Male Fertility
News and Views from the Literature
RIU0382_06-17.qxd 6/17/08 4:39 PM Page 169 Male Fertility Daily Phosphodiesterase Type 5 Inhibitor for Erectile Dysfunction: Is It Ready for Prime Time? The phosphodiesterase type 5 (PDE-5) inhibitors are an unusual class of drugs because they upregulate the effect of cGMP, which itself is activated by NO. Upregulation of cGMP has been shown to inhibit both collagen synthesis and apoptosis of certain parenchymal cells, such as those found in the kidney and the corporal tissues. We in urology are most familiar with the fact that these drugs are classically used for the treatment of ED and are taken on demand when an erection is desired. However, many of the disorders that afflict the genitourinary tract have to do with loss of smooth muscle cells and/or increase in tissue collagen or fibrosis. Examples of these are overactive bladder (OAB), benign prostatic hyperplasia (BPH), and even agingrelated ED, in which there is a loss of corporal smooth muscle cells and an increase in tissue fibrosis. Therefore, it seems reasonable that if PDE-5 inhibitors are antifibrotic and antiapoptotic, they may be considered for the prevention of certain urologic disorders rather than for the on-demand treatment of ED.2 However, this would require that they be taken on a daily basis and possibly early on in life, as one would take a statin or aspirin to prevent certain cardiovascular diseases. Evaluation of the Efficacy and Safety of Once-a-Day Dosing of Tadalafil 5 mg and 10 mg in the Treatment of Erectile Dysfunction: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Porst H, Giuliano F, Glina S, et al. Eur Urol. 2006;50:351-359. To determine whether the daily ingestion of a PDE-5 inhibitor would be safe, Porst and colleagues performed a study in which men with ED were randomized to either placebo (n 54), tadalafil 5 mg (n 109), or tadalafil 10 mg (n 105) daily for 12 weeks. The investigators found that besides the expected efficacy of the drug in men with ED, the side effect profile was no different than that seen with men taking those dosages of the drug on an ondemand basis. Only 8 of the 214 patients (3.7%) who took tadalafil reported an adverse event that precipitated their withdrawal from taking the drug daily. There was a dosedependent increase in headaches (6.4% to 10.5%), dyspepsia (5.5% to 11.4%), back pain (3.7% to 9.5%), upper abdominal pain (2.8% to 8.6%), and myalgias (2.8% to 6.7%) in the patients taking tadalafil. This study opens the way for testing these drugs over the long term in the treatment of some of the aforementioned urologic disorders. Sildenafil, another PDE-5 inhibitor, is currently approved as a daily treatment for pulmonary hypertension, and it does not seem far-fetched that in the future a PDE-5 inhibitor could be one of the drugs, like aspirin for cardiovascular disease, that is taken daily to prevent or delay the onset of certain aging-related urologic disorders, such as OAB, BPH, and even ED. In addition, because the penis is the window to what is occurring within the cardiovascular system, it is also plausible that these drugs may play a role in the treatment of certain cardiovascular disorders, such as heart failure and arteriosclerosis. References 1. 2. Ignarro LJ, Byrns RE, Sumi D, et al. Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide. Nitric Oxide. 2006;15:93-102. Sandner P, Hutter J, Tinel H, et al. PDE5 inhibitors beyond erectile dysfunction. Int J Imp Res. 2007;19:533-543. Male Fertility When Is Azoospermia Not Azoospermia? Reviewed by Jacob Rajfer, MD Department of Urology, University of California at Los Angeles, Los Angeles, CA [Rev Urol. 2008;10(2):169-170] © 2008 MedReviews, LLC en with azoospermia, defined as no sperm in the ejaculate as documented by semen analysis, either have an obstruction to the excretory ductal system or defective spermatogenesis. The observation that more than 60% of men with defective spermatogenesis may have pockets of spermatogenesis within the testis1,2 provides hope that many of these “azoospermic” patients can potentially be fathers with testicular sperm extraction (TESE) or testicular sperm aspiration (TESA) together with intracytoplasmic sperm injection and