Therapy Insight: Parenteral Estrogen treatment for Prostate Cancer—a new dawn for an old therapy

Oral estrogens were the treatment of choice for carcinoma of the prostate for over four decades, but were abandoned because of an excess of cardiovascular and thromboembolic toxicity. It is now recognized that most of this toxicity is related to the first pass portal circulation, which upregulates the hepatic metabolism of hormones, lipids and coagulation proteins. Most of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration, which avoids hepatic enzyme induction. It also seems that a short-term but modest increase in cardiovascular morbidity (but not mortality) is compensated for by a long-term cardioprotective benefit, which accrues progressively as vascular remodeling develops over time. Parenteral estrogen therapy has the advantage of giving protection against the effects of andropause (similar to the female menopause), which are induced by conventional androgen suppression and include osteoporotic fracture, hot flashes, asthenia and cognitive dysfunction. In addition, parenteral estrogen therapy is significantly cheaper than contemporary endocrine therapy, with substantive economic implications for health providers

Transdermal Estradiol Therapy for Prostate Cancer reduces Thrombophilic activation and protects against Thromboembolism

Purpose Oral estrogens were an effective treatment for prostate cancer but were abandoned because of an increased risk of cardiovascular toxicity and particularly thromboembolism. We have recently shown that transdermal estradiol produces an effective tumor response and negligible cardiovascular toxicity. Here we report the influence of transdermal estradiol therapy on the coagulation profile of men with advanced prostate cancer. Materials and Methods A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated using transdermal estradiol patches and the coagulation profile was assessed before and during 12 months therapy. Activation of coagulation was assessed by assaying the levels of activated factor VII (VIIa), activated factor XII (XIIa), prothrombin fragments 1 and 2 (F1 + 2), thrombin-antithrombin III (TAT III) complex and fibrinogen. Inhibition of the coagulation cascade was assayed by protein C, protein S and activated protein C resistance (APC-R). Fibrinolytic activity was determined by assaying tissue plasminogen activator (TPA) and plasminogen activation inhibitor type 1 (PAI-1). D-Dimer levels assessed both coagulation and fibrinolytic (thrombophilic) activity. Venous Duplex, color Doppler ultrasound and photoplethysmography were used to assess for thrombosis. Results Levels of VIIa and XIIa were unaffected by transdermal estradiol therapy. Although levels of TAT III were increased in some patients at 12 months, the increase was markedly less than that observed historically with equivalent doses of oral estrogens. Levels of the inhibitory and fibrinolytic factors including protein C, protein S, APC-R, TPA and PAI-1 remained stable. Reductions in F1+F2, fibrinogen and D-Dimer levels represented a normalization from increased levels to the physiological range. Conclusions These results suggest that transdermal estradiol reduces thrombophilic activation in men with advanced prostate cancer, and protects against the risk of thrombosis

Patient treatment preferences for symptomatic refractory urodynamic idiopathic detrusor overactivity

Introduction: There is a multiplicity of treatments currently available for patients with symptomatic refractory urodynamic idiopathic detrusor overactivity (SRU IDO). We have assessed patient treatment preferences and their outcomes over a 12-month period from January 1 2009 to December 31 2009. Patients and Methods: A retrospective database of all patients with SRU IDO was reviewed for patient demographics, treatment preference, and outcome. All patients attending for treatment in the time period were offered: no further treatment, repeat bladder training ± antimuscarinic (BT ± AM), acupuncture, intravesical botulinum toxin injection, sacral neuromodulation (SNM), clam cystoplasty ± Mitrofanoff channel formation, and ileal conduit. Statistical Analysis Used: Statistical analysis of outcomes was done by Chi–square test, and statistical significance was determined as P< 0.05. Results: A total of 217 patients with SRU IDO underwent primary treatment in this time period, with a median age of 56 years and follow-up for a minimum of 12 months' posttreatment to determine outcome. No patients opted for any further treatment or an ileal conduit. The majority of patients opted for intravesical botulinum toxin injections and SNM with similar success rates (approximately 70%). A small number of patients decided to have nonsurgical interventions (BT ± AM or acupuncture) and had a broadly similar success rate (50%). A minority opted for clam cystoplasty ± Mitrofanoff channel formation – this group reported the highest success rate at 86%. Conclusions: Treatment options in SRU IDO are diverse, with the majority of patients opting for minimally invasive surgery. Clinicians should be familiar with all treatment options for management of SRU IDO

