Sexual activity in men undergoing ADT for localized prostate cancer: a narrative literature review

Abstract

Androgen deprivation therapy (ADT) can negatively affect sexual function, and only a minority of patients report sexual activity. We reviewed the existing literature regarding the proportion of men who remained sexually active during and after ADT. The PubMed database was searched for studies published over the past 20 years. We selected and reviewed randomized clinical trials that provided sexual function data at baseline and during and after ADT. The primary outcome measure was the sexual function. Studies assessed sexual function using quality of life patient-reported outcome measures, which included sexual potency/activity evaluation. Information from 2947 patients was analyzed in this review. The median age of patients was 70 years. At baseline, a median of 49.9% (95% confidence interval [CI]: 49.1%–50.7%) of the patients reported being sexually active. At 6 months, 12 months, and 2 years or later of ADT treatment, a median of 10.3% (95% CI: 10.2%–10.5%), 8.9% (95% CI: 8.6%–9.2%), and 8.3% (95% CI: 8.2%–8.5%) of the patients reported being sexually active, respectively. Considering that half of the patients were sexually active at baseline, it seems probable that more than 10% of the patients who were sexually active before starting ADT remained sexually active when undergoing ADT. In conclusion, despite the common belief that ADT eliminates sexual activity, this analysis found that approximately 1 in 10 men are sexually active when on ADT, and this proportion is likely increased in men who are sexually active before starting ADT. Attention to sexual activity should not be dismissed in men on ADT.

INTRODUCTION

Androgen deprivation therapy (ADT) is often part of the multimodal treatment for locally advanced, recurrent, or metastatic prostate cancer. Such a decline in testosterone levels can cause important sexual side effects, such as decreased libido and erectile dysfunction, which affect sexual activity.1 Because many patients are sexually active before they are diagnosed with prostate cancer, these side effects represent a burden to those who wish to remain sexually active during and after treatment. It is important to keep in mind that in addition to the side effects of ADT, erectile function is also influenced by multiple factors that are frequent in older men, such as age, diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, tobacco use, alcohol consumption, pharmaceutical drugs, and obesity.2 Patients are expected to have decreased erectile function at the beginning and at follow-up when treated with continuous ADT. However, sexual function is not important in all patients,3 and some are not sexually active before beginning ADT. Little is known about the percentage of patients with sexual dysfunction at baseline and during ADT. This narrative literature review sought to quantify the proportion of patients who remained sexually active when treated with ADT for prostate cancer among selected clinical trials. A better understanding by physicians regarding sexual function during and after ADT as well as the desire of certain patients to maintain sexual function is important in maintaining quality of life (QoL).

LITERATURE SEARCH

We searched the literature in the PubMed database using the advanced search feature. The publication date filter has been adjusted over the last 20 years. A search was conducted using the following keywords: (“prostate cancer” OR “prostate carcinoma” OR “prostatic neoplasm”) AND (“hormonal replacement therapy” OR “androgen deprivation therapy” OR “ADT” OR “hormonal antineoplastic agents” OR “hormonal therapy” OR “hormonotherapy” OR “androgen receptor signaling inhibitors” OR “antiandrogen”) AND (“sexual activity” OR “sexual function” OR “sexual outcome” OR “erectile function” OR “sexuality” OR “erectile dysfunction”).

SELECTION PROCESS

Using PubMed’s advanced research features, 500 articles were identified (Figure 1). Only articles presenting randomized controlled trials with at least 50 subjects, relevant to our study question, and published in the last 20 years, were included in this study. Thus, of the 500 identified articles, 476 were excluded based on their titles and abstracts. The main reasons for their rejection were the inadequate study design (cohort study and review) and unrelated study questions. Consequently, 24 articles were included in this study. Only 6 articles were selected for the final analysis because they allowed standardization of the results of all selected studies. Only patients who underwent ADT were included in the study. We selected articles that dealt mostly with nonmetastatic cancers. Except for two studies,4,5 all of these studies described measurements of sexual function using quality-of-life measures.

Figure 1.

Screening and evaluation process for inclusion in this review.