in vitro fertilization, provided these “pockets” of sperm, which theoretically never make it out of the ductal system, can be successfully harvested. TESE in these nonobstructive azoospermic patients requires either the use of a microscope to find the sperm (micro-TESE) or multiple M VOL. 10 NO. 2 2008 REVIEWS IN UROLOGY 169 RIU0382_06-17.qxd 6/17/08 4:39 PM Page 170 Male Fertility continued incision sites in 1 or both testes in the search for these pockets of sperm.3 TESA also requires multiple aspirations in these azoospermic patients, although the success rate with TESA may not be as high as with TESE.4,5 In addition, there is never any guarantee that any of these pockets of sperm will be found when either of these 2 procedures is performed. 6. Timm O Jr, Cedenho AP, Spaine DM, et al. Search and identification of spermatozoa and spermatids in the ejaculate of non-obstructive azoospermic patients. Int Braz J Urol. 2005;31:42-48. Timing of Sperm Harvesting: Is There Room for Improvement? Reviewed by Jacob Rajfer, MD Azoospermia: Is Simple Centrifugation Indicated? A National Survey of Practice and the Oxford Experience Swanton A, Itani A, McVeigh E, Child T. Department of Urology, University of California at Los Angeles, Los Angeles, CA [Rev Urol. 2008;10(2):170-171] © 2008 MedReviews, LLC Fertil Steril. 2007;88:374-378. Because of the time, cost, and invasiveness associated with either a micro-TESE or multiple TESE procedures, it is incumbent upon the urologist and reproductive endocrinologist to be 100% sure that there are definitely no sperm in the ejaculate. Because a semen analysis is usually performed using only a small sample of the specimen, it is possible that if only a few sperm are present in an entire ejaculate, they may be missed using the standard laboratory-performed semen analysis. One option that has been suggested is to centrifuge the ejaculated specimen to determine whether any sperm can be identified in this way. By performing this simple step in the laboratory, Swanton and colleagues found that 22% of 87 men who were azoospermic according to conventional semen analysis had sperm in their centrifuged specimen and therefore did not require TESE for sperm harvesting. This study adds to the evidence that all azoospermic men should have their samples centrifuged,6 because the observation of even 1 or 2 sperm in the ejaculate suggests that spermatogenesis is occurring somewhere within the gonads. This simple observation has significant prognostic and therapeutic implications in men with azoospermia who are considering intracytoplasmic sperm injection with in vitro fertilization. References 1. 2. 3. 4. 5. 170 Kim ED, Gilbaugh JH III, Patel VR, et al. Testis biopsies frequently demonstrate sperm in men with azoospermia and significantly elevated follicle-stimulating hormone levels. J Urol. 1997;157:144-146. Schlegel PN, Palermo GD, Goldstein M, et al. Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia. Urology. 1997;49:435-440. Okada H, Dobashi M, Yamazaki T, et al. Conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia. J Urol. 2002; 168:1063-1067. Hauser R, Yogev L, Paz G, et al. Comparison of efficacy of two techniques for testicular sperm retrieval in nonobstructive azoospermia: multifocal testicular sperm extraction versus multifocal testicular sperm aspiration. J Androl. 2006;27:28-33. El-Haggar S, Mostafa T, Abdel Nasser T, et al. Fine needle aspiration vs. mTESE in non-obstructive azoospermia. Int J Androl. In press. VOL. 10 NO. 2 2008 REVIEWS IN UROLOGY or urologists who treat infertility as part of their practice, it is not unusual to be “on call” to harvest sperm from the male partner of a couple undergoing in vitro fertilization (IVF). The timing of sperm harvesting is directly related to the day that egg retrieval of the female partner is going to occur. Some embryologists (who manipulate the sperm in the IVF laboratory and perform intracytoplasmic sperm injection [ICSI]) strongly believe that the sperm should be retrieved from the male partner on the same day that egg retrieval occurs. Conversely, other embryologists have no objection to performing sperm harvesting the day before egg retrieval, particularly if the sperm harvesting procedure is