effectively with a 5F vertebral catheter
and the right spermatic vein with a 5F headhunter 1 catheter.
In 3/30 patients with cubital access, it was not possible to probe the right spermatic
vein due to opening angle into the inferior vena cava. In these cases an additional
femoral access was created after initial cubital puncture and was then used to probe
the right side via a 5F sidewinder 1 catheter. The catheters were advanced via a guidewire
as far as possible in a distal direction to at least under the iliac crest. Contrast
medium was injected to visualize the caudal spermatic vein and any vertical collaterals
with retrograde contrast enhancement. Since vertical collaterals exert the same hydrostatic
pressure as the spermatic veins on the pampiniform plexus, these must also be embolized
[4] ([Fig. 1]). A foamed mixture of 2 parts polidocanol (Aethoxysklerol, Nycomed) and 3 parts
air was slowly injected for treatment. It was ensured that the previously injected
contrast medium was forced out of the spermatic vein and collaterals by the sclerosing
agent to the greatest extent possible to ensure sufficient occlusion of the vessels.
Fig. 1 Right and left spermatic vein after contrast medium injection.
If a solitary large-caliber spermatic vein was seen, one or two metal coils (Tornado
10 – 4, 6 – 3, 8 – 4 or Nester 14 – 4, 14 – 6, 14 – 8, Cook Medical) were additionally
inserted to securely occlude the vessel. The catheter and introducer were then removed,
the puncture point was manually compressed for several minutes, and a light compression
bandage was applied. Symptom-free patients were discharged after an observation period
of one hour for a cubital puncture and after six hours in the case of a transfemoral
puncture with the condition of returning to the clinic immediately in the case of
a recurrence of symptoms.
6 months after the intervention
-
The abdominal ultrasound scan of both kidneys, the bladder (before and after urination),
the prostate, and both testicles was repeated.
-
The patients were asked to complete both questionnaires again (see above).
-
Laboratory values were determined (PSA, total testosterone)
The results of the questionnaires, the laboratory tests, and the ultrasound scan were
coded as statistically analyzable parameters and the preinterventional data was compared
to the postinterventional data and evaluated. The data are provided as average ± standard
deviation, as median and range (patient age) or as median and interquartile range
(IPSS and QOL). Normal distribution of the data was checked via the D’Agostino-Pearson-Omnibus
test. Normally distributed data were evaluated via paired t-test. Not normally distributed
data and the results of the IPSS and QOL questionnaires were evaluated with the Wilcoxon
signed rank test. A p-value < 0.05 was considered statistically significant.
Results
The age of all treated patients at the time of the intervention was between 46 and
77 years (median 62), and the age of the 16 patients available for follow-up was between
51 and 77 years (median 66.5). All patients had had urologically diagnosed and symptomatic
BPH for at least two years that could no longer be sufficiently treated with medication
(in 23 patients) or for which treatment with medication had been rejected by the patient
(7 patients). All patients were under regular urological monitoring, a clinically
significant prostate carcinoma had already been ruled out in all patients by the treating
urologists, a biopsy of the prostate was performed in 7 of the 30 patients for clarification.
Testicular maldescent was seen in one patient. Occlusion or urological ligation of
the spermatic veins had not been previously performed in any of the patients. Technically
sufficient occlusion was possible in all patients on both sides.
Two injections of the polidocanol/air mixture per side were necessary in 20/30 patients
and three injections were needed in 10/30 patients to reach the main vein as well
as the additional collaterals. A metal coil was additionally inserted on both sides
at the level of the iliac crest in 23/30 patients with a solitary large-lumen spermatic
vein on each side. A double inferior vena cava in two patients ([Fig. 2a, b]) and a circumaortic renal vein in another patient ([Fig. 2c]) were seen as interventionally relevant secondary findings. The intervention time
was 89.5 ± 25.8 min., the fluoroscopy time was 31.3 ± 15.4 min. and the dose was 66.252 ± 54.745 mGy/cm2. During injection of the local anesthetic, one patient had a mild vasovagal reaction,
and a second patient reported mild swelling in the region of the right spermatic cord
for 24 hours after the intervention that resolved spontaneously and without consequences.
A third patient experienced mild flank pain radiating into the groin after the intervention
that also resolved without consequences after 2 days.
Fig. 2 Relevant anatomic variations. Double inferior vena cava with catheter in right a and left b portion. Circumaortic renal vein c.
Follow-up data from at least 6 months was available for 16 of the 30 treated patients
by the cut-off date. Evaluation of the questionnaires after 6 months showed a clear
subjective improvement in symptoms. The IPSS (median 18 [interquartile range 20.75 – 14.50]
vs. 9 [IQR 11.00 – 7.25], p < 0.0001) was significantly lower 6 months after the intervention.
