Prostate cancer (PCa) is the most common malignancy in elderly men. The progressive ageing of the world male population will further increase the need for tailored assessment and treatment of PCa patients. The determinant role of androgens and sexual hormones for PCa growth and progression has been established. However, several trials on androgens and PCa are recently focused on urinary continence, quality of life, and sexual function, suggesting a new point of view on the whole endocrinological aspect of PCa. During aging, metabolic syndrome, including diabetes, hypertension, dyslipidemia, and central obesity, can be associated with a chronic, low-grade inflammation of the prostate and with changes in the sex steroid pathways. These factors may affect both the carcinogenesis processes and treatment outcomes of PCa. Any treatment for PCa can have a long-lasting negative impact on quality of life and sexual health, which should be assessed by validated self-reported questionnaires. In particular, sexual health, urinary continence, and bowel function can be worsened after prostatectomy, radiotherapy, or hormone treatment, mostly in the elderly population. In the present review we summarized the current knowledge on the role of hormones, metabolic features, and primary treatments for PCa on the quality of life and sexual health of elderly Pca survivors.
Prostate cancer (PCa) is the most common malignancy in elderly men. Age is a relevant risk factor, with a proven histological PCa being found in 60% of men by the age of 70 years and 80% by the age of 80 [
Although androgen receptor (AR) pathway is crucial for prostate cancer growth and progression, evidence supporting a favorable risk-benefit ratio of androgen deprivation therapy (ADT) is currently limited to high-risk PCa or metastatic disease [
The current literature suggests an association between metabolic syndrome (MetS) and PCa, although the evidence for a causal relationship remains unknown [
The primary goal of any definitive treatment of PCa is the improvement of survival and QoL: although surgery, radiotherapy, and hormone therapy can lead to long-term survival, these treatments can cause lasting side effects [
The aim of present review is to summarize the current knowledge on the role of androgens pathways, metabolic factors, and primary treatments on the overall QoL and sexual health of elderly PCa survivors.
Prostate volume and function are age- and androgen-dependent [
How actions of AR become tumorigenic and lead to uncontrolled growth remains poorly understood. In a high percentage of PCa, fusions between the androgen-dependent gene TMPRSS2 and ETS transcription factors (such as ERG) occur through chromosomal translocations [
Androgen deprivation therapy (ADT) represents a valuable treatment of metastatic PCa. However, ADT provides palliation but not cure and most PCa regrow as castration-resistant PCa (CRPCa) able to survive and grow in a milieu virtually deprived of androgens. The detailed mechanisms of why ADT ultimately fails and a more aggressive cancer recurs remain unclear (Figure
Schematic representation of the main pathways involved in development of castration-resistant prostate cancer (CRPC). ADT: androgen-deprivation therapy, AR: androgen receptor. Modified from 43.
Interestingly, low expression of mutated AR may drive in vitro growth of CRPCa cell lines also by nongenomic (rapid signalling) mechanisms [
Currently, research is mainly directed to understand the role of these multiple pathways and their interregulation with the aim of identifying potential therapeutical targets. One hot topic of research is aimed at understating the role of AR. In a recent survey of the literature concerning the relationship between AR expression in PCa specimen and disease prognosis, we have highlighted the conflicting results reported so far [
These results substantiate in vitro studies showing that enforced expression of AR in AR-negative PCa cells decreases the metastatic/invasive potential of the cells [
Clinical data supporting a differentiating role of AR in PCa and, as such, limiting invasiveness have been also published. Following androgen ablation metastatic PCa is promoted in vitro [
In such a complex scenario, it is clear that more studies are needed to define the role of AR in the different PCa compartments. In addition, investigations should be aimed at evaluating the different AR variants present in the tumors. Indeed a recent study [
Although a causative role for circulating androgens on PCa has been envisaged since the Huggins and Hodges studies, data clearly showed that such a link is at best unproved. In a meta-analysis of 18 prospective studies, including almost 4000 men with incident PCa and 6500 control subjects, no associations were found between the risk of PCa and serum concentrations of Testosterone (T), calculated FT, DHT, and other androgens [
In line with these data, the pooled odds ratio for Testosterone Replacement Therapy (TRT) derived from 19 randomized clinical trials was 1.09 (0.48–2.49, 95% CI) for PC and 1.19 (0.67–2.09, 95% CI) for PSA > 4 ng/dL or 1.5% increase during study (for review see [
