Intraprostatic botulinum toxin type A administration: evaluation of the effects on sexual function

Authors


F. Cruz, Department of Urology, Hospital S. João, Porto, Portugal. e-mail: cruzfjmr@med.up.pt

Abstract

Study Type – Therapy (case series)

Level of Evidence 4

What’s known on the subject? and What does the study add?

Intraprostatic injection of botulinum toxin type A was shown to be effective in decreasing symptoms of BPH in several recent studies. However, the possible impairment of sexual function caused by the neurotoxin had never been investigated.

This study shows that intraprostatic administration of botulinum toxin type A neither causes deterioration of sexual function (libido, orgasm, erectile function or ejaculation), nor alteration of serum testosterone levels.

OBJECTIVE

• To evaluate the consequences on male sexual function of intraprostatic injection of botulinum toxin type A (BoNT/A) as a treatment for benign prostatic hyperplasia (BPH). Although BoNT/A is effective in decreasing symptoms of BPH, neuronal impairment caused by the neurotoxin might affect emission/ejaculation. These aspects have not been evaluated before.

PATIENTS AND METHODS

• In all, 16 sexually active men aged >60 years with BPH/benign prostatic enlargement (BPE), International Prostate Symptom Score (IPSS) ≥8 and a maximum urinary flow rate (Qmax) <15 mL/s refractory to standard medical therapy volunteered for the study.

• Patients were injected transrectally, under ultrasonographic control, with 200 U of BoNT/A in the prostate. Evaluation was carried out at baseline and 1, 3 and 6 months post-treatment. Erectile function was evaluated using the International Index of Erectile Function – Short Form (IIEF-5) questionnaire.

• Orgasmic/ejaculatory function and libido were evaluated using questions 9, 10, 11 and 12 of the IIEF – Long Form. Total testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin were also investigated.

RESULTS

• The mean age was 73 ± 6 years. The IIEF-5 score was 16.5 ± 6 at baseline, 15.7 ± 6 at 1 month, 16.6 ± 6 at 3 months and 15.7 ± 5 at 6 months (differences nonsignificant).

• The score for ejaculatory/orgasmic function (questions 9 and 10) remained fairly constant from baseline to the sixth month, 8.3 ± 1.9 and 8 ± 2.1 respectively.

• The sexual desire score (questions 11 and 12 of the IIEF) also remained little changed from baseline (5.9 ± 1.6) to month 6 (6.1 ± 2). Total serum testosterone, LH, FSH and prolactin did not change during the study.

CONCLUSIONS

• Intraprostatic injection of BoNT/A in patients with BPE does not impair erectile, orgasmic or ejaculatory functions and does not change libido.

• The male hormonal profile is not altered by BoNT/A injection. This facilitates the acceptance of BoNT/A as a treatment for BPH/BPE lower urinary tract symptoms (LUTS) refractory to standard medical management.

Abbreviations
BoNT/A

botulinum toxin type A

BPE

benign prostatic enlargement

IIEF-5

International Index of Erectile Function – Short Form

IPSS

International Prostate Symptom Score

LH

luteinizing hormone

PVR

postvoid residual urine volume

QoL

quality of life score

SNARE

N-ethylmaleimide-sensitive factor attachment protein receptor

INTRODUCTION

Benign prostatic hyperplasia is one of the most prevalent diseases of ageing men. It is a progressive disease and its incidence and prevalence increase with age [1]. The clinical manifestations of this condition are LUTS, and these symptoms increase gradually with age [2]. Several studies have also shown that LUTS are associated with sexual dysfunction [3,4] and both conditions have a marked impact on the overall quality of life.

At present, several medical and surgical treatments are available for BPH. Although effective, they are not exempt from side-effects, namely on sexual function. The most widely prescribed oral medications for BPH, α-blockers, can be responsible for ejaculatory dysfunction in up to 10% of patients, depending on the compound and dose used [5]. In the case of 5α-reductase inhibitors, a negative effect on libido was observed in 2–10% of patients, erectile dysfunction was reported in 3–16% and ejaculatory disorders in up to 8%[6,7].