In one patient with initially mild symptoms, the IPSS remained unchanged in the 6-month
follow-up ([Fig. 3]). The QOL score (median 4 [interquartile range 5 – 3] vs. 2 [IQR 3 – 1], p < 0.001)
was also significantly lower 6 months after the intervention ([Fig. 4]). However, the improved scores did not have a clear correlate in the prostate volume
measurement that was not significantly changed with 54.31 ± 30.90 vs. 50.50 ± 29.26 ml
(p = n. s.).
Fig. 3 IPSS before and 6 months after intervention.
Fig. 4 Quality of life score before and 6 months after intervention.
4 of 16 patients had a measurable post-void urine volume. The post-void urine volume
remain unchanged 6 months after the intervention in 2 of these patients, decreased
in one patient, and was no longer detectable in one patient. An improvement in the
QOL and IPSS was nonetheless seen in these 4 patients. However, they still had the
feeling of not being able to fully empty the bladder 6 months after the intervention.
A varicocele was diagnosed sonographically in 4 of the 16 patients prior to the intervention
but was no longer able to be detected after 6 months. A trabeculated bladder was diagnosed
in only one patient and sufficient determination of residual urine was not possible
in one further patient with bladder diverticulum.
No significant differences in both the peripheral total testosterone values (4.55 ± 1.27
vs. 3.93 ± 1.00 ng/ml; p = n. s.) and the PSA values (3.74 ± 2.83 vs. 4.06 ± 3.34 ng/ml;
p = n. s.) could be established in the 6-month follow-up.
Discussion
In 2008 Gat et al. formulated the hypothesis that insufficiency of the venous valves
of the spermatic veins is a possible cause for the development of BPH [4]. The incidence of valve insufficiency and varicoceles increases with age and is
approximately 75 % in 70-year-olds [10]
[11]. The hydrostatic pressure caused by a varicocele results in an increase in volume
in the venous drainage system of the prostate and the excessively increased concentrations
of free testosterone can promote prostate hyperplasia. As a result, it was able to
be shown in venographic examinations that the blood column reaches a height of approx.
40 cm in the left spermatic vein and a height of approx. 35 cm in the right spermatic
vein in the case of insufficient valves resulting in a hydrostatic pressure on the
left of over 30 mmHg and on the right of more than 27 mmHg on the distal pampiniform
plexus. Kim et al. concluded that both the height of the blood column and the number
and cross-sectional area of the branches of the pampiniform plexus are responsible
for the increased pressures [12]. This results, as explained by the Bernoulli equation, in increased static pressure
in the pampiniform plexus with simultaneously slower flow rates, with the pressure
increasing as the number of branches and thus the cross-sectional area of the pampiniform
plexus increase. In addition, a relaxing effect of testosterone on varicoceles could
be shown in in-vitro studies so that an additional increase in the cross section of
the pampiniform plexus caused by vasodilation can be assumed [13]
[14]. Venous drainage of the testicles then primarily occurs via the vein of the ductus
deferens. This vein that transports blood from the testicle drains via the vesicular
vein into the internal iliac vein after joining with the prostatic venous plexus (Santorini).
The vesicular vein represents the shared draining vessel for the testicles and prostate.
Due to the significantly increased hydrostatic pressure in the veins coming from the
testicle, the testosterone-rich blood of the testicle is then forced into the prostatic
venous plexus in a retrograde manner ([Fig. 5]). The connection between the vein of the ductus deferens and the prostate could
be shown in experiments on four-legged animals on the basis of an increase in the
intraabdominal pressure since the spermatic veins are horizontal in this case and
do not have any valves [15]
[16]. Color Doppler ultrasound scans of infertile men showed dilation of the periprostatic
veins with a significant retrograde flow and increased flow rates in the case of a
varicocele on both sides [17].
Fig. 5 Simplified diagram of the male urogenital veins. Only left side is shown. Arrows
indicate main blood flow direction. a Normal with functioning spermatic vein valves. b Impaired spermatic vein valves with varicocele. c After occlusion of the impaired spermatic vein and collaterals. P: prostate; H: testicle;
HB: bladder; VCI: inferior vena cava; VIE: external iliac vein; VII: internal iliac
vein.
