Treatment of erectile dysfunction at patients with hypogonadism (для специалистов)

Dmitry Kurbatov, Jury Kuznetsky, Michael Petrichko Moscow, Russia

It is well known that among the reasons of erectile dysfunction (ED) vascular disturbances - arterial, venous or their combination [1,2] prevail. The symptoms of veno-occlusive ED as basic or additional sign of ED, meet not less, than at 30 % of patients. Thus the certain diagnostic and tactical difficulties are represented by patients with venous ED which have a pathological venous drainage (PVD) from cavernous bodies.

The basic methods of venous ED treatment are: therapy by inhibitors phosphodiesterase type 5 (PDE-5), vacuum-constrictors with compressing rings on the basis of a penis, surgical treatment [3,4]. However efficiency of inhibitors PDE-5 is far not high, especially at patients with a low level of plasma testosterone [5, 6]. Therefore at patients with ED, according to the international references, the investigation for revealing a hypogonadism is necessary because its frequency at screening researches is 18,3 % - 50 % [6, 7].

Researches of last years have shown that quality of erectile function rather depends on a level of androgens. Mancini et al. (2005) proved that prevalence of estrogens at elderly patients and patients with D. Mellitus reduces rate of a blood flow in penile arties and leads to development of venous leakage which successfully can be eliminated with administrating of testosterone [8]. It has been established, what even single administration of testosterone can be sufficient for achievement of an adequate erection at 56 % of such patients, and the efficiency of PDF-5 considerably increases at patients with stably normal level of testosterone [5,6]. The first results of PVD treatment of patients with a D. Mellitus and ED by androgens are published in works of Yassin et al. (2005, 2006) [9]. The expediency of a choice of long action Testosterone for replacement therapy has been caused by drug properties and pharmacodynamic features (stable conservation of testosterone in its physiological levels lasting for 3 months and absence of peak rises) are the basic differences from effect of other Testosterone with the short period of action.

The purpose of the study was the evaluation of the androgenotherapy efficiency with using long acting Testosterone “Nebido” in the patients with ED and androgenodeficit. This research is still continue, however the first positive results have caused an opportunity of their publication.

Materials and methods

29 men suffered ED, aged of 32 - 65 years (47±9,7) were included in this study. All patients complained for low libido, the unstable erection, the premature ejaculation, fast detumescence. Diseases lasting were 1,5-5 years. More than half of patients earlier experienced inhibitors PDE-5 with low effect. The diagnosis established on clinical dates, testing on standard questionnaires, dates of laboratory and radial investigation.

Patients were divided on 2 groups depending on presence of venous leakage. 20 patients with ED and venous leakage composed the first group. The second group was made by 9 patients suffered ED, but without symptoms of venous leakage.

For evaluation of the androgenic status at the men we used AMS -questionnaire, expressed in points (weakly expressed attributes of 26-36 points, moderately expressed - up to 49 points and strongly expressed - more than 50 points). We used also questionnaire IIEF-5 for sex function evaluation.

After physical examination all patients underwent ultrasound of a prostate gland and Pharmacodynamic Duplex Sonography (PDS) by a conventional technique. Signs of venous leakage from penis we revealed at 20 patients: V max of blood flow in dorsal vein was higher than 10 mL/s, 30 to 50 per cent increase in vein diameter, change of dorsal vein blood flow into the opposite direction when Valsalva test was performed.

For topical diagnosis of the suspected venous leakage we performed Pharmaco-Cavernosography (PCG) at 9 patients and at 8 patients - Magnetic resonance imaging (МRI) with intracavernous contrast enhancement [10].

Laboratory tests included: total Testosterone, FSG, LG, Prolactinum, blood sample, Glucose, PSA level (at men after 45 years).

