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Abstract

The relationship between androgens and prostate cancer (PC) continues to be a source of much controversy within the urologic community. It is well established that low endogenous testosterone levels correlate with increased prevalence of erectile dysfunction and that exogenous testosterone therapy (TT) significantly decreases this risk. Although TT is often used for these purposes in the general patient population, the application of TT to patients with a history of PC is dismissed due to questions regarding oncologic safety and recurrence risk. However, for patients presenting with symptomatic hypogonadism and no evidence of PC after definitive treatment, the benefits of TT on surgical recovery, erectile function (EF), and quality of life are significant. In this regard, the review seeks to present published data regarding the oncologic safety and therapeutic efficacy of TT use for improved EF recovery in patients with post-radical prostatectomy.

Introduction

Prostate cancer (PC) remains the most common non-cutaneous cancer in American men, as 13% of men will be diagnosed with PC during their lifetime.¹ For the treatment of local disease, the radical prostatectomy (RP) remains the gold standard, with cancer control rates estimated to range from 80% to 95% depending on surgical technique, surgeon skill, and patient demographics.² However, despite the advent of new surgical techniques to minimize the side effects of urinary incontinence and sexual dysfunction,³ these complications are reported to range from 14% to 90% immediately after robot-assisted RP.⁴ For men with normal preoperative function, these side effects create barriers to seeking treatment as they represent a significant potential for decreased quality of life.

The risk of erectile dysfunction (ED) after RP is modulated primarily by a nerve-sparing surgical procedure and each patient's age and level of preoperative sexual function.⁵ From the surgeon's perspective, rates of bilateral nerve-sparing RP among high-volume surgeons are reported to be between 60% and 93%.⁶ Although highly dependent on tumor volume, level of local invasion, and aggressiveness of disease, nerve-sparing procedures have improved in recent years, especially with new advances in minimally invasive techniques.^7,8

Given a nerve-sparing RP, the next most impactful characteristic influencing postoperative ED is age and preoperative erectile function (EF). For those with normal function before surgery (i.e., defined as an International Index of Erectile Function-5 score between 22 and 25), EF recovery rates are significantly higher than those with some level of ED before surgery.⁹ However, even with this increased rate of recovery, long-term outcomes are still incomplete. A systematic review and meta-analysis of patients undergoing robot-assisted RP, for example, reported EF rates of 70–79% at 1–2 years after surgery. This rate has been reported to be as low as 40% for patients undergoing nerve-sparing RP.⁶

It is within this context that the consideration of other risk factors for ED originates. Most often cited are patient-based factors, such as hypertension and vascular comorbidities,¹⁰ metabolic syndromes,¹¹ and adult-onset hypogonadism¹²—the last of which is the cornerstone of much debate within the urologic community. Rooted in an assumed relationship with PC progression, this controversy prevents the treatment of post-RP ED with testosterone therapy (TT), despite its known efficacy in improving ED recovery, overall sexual function, and erection quality. Within this context, the present review seeks to critically analyze the relationship between hypogonadism, PC, and post-RP EF recovery, particularly considering the intersections between patient population and treatment potential.

Materials and Methods

Literature review and identification of relevant studies

A stepwise literature search of studies relating to TT in post-RP patients was carried out using three methods. First, a search of the MEDLINE databases was performed using the PubMed interface. The following keywords and combination(s) thereof were used: [testosterone therapy] or [testosterone supplementation] with and without [radical prostatectomy], [prostatectomy], [surgery], interchanged with [sexual function recovery], [sexual function], [erections], and/or [erectile function]. Second, a hand-search was conducted of four peer-reviewed urologic journals and two peer-reviewed general sexual medicine journals from January 1990 to June 2020.

The selection journals were as follows: European Urology, Journal of Urology, British Journal of Urology International, Urology, Journal of Sexual Medicine, and International Journal of Impotence Research. These journals were selected based on their affiliation with the leading urologic and sexual medicine societies and by their standing as clinical research journals in their respective disciplines. Finally, expert query and review by TA was done to ensure a comprehensive list of studies and publications.

Selection of studies

Inclusion and exclusion criteria were determined a priori. First, studies were only included if the primary purpose was to assess (1) efficacy of TT on EF, (2) safety of TT in patients after RP, and/or (3) impact of TT on EF in patients after RP. Due to the limited number of publications achieving this criterion, all study designs were considered. Studies were excluded in they were published in a non-English language, utilized TT before RP, or were proof-of-concept or animal studies. Commentaries and letters to the editor were also excluded, but the citations list of each of these was reviewed to ensure the inclusion of all relevant studies.

Utilizing the aforementioned stepwise methodology, studies were reviewed by the study team against the inclusion and exclusion criteria cited earlier. First, the titles and abstracts were screened such that nonrelevant studies were excluded; next, full manuscripts were reviewed for their primary purpose and study populations. Systematic review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analysis) standards.

Results

Testosterone and EF

Endogenous testosterone levels and EF

Before considering the role of TT for EF recovery after RP, the effect of endogenous testosterone levels on baseline function must also be explored. Mechanistically, it is well known that androgens play a key role in overall EF and in penile rehabilitation.¹³ When sexual stimulation occurs, nitric oxide is released in the penis, causing corporal smooth muscle relaxation through the activation of cyclic guanosine monophosphate/protein kinase G signaling cascades. The ED results when this system is weakened—more specifically, by over-activation of the competing RhoA/Rho-kinase signaling pathways.