As mentioned above, intraprostatic androgen synthesis may support PCa cell growth even in the virtual absence of androgens contributing to development of CRPCa [
Several studies have analyzed the modifications in the levels of T and gonadotropins following radical treatment, producing controversial results [
Recently, we enrolled 100 men affected by PCa in a single center prospective study, with the aim to evaluate the changes in the serum levels of T, LH, and FSH within the first 3 months after RP for clinically localized PCa and to analyze the correlation between LH and T at various follow-up times [
To confirm these data and to analyze the influence of T on sexual activity and urinary continence in men with PCa, we consecutively enrolled 257 patients treated with RP in our center [
Metabolic syndrome describes the combination or clustering of several metabolic abnormalities including central obesity, dyslipidemia, hypertension, insulin resistance with compensatory hyperinsulinemia, and glucose intolerance [
Although the only well-established risk factors associated with PCa are age, race, and family history, the large geographical variations in PCa risk suggest that lifestyle and environmental factors may also contribute to its etiology. The possibility to prevent and treat MetS and its components led to novel therapeutic approaches that have been proposed as a new frontier in the prevention and treatment of PCa [
MetS is a constellation of physiological and biochemical abnormalities characterized by diabetes or high fasting glucose, central obesity, abnormal cholesterol and triglyceride levels, and hypertension [
Prevalence of MetS increases linearly from the age of 20 until age of 50, when it plateaus and affects more than 40% of the population in the United States and nearly 30% in Europe [
In most cases MetS develops as a result of poor eating habits and/or sedentary lifestyles which are associated with IR and obesity. IR occurs when there is a decrease in the responsiveness of peripheral tissues (skeletal muscle, fat, and liver) to the effect of insulin with a concomitant hyperinsulinemia [
Central obesity is also considered an early step in the development and progression of MetS. Visceral adipose tissue secretes various bioactive substances known as adipocytokines which can induce IR and have proinflammatory and proatherogenic effects (Figure
The pathophysiological loop of metabolic syndrome.
MetS has also been associated with a state of chronic, low-grade inflammation. Several studies showed that patients with MetS were more likely than those without to have elevated levels of a marker of inflammation such as C-reactive protein (CRP) as well as proinflammatory cytokines such as TNF-
MetS has frequently been associated in human and animal models with carcinogenesis (see Table
Relevant clinical studies of the relationship between MetS and prostate cancer.
Authors, year | Study design | Country | Population | Time | Age years (range or mean |
Cohort size | Exposure assessment: MetS criteria | Number of cases | Results (outcome: PCa) | Level of evidence |
---|---|---|---|---|---|---|---|---|---|---|
Laukkanen et al., 2004 [ |
Longitudinal cohort study | Finland | Kuopio communities | 1984–2001 | 42–62 | 1880 (White) | WHO | 56 | Risk increase (RR: 1.94, 95% CI: 1.06–3.53) | 2b |
Håheim et al., 2006 [ |
Longitudinal cohort study | Norway | Oslo study | 1972–1998 | 40–49 | 15 933 (White) | Upper quartile levels ATP III criteria | 507 | Risk increase (RR: 1.56; 95 %CI: 1.21–2) | 2b |
Martin et al., 2009 [ |
Longitudinal cohort study | Norway | Nord-Trondelag Health study (HUNT 2) | 1996–2005 |
|
29 364 (White) | NCEP: ATP III | 687 | No association (HR: 0.91, 95% CI, 0.877–1.09) | 2b |
Beebe-Dimmer et al., 2009 [ |
Case-control study | USA | Gene Environment and Prostate Cancer study (GECAP) | 2001–2004 |
|
881 (56% White; 44% African-American) | NCEP: ATP III | 637 | Risk increase in African-American population (OR: 1.71, 95% CI; 0.97–3.01) | 3 |
Tande et al., 2006 [ |
Longitudinal cohort study | USA | Atherosclerosis Risk in Communities (ARIC); | 1987–2000 | 45–64 | 6429 (49% White; 61% African-American) | NCEP: ATP III | 385 | Risk reduction (RR: 0.77; 95% CI, 0.51–1.05) | 2b |
Kheterpal et al., 2012 [ |
Longitudinal cohort study | USA | Robotic radical prostatectomy | 2005–2008 | 45–65 | 2756 | BMI ≥30 and ≥2 of the following: hypertension, diabetes or elevated blood glucose, and dyslipidemia | 357 | Greater pathology Gleason grade ( |
3 |
C. De Nunzio et al., 2011 [ |
Cohort study | Italy | Prostate biopsy cohort study | 2009-2010 | 47–83 | 195 (White) | NCEP: ATP III | 102 | No association (OR: 0.97, 95% CI: 0.48–1.95); Increased risk for Gleason score |
3 |
Moreover, obesity was associated with an increased risk of intraoperative and perioperative complications and with a worse functional outcome, in men treated with RP [
In conclusion, further basic and clinical studies are needed to evaluate this association by investigating all these metabolic conditions as a whole and to better evaluate the role the MetS and its mediators with the development and progression of PCa.