After signing the informed consent to all men the long action Testosterone «Nebido» (Ваer-Schering Pharma) was administrated. This agent injected intramusculary according the scheme recommended by the company: the first and second injections - with an interval of 6 weeks, the subsequent - in 10-12 weeks, depending on patient’s complaints. Duration of therapy - 30 weeks was at 20 men and no more than 18 weeks - at 9 (from them 6 weeks - at 2, 18 weeks - at 7 patients).

After 3 injections (on 20-21 week) we checked a level of total Testosterone and tested the the prostates by digital rectal examination and ultrasound. 9 patients with venous leakage repeated PCG (5) or MRI (4).

Results

Initial inspection has shown, that all 29 patients with ED had clinical picture of androgenodeficit, but biochemical data had 21 patients.

2 patients had the D. Mellitus 2 types, 4 - an arterial hypertension. 3 men had signs of the low urinary tract symptoms (LUTS) caused BPH (V prostates 43,5 ± 4,6 cm, IPSS - 19±3 ball, QOL - 3-4 ball., V p. - 39,5 ±1,7 cm3, V r.-24 ±6 ml, Q maх.-10,3 ± 2,6 ml/sec).

We noted a positive influence of hormonal therapy on the common status at all men of 1 and 2 groups: increasing of physical activity, improvement of mood and a vitality. In 1 group positive changes men noted already after 1 injection: 8 men within 7-10 days after an injection, at others - in 2 weeks. The general health of patients essentially changed. Sexual acts became regular; at patients with the premature ejaculation the sexual act was considerably extended. Thus substantial improvement of libido, qualities of erectile function at the majority of patients (table 1) has noted been.

Table 1. Changes of the basic parameters at hypogonadal patients of 1 group (n=20) with ED and venous leakage before the treatment by Testosterone undecanoat «Nebido».

Parameter	Prior to the beginning of treatment	In 12 weeks	In 30 weeks
N patients	20	20	20
Testosteron total (nmol/l)	9,8±3,1	18±0,25	21,5±2,3
Libido IIEF-5 (points)	4,1±1,2	7,5±2,2	8,3±2,3
Erectile Function IIEF-5 (points)	9,4±1,8	18,5±0,5	25±0,4
AMS (points)	48 (40-55)	29 (20-37)	23
V prostate (сm³)	32,4±8,4	34,2±4,3	33,1±5,7
PSA (ng/ml)	1,82±0,9	2,0±0,32	2,1±0,28

The control level of Testosterone at all patients was enlarged up to normal parameters (18±0,25 nmol/l) after 12 week of treatment and after finishing of the treatment - 21,5±2,3 nmol/l. The parameter of sex desire on questionnaire IIEF-5 was enlarged from 4,5±1,2 to 8,3±2,3 points, and the parameter of erectile function enlarged from 9,4±1,8 to 25±0,4 points.

The level of the total PSA remained within the normal limits. Changes of the prostate sizes were not noted.

Similar results have been received in the second group (n=9). The clinical symptoms of SLOH disappeared already after 1 injection of Nebido at 2 patients and after 2 injections - at the others. The level of total testosterone remained within the normal limits of physiological norm, the level of the total PSA remained within the normal limits as well, and volume of a prostate, despite of presence at 3 patients BPH, authentically did not increase. The clinical normalization of the patient’s condition and restoration of quality of a life have allowed to refuse further injections of Nebido at all patients of this group (Table 2).

Table 2 Estimation of the treatment efficiency by Testosterone undecanoat «Nebido» at 2 group (n=9) with ED, but without venous leakage

Parameter	Prior to the beginning of the treatment	6 weeks (2 injection)	18-20 weeks (3 injection)
N patients	9	7	-
Testosteron total (nmol/l)	12,7±1,4	16,3±0,25	17,8±0,4
Libido IIEF-5 (points)	3,6±1,7	8,5±1,2	8,7±0,3
Erectile Function IIEF-5 (points)	8,6±1,2	23,4±0,2	27±0,2
AMS (points)	48 (40-55)	29 (20-37)	22
V prostate (сm³)	37,2±4,4	39,8±4,1	41,2±3,1
PSA (ng/ml)	1,3	1,9	2,1

As a result of the treatment 18 from 29 patients (62 %) have restored satisfactory sexual activity only on a background of application of monotherapy Nebido: 11 men from the first group and 7 - from the second. 10 (34, 4 %) from 29 patients, owing to an insufficient axial rigidity of a penis, combined the therapy by Testosterone with inhibitor PDE-5 – Levitra of 10 mg 2 times a week before coitus, with expanding of therapy in 3 months.

