SEARCH

SEARCH BY CITATION

Keywords:

  • testicular cancer;
  • post-chemotherapy;
  • retroperitoneal lymph node dissection;
  • anejaculation

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Study Type – Outcomes (cohort)

Level of Evidence 2b

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

Modern surgical techniques have allowed preservation of fertility in most patients after post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND), but some patients still have infertility after surgery. We reviewed our experience treating infertility in 26 men after PC-RPLND. Using a structured clinical pathway we obtained sperm in 81% of men for use in assisted reproduction.

OBJECTIVE

  • • 
    To evaluate the effectiveness of a clinical pathway on sperm retrieval outcomes in patients presenting with infertility after post-chemotherapy (PC) retroperitoneal lymph node dissection (RPLND).

PATIENTS AND METHODS

  • • 
    We carried out a retrospective review of patients with advanced testicular cancer, presenting with infertility after PC-RPLND in a large reproductive urology practice.
  • • 
    We implemented a clinical pathway where pseudoephedrine was first administered. If this medication failed, electroejaculation (EEJ) and/or testicular sperm extraction (TESE) was carried out.
  • • 
    The primary outcome was retrieval of sperm for use in assisted reproduction.

RESULTS

  • • 
    Four men had retrograde ejaculation, of whom two converted to antegrade ejaculation with medical therapy.
  • • 
    In all, 22 patients had failure of emission (FOE) and, of these, no patient converted to antegrade ejaculation with medication.
  • • 
    In patients with FOE, sperm was found in 15/20 of those experiencing a successful EEJ.
  • • 
    Seven patients underwent TESE for azoospermia on EEJ or no ejaculate on EEJ, three of whom had sperm found on TESE.
  • • 
    Sperm was found for assisted reproduction in 81% (21/26) patients.

CONCLUSIONS

  • • 
    There appears to be no role for the use of pseudoephedrine therapy in patients with FOE after PC-RPLND.
  • • 
    The use of a structured clinical pathway may optimize patient care.

Abbreviations
PC

post-chemotherapy

RPLND

retroperitoneal lymph node dissection

EEJ

electroejaculation

TESE

testicular sperm extraction

FOE

failure of emission

NSGCT

non-seminomatous germ cell tumour

RE

retrograde ejaculation.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The modern multimodal approach to testicular cancer treatment represents one of the success stories of modern oncology, with survival rates >90% [1]. While the exact indications may be controversial, it is indisputable that retroperitoneal lymph node dissection (RPLND) is a vital tool in the management of advanced non-seminomatous germ cell tumour (NSGCT) [2]. In the modern era of treatment for advanced NSGCT, post-chemotherapy (PC) RPLND is an important adjunct in attaining cure for these patients. Apart from enlarged masses or rising serum tumour markers, there are no reliable preoperative predictors for the exclusion of PC-RPLND in appropriate patients after induction chemotherapy [3,4].

With improved survival and decreased morbidity from treatment [5], focus has shifted to improvements in quality of life, which is negatively affected by the long-term toxicity of treatment. One of the most significant factors after treatment for a patient with testis cancer is fertility. Specific challenges are reduced spermatogenesis secondary to chemotherapy as well as anejaculation after treatment. As testicular cancer strikes at an early age, patients often have yet to start a family. Indeed, in a survey of young cancer survivors, 55% of men who already had children wanted more, and 77% of men without children wanted children in the future [6].

The aim of the present study was to evaluate fertility outcomes and the effect of the use of a structured clinical pathway in patients referred for infertility after PC-RPLND at a major cancer referral centre.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

STUDY POPULATION

Institutional databases registered with the respective institutional review board committees from two medical centres were retrospectively reviewed. The study population consisted of men who: (i) were referred for infertility evaluation; (ii) experienced a lack of antegrade ejaculation; and (iii) had a history of NSGCT requiring PC-RPLND. All patients underwent a full history and physical examination. Early morning total testosterone and gonadotropin levels were measured.

EJACULATORY FUNCTION ASSESSMENT

Anejaculation was determined by patient report at the time of the initial interview and was defined as the persistent absence of antegrade seminal fluid at orgasm. To determine whether this represented retrograde ejaculation (RE) or failure of emission (FOE), patients underwent a retrograde semen analysis. This was conducted in the following manner: (i) patients were sent to a semen analysis laboratory; (ii) they were instructed to void to completion prior to masturbation; (iii) they were instructed to masturbate to orgasm and collect any ejaculated fluid into a container; and (iv) they were instructed to wait 10–15 min and then to void into a urine container. The post-orgasm urine specimen was evaluated for the presence of seminal fluid and it was centrifuged for the presence of sperm. RE was defined as the presence of seminal fluid in the post-orgasm urine specimen. FOE was defined as lack of seminal fluid or sperm on antegrade and retrograde semen analysis.