Any treatment of PCa can affect urinary and sexual activity, psychosocial function, and overall wellbeing. Several validated questionnaires have been used to asses QoL after RP. An effective evaluation should consider at least 3 categories of QoL: (1) the organ specific function (urinary and sexual); (2) the physical status and the mental health in the patients with any type of cancer; (3) the general health status. The following validated questionnaires are the most accurate to assess the overall health and quality of life for men with PCa.
The University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) is very accurate to evaluate all aspects related to QoL before and after any treatment for PCA. This questionnaire investigates urinary, bowel and sexual function (UF, BF, and SF), and bowel and sexual bother (UB, BB, and SB) and has been designed either for urologists or radiotherapists [
This validated questionnaire, designed to evaluate the QoL in men affected by or treated for any cancer, is a 30-item questionnaire composed of multi-item scales and single items that reflect the multidimensionality of the quality-of-life construct [
The SF-12 is the short version of the SF-36 questionnaire [
The IIEF questionnaire is a validated multidimensional self-administered questionnaire used to assess the erectile function and the response to treatment in clinical trials. A score of 0–5 is awarded to each question that evaluates 4 domains of sexual health: sexual desire, erectile function, orgasmic function, and intercourse satisfaction [
Currently, more than half of all PCa are clinically localized at the diagnosis, with a 5-year biochemical disease-free survival above 85% [
In particular, erectile dysfunction and urinary incontinence after RP, bowel, urinary, and sexual complications after radiotherapy or sexual and continence and mood bothersome after hormone treatment can have a negative impact on all the aspects of QoL, including vitality, social and physical, and emotional limitations.
The appropriate management of the older men can be a challenge: elderly men are more likely to be diagnosed with higher-grade cancer and the presence of comorbidity and functional decline can impact on treatment tolerance and side effects [
PC is often diagnosed as a result of routine screening in asymptomatic patients, so the development of late treatment sequelae may be particularly alarming [
QoL is a key criterion in the choice of treatment, particularly for early PC or elderly patients, but it is difficult to assess despite the availability of validated questionnaires [
Generally, recent cohort prospective studies of patients show a different pattern of late sequelae: an increased prevalence of urinary incontinence after prostatectomy, of urinary irritative obstructive symptoms after brachytherapy, of bowel side effects after EBRT, whereas sexual dysfunction as common late event after all these treatment including ADT [
In particular, erectile dysfunction (ED) is a critical point related to QoL in men treated for PCa and it is strongly associated with depression and significant distress [
The major concerns for patients undergoing RP are postprostatectomy incontinence (PPI) and ED. Both QoL and sexual health after RP are strongly dependent on patient age, aging, tumor characteristics, and disease progression [
One of the leading determinants of QoL and sexual health after RP is the surgical approach: a more conservative procedure, sparing neurovascular bundles, bladder neck, and proximal urethra can strongly increase the chance of better functional outcomes [
The complete recovery of urinary continence after RP is mandatory to preserve general health and to maximize the outcomes of sexual rehabilitation: after catheter removal, most patients reported some level of urinary incontinence [
ED and urinary continence can improve even beyond more than 1 year postoperatively, with an average time to sexual and urinary recovery of >6 months [
During the natural aging process in disease-free survivors after RP, both urinary and sexual symptoms and bother can be strongly modified, due to hormonal modification and both vascular and nerve impairment. Moreover, after long-term disease-free follow-up, several men reconsider their QoL status [
Comparison of function and bother in long-term disease-free survivors after nerve sparing RP without hormone treatment: UF: urinary function; UB: urinary bother; SF: sexual function; SB: sexual bother; RP: radical prostatectomy (adapted from [
Current indications for external-beam radiotherapy (EBRT) in PC include primary treatment (in localized intracapsular tumors or combined with ADT in locally advanced and high-risk PC), adjuvant treatment in patient with adverse pathologic features, (extracapsular extension, positive surgical margins), and salvage radiotherapy (after radical prostatectomy) [
However, over recent years, radiotherapy (RT) has seen major advances such as the introduction of intensity-modulated radiation therapy (IMRT) and image-guided RT (IGRT) [
Sanda et al. concluded a substantial decline from baseline of sexual function at 2 years after surgery, but only a moderate decline after EBRT or brachytherapy. Recovery of sexual function was worse in patients treated with androgen suppression combined with radiotherapy, in older patients, obese patients, and patients with a larger prostate size and a high pretreatment PSA. The patient’s QoL concerning sexual function was also significantly related to satisfaction in the partner [
Pardo et al., in a Spanish study, had similar results after a follow-up of 3 years in patients treated by surgery or EBRT or brachytherapy [
In their report of a long-term follow-up, Resnick et al. [
The Radiation Therapy Oncology Group 9406 trial examined 158 men with a regular erectile function at baseline and found a greater risk of impotence with a penile mean dose >52.5 Gy (