Serum prostate-specific antigen to predict the presence of bladder outlet obstruction in men with urinary symptoms

OBJECTIVE: To determine whether prostate specific antigen (PSA) level can usefully predict or exclude bladder outlet obstruction (BOO), in men with lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: A cohort of men from 1996 to 1999 who had LUTS caused by BPH was evaluated by serum PSA and pressure-flow urodynamic studies, and a blinded comparison made. The settings were teaching hospitals in London, UK and L'Aquila, Italy. Men (302) were referred by primary-care practitioners with LUTS and a PSA of &lt;10 ng/mL. Regression analysis was used to predict the extent of BOO, and create likelihood ratios and predictive values for BOO according to the PSA value. RESULTS: PSA was significantly associated with BOO (P &lt; 0.001 ; r2 0.07), with significant likelihood ratios altering the probability of BOO. If the PSA was &gt;4 ng/mL, mild or definite BOO was likely (89%), whereas if the PSA was &lt;2 ng/ mL, there was about a one-third chance each of no, mild and definite BOO. CONCLUSION: High PSA levels in patients with LUTS are significantly associated with BOO; low PSA levels mean that definite BOO is unlikely

Changes in vascular flow after transdermal oestradiol therapy for prostate cancer: a mechanism for cardiovascular toxicity and benefit?

OBJECTIVE: To report the influence of transdermal oestradiol therapy on the vascular dynamics of men with advanced prostate cancer. PATIENTS ANDMETHODS: Twenty patients with newly diagnosed locally advanced or metastatic prostate cancer (10 each) were treated using transdermal oestradiol patches. The vascular flow was assessed 6-monthly before and during a year of therapy using arterial and venous Doppler and duplex ultrasonography, arterial and venous photoplethysmography and opto-electronic plethysmography. RESULTS: Arterial flow, as measured by the mean and peak systolic velocities and photoplethysmography, significantly increased over time. Arterial compliance initially decreased but had normalized after 12 months. The venous variables were unaffected. As a result, the total limb blood flow and the capillary filtration rate were significantly increased. CONCLUSION: Transdermal oestradiol therapy causes an increase in arterial but not venous flow, and an initial decrease in arterial compliance, which adapts to the physiological range with time. It is possible that these changes may account for the increase in cardiovascular toxicity seen in the early phase of oestrogen therapy, and the cardioprotective effect that accrues thereafter

Overnight Ambulatory Urodynamics Change Patient Management Strategies and Improve Symptomatic Outcomes

ObjectivesTo determine the diagnostic value of overnight ambulatory urodynamics (aUDS) and to assess if a urodynamic diagnosis of detrusor overactivity (DO) or nocturnal enuresis resulted in a change in patient management and an improvement in their urinary symptoms. MethodsA retrospective review of 25 consecutive patients (28% male) with a median age of 38 years (range 18 to 86) having overnight aUDS for bothersome urinary symptoms of primarily nocturia and/or nocturnal enuresis following non-diagnostic conventional urodynamics between November 1998 and August 2018. Urinary symptoms were assessed before overnight aUDS and again after urological treatment following any changes in urodynamics diagnosis and treatment. Six patients were excluded as follow-up data were not available. ResultsTwenty-four patients (96%) presented with nocturia and 20 (80%) presented with nocturnal enuresis. DO was demonstrated in 19 (76%) patients (mean pressure 69.1±53.3 cmH2O). UUI was demonstrated in 16 (80%) out of the 20 patients who complained of nocturnal enuresis. Of the 19 patients with follow-up data, following overnight aUDS a change in urodynamic diagnosis was made in 15 patients (79%); 16 patients (84%) also had their clinical diagnosis and subsequent management changed; and 15 patients (79%) reported an improvement in their urinary symptoms following these changes in diagnosis and treatment. There was a significant improvement in ICIQ-OAB (120±44 versus 32±53, P < 0.0001) scores following the changes to clinical management post-overnight aUDS. ConclusionIn our study cohort, change in primary diagnosis following overnight aUDS led to a significant change in treatment care pathway and resulted in significant improvement in urinary symptoms at follow-up