MEDICAL THERAPY

The treatment algorithm used in our practice starts with the use of pseudoephedrine. Pseudoephedrine was chosen because of its wide availability and its common usage. Other medications have significant side effects and, without level 1 evidence to guide our choice, pseudoephredrine was chosen by clinical judgment. Failure of medication is followed by a trial of electroejaculation (EEJ). At the time of EEJ, the sample is examined for the presence of sperm. Lack of sperm or poor-quality sperm leads to the performance of testicular sperm extraction (TESE). In the present series of patients, pseudoephedrine was commenced at a dose of 60 mg four times daily for 2 days before attempted sperm retrieval by masturbation. Patients were instructed to perform this on three separate occasions, each separated by at least 1 week. The patients then communicated with us by phone to inform us of the response. If semen was produced, another semen analysis was performed. If not, EEJ was performed.

ELECTROEJACULATION

Under general anaesthesia (with the avoidance of paralytic agents), the patient was catheterized in the supine position. Mineral oil was used for catheter lubrication, 30 mL of sperm transport medium was instilled into the bladder and the patient was repositioned in the lateral decubitus position. DRE and anoscopic examination was performed before placement of the rectal probe. A 3.2–3.8 cm probe was used. Stimulation was carried out using a Seager electroejaculator (Dalzell USA Medical Systems, The Plains, VA, USA) with a standard ‘square wave’ pattern, with cycles of five stimulations at a voltage of 25 V. Between each stimulation, a pause of 1 s occurred. The protocol used 3–7 cycles, based upon the degree of penile tumescence and the achievement of antegrade ejaculation. Any fluid from the meatus was collected as the antegrade ejaculated specimen. The maximum temperature permitted was 38 °C. Anoscopy was performed again after completion of the procedure to ensure documentation of any rectal mucosal injury. The patient was finally placed supine, urethral catheterization was repeated and urine was collected for analysis as the retrograde specimen. Antegrade and retrograde specimens were placed into sperm transport medium. The antegrade specimen was surveyed under a phase contrast-enabled table microscope with a survey of 40 high power fields. The presence of <1 sperm/10 high power fields, or the presence of only non-motile sperm, prompted the performance of TESE.

TESTICULAR SPERM EXTRACTION

A median raphe incision was made in the scrotum of ≈ 2.5–5 cm. The tunica albuginea of the testis was incised and seminiferous tissue extruded and inspected. A touch preparation was performed and examined under high power magnification using the same microscope as that used for EEJ. The absence of sperm prompted the performance of bilateral TESE. All specimens were placed in sperm transport media and transported to the laboratory for extensive analysis.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

BASELINE CHARACTERISTICS

Twenty-six men presented with anejeculation after PC-RPLND and were included in the present study. The mean (sd) age at presentation was 27 (9) years. All of the patients presented within 12 months (mean (sd) 8 [4] months) of the PC-RPLND. At presentation, the mean (sd) total testosterone level of the patients was 362 (180) ng/ dL. The mean (sd) FSH level was 12.8 (7.2) IU/ mL. Four (15%) patients were found to have RE on post-orgasm urine analysis, while FOE was found in 22 (85%) patients.

TREATMENT OUTCOMES

Figure 1 shows the outcomes for the four patients who were diagnosed with RE. Two out of the four patients produced antegrade ejaculation with pseudoephedrine, while two patients required EEJ. In three of the four patients, we were able to obtain sperm through a combination of masturbation, EEJ and TESE.

image

Figure 1. Results for patients with RE.

Download figure to PowerPoint

Figure 2 shows the results for the 22 patients who presented with FOE. All patients in this group failed pseudoephedrine therapy and proceeded to EEJ. Semen was retrieved in 20 of these 22 patients. Overall, sperm was found by EEJ in 15/22 patients, although 12 of these patients had sufficiently poor-quality sperm to lead to the performance of TESE. All 12 of these patients had successful sperm retrieval. Of the five patients who were azoospermic on EEJ, the TESE sperm retrieval was achieved in two patients. Overall, sperm was retrieved in 18/22 patients with FOE.

image

Figure 2. Results for patients with FOE.

Download figure to PowerPoint

For the overall group, we were able to find sperm in 81% of men.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Currently, RPLND is an essential tool in the management of advanced NSGCT after induction chemotherapy [1]. Bilateral RPLND damages the lumbar splanchnic nerves and hypogastric plexus resulting in the permanent loss of emission and ejaculation [7]; however, advances in surgical treatment have allowed sympathetic nerve sparing even in the PC setting, where fibrosis and desmoplastic reaction of tumour to chemotherapy makes identification and sparing of nerves exceedingly difficult [8–13]. At our institutions, ≈40% of patients needing PC-RPLND are candidates for nerve-sparing surgery, and modern series of patients who have undergone nerve-sparing PC-RPLND report preservation of some antegrade ejaculation in 74–96% of cases [8,11,14–16].