In animal models, it has been observed that castration increases levels of the RhoA/Rho-kinase proteins,^14,15 resulting in reduced smooth muscle contractility. Although findings related to castration have not yet been applied to clinical settings, several groups have found over-activation of these pathways in processes related to ED. These include, but are not limited to, patients with diabetes mellitus or metabolic syndrome, in older men, and patients with hypogonadism and/or those who have low serum testosterone.^16,17

Although there is no universal agreement regarding the exact definition of hypogonadism, it is generally accepted that the term refers to the presence of symptomatic, persistently low circulating testosterone, when compared with a normal range derived from healthy young and middle-aged men. This range is ∼300 to 1000 ng/dL, as defined by the Endocrine Society and the Sexual Medicine Society of North America in most assays of serum total testosterone.¹⁸ By definition, hypogonadism is accompanied with nonspecific clinical symptoms, including fatigue, anemia, decreased bone density, decreased lean body mass, increased body fat, and, more often than not, ED.¹⁹

Within the context of these definitions, the effect of testosterone on EF is immutable, with rates of hypogonadism among men with ED reported to be up to 35%.²⁰ Further, although screening for hypogonadism often relies on serum total testosterone, the ambiguity of associated clinical symptoms often leads to false positives and failure to diagnose symptomatic men. In this regard, several groups highlight the use of calculated free testosterone in risk stratification.^21,22 Indeed, a prospective, population-based study of 733 patients by Luo et al in 2015 found low free testosterone levels to be an independent risk factor of ED in young men, such that those with low free testosterone in the lowest tertile had an ∼4.6 times increased likelihood of having ED.²²

Fortunately, what is true at one extreme of the distribution also extends to the other. The relationship between testosterone and EF also produces a protective benefit for patients with high serum testosterone levels.^23–25 In the same study by Luo et al, patients with the highest tertile of free testosterone had a relative risk ratio of 0.21 of having ED, after adjusting for sex hormone binding globulin and total testosterone levels.²² These findings were also supported by a 2011 study, including eight European centers and 2838 men, finding that high total and free testosterone levels were protective against sexual dysfunction among middle-aged and older men.

This held true when EF was defined both as erections observed during intercourse and as those obtained during self-stimulation.²³ Moreover, men with high testosterone were less likely to be overweight/obese, had lower rates of diabetes mellitus, and decreased prevalence of cardiovascular disease.²⁴

Finally, not only are endogenous testosterone levels an integral component of baseline EF, but they are also a modulator of ED treatment response. In several trials of ED treatment via phosphodiesterase type 5 inhibitors, patients with refractory ED were found to most often be hypogonadal.²⁵ In a 2006 clinical trial exploring the use of sildenafil citrate for the treatment of ED, it was found that 24 out of 90 men who initially failed treatment had testosterone levels less than 400 ng/dL. Given this finding, these men first had their testosterone levels normalized via administration of a testosterone gel before re-entering the trial. Once normalized, 22 out of the 24 men experienced significant improvements in EF and erection quality, thus underscoring the importance of normal testosterone levels in ED recovery and treatment.²⁶ These findings parallel two previously published clinical trials on the use of testosterone supplementation for the improvement of EF.^27,28

Exogenous testosterone and EF

Given the direct relationship between endogenous testosterone levels and EF, it is not surprising that exogenous supplementation can improve EF. Table 1 summarizes the current evidence detailing the efficacy of TT in patients with ED.^29–43

Table 1.

Review of Randomized Control Trials on the Efficacy of Testosterone Therapy on Erectile Function

Author	Year	Patient population	n =	Trial duration	Outcome measure	Significance
Cavallini et al²⁹	2004	Hypogonadal men >60 years	120	24 Weeks	IIEF-15	IIEF-15 EF and sexual desire domain scores increased at 3 months (p < 0.01) + EF increased at 6 months (p < 0.01). Sexual intercourse satisfaction increased at 6 months (p < 0.01) but NS at 3 months. General sexual well-being and orgasm domain changes were NS.
Svartberget et al³⁰	2004	Men aged 54–75 with moderate to severe COPD	29	26 Weeks	IIEF-5 Sexual Quality of Life	Treatment group week 26 versus baseline (17.5 ± 6.3 vs. 15.1 ± 8.7; ns) Control group week 26 versus baseline (10.77 ± 8.8 vs. 13.2 ± 7.5; p < 0.05) Treatment group week 26 versus control group week 26 (17.5 ± 6.3 vs. 10.7 ± 8.8; p < 0.05) Treatment group week 26 versus baseline (2.2 ± 1.4 vs. 2.6 ± 1.7; ns) Treatment group week 12 versus control group week 12 (1.7 ± 1.1 vs. 2.5 ± 1.2; p < 0.05)
Chiang et al³¹	2009	Hypogonadal men 20–75 years	40	12 Weeks	IIEF-5 IPSS	IIEF-5 scores significantly increased at 3 months. (p = 0.01). IPSS index differences between treatment and placebo groups were NS.
Allan et al³²	2008	Non-obese hypogonadal men 55+ years	62	52 Weeks	IIEF-15	Improved sexual desire versus placebo (p = 0.04) Other parameters of sexual function were NS.
Chiang et al³³	2009	Hypogonadal men 20–75 years	40	12 Weeks	IIEF-15	IIEF-5 EF, orgasmic function, and intercourse satisfaction scores significantly increased at 3 months. (p < 0.1). Sexual desire/overall satisfaction were NS.
Giltay et at.³⁴	2010	Hypogonadal men 35–69 years with metabolic syndrome	184	30 Weeks	IIEF-5 Beck Depression Inventory Aging Males' Symptoms	+3.1 points; 95%CI: +1.8; +4.4; p < 0.001 2.5 points; 95%CI: -0.9; -4.1; p = 0.003 7.4 points; 95%CI: -4.3; -10.5; p < 0.001
Aversa et al³⁵	2010	Hypogonadal men 50–65 years with metabolic syndrome and/or T2DM	52	48 Weeks	IIEF-5 Aging Males' Symptoms	IIEF-5 and Aging Males' Symptoms scores increased at 6 months (p < 0.01).
Jones et al³⁶	2011	Hypogonadal men 40+ years with T2DM and/or metabolic syndrome	205	52 Weeks	IIEF-15 Aging Males' Symptoms	IIEF total score, sexual desire, and intercourse satisfaction domain scores increased at 12 months (p < 0.05, p < 0.01, p < 0.05, respectively).
Hackett et al³⁷	2013	Hypogonadal men 33–83 years with T2DM	199	30 Weeks	IIEF-15	All domains of sexual function increased, with benefit as early as 6 weeks
Gianatti et al³⁸	2014	Hypogonadal men 35–70 yrs with T2DM	85	40 Weeks	IIEF-5 Aging Males' Symptoms	NS
Basaria et al³⁹	2015	Me 60 years + with low or low-normal testosterone levels	308	156 Weeks	IIEF-5 Medical Outcomes Study 36-item short form health	Intercourse satisfaction domain score improved (p = 0.05). Sexual desire, EF, overall sexual function scores, partner intimacy, and health-related quality of life were NS.
Paduch et al⁴⁰	2015	Hypogonadal men with one or more ED symptoms	76	16 Weeks	Male Sexual Health Questionnaire-Ejaculatory Dysfunction-Short Form IIEF-15 orgasmic domain	NS
Brock et al⁴¹	2016	Hypogonadal men 18+ yrs	558	16 Weeks	Hypogonadism Energy Diary Sexual Arousal Interest and Drive Scale	Improved Sexual Arousal, Interest, and Drive score (both p < 0.001) and Hypogonadism Energy Diary score (both p < 0.001) during the open label phase
Snyder et al⁴²	2016	Hypogonadal men 65+ years	790	52 Weeks	Psychosexual Daily Questionnaire IIEF-15 DISF-M-II	Increased sexual activity (PDQ-Q4, p < 0.001), sexual desire (DISF-M-II, p < 0.001), and EF (IIEF-15, p < 0.001).
Miranda et al⁴³	2021	Hypogonadal men post-RP	32	156 Weeks	IIEF-EFD	NS