All patients paid attention to the fact, that before the finishing of Testosteron’s action (usually on 6, 10, 28-29 week), the previously achieved therapeutic effect diminished – penile rigidity decreased during sex activity and a detumescence became more quickly. However everyone of the subsequent decreasing points was on subjectively smaller size, than previous. In other words, there was a cumulating during Nebido treatment and this fact proved the curative effect of androgenreplacing therapy.

9 patients with venous leakage carried out PCG (5) or MRI (4) as control methods for checking out the grade of the leakage. Decrease of intensity of previously documented venous leakage has been confirmed in all patients ( Fig. 1,2,3).

No one of patients informed about cases of inflammation or a pain in the injections places or about any other complications. All patients are under the observation.

From all 29 patients only one man (3,4 %) stopped the treatment. Man of 39 y.o. had ED during 2 years with venous leakage of mixed type (according to MRI) and a level of testosterone 8,1 nmol/l . Quantity of IIEF-5 points were 10. It has been found out, that in a week after each injection the patient marked minor improvement of erectile function - the rigidity a little amplified, a detumescence became more slowly. The level of testosterone raised to 15 nmol/l after 12 weeks of the therapy. Quantity of IIEF-5 points enlarged up to 17. However a week after the third injection initial complaints renewed. Due to dissatisfaction of conservative therapy the patient had the choice in favor of surgical treatment – penile prosthesis implantation. The conventional operation was performed. The biopsy of cavernous tissue showed the cavernous fibrosis, that was apparently the reason of unsatisfactory result of treatment.

Discussion

It is known, that sufficient inflow in to cavernous arteries and satisfactory veno-occlusive function are two equilibrium components which are necessary for maintenance of high intracavernous pressure during an erection [9]. Accordingly, misbalance in hemodynamic parameters (low arterial inflow and/or PVD), means an inadequate rigidity of a penis and development of ED.

Veno-occlusive dysfunction (VOD) is the most frequent reason of ED at the patients who are not responded to conservative therapy [11]. Data obtained by means of electronic microscopy have allowed to confirm, that venous leakage is not only consequence of tunica albuginea structure damage, and a result of a degeneration of a smooth muscles of cavernous tissue, or insufficient of neurotransmitters [12]. Besides it was proved, that disturbances of a smooth muscles of cavernous tissue are age-related [13], consequence of damage effect of toxins (a nicotine, a lipidemia) or damages of an innervations (a surgical intervention, a trauma, D.Mellitus) [14]. On the other hand, a D. Mellitus itself and also age changes lead to impossibility to achieve the necessary axial penile rigidity owing to inadequate veno-occlusive mechanism [15].

Hatzichristou DG et al. (1995) established, that the full erection with a necessary axial rigidity should be caused by a combination of several parameters, such as a grade of intracavernous pressure and the mechanical properties of a cavernous tissue (its ability to expansion) [16]. The expansibility of a cavernous tissue is critical parameter as it is obvious, that greater expansibility for maintenance of penile axial rigidity has normal cavernous tissue, rather than a tissue with low expansibility (a fibrous tissue) [17]. That fact is rather significant for a necessary compression of subtunical veins, blocking of venous outflow and maintenance of an erection.