Patients managed with interventional therapy report sexual dysfunction even more frequently. TURP remains the gold standard of surgical treatment for BPH, although it is being challenged by new minimally invasive treatments such as transurethral microwave thermotherapy, transurethral needle ablation of the prostate and laser interventions. All these procedures are a cause for erectile and ejaculatory dysfunction [8]. TURP can be associated with a 10% incidence of erectile dysfunction and a 65% incidence of ejaculatory dysfunction [8]. Transurethral microwave thermotherapy causes 2–49% of ejaculatory dysfunction and 0–8% of erectile dysfunction. Reports on transurethral needle ablation of the prostate indicate an incidence of 1–10% of ejaculatory dysfunction and 1–6% of erectile dysfunction [8]. Recently potassium titanyl phosphate (KTP) laser vaporization of the prostate has been introduced, but retrograde ejaculation is observed in >50% of the treated patients [9].

In recent years, several studies have been published concerning intraprostatic administration of botulinum toxin type A (BoNT/A) [10–17]. There has been a rapid and long-lasting decrease in LUTS in all the pilot studies carried so far [13,17,18]. In addition, it seems that BoNT/A injection can reduce prostate volume in large-to-moderate prostate glands [10,16]. Although these studies did not report significant adverse events (AEs), no study has specifically addressed the possible effects of the intraprostatic neurotoxin on emission, ejaculation and erectile function of treated patients. These AEs can be envisaged as a possibility, as BoNT/A impairs the release of neurotransmitters such as acetylcholine and noradrenaline from cholinergic and sympathetic nerves [19], after preventing the fusion of synaptic vesicles with the neuronal membranes [20]. In the present study, we investigate for the first time the effect of BoNT/A injection on the sexual function of treated patients.

patients AND METHODS

In all, 16 sexually active men (in a stable relationship and engaging in sexual intercourse at least twice per month) were enrolled in the present study between January 2008 and March 2009. This open-label study was conducted at the Department of Urology of the Hospital of S. João, Porto after approval by the Ethics Committee of our institution.

Inclusion criteria for BoNT/A treatment were moderate-to-severe LUTS refractory to standard medical therapy and a significant contraindication for surgical treatment. All patients had to had a maximum urinary flow rate (Qmax) <15 mL/s, total PSA level <10 ng/mL, a non-suspicious DRE for prostate cancer and were sexually active. Patients with lower urinary tract malignancy, previous pelvic surgery or trauma, previous BPH surgery or neurological disorders were excluded from the study. Patients with a PSA level between 4 and 10 ng/mL who were concerned they might have prostate cancer could undergo prostate biopsy to exclude malignancy.

All patients received the standard evaluation for benign prostatic enlargement, which comprised LUTS evaluation, physical examination, including DRE, TURP to measure the prostate volume, kidney and bladder ultrasonography (US), and biochemical blood tests, including a total PSA. In addition, a uroflowmetry test was carried out and the postvoid residual urine volume (PVR) was determined.

At baseline, sexual evaluation was carried out using the International Index of Erectile Function – Short Form (IIEF-5). Orgasmic and ejaculatory function was investigated using questions 9 and 10 of the IIEF and a supplementary question enquiring how satisfied the patient was with his ejaculation. The score of these questions ranges from 0 to 10 (severe dysfunction to no dysfunction) [21]. To evaluate sexual desire, questions 11 and 12 of the IIEF were applied. The sum of these questions varies between 0 and 10 (severe dysfunction to no dysfunction) [21]. All patients had blood taken for hormonal determinations (total serum testosterone, luteinizing hormone [LH], FSH and prolactin). Concomitant with sexual evaluation, International Prostate Symptom Score (IPSS) score, Qmax and prostate volume were determined.

Botulinum toxin type A injections were carried out by transrectal approach under US guidance. Two vials of Botox®, each one containing 100 U of neurotoxin (Allergan, Irvine, CA, USA) were diluted in 8 mL of saline. A 21-G, 20-cm-long Chiba needle was used to inject 4 mL (100 U) in two different places in each transitional zone while the diffusion was controlled by US. Anaesthesia was not required for the procedure. Patients were instructed to start ciprofloxacin 500 mg twice daily 2 days before the procedure and to complete a full 7 days of treatment. At 1, 3 and 6 months after treatment, patients underwent evaluation as performed at baseline.