COPD, chronic obstructive pulmonary disease; DISF-M, Derogatis Inventory of Sexual Function Men; ED, erectile dysfunction; EF, erectile function; IIEF-5, International Index of Erectile Function–5; IIEF-15, International Index of Erectile Function–15; IPSS, International Prostatism Symptom Score; NS, not significant; PDQ-Q4, Peyronie's Disease Questionnaire; RP, radical prostatectomy; T2DM, Type II Diabetes Mellitus.

These findings are further corroborated by a 2017 meta-analysis including 14 clinical trials and 2298 participants. At a mean follow-up of 40 weeks, TT significantly improved ED and overall sexual function in men with baseline testosterone deficiency. Even further, patients with more severe hypogonadism (as defined as a total testosterone less than 8 nmmol/L) reported a significantly greater improvement in EF, as compared with those with less severe T deficiency.⁴⁴

Key to the findings by Corona et al, however, is the implication that TT should be extended to patients with any symptoms indicative of hypogonadism. Although the Food and Drug Administration currently recommends TT only to men with a limited list of underlying conditions (termed “classic hypogonadism”), the presentation of clinical hypogonadism is highly heterogeneous. Further, these symptoms are often masked by or attributed to comorbid conditions.^17,45 Given this and the results paralleled by Isidori et al⁴⁶ and Aversa et al,⁴⁷ TT may prove to have significant benefits for symptomatic testosterone-deficient men, regardless of the underlying etiology. Although these benefits encompass sexual function, they also include a decreased risk of cardiovascular disease and metabolic syndrome and improved overall vitality.⁴⁵

Testosterone and PC

Although normal/high testosterone levels are closely correlated with decreased risk of ED, improved sexual function, and increased ED treatment response, the potential impact of TT is often deprioritized in men with PC due to their controversial history.

The initial recognition of the association between PC and androgens was published by Huggins and Hodges in 1941, wherein it was demonstrated that castration reduced prostatic acid phosphatase and PC burden.⁴⁸ From this perspective, it also appeared that testosterone administration had the opposite effect, stimulating high levels of prostatic acid phosphatase.⁴⁹ This secondary notion was further advanced by Gann et al via the Physician Health Study of 1966, reporting that men with higher levels of testosterone were more likely to develop PC.⁵⁰ Ultimately, these two studies led to a widespread fear of high serum testosterone and several policies against the use of exogenous TT in men with, or suspected of having, PC.⁵¹

After the publication of these studies, however, several groups noted the impact of testosterone on men's health, especially within the context of PC. In 1996, Morgentaler et al observed a high prevalence of biopsy-confirmed PC in men with low total or free testosterone levels.⁵² Ten years later, the same group documented a dose-response relationship between testosterone levels and likelihood of PC. Of the 345 hypogonadal men with a prostate specific antigen (PSA) less than 4.0 ng/mL, PC was detected in 21% of men with testosterone levels less than 250 ng/dL versus only 12% of men with a testosterone level greater than 250 ng/dL.

From these findings, a saturation model was proposed: In human prostatic tissue, the androgen receptor appeared to be saturated (and therefore, unreceptive to further increases in testosterone concentrations) at ∼240 ng/dL.^53,54 It is from this saturation model that several other groups have considered the use of TT within the context of PC,⁵⁵ whether it be its use among groups at high risk for PC, those under active surveillance for low-grade PC, or those recently treated.

Testosterone following RP

Testosterone supplementation after RP presents a unique patient population with its own set of risks and benefits. First is the question of patient selection: Since these men are assumed to have been treated for their PC and have undetectable PSA levels, the risk of TT use in this subset is significantly reduced as these patients have undergone curative treatment and no longer have detectable disease.⁵¹ Second, the population of men undergoing RP for the treatment for localized PC and concordant low FT with or without hypogonadal symptoms represent a group at a higher risk of biochemical recurrence (BCR) and/or late onset hypogonadism, due to overlapping risk factors of increased age, increased body mass index, decreased sexual activity, and a higher probability of comorbid conditions.⁵⁶ Further, the oncologic disease process associated with PC makes these men even more vulnerable to hypogonadism and attendant sexual dysfunction after surgery. Due to the large overlaps in these risk factors, these men stand to significantly benefit from TT.