Occlusion of the insufficient spermatic veins and their vertical collaterals should
therefore lower the pathologically increased hydrostatic pressure. As a result, the
blood flows out of both flow regions via the vesical vein. The testosterone-rich blood
from the testicle thus also largely flows properly past the prostate into the vena
cava so that when it reaches the prostate it is diluted 70 – 100 times [18] and bound to the sex hormone binding globulin (SHGB) ([Fig. 5]). Thus, only less than 2 % of the total testosterone reaches the prostate as free
testosterone [1]. As a result of the consequently normalized intraprostatic pressure and the decreased
hormone load, the volume load and hyperplasia can be reversed. However, in the case
of insufficient valves, the largely undiluted testosterone-rich blood reaches the
prostate via the above-described shunt in a concentration that is up to 100 times
higher.
A technically successful intervention without major complications was possible in
all patients. In principle, the intervention is technically comparable with sclerotherapy
of varicoceles via selective embolization of the spermatic vein in infertile young
men so that similar undesired side effects and complications can be assumed ([Table 1]). In a study by Wunsch et al. including approx. 5,500 patients, the treatment is
described as safe and efficient [9]. On the whole, the rate of possible complications from the occlusion of spermatic
veins is significantly lower than in surgical therapy of BPH. Consequently, complication
rates of up to 20 % are indicated for transurethral prostate resection (TURP) [19]. Spermatic vein should be occluded on both sides since insufficient veins occur
on both sides in approximately 84 % of patients, only on the left side in 14 % and
only on the right side in 2 % [20]. As performed by us, the occlusion should be carried out slightly below the level
of the iliac crest. There are smaller retroperitoneal collaterals above this point
in approximately 75 % of patients. These do not have valves and exert the same hydrostatic
pressure since this does not depend on the vessel diameter but only on the height
of the blood column [20].
The testicular veins that were able to be probed were dilated in all patients and
a retrograde contrast medium flow was seen which was considered diagnostic for a varicocele.
Interestingly, a varicocele could be detected sonographically in only 4/16 patients
prior to intervention. Therefore, in a comparative study, only approximately 71 %
of varicoceles could be detected with unenhanced ultrasound and approximately 93 %
with Doppler ultrasound [21]. In addition, there are currently no valid criteria for the sonographic diagnosis
of a varicocele [22].
The discrepancy between the subjective improvement in symptoms and the transabdominally
determined insignificant change in prostate volume 6 months after the intervention
was striking. An increased response of the periurethral zone to the expected androgen
deprivation which can only be insufficiently detected by transabdominal ultrasound
is given as a possible reason. Benign prostate hyperplasia occurs primarily in the
periurethral and transition zones of the organ which can be attributed to an increased
androgen receptor density in these regions. These zones include the cranial 2/3 of
the prostatic urethra from the bladder neck to the opening of the ejaculatory duct
and result in flow or urination problems in the case of hyperplasia [23]
[24]. Androgen deprivation via medication also results in a volume reduction preferably
of the periurethral and transition zones [25]
[26]. More extensive studies involving greater patient collectives with more precise
volumetry of the prostate via transrectal ultrasound or magnetic resonance imaging
(MRI) are necessary.
Major fluctuations in the PSA and total testosterone values were seen in the interindividual
comparison and no significant changes were seen in the six-month follow-up. Since
PSA is organ-specific but not disease-specific and can be falsified by inflammation,
trauma or manipulation of the prostate, the determination of this value in the diagnosis
of BPH and prostate carcinoma is still controversial [5].
Occlusion of the prostatic artery is another interventional method for treating BPH.
A metaanalysis of nine studies showed a significant reduction of the IPSS from on
average 23.31 to 11.92, of the QOL from 4.34 to 2.4 and of the prostate volume from
83.6 to 66.4 ml already one month after intervention [27]. The fast onset of action due to the induction of necrosis is accompanied by the
– albeit minimal – risk of ischemia, in particular of the bladder wall (approx. 1 %)
and the rectum (approx. 2.8 %). Our average intervention time in venous occlusion
treatment is approximately 10 % longer than the indicated intervention times for arterial
embolization [27], which can be attributed to the difficult probing conditions of the testicular veins.
The average fluoroscopy time for venous occlusion (31.3 min.) is slightly less than
the times specified for arterial embolization (average of the averages 36.5 min.)
[28]. Moreover, additional dose-relevant imaging of the abdomen for visualizing the vessel
anatomy is not necessary prior to venous occlusion [28].
The results of our study are limited by the currently low number of treated patients.
Moreover, there are no results from long-term follow-ups.
In summary, venous occlusion treatment of BPH is an outpatient procedure with a low
complication rate and satisfactory intermediate result. The long-term results and
pathophysiological mechanisms of the method must be further evaluated.
Clinical Relevance of the Study
-
Venous occlusion treatment of BPH is an outpatient procedure with a low complication
rate.
-
A satisfactory intermediate result was seen 6 months after occlusion.
-
The medium and long-term results as well as the pathophysiological mechanisms of the
method must be further evaluated.