While ‘dry ejaculate’ is often the outcome measured in oncological studies, in reality a lack of seminal fluid at the time of orgasm may be attributable to either RE or FOE. RE, in which seminal fluid travels into the urinary bladder, is attributable to incompetence of the bladder neck. Thus, with orgasm, little or no seminal fluid is ejaculated. FOE, on the other hand, is the complete absence of seminal fluid deposition into the prostatic urethra. This represents greater damage to the innervations of the seminal vesicles and the prostate.

Conventional treatment for those who are anejaculatory often includes the use of sympathomimetics to enable antegrade ejaculation. For those who fail, a retrograde specimen can be obtained from the urinary bladder by catheterization. This is followed by use of EEJ or surgical sperm retrieval. There are very few data to guide treatment selection after chemotherapy in these patients with testicular cancer. Jacobsen et al. [14], in their series of PC-RPLND patients had 9 anejaculatory patients, of which 7 utilized cryopreserved sperm while two were successfully treated with sympathomimetics. Rosenlund et al. [17] found a live birth rate/ongoing pregnancy rate in 11/15 couples where collection was mostly by EEJ. Chan et al. [18] and Damani et al. [19] have both reported successful treatment of persistent PC azoospermia with retrieval of testicular sperm coupled with intracytoplasmic sperm injection. Hsiao et al. [20] later updated the series at Weill Cornell. In these series, representing the outcomes of three major fertility centres, sperm was successfully retrieved in 37–65% of men with pregnancy rates of 30–50%. Overall, a weakness of published studies is their focus on the efficacy of single procedures and resulting fertility outcomes. In our opinion, more research is needed on the use of clinical care pathways for these patients and the resulting outcomes.

We undertook the present study to evaluate our outcomes in men with anejaculation after PC-RPLND in our reproductive medicine practice. Our approach is as follows: an initial trial of medical therapy is followed by the use of EEJ with subsequent TESE (in the same session) if EEJ revealed azoospermia or extremely poor sperm quality. Using this algorithm, we found that no patients with FOE responded to medication, suggesting the futility of medical treatment for those with FOE. In addition, although EEJ was technically successful in 20/22 (90%) of patients, sperm was found in only 15/22 (68%) of men. Finally, of the seven patients with FOE who were either azoospermic or did not have emission during EEJ, three had sperm found on TESE. Overall, we were able to find sperm in 21/26 (81%) of our patients.

Based on our results, we recommend a clinical care pathway (Fig. 3). In this pathway, the initial evaluation for a patient with anejaculation includes a retrograde semen analysis. For those with RE, based on our data, a trial of medical therapy is warranted, followed by EEJ and TESE. Men with FOE should proceed directly to EEJ and then to TESE, if needed.

image

Figure 3. Proposed clinical care pathway. ART, assisted reproductive technique; AID, artificial insemination with donor sperm.

Download figure to PowerPoint

The weaknesses of the present study are its retrospective nature and its relatively small number of patients, as well as the lack of pregnancy and reproductive outcomes. In addition, some may question our use of pseudoephredrine for medical therapy. We treated all patients with pseudoephedrine (60 mg four times daily for 2 days), which is a widely used and easily available α-agonist. While other medical treatments, e.g. imipramine, midodrine or ephedrine, can also be used to increase sympathetic tone to the bladder (or decrease parasympathetic tone), there are specific concerns with the use of each. Midodrine and ephedrine can have major effects on systemic blood pressure. And though Kamischke and Nieschlag [21] point out, in a well written review, that imipramine has the highest effectiveness for converting RE to antegrade ejaculation, comparative controlled trials are needed to establish superiority over other drugs, as most of the published trials were small and not well controlled. Drawbacks of imipramine include its numerous side effects, e.g. dry mouth, drowsiness and nausea, and although doses used for ejaculatory dysfunction are lower than those used for depression, there is a potential risk of fatal tricyclic antidepressant overdose with imipramine. Without level 1 evidence to guide our choice, our clinical judgement led us to use pseudoephredrine, a widely available and commonly administered drug for this indication.

We believe that the present study shows an organized approach to the clinical problem of anejaculation after PC-RPLND.

In summary, the main cause of PC-RPLND-associated anejaculation was FOE in the present series. α-agonist medication was only effective in some of the patients with RE and not in the patients with FOE. EEJ is highly successful in patients with FOE, with sperm found in the majority of such patients on either EEJ or TESE. The use of a clinical pathway optimizes results in patients with anejaculation after PC-RPLND.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Dr Hsiao was supported by a grant from the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES