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Video: Co-administration of TRPV4 and TRPV1 antagonists

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Co-administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiate the effect of each drug in a rat model of cystitis

Ana Charrua†‡§, Célia D. Cruz‡§, Dick Jansen¶ , Boy Rozenberg¶ , John Heesakkers¶ and Francisco Cruz*†§

*Department of Urology, S. João Hospital, †Department of Renal, Urologic and Infectious Disease, ‡Department of Experimental Biology, Faculty of Medicine of the University of Porto, §IBMC – Instituto de Biologia Molecular e Celular da Universidade do Porto, Porto, Portugal, and ¶Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

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OBJECTIVE

To investigate transient receptor potential vanilloid 4 (TRPV4) expression in bladder afferents and study the effect of TRPV4 and TRPV1 antagonists, alone and in combination, in bladder hyperactivity and pain induced by cystitis.

MATERIALS AND METHODS

TRPV4 expression in bladder afferents was analysed by immunohistochemistry in L6 dorsal root ganglia (DRG), labelled by fluorogold injected in the urinary bladder. TRPV4 and TRPV1 co-expression was also investigated in L6 DRG neurones of control rats and in rats with lipopolysaccharide (LPS)-induced cystitis. The effect of TRPV4 antagonist RN1734 and TRPV1 antagonist SB366791 on bladder hyperactivity and pain induced by cystitis was assessed by cystometry and visceral pain behaviour tests, respectively.

RESULTS

TRPV4 is expressed in sensory neurones that innervate the urinary bladder. TRPV4-positive bladder afferents represent a different population than the TRPV1-expressing bladder afferents, as their co-localisation was minimal in control and inflamed rats. While low doses of RN1734 and SB366791 (176.7 ng/kg and 143.9 ng/kg, respectively) had no effect on bladder activity, the co-administration of the two totally reversed bladder hyperactivity induced by LPS. In these same doses, the antagonists partially reversed bladder pain behaviour induced by cystitis.

CONCLUSIONS

TRPV4 and TRPV1 are present in different bladder afferent populations. The synergistic activity of antagonists for these receptors in very low doses may offer the opportunity to treat lower urinary tract symptoms while minimising the potential side-effects of each drug.

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Article of the Week: Robotic management of GU injuries from obstetrical and gynecological operations

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Ronald Boris, discussing his paper. 

If you only have time to read one article this week, it should be this one.

Robotic management of genito-urinary injuries from obstetrical and gynecological operations: a multi-institutional report of outcomes

Paul T. Gellhaus, Akshay Bhandari*, M. Francesca Monn, Thomas A. Gardner,Prashanth Kanagarajah*, Christopher E. Reilly†, Elton Llukani†, Ziho Lee†, Daniel D. Eun†,Hani Rashid‡, Jean V. Joseph‡, Ahmed E. Ghazi‡, Guan Wu‡and Ronald S. Boris

Department of Urology, Indiana University, Indianapolis, IN, *Division of Urology, Columbia University at Mount Sinai,Miami Beach, FL,†Department of Urology, Temple University, Philadelphia, PA, and‡Department of Urology, University ofRochester, Rochester, NY, USA

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OBJECTIVE

To evaluate the utility of robotic repair of injuries to the ureter or bladder from obstetrical and gynaecological (OBGYN) surgery

PATIENTS AND METHODS

A retrospective review of all patients from four different high-volume institutions between 2002 and 2013 that had a robot-assisted (RA) repair by a urologist after an OBGYN genitourinary injury.

RESULTS

Of the 43 OBGYN operations, 34 were hysterectomies: 10 open, 10 RA, nine vaginally, and five pure laparoscopic. Nine patients had alternative OBGYN operations: three caesarean sections, three oophorectomies (one open, two laparoscopic), one RA colpopexy, one open pelvic cervical cerclage with mesh and one RA removal of an invasive endometrioma. In all, 49 genitourinary (GU) injuries were sustained: ureteric ligation (26), ureterovaginal fistula (10), ureterocutaneous fistula (one), vesicovaginal fistula (VVF; 10) and cystotomy alone (two). In all, 10 patients (23.3%) underwent immediate urological repair at the time of their OBGYN RA surgery. The mean (range) time between OBGYN injury and definitive delayed repair was 23.5 (1–297) months. Four patients had undergone prior failed repair: two open VVF repairs and two balloon ureteric dilatations with stent placement. In all, 22 ureteric re-implants (11 with ipsilateral psoas hitch) and 15 uretero-ureterostomies were performed. Stents were placed in all ureteric cases for a mean (range) of 32 (1–63) days. In all, 10 VVF repairs and two primary cystotomy closures were performed. Drains were placed in 28 cases (57.1%) for a mean (range) of 4.1 (1–26) days. No case required open conversion. Two patients (4.1%) developed ureteric obstruction after RA repair requiring dilatation and stenting. The mean (range) follow-up of the entire cohort was 16.6 (1–63) months.

CONCLUSIONS

RA repair of GU injuries during OBGYN surgery is associated with good outcomes, appears safe and feasible, and can be used successfully immediately after injury recognition or as a salvage procedure after prior attempted repair. RA techniques may improve convalescence in a patient population where quick recovery is paramount.

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Editorial: The robot to the rescue!

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Fortunately injuries to the urinary tract remain rare in obstetric and gynaecological surgery. Their potential for causing serious morbidity, not to mention the substantial medico-legal implications ensure that it remains a highly researched and evocative area [1].

Iatrogenic urinary tract injuries can be broadly divided into two groups; acute complications, such as bladder and ureteric lacerations or ligation and more chronic complications, such as vesicovaginal or ureterovaginal fistulae and ureteric strictures. Historically, iatrogenic trauma to the urinary tract most commonly followed open, abdominal hysterectomy with the most frequent complication being direct bladder injury. Gross bladder injuries are generally both detected and treated intraoperatively. In contrast, the management of more complex ureteric injuries and their long-term sequelae, such as fistula, pose greater surgical challenges. The complexity of these injuries is often further compounded by delay in diagnosis. It is generally accepted that, if possible, immediate repair provides the optimal treatment. However, when diagnosis is delayed, there is little consensus on the best management approach, although the current tendency is towards early repair [2].

The multicentre, retrospective study of robotic repair of 49 iatrogenic genitourinary injuries by Gellhaus et al. [3] should therefore serve to reassure gynaecologists with respect to the incidence of this feared complication. This paper, mainly looking at ureteric re-implants and fistula repairs, constitutes the largest cohort of robotic reconstructions to date. A zero conversion rate to open surgery suggests excellent case selection by the robotic surgeons. Four cases had undergone previous failed open or endoscopic management and this is clearly a challenging cohort. Yet, with the absence of total numbers of urology referrals received for such injuries, it is important to remember that it may not be a panacea for all.

There has been a considerable shift in the management of urological trauma from open to laparoscopic techniques. While the repair of basic injuries has been proven to be effective, less data is available to support the management of more complex injuries, such as ureteric transections or fistulae [4]. Numerous techniques for repairing ureteric injuries and fistulae have been described; nonetheless, the surgery remains technically challenging even for experienced laparoscopic surgeons and is generally limited to high-volume centres [5].

In comparison, this article [3] provides strong evidence for the effectiveness of robot-assisted (RA) repairs, even for complex injuries. The enviable 95.9% success rate from 47 operations is complemented by short recovery times and low complication rates. These results are especially impressive in view of the mean 23.5-month delay time to repair. But the authors do not report the reasons for these delays. Immediate robotic repair of RA injuries is clearly feasible especially in larger units. Whether immediate RA repair should be performed for other iatrogenic injuries needs further discussion. Is it realistic to convert to the robot in the case of laparoscopic trauma or should RA repairs remain a planned return to theatre?

The demand for RA reconstructive surgery and experienced robotic pelvic surgeons is likely to rise in the near future. As the authors note, the continued expansion of minimally invasive procedures is likely to lead to a shift in the patterns of complications from more straightforward bladder injuries to complex ureteric injuries. As mentioned previously these types of injury are more likely to be initially undetected.

Whilst rates of surgical complications involving the urinary tract remain low, obstetrical and gynaecological procedures account for 75% of these injuries. This article provides robust evidence for the key role that RA surgery can play in the management of these complex and feared injuries. When faced with such situations, Gellhaus et al. [3] have shown that it is increasingly likely that the robot saves the day.

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Nicholas Raison and Ben Challacombe

Department of Urology, Guy’s and St Thomas’ Hospital,London, UK

References

1 Preston JM. Iatrogenic ureteric injury: common medicolegal pitfalls. BJUInt 2000; 86: 313–7

2 El-Tabey NA, Ali-el-Dein B, Shaaban AA et al. Urological trauma aftergynecological and obstetric surgeries. Scand J Urol Nephrol 2006; 40:225–31

3 Gellhaus PT, Bhandari A, Monn MF et al. Robotic management ofgenito-urinary injuries from obstetrical and gynecological operations: amulti-institutional report of outcomes. BJU Int 2015; 115: 430–6

4 De Cicco C, Ussia A, Koninckx PR. Laparoscopic ureteral repairin gynaecological surgery. Curr Opin Obstet Gynecol 2011; 23:296–300

5 Rassweiler J, Pini G, Gözen AS, Klein J, Teber D. Role of laparoscopy inreconstructive surgery. Curr Opin Urol 2010; 20: 471–82

 

Article of the Week: The effect of hypogonadism and testosterone-enhancing therapy on AP and BMD

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorialwritten by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Darius Paduch discussing his paper. Make sure you have a stable internet connection. In order to have the best telehealth experience possible, you must be using a strong, stable internet connection. Keep your hands free. If you can find a comfortable stand for your video device or have something to prop it up against, will free up your hands to take part in the physical therapy session. Remember to use a compatible internet browser. Below is a list of compatible internet browsers for your telehealth session. Whichever browser you are using, make sure to keep it updated to the most recent version. Laws governing telehealth reimbursement vary in each state. In our experience, most health plans have covered these services however, every insurance company is different. Well medical malpractice insurance cost and quality are always good to afford. We recommend checking with your insurance provider or the clinic prior to your appointment to make sure you’re covered. All 50 states, the District of Columbia, and the US Virgin Islands allow patients to seek some level of treatment from a licensed physical therapist without a prescription or referral from a physician. There may be some restrictions in your state but for the most part this means is that you can now receive physical therapy, even virtually, without a physician’s referral/prescription. Check with your state’s regulations or your clinic prior to your appointment. you can discover more here for Telehealth.

 If you only have time to read one article this week, it should be this one.

The effect of hypogonadism and testosterone-enhancing therapy on alkaline phosphatase and bone mineral density

Ali A. Dabaja, Campbell F. Bryson, Peter N. Schlegel and Darius A. Paduch
Department of Urology, Weill Cornell Medical College, New York, NY, USA
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OBJECTIVE

To evaluate the relationship of testosterone-enhancing therapy on alkaline phosphatase (AP) in relation to bone mineral density (BMD) in hypogonadal men.

PATIENTS AND METHODS

Retrospective review of 140 men with testosterone levels of <350 ng/dL undergoing testosterone-enhancing therapy and followed for 2 years. Follicle-stimulating hormone, luteinising hormone, free testosterone, total testosterone, sex hormone binding globulin, calcium, AP, vitamin D, parathyroid hormone, and dual-energy X-ray absorptiometry (DEXA) scans were analysed. A subgroup of 36 men with one DEXA scan before and one DEXA 2 years after initiating treatment was performed.

RESULTS

Analysis of the relationship between testosterone and AP at initiation of therapy using stiff linear splines suggested that bone turnover occurs at total testosterone levels of <250 ng/dL. In men with testosterone levels of <250 ng/dL, there was a negative correlation between testosterone and AP (R2 = −0.347, P < 0.001), and no correlation when testosterone levels were between 250 and 350 ng/dL. In the subgroup analysis, the mean (sd) testosterone level was 264 (103) ng/dL initially and 701 (245), 539 (292), and 338 (189) ng/dL at 6, 12, and 24 months, respectively. AP decreased from a mean (sd) of 87 (38) U/L to 57 (12) U/L (P = 0.015), 60 (17) U/L (P < 0.001), and 55 (10) U/L (P = 0.03) at 6, 12, and 24 months, respectively. The BMD increased by a mean (sd) of 20 (39)% (P = 0.003) on DEXA.

CONCLUSION

In hypogonadal men, the decrease in AP is associated with an increase in BMD on DEXA testing. This result suggests the use of AP as a marker of response to therapy.

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Editorial: On the Mark? Is AP a surrogate for BMD in hypogonadal men?

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The current issue of the BJUI contains a paper by Dubaja et al. [1] that may be of interest to physicians who have patients with hypogonadism. The authors speak to an unappreciated aspect of low testosterone; namely, the loss of bone in men and the possible recovery with treatment. Their retrospective study looked at 140 men with hypogonadism treated with exogenous testosterone replacement or clomiphene citrate testosterone enhancement. These men were also assessed for bone mineral density (BMD) markers at 6, 12 and 24 months after initial treatment. Importantly, dual-energy X-ray absorptiometry (DEXA) was performed a second time after 2 treatment years for a subset of these men. DEXA showed that there was a gain in BMD and a loss of serum alkaline phosphatase (AP) for all the men over time. The loss of AP was rapid but stabilized at 6 months. Testosterone and free testosterone increased as expected but there were no changes in vitamin D, calcium, parathyroid hormone or sex hormone-binding globulin. There was a correlation between AP and testosterone. The authors recognized poor bone density at baseline in those men with testosterone levels

Bone mineral density is the best way to predict osteoporosis and fragility fractures [2]. Women loose BMD after menopause and that is accompanied by many changes, including gains in AP [3]. The decline in serum oestrogens is a factor for women, and oestrogen replacement therapy historically has been used to prevent that loss. Not all men undergo a similar loss, i.e. andropause is not recognized in the same way as menopause. Even though osteoporosis is less common in men, the associated comorbidity may be more significant.

There is an age-related decline in testosterone and an acute loss for some men such that they approach their physicians with symptoms. The underlying cause of bone loss in men and women may be the same: serum oestrogen loss. Men who lose testosterone are also losing oestrogen because testosterone is the precursor via aromatase. Repros Therapeutics is developing a way to treat men with secondary hypogonadism. An ongoing 1-year DEXA study recruited eligible men. Key inclusion factors were age < 60 years and body mass index > 25 kg/m2. Remarkably 24% of men failed the screening test because of osteopenia, despite the fact that few of them were old or underweight.

The present paper by Dubaja et al. suggests that a readily available serum test may be able to monitor men on testosterone therapies for gain in BMD. Given the relatively low incidence of osteoporosis, screening every man by DEXA is not cost-efficient. The 1 year or more needed to find BMD loss by DEXA also wastes time and resources. Quantitative CT is more costly and is accompanied by high radiation exposure. The use of AP, as suggested in the present study, may represent a reasonable alternative.

The paper is not without its weaknesses. There was no indication of whether these men had primary or secondary hypogonadism. Transdermal testosterone should raise testosterone and oestrogen in both groups of men whereas clomiphene citrate works through changes in LH and FSH and requires an intact hypothalamic-pituitary-gonadal axis (useful in men with secondary hypogonadism only). Indeed, the two kinds of treatment will have the opposite effect on LH and FSH [4]. The authors recognized the importance of Leydig cells in producing testosterone, yet the effects of a transdermal testosterone would be to shut down testosterone production. We commend their suggestion that other factors that contribute to both bone and Leydig cell function, insulin-like 3 [5] and osteocalcin [6] should be studied in relation to AP. The loss of subjects throughout the 2 years was troubling, but it is known that men on transdermal treatments discontinue with disturbing frequency despite satisfaction [7]. If those who stayed in the present study were those with the best outcomes in terms of testosterone and BMD, potential bias may exist. If men can be encouraged to continue therapy through positive effects on BMD being detected as early as 6 months, AP monitoring may improve patient compliance. Only DEXA can give that assurance now. The authors noted the need for a larger prospective trial. Nevertheless, their paper provides a rationale for monitoring men on testosterone therapies that can be implemented with minimal cost or the need for new diagnostics.

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Martin C. Michel
Department of Pharmacology, Johannes Gutenberg University, Mainz, German
References
1 Dabaja A, Bryson C, Schlegel P, Paduch D. The effect of hypogonadism and testosterone-enhancing therapy on alkalinephosphatase and bone mineral density. BJU Int 2015; 115: 3
2 NIH Consensus Development Panel. Osteoporosis prevention, diagnosis and therapy. JAMA 2001; 285: 785–95
3 Biver E.Use of bone turnover markers in clinical practice. Curr O pin Endocrinol Dia betes Obes 2012; 19: 468–73
4 Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. JSexMed2013; 10: 1628–35
5 Ivell R, Anand-Ivell R. Biology of insulin-like factor-3 in human reproduction. Hum Reprod Update 2009; 15: 463–76
6 Karsenty G. Bone endocrine regulation of energy metabolism and male reproduction. CRBiol2011; 334: 720–4
7 Kovac J, Rajanahally S, Smith R, Coward R, Lamb D, Lipshultz L. Patient satisfaction with testosterone replacement therapies: the reasons behind the choices. JSexMed2014; 11: 553–62

 

Video: Hypogonadism and testosterone-enhancing therapy on alkaline phosphatase and BMD

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The effect of hypogonadism and testosterone-enhancing therapy on alkaline phosphatase and bone mineral density

Ali A. Dabaja, Campbell F. Bryson, Peter N. Schlegel and Darius A. Paduch

 

Department of Urology, Weill Cornell Medical College, New York, NY, USA

 

Read the full article
OBJECTIVE

To evaluate the relationship of testosterone-enhancing therapy on alkaline phosphatase (AP) in relation to bone mineral density (BMD) in hypogonadal men.

PATIENTS AND METHODS

Retrospective review of 140 men with testosterone levels of <350 ng/dL undergoing testosterone-enhancing therapy and followed for 2 years. Follicle-stimulating hormone, luteinising hormone, free testosterone, total testosterone, sex hormone binding globulin, calcium, AP, vitamin D, parathyroid hormone, and dual-energy X-ray absorptiometry (DEXA) scans were analysed. A subgroup of 36 men with one DEXA scan before and one DEXA 2 years after initiating treatment was performed.

RESULTS

Analysis of the relationship between testosterone and AP at initiation of therapy using stiff linear splines suggested that bone turnover occurs at total testosterone levels of <250 ng/dL. In men with testosterone levels of <250 ng/dL, there was a negative correlation between testosterone and AP (R2 = −0.347, P < 0.001), and no correlation when testosterone levels were between 250 and 350 ng/dL. In the subgroup analysis, the mean (sd) testosterone level was 264 (103) ng/dL initially and 701 (245), 539 (292), and 338 (189) ng/dL at 6, 12, and 24 months, respectively. AP decreased from a mean (sd) of 87 (38) U/L to 57 (12) U/L (P = 0.015), 60 (17) U/L (P < 0.001), and 55 (10) U/L (P = 0.03) at 6, 12, and 24 months, respectively. The BMD increased by a mean (sd) of 20 (39)% (P = 0.003) on DEXA.

CONCLUSION

In hypogonadal men, the decrease in AP is associated with an increase in BMD on DEXA testing. This result suggests the use of AP as a marker of response to therapy.

Read more articles of the week

Article of the Month: Is there an anti-androgen withdrawal syndrome with enzalutamide?

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Is there an anti-androgen withdrawal syndrome with enzalutamide?

Alejo Rodriguez-Vida1, Diletta Bianchini2, Mieke Van Hemelrijck3, Simon Hughes1, Zafar Malik4, Thomas Powles5, Amit Bahl6, Sarah Rudman1, Heather Payne7, Johann de Bono2 and Simon Chowdhury1,*

1 Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, UK, 2 Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, UK, 3 King’s College London, Division of Cancer Studies, Cancer Epidemiology Group, London, UK, 4 Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, UK, 5 St. Bartholomew’s Hospital NHS Foundation Trust, London, UK, 6 University Hospitals Bristol NHS Foundation Trust, Bristol, UK, 7 University College Hospital, London, UK

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OBJECTIVE

To examine prostate-specific antigen (PSA) levels after enzalutamide discontinuation to assess whether an antiandrogen withdrawal syndrome (AAWS) exists with enzalutamide.

METHODS

We retrospectively identified 30 consecutive patients with metastatic prostate cancer who were treated with enzalutamide after docetaxel. Post-discontinuation PSA results were available for all patients and were determined at 2-weekly intervals until starting further anticancer systemic therapy. PSA withdrawal response was defined as a PSA decline by ≥50% from the last on-treatment PSA, with a confirmed decrease ≥3 weeks later. Patient characteristics were evaluated in relation to the AAWS using univariate logistic regression analysis.

RESULTS

The median (range) patient age was 70.5 (56–86) years and the median (range) follow-up was 9.0 (0.5–16) months. The most common metastatic sites were the bone (86.7%) and lymph nodes (66.7%). Most patients (70%) had previously received abiraterone and 12 patients (40%) had also received cabazitaxel. The median (range) treatment duration with enzalutamide was 3.68 (1.12–21.39) months. PSA levels after enzalutamide withdrawal were monitored for a median (range) time of 35 (10–120) days. Only one patient (3.3%) had a confirmed PSA response ≥50% after enzalutamide discontinuation. One patient (3.3%) had a confirmed PSA response of between 30 and 50% and another patient (3.3%) had an unconfirmed PSA response of between 30 and 50%. The median overall survival was 15.5 months (95% CI 8.1–24.7). None of the factors analysed in the univariate analysis were significant predictors of PSA decline after enzalutamide discontinuation.

CONCLUSIONS

This retrospective study provides the first evidence that enzalutamide may have an AAWS in a minority of patients with metastatic castration-resistant prostate cancer. Further studies are needed to confirm the existence of an enzalutamide AAWS and to assess its relevance in prostate cancer management.

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Editorial: Enzalutamide withdrawal syndrome: is there a rationale?

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Enzalutamide is a second generation non-steroidal antiandrogen (AA), which significantly improved overall  survival (OS) and progression-free survival (PFS) after docetaxel (AFFIRM study), and OS and radiographic PFS before chemotherapy (PREVAIL study) in patients with metastatic castration-resistant prostate cancer (mCRPC) [1].

Being a potent androgen receptor (AR) antagonist, an enzalutamide withdrawal syndrome (EWS) appeared unlikely [2,3]. In contrast with this position, and considering the well-known AR structural alterations in CRPC, very recent preclinical and clinical data support the possibility of the existence of an EWS after the discontinuation of this drug, in a castration-resistant setting.

In patients with mCRPC progressing on androgen-deprivation therapy (ADT), the AAWS, due to the interruption of first generation AAs (flutamide, bicalutamide, nilutamide, cyproterone acetate and megestrol acetate), often pursues as a further hormonal manipulation, although no level one studies supported its efficacy. AAWS leads to a PSA reduction in 15–30% of patients, with concomitant symptomatic relief and radiographic responses in some cases, without impacting on survival [1]. The molecular mechanisms of the AAWS are still unclear. One of the possible mechanisms responsible for the AAWS is the mutation of the AR. In vitro models showed that bicalutamide may switch from antagonist to agonist in LNCaP-cxD cell lines, due to an additional AR mutation in codon 741 during bicalutamide treatment [4]. Similarly, preclinical in vitro and in vivo studies demonstrated that initially enzalutamide exerts its AR antagonist activity, but during the treatment enzalutamide potently induces an AR mutation, leading to the mutant ARF876L, which confers agonism to enzalutamide, and resistance to enzalutamide therapy [1]. In the clinical setting, the first evidence of possible EWS has begun to appear. Phillips [5] observed EWS in one patient, 40 days after enzalutamide discontinuation. Rodriguez-Vida et al. [1] showed EWS in three of 30 (10%) patients with mCRPC after the drug cessation, although none of the 17 factors examined were statistically significant predictors of PSA decline after enzalutamide interruption. Considering the clinical characteristics of the three patients showing EWS, interestingly all of them were aged <70 years, had Gleason score ≥7, had bone and/or lymph node metastases without visceral sites of disease, and had had previous treatments with bicalutamide and docetaxel. In all three patients, EWS seems to have no correlation with: prostate cancer staging at diagnosis (M0 vs M1), PSA value before enzalutamide, PSA decline on enzalutamide treatment, LHRH analogues and enzalutamide therapy duration. Similarly to bicalutamide WS, in all three patients no symptomatic improvement was recorded during EWS.
Focusing on patient 1, interestingly he displayed initially a PSA response during enzalutamide and later a further PSA decline plus radiological response after enzalutamide interruption (i.e. EWS), showing a sensitivity either to initial enzalutamide antagonism and to subsequent agonism, and exhibiting an EWS not preceded by a bicalutamide WS. This supports previous data concerning different AR mutations for the two different AAs, without subsequent clinical correlations between the two different AAWSs. A LHRH analogue duration treatment (5 months) shorter than a subsequent enzalutamide duration therapy (21.4 months) suggests different tumoral cells sensitivity to different ADTs, in different stages (hormone naïve and castration-resistant prostate cancer), likely related to several AR structural alterations collected along the disease. Intriguingly, patient 3 discontinued enzalutamide after only 1.2 months, maybe due to primary resistance [6]; nevertheless, he showed a PSA
response after enzalutamide interruption, suggesting that EWS, characterised by the switch from enzalutamide antagonism to agonism, could occur even in prostate cancer patients primary resistant to this drug. Limitations of the two first clinical reports related to EWS include a restricted sample size, a reduced number of EWS events and a short duration of follow-up after enzalutamide discontinuation. Furthermore, preclinical studies on EWS and published data concerning AAWS described more frequently early stage mCRPC, while the two papers considered heavily pretreated patients with mCRPC, in whom EWS incidence could be reduced due to several previous treatments, which probably produced various AR alterations.

In conclusion, the preclinical models have demonstrated one possible plausible mechanism responsible for EWS and enzalutamide resistance. First clinical reports suggest the possibility of EWS in a minority of patients after enzalutamide discontinuation in mCRPC. Further studies are needed to confirm and detail the EWS, before translating these data into clinical practice.

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Alessandra Mosca
Medical Oncology, ‘Maggiore della Carità’ University Hospital, Novara, Italy

References

1 Rodriguez-Vida A, Bianchini D, Van Hemelrijck M et al. Is there an antiandrogen withdrawal syndrome with enzalutamide? BJU Int 2015; 115: 373–80

2 von Klot CA, Kramer MW, Böker A et al. Is there an anti-androgen withdrawal syndrome for Enzalutamide? World J Urol 2014; 32: 1171–6

3 von Klot CA, Kuczyk MA, Merseburger AS. No androgen withdrawal syndrome for enzalutamide: a report of disease dynamics in the postchemotherapy setting. Eur Urol 2014; 65: 258–9

4 Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 2003; 63: 149–53

5 Phillips R. An enzalutamide antiandrogen withdrawal syndrome. Nat Rev Urol 2014; 11: 366

6 Efstathiou E, Titus M, Wen S et al. Molecular characterization of Enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur Urol 2015; 67: 53–60

 

Article of the Week: Testosterone Therapy and Cancer Risk

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Michael Eisenberg discussing his paper. 

If you only have time to read one article this week, it should be this one.

Testosterone Therapy and Cancer Risk

Michael L. Eisenberg*†, Shufeng Li*‡, Paul Betts§, Danielle Herder, Dolores J. Lamb¶ and Larry I. Lipshultz

 

Departments of *Urology, †Obstetrics/Gynecology and ‡Dermatology, Stanford University School of Medicine, Stanford, CA, §Cancer Epidemiology and Surveillance Branch, Texas Cancer Registry, Texas Department of State Health Services, Austin, TX, and Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

 

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OBJECTIVE

To determine if testosterone therapy (TT) status modifies a man’s risk of cancer.

PATIENTS AND METHODS

The Urology clinic hormone database was queried for all men with a serum testosterone level and charts examined to determine TT status. Patient records were linked to the Texas Cancer Registry to determine the incidence of cancer. Men accrued time at risk from the date of initiating TT or the first office visit for men not on TT. Standardised incidence rates and time to event analysis were performed.