Results are presented as means ±sd. All values were compared by a two-tailed Student’s paired t-test for means except when stated otherwise. P < 0.05 was considered to indicate statistical significance.

RESULTS

The mean (±sd) age of the cohort was 73.3 ± 6.3 years. Injection was done as an office procedure and was well tolerated, with no patients demanding analgesic therapy or developing haematuria, urethral bleeding or systemic botulism. Four patients developed mild symptoms of prostatitis 1 month after injection and were managed with an additional period of antibiotherapy. One patient abandoned the study after the third month’s visit; unsatisfied with the LUTS outcome, he decided to undergo TURP. The baseline variables are shown in Table 1.

Table 1.  Baseline characteristics and results at the 1-, 3- and 6-month evaluations. Results were compared against baseline measurements (P < 0.05 was considered to indicate statistical significance). Values are means ±sd
 Baseline1 month3 months6 months
IIEF score (5–25)16.5 ± 615.7 ± 6 (P= 0.7)16.6 ± 6 (P= 0.95) 15.7 ± 5 (P= 0.69)
Libido (0–10) 5.8 ± 1.6 6.3 ± 1.7 (P= 0.46) 6.3 ± 1.9 (P= 0.48)  6.1 ± 2 (P= 0.7)
Orgasm/ejaculation function (0–10) 8.3 ± 1.9 8.1 ± 1.9 (P= 0.7) 7.9 ± 2 (P= 0.5)     8 ± 2.1 (P= 0.7)
Total testosterone, ng/mL4.91 ± 1.24.93 ± 0.9 (P= 0.96)  4.92 ± 1.8 (P= 0.99)
LH, mUI/mL5.56 ± 2.24.94 ± 1.9 (P= 0.4)  4.67 ± 1.8 (P= 0.26)
FSH, mUI/mL8.86 ± 78.43 ± 7 (P= 0.86) 10.76 ± 7.8 (P= 0.54)
Prolactin, ng/mL7.92 ± 2.88.56 ± 3.4 (P= 0.58)  8.34 ± 4 (P= 0.77)
Prostate volume, mL75.9 ± 4150.2 ± 25 (P= 0.04)39.7 ± 24 (P= 0.006)     39 ± 19 (P= 0.004)
Total PSA, ng/mL 2.6 ± 1.5 2.5 ± 1.2 (P= 0.8) 2.7 ± 1.9 (P= 0.7)  2.5 ± 1.6 (P= 0.9)
PVR, mL  130 ± 114   92 ± 87 (P= 0.29)   67 ± 72 (P= 0.07)    66 ± 56 (P= 0.06)
Qmax, mL/s 8.9 ± 3 11.5 ± 4 (P= 0.04)12.9 ± 6 (P= 0.02)  11.4 ± 4 (P= 0.07)
IPSS score (0–35)19.5 ± 514.1 ± 4 (P= 0.003) 9.3 ± 4 (P < 0.005)  8.9 ± 3 (P < 0.005)
QoL score (0–6)3.75 ± 0.92.69 ± 0.9 (P= 0.003)    2 ± 1 (P < 0.005)  2.07 ± 0.9 (P < 0.005)

No patients reported loss of libido or changes in the quality of their erections, ejaculation or orgasm after BoNT/A injection. Patients reported that the number of successful acts of sexual intercourse did not change before and after treatment. The baseline IIEF-5 score was 16.5 ± 6 and showed no significant difference during follow-up. It was 15.7 ± 6 at 1 month and 16.6 ± 6 at 3 months. At 6 months the 15 patients remaining in the study had a score of 15.7 ± 5.

The total score for questions 9 and 10 of the IIEF – Complete Form (orgasmic function) was 8.3 ± 2 at baseline, and maintained similar values during the period of study, being 8 ± 2 at 1 month, 7.9 ± 2 at 3 months and 8 ± 2 at 6 months (15 responders). No patient reported changes to the volume of ejaculate or the time necessary to achieve ejaculation. Overall satisfaction with ejaculation was maintained.