Regarding alternative fractionations, the low
Finally, the few studies available concerning QoL after dose-escalated radiotherapy (thanks to advances in radiotherapy techniques) suggest an increased radiation dose does not result in decline of QoL [
Approximately 50% of men with PCa receive ADT at some time after diagnosis, and most will take it for at least 2 to 3 years [
ADT presents several symptoms of “castration syndrome” as side effects, based on low serum T concentration. The symptoms include loss of libido and sexual interest, erectile dysfunction, general fatigue, decreased intellectual ability, depression, loss of muscle strength, increased abdominal fat mass, and loss of vigor [
Regarding the side effects of hormonal therapy, in a Canadian retrospective study of Joly et al. [
In an Australian longitudinal study the authors investigated the change to QoL and T level in men starting an intermittent maximal androgen blockade program. Two hundred and fifty men were recruited in this multicentre study: T suppression leads to a significant reduction in global QoL and deterioration in most function as sexual function. Complete loss of libido increased from 37.2% before treatment to 72.2% after hormonal deprivation. Complete sexual inactivity increased from 54.3% to 86.9%. Following treatment cessation, T recovery was gradual and median time to eugonadal levels of the hormone was 9.3 months with an improvement in emotional function, sexual function, fatigue, sleep, and hot flushes [
In the American study of Lubeck, QoL of 1178 newly diagnosed patients was examined (mean age at diagnosis was 73 years) which were enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor Database. General and disease specific QoL outcomes were measured with tests at study entry and quarterly thereafter. Patients were randomized in 3 groups: ADT, surveillance, radical prostatectomy, or EBRT. Men receiving ADT reported poorer urinary and sexual function and a higher rate of urinary and sexual symptoms than patients selecting surveillance. ADT and surveillance QoL scores remained low in the year after treatment, whereas men treated by RP showed improvement in these scales [
In the Australian phase 3 trial of Denham, all patients were given six months of leuprorelin, and radiotherapy to the prostate and seminal vesicles after 5 months from randomisation. After leuprorelin, patients were given either no further treatment or an additional 12 months of leuprorelin. In addition to androgen suppression, men who were randomly allocated to the two bisphosphonate groups were given zoledronic acid for 18 months. In this study, 18 months of androgen suppression worsened the adverse changes in the “patients-reported-outcome” score caused by 6 months of androgen suppression and radiotherapy. However, these increases were restricted to only sexual activity, hormone treatment related symptoms, fatigue, and financial problems at 18 months after randomization. The increases were also restricted in time [
Mature survival data from men with previously untreated, locally-advanced disease reveal that bicalutamide monotherapy provides survival benefits that do not differ significantly from castration, while offering important advantages with respect to the maintenance of physical capacity and sexual interest [
In the two largest phase III studies comparing bicalutamide 150 mg/die monotherapy with castration (orchiectomy or the LH-RH agonist goserelin acetate) in 1453 patients, the combined analysis at 12 months showed that bicalutamide was associated with a significant advantage for sexual interest compared with castration (
In conclusion, the present review underlines the double role of androgens and the androgen receptor in the development and proliferation of PCa as well as in maintaining a correct functional state of the prostate of elderly men. Evidence in the literature suggests that maintaining a correct function of the androgen receptor may limit PCa progression by keeping a more differentiate state of the cells. Although more RCT are needed to better define the risk/benefit of androgen therapy in elderly men previously cured for PCa, current evidence indicates that treatment with androgens of hypogonadal men with previous PCa may be safe and may ameliorate both sexual health and QoL.
There are several lines of evidence regarding the emerging role of MetS and its components in PCa development and progression. Moreover, MetS can be associated with a state of chronic, low-grade inflammation, in particular in elderly men. We have summarized the evidence about the involvement of MetS in the pathogenesis of PCa, particularly of high-grade disease and we suggested that MetS should be assessed as a new domain in basic and clinical research in elderly men with PCa. In particular, all the components of MetS should be adequately assessed either before or after any treatment of PCa.
It is mandatory to use validated questionnaire to provide adequate details to patients not only regarding urinary and bowel symptoms, but also regarding their sexual function in order to avoid anxiety in patients and their families, to provide adequate medical and psychological counseling, and to analyze the progressive modifications during the follow-up of PCa survivors.
The adverse effects of surgery, radiotherapy, or androgen deprivation may be more pronounced in the elderly population, especially those with lower functional status and increased comorbidities, in particular regarding their sexual health. Therefore it is important to consider the specific benefits and risks for each treatment modality as they apply to the elderly because of the greater risk in both short- and long-term postoperative complications and mortality following any radical treatment.
The authors declare that there is no conflict of interests regarding the publication of this paper.