Table 2 summarizes current studies exploring the use of TT in patients after RP.^57–66 All referenced studies concluded that TT after definitive treatment appeared to be safe and did not contribute to cancer progression. Even further, of those reporting quality life and/or sexual function outcomes, all endorsed significant improvement after testosterone administration.

Table 2.

Review of Evidence on the Safety of Testosterone Therapy in Patients Following Radical Prostatectomy

Authors	Year	Patients	Design	N	Follow-up	BCR definition	Analysis	Significance
Kaufman and Graydon⁵⁷	2004	Hypogonadal men, post-RP	Retrospective, single arm	7	1–12 Years	PSA >0.1 ng/mL	BCR	No biochemical or clinical evidence of cancer recurrences
Agarwal et al⁵⁸	2005	Hypogonadal men, post-RP	Retrospective, single arm	10	19 Months	PSA >0.1 ng/mL	BCR QoL	No biochemical recurrences Hormone domain of EPIC QoL questionnaire increased significantly (38 ± 5 vs. 49 ± 3; p = 0.0005)
Khera et al⁵⁹	2007	Hypogonadal men, post-RP	Retrospective, single arm	21	12 Months	Unspecified.	BCR EF	No biochemical recurrences 9 versus 1 man with positive response to ADAM post-TT (p = 0.02)
Khera et al⁶⁰	2009	Men receiving TT post-RP	Retrospective, single arm	57	36 Months	N/A	PSA	No increase in PSA values after the initiation of TT; no biochemical recurrences
Pastuszak et al⁶¹	2013	Hypogonadal men, post-RP	Retrospective, treatment versus control arm	103	27.5 Months	PSA >0.2 ng/mL	BCR	4/103 versus 8/49 cancer recurrences in treatment versus control groups, respectively (NS)
Kühn et al⁶²	2015	Men receiving TT post-RP	Retrospective questionnaire	26	Unspecified	Unspecified.	BCR	No biochemical recurrences
Ory et al⁶³	2016	Men receiving TT post-PC treatment	Retrospective, single arm	22	41 Months	Dependent on treatment modality.	BCR	No biochemical recurrences in post-RP patients
Ahlering et al⁶⁴	2020	Men receiving TT post-RP	Prospective	152	3.5 Years	PSA >0.2 ng/mL	BCR	Patients on TT had significantly reduced BCR and delayed time to BCR, compared with those not on TT
Sarkar et al⁶⁵	2020	Men receiving TT post-PC treatment	Cross-sectional	469	Unspecified	PSA >0.2 ng/mL	BCR PCSM Mortality	No significant differences in BCR No significant differences in PCS No significant differences in mortality
Morgantaler et al⁶⁶	2021	Men receiving TT with BCR and/or metastatic PC	Retrospective	22	12 Months	N/A	Progression	No associations with the progression of PC in men with BCR and metastatic PC

ADAM, Androgen Deficiency in Aging Males; BCR, biochemical recurrence; EPIC, Expanded Prostate Cancer Index; PC, prostate cancer; PCSM, prostate cancer specific mortality; PSA, prostate specific antigen; QoL, quality of life; TT, testosterone therapy.

To highlight these findings, the first is a large cohort analysis of 69,984 men with localized PC identified via the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database.⁶⁵ Of these patients, 28,651 underwent RP and 41,333 received radiation therapy for primary treatment of PC; after this, 469 RP and 543 radiation patients received TT. At a median follow-up of 6.95 years, there were no differences in biochemical recurrences between those receiving TT and those who did not. The PC specific mortality and overall mortality also showed no differences. Although these findings are limited by the cross-sectional study design, this exploration represents the largest cohort of patients receiving TT after primary treatment for PC.

These findings were then echoed by a 2020 study of 850 patients undergoing RP by a single surgeon.⁶⁴ Compared with the previous study, a higher proportion of patients were started on TT: 152 of 850, or 18% of patients. All patients were screened initially for low serum free testosterone and impaired EF recovery and patients receiving TT were compared with proportionally matched controls not receiving TT. After a median follow-up of 3.5 years, 11 out of 152 (7.2%) patients in the TT group experienced biochemical recurrence, compared with 53 out of 419 (12.6%) in the control group.

In adjusted time to event analysis, TT was an independent predictor of recurrence-free survival, after accounting for Gleason grade, pathologic stage, preoperative PSA level, and calculated free testosterone. Not only was recurrence not significantly higher in the group with TT, but also this group was ∼54% less likely to recur (hazards ratio 0.54, 95% confidence interval [CI] 0.292–0.997). Even further, among the patients who would eventually recur, TT delayed the time to recurrence by 1.5 years. Even further, by two years post-RP, 96% of patients in the TT group had recovered EF, despite having experienced delayed recovery before TT administration.⁶⁴

To this end, several population-based studies have also confirmed the safety of TT in post-RP patients and provide significant support for the extension of use to patients undergoing PC treatment.^67,68 Results of the earlier referenced studies were included in a recent meta-analysis of 21 studies aiming at evaluating the association between TT after definitive therapy and rate of BCR. Of these studies, the pooled biochemical recurrence rate was ∼0.01 (95% CI 0.00–0.02), suggesting a lack of association between TT and BCR; more specifically, in men treated with RP, pooled BCR rates were 0.00% (95% CI 0.00–0.02) after the administration of TT.