Statistical analyses

Pooled estimations were calculated using the relative rate of patients reporting sexual activity. The data were derived from different patient-reported outcome measures over time and in relation to the duration of the ongoing or after completion of the ADT. In studies with more than one measurement after 2 years, the most recent measurement was chosen. Only the patients who underwent ADT were included in this study. The results were validated using different definitions for measures of sexual activity (i.e., proportion of men reporting sexual activity) of men reporting erections adequate for penetration or of men reporting no severe erectile dysfunction. This analysis assumes a normal distribution of values, which may not necessarily be the case.

RESULTS

Within the six included studies, 2947/4962 (59.4%) patients received ADT at some point in the selected studies and were included in the analysis (Table 1). The median age of patients was 70 (interquartile range [IQR]: 68–70) years. The six studies included patients treated with radiotherapy, of which one study included patients treated with ADT for recurrent cancer after radiation therapy or radical prostatectomy for nonmetastatic cancer.8

Table 1.

Characteristics of the studies included in this narrative review

Study	Period	Study arms	Patient (n)	Cancer stage	Mean age (year)	Patient-reported sexual measures	Tool for measurement of sexual function
Lane et al.6 2022	1999–2009	AM or RP or EBRT/BT + ADT	Total=2565 Monitoring: n=1135 RP: n=750 EBRT: n=603* BT: n=77	Localized	62	Baseline=38%  1 year=69%  2 years=66%  3 years=68%  4 years=69%  5 years=71%  6 years=74%	EPIC
Rodda et al.4 2017	2002–2011	ADT + EBRT or LDR-BT	Total=398 EBRT: n=200* LDR-BT: n=198*	High-risk and intermediate localized	68	LDR-PB  Baseline=36.2%  1 year=94.8%  5 years=66.1%	Assessment if “erections adequate for penetration”
						EBRT  Baseline=39%  1 year=92.9%  5 years=69.4%
Roy et al.7 2021	2002–2012	Timing of ADT during EBRT (neo-adjuvant vs adjuvant)	Total=391 Neoadjuvant: n=194* Adjuvant: n=197*	Localized	70	Arm A  Baseline=26.3%  14 months=46.8%  26 months=30.7%  3 years=25.5%  4 years=26.5%  5 years=28.9%	EORTC-QLQ-PR25
						Arm B  Baseline=19.6%  14 months=46.5%  26 months=25.5%  3 years=22.6%  4 years=29.3%  5 years=32.9%
Duchesne et al.8 2017	2004–2012	Timing of ADT: delayed (2 years) or immediate	Total=293 Delayed: n=151* Immediate: n=142*	Biochemical recurrence (M0) after RP (96/261) or EBRT (155/261)	70	Arm A  Baseline=32.41  1 year=28.63  2 years=25.88  3 years=24.75  4 years=15.31  5 years=18.39	EORTC-QLQ-PR25
						Arm B  Baseline=29.53  1 year=13.76  2 years=15.64  3 years=15.26  4 years=13.49  5 years=9.86
Laughlin et al.5 2023	2012–2019	EBRT±ADT	Total=110 EBRT + ADT: n=55* EBRT-ADT: n=55	Localized	68	Arm A  Baseline=50%  3 months=25%  6 months=24%  1 year=38%	Common terminology criteria for adverse events (version 4)
						Arm B  Baseline=60%  3 months=52%  6 months=48%  1 year=52%
Brundage et al.9 2015	1995–2004	ADT±EBRT	Total=1205 ADT: n=602* ADT + EBRT: n=603*	Locally advanced	69.7 (median)	Arm A  Baseline=74.6%  6 months=14.6%  1 year=18%  3 years=18%	FACT-P
						Arm B  Baseline=69.4%  6 months=22.8%  1 year=25%  3 years=24.8%

^*The subcohort of patients included in the final analysis. EBRT: external beam radiotherapy; ADT: androgen deprivation therapy; RP: radical prostatectomy; LDR-BT: low-dose rate brachytherapy; AM: active monitoring; BT: brachytherapy; FACT-P: functional assessment of cancer therapy – prostate; EPIC: expanded prostate cancer index composite; EORTC: European Organisation for Research and Treatment of Cancer; QLQ-PR25: prostate cancer module