Sexual desire or libido was evaluated by questions 11 and 12 of the IIEF – Long Form and there were no significant differences during the study. The score was 5.9 ± 1.6 at baseline, 6.3 ± 1.7 at 1 month, 6.3 ± 1.9 at 3 months and 6.1 ± 2 at 6 months (15 responders).

Total serum testosterone was not changed by intraprostatic injection of BoNT/A (4.91 ± 1.2 ng/mL at baseline, 4.93 ± 1 ng/mL at 1 month, and 4.91 ± 1.8 ng/mL at 6 months) . Also, LH, FSH and prolactin serum concentrations were not changed by the treatment, as shown in Table 1.

At baseline, the mean IPSS score was 19.5 ± 4.9 and the associated quality of life score (QoL) was 3.75 ± 0.9. At 1 month, the IPSS and QoL decreased to 14.1 ± 4 and 2.7 ± 0.9, respectively (P= 0.003). At 3 months, the IPSS decreased to 9.3 ± 4.4 (P < 0.005) and the QoL decreased to 2 ± 1 (P < 0.005). At 6 months, the IPSS and QoL scores were 8.9 ± 3 and 2 ± 0.9, respectively (P < 0.005). The mean prostate volume at baseline was 75.9 ± 41 mL and decreased in all patients after treatment. The mean volume was 50.2 ± 25 mL (P= 0.04) at 1 month, 39.7 ± 24 mL (P= 0.006) at 3 months and 39 ± 19 mL (P= 0.004) at 6 months. The mean PVR was 130 ± 114 mL at baseline and decreased to 92 ± 87 mL at 1 month, 67 ± 72 mL at 3 months and 66 ± 56 mL at 6 months; these values were not statistically different. At the baseline, mean Qmax was 8.9 ± 3 mL/s and increased to 11.5 ± 4 mL/s at 1 month (P= 0.04). At the 3-month evaluation, mean Qmax increased again to 13 ± 6 mL/s (P= 0.02) and at 6 months it was 11.4 ± 42 mL/s (P= 0.07).

DISCUSSION

Botulinum neurotoxin type A is the strongest biologic toxin known to humans [19]. Nonetheless, local injections of BoNT/A have been approved by the USA’s Food and Drug Administration to treat eye conditions, blepharospasm and strabismus, striated muscle dystonias and primary axillary hyperhidrosis. Investigational uses for BoNT/A include neurogenic and non-neurogenic bladder dysfunction and oesophageal achalasia [19]. BoNT/A is a neurotoxin that prevents the N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent release of neurotransmitters. In terminal nerve endings, BoNT/A cleaves synaptosomal-associated protein 25 (SNAP-25), one of the SNARE proteins in presynaptic nerve endings, thereby inhibiting the fusion of neurotransmitter-containing synaptic vesicles with the neuronal membrane [20]. These events decrease the amount of neurotransmitters released from sympathetic, parasympathetic and sensory nerves [19].

The mechanism of action of BoNT/A at the prostatic level has been shown to be essentially dependent on sympathetic chemodenervation. The decrease in noradrenaline release from sympathetic nerve endings was shown to promote prostate cell apoptosis [22], an effect that certainly contributes to the prostate volume decrease previously reported in medium-to-large glands [17], and which has been confirmed once more in the present study. In addition, the decrease in sympathetic mediators might contribute to a decrease in smooth muscle tonus, as observed in the dog after neurotoxin administration [23].

Several recent studies have suggested that intraprostatic injection of BoNT/A improves LUTS and urinary flow in patients with BPH for all volumes of prostate glands [10–18,24]. The simplicity of the procedure makes intraprostatic injection of BoNT/A extremely attractive to patients for whom an interventional treatment under general anaesthesia is the alternative. In fact, BoNT/A injection is carried out as an office procedure without local anaesthetic or analgesic support. Until now, no important side-effects have been reported after intraprostatic injection of the neurotoxin in doses ranging between 100 and 300 U [10–18,24]. AEs that have been investigated so far include safety variables such as clinical botulism and urinary incontinence. However, prostatic therapies, both medical and surgical, can have a negative impact on sexual function, namely emission and ejaculation [25], but this aspect had never been fully investigated after BoNT/A injection.