Long time it was considered that testosterone acts on libido and only secondary to erectile function. However it was established recently the close relation between a level of plasma testosterone and a presence of VOD. Traish et al. (2003), Morelli et al. (2004) showed that intracavernous pressure, the alpha-1 of adrenoreceptors expression and PDE-5 activity are androgenrelated [18,19]. Thus it was proved what even 50 % decreasing of a circulating testosterone level reduced intracavernous pressure which did not increased after administering of inhibitors PDE-5.

It was established that deficiency of testosterone induces as functional, as structure changes of cavernous tissue. During animals experiment Shen et al. (2003) proved that androgen deprivation at rats leads to decreasing of elastic fibers amount in tunica albuginea and the amount of smooth muscles cells of cavernous bodies, with its replacement by collagen fibers. Function and an elasticity of collagen fibers also are regulated by androgens. Even the "healthy" structure of tunica albuginea is androgendepended [20]. Androgens play a key role in restoration and maintenance of structure and function of a smooth muscles of a cavernous tissue [9,21.] Aversa et al. (2003) proved that additional insertion of androgens increase arterial inflow in to cavernous arteries [22]. Foresta et al. (2004) also confirmed that spontaneous and adequate erections improved due to normalization of arterial inflow to cavernous arteries owing to restoration of testosterone level in a blood plasma up to normal parameters [23].

From our point of view, as this factor, as presence and a severity of PVD at patients with veno-occlusive ED will cause response or its absence to the androgenotherapy.

In this connection, the most reliable and pathogenic method of ED treatment at hypogonadal men is androgen substitute therapy by testosterone where long action Testosterone will be preferable because it provides its stable concentration in a blood for a long time and due to absence of its nonphysiological peaks [9].

At patients with ED, clinical symptoms of SLOH and a low level of testosterone was received the good clinical effect to Nebido as monotherapy, as combined with inhibitors PDE-5 during a short course (3-4 мес). Considerable decreasing and even eradication of clinical and biochemical symptoms of SLOH after 1-2 injections of Nebido allows to consider this method of treatment as «start-up therapy» and to recommend it for a clinical practice.

The further researches in this direction should take out that restraint for assignment of Testosterone which is available now. This opinion proves to be true by researches of other authors applied in such cases Testosterone [24].

Conclusions

Despite of successful introduction in a clinical practice new therapeutic agents for ED treatment or an opportunity of radical treatment by means implantations of penile prostheses, it becomes more necessary etiopatogenic approach for correction of that disease. Not recognized reasons of ED development (in particular - androgenodeficit) can lead to a choice inadequate (psychotherapy) or unfairly aggressive kind of treatment (venous surgery, penile implantation).

New data about the role of testosterone on erection phenomenon should promote development of the new concept of pathogenetic correction of veno-occlusive ED. Elimination of androgenodeficit at hypogonadal patients with veno-occlusive ED can be surveyed as one of directions for treatment strategy. Thus the combination of a hormonetherapy with inhibitors PDE-5 considerably will improve results of treatment.

The further researches are necessary to find out clear indications for hormonal therapy at hupogonadal patients with veno-occlusive ED.

PICTURES

Pic. 1 а) Patient К., 50 y.o. PCG before treatment. Mixed type PVD: venous leakage to the deep dorsal vein, glans penis, veins of periprostatic plexus.

Pic. 1 b) PCG after 21 weeks. PVD intensity decreased

Pic. 2 Patient U., 34 y.o. Mixed type PVD. а) MRI with contrast enhancement before the treatment;

Pic. 2 Patient U., 34 y.o. Mixed type PVD. b) MRI after 24 weeks: decreased the intensity of venous leakage to the deep dorsal vein, glans penis, veins of periprostatic plexus.

Pic. 3 Patient B., 56 y.o. Mixed type PVD. а) MRI with contrast enhancement before the treatment;

Pic. 3 Patient B., 56 y.o. Mixed type PVD. b) MRI after 30 weeks: decreased the intensity of venous leakage to the deep dorsal vein, veins of periprostatic plexus, spongiosal body.