Table 2 details the percentage of men reporting sexual activity without severe erectile dysfunction during and after hormonal therapy for nonmetastatic prostate cancer. A median of 49.9% (95% confidence interval [CI]: 49.1%–50.7%) of men reported being sexually active at baseline. At 6 months, 12 months, and 2 years or later of follow-up, 10.3% (95% CI: 10.2%–10.5%), 8.9% (95% CI: 8.6%–9.2%), and 8.3% (95% CI: 8.2%–8.5%) of patients reported remaining sexually active, respectively. The data on the 20 252 patients who had radiotherapy only are shown in Table 3.

Table 2.

Percentage of patients among the selected studies reporting sexual activity without severe erectile dysfunction during and after hormonal therapy for nonmetastatic prostate cancer (n=2947)

Time point of ADT treatment	Patient with measurements (n)	Patient reporting sexual activity (%), median (95% CI)
Baseline	2947	49.9 (49.1–50.7)
Under ongoing ADT
6 months	1402	10.3 (10.2–10.5)
1 year	1896	8.9 (8.6–9.2)
≥2 years	1498	8.3 (8.2–8.5)
After completion of ADT
6 months	1051	47.7 (47.1–48.4)
1 year	1051	45.4 (44.2–46.6)
≥2 years	1449	38.3 (37.3–39.3)

ADT: androgen deprivation therapy; CI: confidence interval

Table 3.

Percentage of patients having had radiotherapy only reporting sexual activity without severe erectile dysfunction during and after hormonal therapy for nonmetastatic prostate cancer (n=2052)

Time point of ADT treatment	Patient with measurements (n)	Patient reporting sexual activity (%), median (95% CI)
Baseline	2052	–
Under ongoing ADT
6 months	658	9.3 (9.0–9.7)
1 year	1001	6.1 (6.0–6.1)
≥2 years	603	6.0 (5.9–6.1)
After completion of ADT
6 months	1051	47.7 (47.1–48.4)
1 year	1051	45.4 (44.2–46.6)
≥2 years	1449	38.3 (37.3–39.3)

ADT: androgen deprivation therapy; CI: confidence interval; –: none

After completion of ADT, at the end of 6 months, 12 months, and 2 years or later of follow-up, a median of 47.7% (95% CI: 47.1%–48.4%), 45.4% (95% CI: 44.2%–46.6%), and 38.3% (95% CI: 37.3%–39.3%) of men reported sexual activity, respectively. After treatment completion, the number of sexually active patients gradually decreased during follow-up. No major decrease was reported over time. This indicates that sexual function is most affected during ADT, with approximately 10% of patients or less were sexually active. Figure 2 shows a pooled estimation of men reporting sexual activity without severe erectile dysfunction during and after hormonal therapy for nonmetastatic prostate cancer.

Figure 2.

Pooled estimation of men reporting sexual activity without severe erectile dysfunction during and after hormonal therapy for nonmetastatic prostate cancer with 95% CI (n = 2947). ADT: androgen deprivation therapy; CI: confidence interval.

DISCUSSION

Androgenic pathways play pivotal roles in regulating libido and arousal in the brain.10 Testosterone is a key hormone for sexual health and function in men. Many studies have shown that low testosterone levels are associated with adverse sexual effects.11 We found that, at baseline, only a median of 49.9% (95% CI: 49.1%–50.7%) of patients were sexually active. When treated with ADT, this percentage declined to 10.3% (95% CI: 10.2%–10.5%) at 6 months, 8.9% (95% CI: 8.6%–9.2) at 12 months, and 8.3% (95% CI: 8.2%–8.5%) at 2 years or later. Therefore, considering that only half of the patients were sexually active at baseline, it seems probable that more than 10% of the patients who were sexually active before starting ADT remained sexually active when undergoing ADT. With ongoing ADT, the greatest decrease in men’s sexual activity was observed between baseline and 6 months of treatment. Beyond the last time point, the proportion of sexually active patients did not change significantly.