More recently, these findings have also been explored in men after biochemical recurrence and separately, those with metastatic PC. In 2021, Morgentaler et al published their initial experience with 7, 13, and 2 men with recurrent PC, metastatic disease, or those currently on androgen deprivation therapy after PC diagnosis, respectively. The mean duration of TT was 12 months overall, spanning 20 months for men with BCR and 9.5 months for men with metastatic disease. After TT administration, mean serum testosterone increased from 210 to 1111 ng/dL.

This increase was accompanied with a significant median PSA increase in all three groups. However, despite the increase in PSA and PSA velocity, follow-up imaging in 7 out of 10 patients within 12 months of TT showed no evidence of clinical progression. Given these findings, the group concluded that TT in patients with recurrence and/or metastatic disease was not associated with the progression of PC.⁶⁶ Rather, the significant positive impacts of TT on these men's quality of life and EF warrant its consideration, even in this high-risk population.

Testosterone for EF recovery after prostatectomy

Table 3 summarizes current literature on the use of TT for EF recovery after RP. Of note, given the safety concern associated with the use of TT in patients with a prior history of PC, all studies only utilized TT in men with organ-confined disease, negative surgical margins, and/or a history of undetectable PSA after surgery.

Table 3.

Review of Evidence on the Impact of Testosterone Therapy on Erectile Function in Patients Following Radical Prostatectomy

Author	Year	Patient population	Design	n	Follow-up	Outcome measure	Significance
Agarwal and Oefelein⁵⁸	2005	Hypogonadal men post-RP	Retrospective	10	19 Months	Extended Prostate Inventory Compositive Health Related Quality of Life questionnaire	The Hormone Domain of the Extended Prostate Inventory Composite Health Related Quality of Life questionnaire increased significantly from 38 ± 5 to 49 ± 3 (p = 0.00005).
Wynia et al⁶⁹	2014	Hypogonadal men post-RP	Prospective	111	24 Months	SHIM	63% reported improvement in erections; 87.5% had improvement in libido (measured by SHIM). 77.3% endorsed subjective improvement in energy level.
Khera et al⁵⁹	2009	Hypogonadal men on TT post-RP	Retrospective	21	13 Months	ADAM questionnaire	Positive hypogonadism screen post-TRT decreased from 9 men to 1 (p = 0.02). Significant decrease in symptoms, including decreased libido, lack of energy, ED, and fatigue
Ahlering et al⁶⁴	2020	Men with delayed EF recovery post-RP	Prospective	152	40.8 Months	IIEF-5	96% of men on TT recovered sexual function as measured by the IIEF-5 and by erections sufficient for intercourse

SHIM, Sexual Health Inventory in Men Questionnaire; TRT, testosterone replacement therapy.

The first exploration of TT for a quality of life-related indication after RP was a retrospective study of ten hypogonadal patients by Agarwal and Oefelein in 2005. All patients had no evidence of disease by clinical and PSA criteria and presented with symptoms of hypogonadism (i.e., hot flashes, ED, decreased libido, fatigue, and/or cognitive impairment).

After TT via topical, transdermal, or intramuscular formulations, for a median follow-up of 19 months, all patients maintained an undetectable PSA while experiencing a significant increase in serum testosterone levels. Further, when queried via the Extended Prostate Inventory Compositive Health Related Quality of Life questionnaire, these patients reported a significant increase in quality of life, primarily due to increased energy level, increased sexual function, and decreases in hot flashes.⁵⁸

Following this study was a prospective series of 111 men (57 on TT, compared to 54 control patients) by Wynia et al in 2014.⁶⁹ At a median follow-up of 2 years after the diagnosis of hypogonadism, there were fewer biochemical recurrences in the treatment group (1 vs. 8, p < 0.01). Even further, among those in the treatment group, 63% reported improved erections, 87.5% endorsed improvement in libido, and 77.3% experienced a subjective improvement in energy level.

Finally, after TT was discontinued, the mean PSA peak was 0.017 ng/mL, confirming the safety of TT in this cohort of patients. These findings were echoed by Khera et al, in a group of 21 men on TT after RP.⁵⁹ Utilizing the Androgen Deficiency in Aging Males (ADAM) questionnaire, the number of men with a positive hypogonadism screen decreased from 9 to 1 following testosterone replacement therapy after an average follow-up of 12 months (p = 0.02). Pre- versus post-treatment scores were also significantly improved, supporting a significant decrease in symptoms, including decreased libido, lack of energy, ED, and fatigue.⁶⁰

In contrast to the earlier studies that utilized TT for the treatment of clinical hypogonadism after RP, the 2020 study by Ahlering et al was the first to explore the use of TT specifically for EF recovery after RP.⁶⁴ Beginning in 2009, the group began examining whether low testosterone levels could be related to decreased sexual function recovery in post-RP men. This group had previously reported that patients with a normal preoperative International Index of Erectile Function–5 (IIEF-5) had significantly lower rates of EF recovery if they also had low levels of calculated free testosterone.

This effect persisted after controlling for patient comorbidities, baseline demographics, and nerve-sparing techniques. As such, the group prospectively evaluated these patients for hypogonadism and prescribed TT for patients with a low-risk disease status and undetectable PSA levels. When compared with a control group of patients, the group of 152 men receiving TT in this cohort not only experienced a decreased rate of biochemical recurrence, but also endorsed significant improvements in sexual function recovery. By the median follow-up of 3.4 years, 96% of men on TT had recovered sexual function as measured by the IIEF-5 and by erections sufficient for intercourse.⁶⁴ Although these four studies are the only to apply TT specifically within the context of EF treatment, the benefit of TT extends well into this patient population.

Clinical Application and Patient Considerations

The body of literature accumulated to date suggests that the effects of TT are diverse within the context of PC, especially when considering the treatment for PC patients experiencing symptoms of hypogonadism. These effects have shown benefit in reversing and reducing the symptoms of hypogonadism, the possible reduction of risk of biochemical recurrence after surgery, as well as improving patient recovery and quality of life.