The most important finding of the present study is therefore the observation that intraprostatic injection of BoNT/A does not result in a deterioration of any domain of sexual function. The prostate gland is a fundamental sexual organ determining and/or influencing ejaculate volume, ejaculation proper, and the occurrence and quality of orgasm. Neuronal control of the gland is essential for processes either by promoting acinar secretion (parasympathetic nerves) or by increasing muscular tonus necessary for emission of prostate fluid (sympathetic nerves). Therefore, a decrease, or even a loss, of emission and ejaculation could be feared after BoNT/A administration. The results of the present study, however, showed that, despite a decrease in prostatic nerve fibres after BoNT/A injection [22] this is not enough to diminish sexual function. In particular, a retrograde ejaculation, so frequent after α-blocker medication or surgical interventions for BPH [8], was not detected. A probable explanation for the maintenance of an anterograde ejaculation is that bladder neck sympathetic innervation is not affected after intraprostatic injection of BoNT/A. In fact, results from our group confirm that, in the case of the prostate, BoNT/A does not diffuse markedly from the injection site, the prostatic transition zone [16]. For the same reason BoNT/A is not expected to interfere with the contractility of the vas deferens and seminal vesicles, therefore preserving emission. It is worth recalling that some α-blockers severely impair seminal emission [26].

Decreased libido is frequently detected after administration of 5α-reductase inhibitors. Such a problem was not detected in the present study. A decrease in libido is not expected due to the lack of systemic effects of intraprostatic BoNT/A injection. Nevertheless, the present study shows that intraprostatic BoNT/A did not cause any change in total serum testosterone or other sexual hormones. It is therefore safe to assume that this treatment will not alter the hormonal profile of patients with BPH.

As in our previous studies [16,18], in the cohort in the present study we confirmed that intraprostatic BoNT/A injection improved LUTS. LUTS have been shown to influence sexual function negatively. In fact, it is well known that sexual activity decreases in all ages whenever BPH-related LUTS become severe and that the presence and severity of LUTS are independent risk factors for sexual dysfunction in older men [3,27]. During treatment of BPH-associated LUTS with α-blockers it has also been shown that improvement in the IPSS, IPSS-QoL and mean uroflow significantly correlates with an increased score in the IIEF-5 [28]. Also, in the Treatment of Mild Hypertension Study [29], the group of patients treated with the α-blocker, doxazosin, experienced the lowest incidence of erection problems, and in some, erection problems disappeared throughout the study. However, in the present study, although there was amelioration of LUTS, there was no parallel improvement in sexual function. Several factors might have contributed to this finding. The cohort was small and the mean age of the participants high. All the patients had co-morbidities severe enough to increase the overall risk of standard BPH surgery. In addition, the baseline IIEF score showed there was already a moderate impairment of sexual function in the patients, and it is probable that other risk factors prevented an improvement in sexual function. It is possible, therefore, that in future studies with a younger population and a longer follow-up, improvement in LUTS observed after BoNT/A injection might be associated with a general sexual improvement.

Although it is novel in this field, the present study has several limitations. The number of patients was small and the cohort was elderly, with a mean IIEF-5 score of 16, which means that they already presented a moderate degree of erectile dysfunction. Therefore, the absence of severe side-effects with regard to sexual function, although reassuring, should not be presumed for a younger and more sexually active population. The antibiotic prophylaxis regimen should also be reviewed to reduce the risk of prostatitis.

In conclusion, intraprostatic BoNT/A injection via the transrectal route did not cause any significant sexual AEs in an elderly population of patients with BPH, with LUTS refractory to medical treatment. This finding warrants further studies of the neurotoxin on BPH and LUTS.

CONFLICT OF INTEREST

Francisco Cruz is a paid consultant to Allergan, Astellas. Source of Funding: this work was supported by a grant from Hospital S. João.

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