Normal sexual activity in men involves a combination of physiological and psychological factors. Multiple factors can have an influence on sexual activity, such as advanced age. Other contributing factors are comorbidities such as diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, tobacco use, alcohol intake, pharmaceutical drugs, and obesity.2 ADT administered to patients diagnosed with prostate cancer may severely disrupt this equilibrium and cause long-term adverse effects on sexual function. In a study by Potters et al.,12 erectile function in 482 patients with prostate cancer was assessed after brachytherapy with or without neoadjuvant androgen deprivation. Treatment of sexual dysfunction in these patients is difficult. There are few data regarding the success of medical treatment of ED during ADT. ADT is known to reduce the response to phosphodiesterase type 5 inhibitors (PDE5i) and penile contractility.13 Despite this, approximately 50% of patients undergoing treatment for ED when undergoing ADT seem to have a treatment response, defined as an erection sufficient for penetration and successful completion of sexual intercourse.14

All patients were able to maintain an erection suitable for intercourse before treatment with prostate brachytherapy. The addition of ADT worsened the potency preservation rate. A study conducted by the Prostate Cancer Outcomes Study of the Surveillance, Epidemiology, and End Results Program stated that 69% of men who had sexual function before ADT, no longer did following ADT.15 Additionally, in the study by Potosky et al.,16 88 sexually potent patients were assessed using a QoL questionnaire before treatment with ADT. Of these patients, 80% of patients reported being impotent after 1 year of treatment compared to 30% of those receiving no treatment (P = 0.001). Erectile dysfunction may be seen as the natural fate of most PCa treatment survivors in the long run. Fifteen years after local therapy, more than 85% of men with initial local therapy reported an inability to achieve sufficient erection for intercourse.3

Of note, a diagnosis of prostate cancer itself can reduce or disturb sexual function because of its psychological impact. Aging is also a well-known risk factor for erectile dysfunction, and sexual function may already be compromised before ADT initiation. For example, the European Male Aging Study17 found that 30% of all men reported ED at ≥40 years of age. At 70 years of age, 64% of men experienced ED. A study by Incrocci et al.18 conducted on men who were yet to receive prostate cancer treatment found that 20% reported reduced sexual activity, 15% had decreased libido, and 10% reported erectile dysfunction. This may be explained in part because some men diagnosed with prostate cancer anticipate reduced sexual function following treatment. The biopsychosocial approach implies that every sexual expression consists of an interaction among biological, psychological, and social factors. Although testosterone plays a pivotal role in sexual function, especially desire, it has been known since ancient times that testosterone is not essential for sexual function. Hypogonadism is mostly correlated with libido.19 Testosterone replacement therapy in hypogonadal men seems to have little effect on erectile function.20,21

This review has several limitations that deserve mention. We included only patients with nonmetastatic disease. Therefore, many patients also received treatment for their primary cancer, which could have caused an additional worsening of sexual function. Thus, the possibility of restoring sexual function during ADT is limited. Sex therapy has only limited effectiveness, and penile prostheses are rarely offered.22 Physical exercise appears to have the greatest potential to address biological and psychological effects.23 Understanding the neurobiological mechanisms underlying sexual desire and function and how some men remain sexually active could help improve the quality of life of patients who lose their sexual activity.24

CONCLUSION

ADT often disrupts sexual function in men. However, a certain proportion of patients clearly preserved their erectile function and/or engaged in sexual activity; based on this analysis, 49.9% of men were sexually active before treatment with ADT, and this percentage dropped to approximately 10% of men during ADT. Given these data, practitioners should proactively address the possibility of maintained sexual function in patients who have the desire rather than assume that loss of sexual function is an inevitable consequence of ADT.

AUTHOR CONTRIBUTIONS

LC analyzed and selected the studies and drafted the manuscript. FF carried out the statistical analysis. DT, FP, FS, and FF helped draft the manuscript. DT organized the funding and the logistics. All authors read and approved the final manuscript.

COMPETING INTERESTS

LC was supported by a fund from Tolmar (Tolmar Mississauga, ON, Canada). Tolmar had no influence on the research or the interpretation. All other authors declare no competing interests.