Although these findings may be at odds to Huggins' observations of androgen dependency in PC, we must not overlook the merits of contradictory studies—especially given the potential benefits to patients recovering from EF after RP. Not only can TT be applied safely and efficaciously in these patients, but the benefits also extend to improving body habitus, preventing metabolic syndrome, and the possible reduction in the risk of PC recurrence. Although this objective may be controversial, the current evidence suggests that a history of PC is not an absolute contraindication of TT provided that the patient has undetectable PSA after RP. Therefore, TT may be feasible in carefully selected post-RP PC patients, it may not be a low-risk approach in those treated with radiation therapy since residual prostatic tissue remains and may still be susceptible to exogenous supplementation.

With TT in PC patients (whether for EF recovery or for the treatment of other hypogonadal symptoms), several key considerations remain. First, frequent and longitudinal monitoring of PSA and testosterone levels is required. Since supraphysiologic levels of serum testosterone are not needed to improve symptoms in patients, TT should be titrated within the first few months of supplementation. Then, serum free and total testosterone should be monitored every 1–2 months during the first year. Subsequently, the interval between measurements can be extended to evert 3–6 months.

Second, patients experiencing increases in PSA measurements (i.e., increasing but below levels considered a biochemical recurrence) should be monitored closely and considered for TT termination. PSA and testosterone levels should be assessed after discontinuing TT. Finally, in our practice, we recommend the use of topical TT, with gel or intramuscular formulations reserved for refractory patients.

Conclusion

The diagnosis and treatment of hypogonadism within the context of PC is experiencing a paradigm shift. Although it was previously well known that high testosterone levels benefit EF and TT administration mirrors this benefit in hypogonadal men, it was unclear whether patients suffering from delayed EF recovery after RP could stand to benefit from the therapy. This question was further complicated by the controversial relationship between androgens and PC.

However, given that all studies examining the use of TT in patients with organ-confined disease and undetectable PSA levels have reported no increases in PC recurrence, several groups have begun exploring its use specifically for EF recovery after RP. Although clinical evidence for this specific setting may still be in its infancy, there is no question that past research unanimously supports the use of TT to increase EF, enhance libido, and improve patient quality of life. Given stringent patient selection and persistent follow-up, post-RP patients with decreased EF stand to significantly benefit from TT administration.

Footnotes

Authors' Contributions

Conception and design: T.E.A. and L.M.H.; All authors participated in data acquisition and analysis; Drafting article: L.M.H. and R.G.; All authors participated in the revising and approval of the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Abbreviations Used

References

US Preventive Services Task

Force

, Grossman

, Curry

, et al. Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. JAMA, 2018; 319(18):1901–1913; DOI: 10.1001/jama.2018.3710.

Novara

, Ficarra

, Mocellin

, et al. Systematic review and meta-analysis of studies reporting oncologic outcome after robot-assisted radical prostatectomy. Eur Urol, 2012; 62(3):382–404; DOI: 10.1016/j.eururo.2012.05.047.

Asimakopoulos

, Annino

, D'Oraxio

, et al. Complete periprostatic anatomy preservation during robot-assisted laparoscopic radical prostatectomy (RALP): The New Pubovesical Complex-Sparing Technique. Eur Urol, 2010; 58(3):407–417; DOI: 10.1016/j.eururo.2010.04.032.

Tal

, Alphs

, Krebs

, et al. Erectile function recovery rate after radical prostatectomy: A meta-analysis. J Sex Med, 2009; 6(9):2538–2546; DOI: 10.1111/j.1743–6109.2009.01351.x.

Catalona

, Bigg

. Nerve-sparing radical prostatectomy: Evaluation of results after 250 patients. J Urol, 1990; 143(3):538–544; DOI: 10.1016/s0022-5347(17)40013-9.

Ficarra

, Novara

, Ahlering

, et al. Systematic review and meta-analysis of studies reporting potency rates after robot-assisted radical prostatectomy. Eur Urol, 2012; 62(3):418–430; DOI: 10.1016/j.eururo.2012.05.046.

Tavukçu

, Aytac

, Atug

. Nerve-sparing techniques and results in robot-assisted radical prostatectomy. Investig Clin Urol, 2016; 57(Suppl 2):S172–S184; DOI: 10.4111/icu.2016.57.S2.S172.

Kumar

, Patel

, Panaiyadiyan

, et al. Nerve-sparing robot-assisted radical prostatectomy: Current perspectives. Asian J Urol, 2021; 8(1):2–13; DOI: 10.1016/j.ajur.2020.05.012.

Kilminster

, Müller

, Menon

, et al. Predicting erectile function outcome in men after radical prostatectomy for prostate cancer. BJU Int, 2012; 110(3):422–426; https://doi.org/10.1111/j.1464-410X.2011.10757.x.

10.

Müller

, Parker

, Waters

, et al. Penile rehabilitation following radical prostatectomy: Predicting success. J Sex Med, 2009; 6(10):2806–2812; DOI: 10.1111/j.1743–6109.2009.01401.x.

11.

Marien

, Sankin

, Lepor

. Factors predicting preservation of erectile function in men undergoing open radical retropubic prostatectomy. J Urol, 2009; 181(4):1817–1822; DOI: 10.1016/j.juro.2008.11.105.

12.

Zarotsky

, Huang

, Carman

, et al. Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology, 2014; 2(6):819–834; DOI: 10.1111/andr.274.

13.

Traish

, Goldstein

, Kim

. Testosterone and erectile function: From basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol, 2007; 52(1):54–70; DOI: 10.1016/j.eururo.2007.02.034.

14.

Wingard

, Moukdar

, Prasad

, et al. Reversal of voltage-dependent erectile responses in the Zucker obese-diabetic rat by rosuvastatin-altered RhoA/Rho-kinase signaling. J Sex Med, 2009; 6 Suppl 3(Suppl 3):269–278; DOI: 10.1111/j.1743–6109.2008.01184.x.