to be testicular sperm extraction (TESE). With TESE the sperm that are extracted from the tubules of the testicular tissue may take a while to obtain motility, which is the main in vitro criterion for choosing which sperm are to be used for the IVF plus ICSI process. By performing TESE the day before egg retrieval, the laboratory personnel allow themselves enough time to dissect the testicular tissue and retrieve the sperm, particularly in the case of nonobstructive azoospermic patients, for whom spermatogenesis may be severely impacted and in whom it may take a long time, relatively speaking, to find sperm in the tissue. However, some embryologists insist that sperm retrieved the day before egg retrieval do not “survive” as well as sperm retrieved the day of egg retrieval. This inconsistency and variability between IVF laboratories and their embryologists is most likely due to the individual experience of each laboratory rather than any solid, evidence-based data. If it could be demonstrated that harvesting sperm earlier than the day of egg retrieval does not severely impact the ability of the sperm to undergo fertilization, this could make life easier for all concerned because on many occasions the actual day of egg retrieval does not fall on the date originally targeted. In fact, in some cases, the day of egg retrieval may be a week or so later than anticipated at the beginning of the stimulation cycle of the female F RIU0382_06-17.qxd 6/17/08 4:39 PM Page 171 Prostate Cancer 100 Percentage 80 60 40 Motility Viability 20 Membrane Integrity Morphology (Head) Morphology (Tail) 0 0 1 2 3 Days 4 5 6 7 Figure 1. Motility, viability, morphology, and membrane integrity patterns exhibited by spermatozoa in culture for 7 days. Values represent the mean standard error of 11 samples for each parameter at each time point. Reproduced with permission from Hossain AM et al, Fertil Steril. 2008;89:237-238. partner. For urologists harvesting sperm in such a situation, this can play havoc with their daily routine and schedule. Extended Culture of Human Spermatozoa in the Laboratory May Have Practical Value in the Assisted Reproductive Procedures Hossain AM, Osuamkpe CO, Nagamani M. definitely make life easier for those of us who have to rearrange our schedules on an almost daily basis when an egg retrieval is imminent. Prostate Cancer Fertil Steril. 2008;89:237-238. In an attempt to determine whether sperm function is impacted by keeping them in culture for an extended period after retrieval, Hossain and colleagues took 11 semen samples from supposedly normal men and kept them in culture for 7 days. They observed that the only function that significantly decreased after 24 hours was sperm motility, but even this parameter only demonstrated a decrease of approximately 20% (Figure 1). Sperm viability did not significantly decrease, which suggests that the majority of sperm that eventually became nonmotile at 24 hours in culture were still viable. Therefore, this pilot study suggests that sperm harvested from normal patients can be successfully retrieved and stored in culture for at least 24 to 48 hours or possibly longer before egg retrieval without significantly compromising their viability. Although the overall motility of the sperm did decrease after 24 hours, this was by only 20%, with the majority of the sperm still motile by that time. What obviously needs to be confirmed now is whether sperm from oligospermic patients behave in a similar manner. Such an observation in oligospermic men would Weighing the Risks: Prostate Cancer Versus Cardiovascular Disease Reviewed by Danil V. Makarov, MD, and Alan W. Partin, MD, PhD The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD [Rev Urol. 2008;10(2):171-173] © 2008 MedReviews, LLC he treatment of prostate cancer can be a very casespecific decision. Although it is clear that surgery provides a cure for some patients, there can be negative side effects that would make it the wrong therapeutic option for others. Some patients who are older and have low-volume prostate cancer may be excellent candidates for the expectant management of prostate cancer, whereas this would certainly be the wrong choice for a T VOL. 10 NO. 2 2008 REVIEWS IN UROLOGY 171