RESULTS

In all, 247 men were on TT and 211 did not use testosterone. In all, 47 men developed cancer, 27 (12.8%) were not on TT and 20 (8.1%) on TT. There was no significant difference in the risk of cancer incidence based on TT (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.57–1.9; P = 1.8). There was no difference in prostate cancer risk based on TT status (HR 1.2, 95% CI 0.54–2.50).

CONCLUSION

There was no change in cancer risk overall, or prostate cancer risk specifically, for men aged >40 years using long-term TT.

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Editorial: Malignant medication? Testosterone and cancer

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Testosterone therapy (TTh) in men with hypogonadism is becoming more commonplace among urologists, endocrinologists and even primary practitioners. While the definition of hypogonadism remains a moving target, the literature reflects very clear benefits of TTh in appropriately selected patients. As with any drug, the adverse effect profile helps to dictate the risk:benefit ratio and, over the past several years, numerous, primarily retrospective, analyses have provided mixed insights into the impact of TTh on cardiovascular disease and cancer, specifically prostate cancer.

Eisenberg et al. [1] take a step back from the focus on prostate cancer and evaluate the impact of TTh on general cancer incidence in a cohort of men treated in a single, large-volume andrology practice over 20 years. The authors found no difference in either overall cancer incidence or in the prostate cancer incidence in men on TTh in comparison with men not on TTh. This finding is significant as it supports the hypothesis that testosterone does not harmfully affect either hormonally responsive (prostate cancer) or non-hormonally responsive malignancies. Interestingly, the authors also observe a lower rate of all cancers in men on testosterone therapy. While not statistically significant, this finding is consistent with that of at least one other study focused on prostate cancer, in which men with high-risk prostate cancer receiving exogenous testosterone had a lower recurrence rate than a matched control group [2]. If borne out in future studies, a protective relationship between TTh and cancer would indeed reflect a novel benefit of treatment.

Nevertheless, at this time the jury remains out on a definitive assessment of the effects of TTh on both cancer as well as cardiovascular disease, and will probably continue to do so until controlled, prospective studies are completed. Numerous, mostly retrospective studies have examined the effects of endogenous testosterone and of the administration of exogenous testosterone, primarily on prostate cancer. While the details of these studies are beyond the scope of the present editorial, their findings have varied with regard to whether testosterone does or does not have effects on cancer incidence, biopsy findings, grade, recurrence rates and margin status, preventing a clear perspective on the effects of testosterone on cancer. Similarly, studies evaluating the impact of TTh on cardiovascular disease have also widely varied in their conclusions [3, 4]. Several recent large retrospective studies have found a detrimental relationship between TTh and cardiovascular disease in specific male populations, but have come under withering criticism from the community, with significant doubts cast regarding the veracity of their findings [5, 6].

The growing popularity of TTh has subjected it to a level of scrutiny applied to few other medications, resulting in a slew of peer-reviewed publications of varying quality and conclusions. In the effort to safeguard patients, investigators have hurriedly carried out retrospective data evaluation, which, by design, limits compensation for confounding factors and unfortunately results in an overall murky understanding of long-term adverse events related to TTh. Nevertheless, the clinical benefits of TTh are clear, and many patients are satisfied with the results of treatment. While physicians should remain the stewards of patient care, informed consent and a patient’s acceptance of both the known as well as the unknown risks of testosterone treatment should continue to be an integral part of the initiation and continuation of TTh, until additional high-quality data from clinical trials become available in the coming years.

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Alexander W. Pastuszak
Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

 

References

 

1 Eisenberg ML, Li S, Betts P et al. Testosterone therapy and cancer risk. BJU Int 2015; 115: 317–21

 

2 Pastuszak AW, Pearlman AM, Lai WS et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol 2013; 190: 639–44

 

3 Basaria S, Coviello AD, Travison TG et al. Adverse events associated with testosterone administration. NEnglJMed2010; 363: 109–22

 

4 Shores MM, Smith NL, Forsberg CW et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012; 97: 2050–8

 

5 Vigen R, O’Donnell CI, Baron AE et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: 1829–36

 

6 Finkle WD, Greenland S, Ridgeway GK et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE 2014; 9: e85805

 

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