15.

Vignozzi

, Morelli

, Filippi

, et al. Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes. J Sex Med, 2007; 4(3):620–632; DOI: 10.1111/j.1743–6109.2007.00440.x.

16.

Leguina-Ruzzi

, Pereira

, Pereira-Flores

, et al. Increased RhoA/Rho-kinase activity and markers of endothelial dysfunction in young adult subjects with metabolic syndrome. Metab Syndr Relat Disord, 2015; 13(9):373–380; DOI: 10.1089/met.2015.0061.

17.

Mazur

, Helfand

, McVary

. Influences of neuroregulatory factors on the development of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction in aging men. Urol Clin North Am. 2012; 39(1):77–88; DOI: 10.1016/j.ucl.2011.09.005.

18.

Bhasin

, Brito

, Cunningham

, et al. Testosterone therapy in men with hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2018; 103(5):1715–1744; DOI: 10.1210/jc.2018-00229.

19.

Bhasin

, Brito

, Cunningham

, et al. Testosterone therapy in men with hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2018; 103(5):1715–1744; DOI: 10.1210/jc.2018-00229.

20.

Salonia

, Bettocchi

, Boeri

, et al. European Association of Urology Guidelines on Sexual and Reproductive Health-2021 Update: Male sexual dysfunction. Eur Urol, 2021; 80(3):333–357; DOI: 10.1016/j.eururo.2021.06.007.

21.

Huynh

, Huang

, Towe

, et al. Evidence for the integration of total and free testosterone levels in the management of prostate cancer. BJU Int, 2021In Press; DOI: 10.1111/bju.15626.

22.

Luo

, Zhang

, Liao

, et al. Sex hormones predict the incidence of erectile dysfunction: From a Population-Based Prospective Cohort Study (FAMHES). J Sex Med, 2015; 12(5):1165–1174; DOI: 10.1111/jsm.12854.

23.

O'Connor

, Lee

, Corona

, et al. The relationships between sex hormones and sexual function in middle-aged and older European men. J Clin Endocrinol Metab, 2011; 96(10):E1577–E1587; DOI: 10.1210/jc.2010-2216.

24.

Kelly

, Jones

. Testosterone: A metabolic hormone in health and disease. J Endocrinol, 2013; 217(3):R25-R45; DOI: 10.1530/JOE-12-0455.

25.

Buvat

, Montorsi

, Maggi

, et al. Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). J Sex Med, 2011; 8(1):284–293; DOI: 10.1111/j.1743–6109.2010.01956.x.

26.

Rosenthal

, May

, Metro

, et al. Adjunctive use of AndroGel (testosterone gel) with sildenafil to treat erectile dysfunction in men with acquired androgen deficiency syndrome after failure using sildenafil alone. Urology, 2006; 67(3):571–574; DOI: 10.1016/j.urology.2005.09.032.

27.

Shabsigh

, Kaufman

, Steidle

, et al. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol, 2004; 172(2):658–663. DOI: 10.1097/01.ju.0000132389.97804.d7.

28.

Shabsigh

, Seftel

, Kim

, et al. Efficacy and safety of once daily tadalafil in men with erectile dysfunction who reported no successful intercourse attempts at baseline. J Sex Med, 2013; 10(3):844–856; DOI: 10.1111/j.1743-6109.2012.02898.x.

29.

Cavallini

, Caracciolo

, Vitali

, et al. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology, 2004; 63(4):641–646; DOI: 10.1016/j.urology.2003.11.009.

30.

Svartberg

, Aasebø

, Hjalmarsen

, et al. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial. Respir Med, 2004; 98(9):906–913; DOI: 10.1016/j.rmed.2004.02.015.

31.

Chiang

, Hwang

, Hsui

, et al. Transdermal testosterone gel increases serum testosterone levels in hypogonadal men in Taiwan with improvements in sexual function. Int J Impot Res, 2007; 19(4):411–417; DOI: 10.1038/sj.ijir.3901562.

32.

Allan

, Forbes

, Strauss

, et al. Testosterone therapy increases sexual desire in ageing men with low-normal testosterone levels and symptoms of androgen deficiency. Int J Impot Res, 2008; 20(4):396–401; DOI: 10.1038/ijir.2008.22.

33.

Chiang

, Cho

, Lin

, et al. Testosterone gel monotherapy improves sexual function of hypogonadal men mainly through restoring erection: Evaluation by IIEF score. Urology, 2009; 73(4):762–766; DOI: 10.1016/j.urology.2008.10.019.

34.

Giltay

, Tishova

, Mskhalaya

, et al. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J Sex Med, 2010; 7(7):2572–2582; DOI: 10.1111/j.1743-6109.2010.01859.x.

35.

Aversa

, Bruzziches

, Francomano

, et al. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest, 2010; 33(11):776–783; DOI: 10.1007/BF03350341.

36.

Jones

, Arver

, Behre

, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care, 2011; 34(4):828–837; DOI: 10.2337/dc10-1233.

37.

Hackett

, Cole

, Bhartia

, et al. Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes. J Sex Med, 2013; 10(6):1612–1627; DOI: 10.1111/jsm.12146.

38.

Gianatti

, Dupuis

, Hoermann

, et al. Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab, 2014; 99(10):3821–3828; DOI: 10.1210/jc.2014-1872.

39.

Basaria

, Harman

, Travison

, et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: A randomized clinical trial. JAMA, 2015; 314(6):570–581; DOI: 10.1001/jama.2015.8881.

40.

Paduch

, Polzer

, Ni

, et al. Testosterone replacement in androgen-deficient men with ejaculatory dysfunction: A randomized controlled trial. J Clin Endocrinol Metab, 2015; 100(8):2956–2962; DOI: 10.1210/jc.2014-4434.

41.

Brock

, Heiselman

, Knorr

, et al. 9-Month efficacy and safety study of testosterone solution 2% for sex drive and energy in hypogonadal men. J Urol, 2016; 196(5):1509–1515; DOI: 10.1016/j.juro.2016.04.065.

42.

Snyder

, Ellenberg

, Farrar

. Testosterone treatment in older men. N Engl J Med, 2016; 375(1):90; DOI: 10.1056/NEJMc1603665.

43.

Miranda

, Benfante

, Kunzel

, et al. A randomized, controlled, 3-arm trial of pharmacological penile rehabilitation in the preservation of erectile function after radical prostatectomy. J Sex Med, 2021; 18(2):423–429; DOI: 10.1016/j.jsxm.2020.10.022.

44.

Corona

, Rastrelli

, Morgentaler

, et al. Meta-analysis of results of testosterone therapy on sexual function based on international index of erectile function scores. Eur Urol, 2017; 72(6):1000–1011; DOI: 10.1016/j.eururo.2017.03.032.

45.

Snyder

, Bhasin

, Cunningham

, et al. Effects of testosterone treatment in older men. N Engl J Med, 2016; 374(7):611–624; DOI: 10.1056/NEJMoa1506119.

46.

Isidori

, Giannetta

, Gianfrilli

, et al. Effects of testosterone on sexual function in men: Results of a meta-analysis. Clin Endocrinol (Oxf), 2005; 63(4):381–394; DOI: 10.1111/j.1365-2265.2005.02350.x.

47.

Aversa

, Francomano

, Lenzi

. Does testosterone supplementation increase PDE5-inhibitor responses in difficult-to-treat erectile dysfunction patients?. Expert Opin Pharmacother, 2015; 16(5):625–628; DOI: 10.1517/14656566.2015.1011124.

48.

Huggins

, Hodges

. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol, 2002; 168(1):9–12; DOI: 10.1016/s0022-5347(05)64820-3.

49.

Hansson

, Moll

, Schultheiss

, et al. Huggins' Nobel Prize for Hormonal Treatment of Prostatic Cancer at its 50th Anniversary. Eur Urol, 2016; 69:971–972; DOI: 10.1016/j.eururo.2016.01.030.

50.

Gann

, Hennekens

, Ma

, et al. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst, 1996; 119;88:1118–1126; DOI: 10.1093/jnci/88.16.1118.

51.

Bhasin

, Cunningham

, Hayes

, et al. Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2010; 95(6):2536–2559; DOI: 10.1210/jc.2009-2354.

52.

Morgentaler

, Bruning III

, DeWolf

. Occult prostate cancer in men with low serum testosterone levels. JAMA, 1996; 276(23):1904–1906.

53.

Traish

, Williams

, Hoffman

, et al. Validation of the exchange assay for the measurement of androgen receptors in human and dog prostates. Prog Clin Biol Res, 1988; 262:145–160. PMID: 3375279.

54.

Rastrelli

, Corona

, Vignozzi

, et al. Serum PSA as a predictor of testosterone deficiency. J Sex Med, 2013; 10(10):2518–2528; DOI: 10.1111/jsm.12266.

55.

Kaplan

, Hu

, Morgentaler

, et al. Testosterone therapy in men with prostate cancer. Eur Urol, 2016; 69(5):894–903; DOI: 10.1016/j.eururo.2015.12.005.

56.

Zarotsky

, Huang

, Carman

, et al. Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology, 2014; 2(6):819–834; DOI: 10.1111/andr.274.

57.

Kaufman

, Graydon

. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol, 2004; 172(3):920–922; DOI: 10.1097/01.ju.0000136269.10161.32.

58.

Agarwal

, Oefelein

. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol, 2005; 173(2):533–536; DOI: 10.1097/01.ju.0000143942.55896.64.

59.

Khera

, Colen

, Grober

, et al. The safety and efficacy of testosterone replacement therapy following radical prostatectomy. J Urol, 2012; 187(4):E602–E603.

60.

Khera

, Grober

, Najari

, et al. Testosterone replacement therapy following radical prostatectomy. J Sex Med, 2009; 6(4):1165–1170; DOI: 10.1111/j.1743–6109.2009.01161.x.

61.

Pastuszak

, Pearlman

, Lai

, et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol, 2013; 190(2):639–644; DOI: 10.1016/j.juro.2013.02.002.

62.

Kühn

, M, Strasser

, Romming

, et al. Testosterone replacement therapy in hypogonadal men following prostate cancer treatment: A Questionnaire-Based Retrospective Study among Urologists in Bavaria, Germany. Urol Int, 2015; 95:153–159; DOI: 10.1159/000371725.

63.

Ory

, Flannigan

, Lundeen

, et al. Testosterone therapy in patients with treated and untreated prostate cancer: Impact on oncologic outcomes. J Urol, 2016; 196(4):1082–1089; DOI: 10.1016/j.juro.2016.04.069.

64.

Ahlering

, My Huynh

, Towe

, et al. Testosterone replacement therapy reduces biochemical recurrence after radical prostatectomy. BJU Int, 2020; 126(1):91–96; DOI: 10.1111/bju.15042.

65.

Sarkar

, Patel

, Parsons

, et al. Testosterone therapy does not increase the risks of prostate cancer recurrence or death after definitive treatment for localized disease. Prostate Cancer Prostatic Dis, 2020; 23(4):689–695; DOI: 10.1038/s41391-020-0241-3.

66.

Morgentaler

, Abello

, Bubley

. Testosterone therapy in men with biochemical recurrence and metastatic prostate cancer: Initial observations. Androg Clin Res Ther, 2021; 2(1):121–128.

67.

Kaplan

, Trinh

, Sun

, et al. Testosterone replacement therapy following the diagnosis of prostate cancer: Outcomes and utilization trends. J Sex Med, 2014; 11(4):1063–1070; DOI: 10.1111/jsm.12429.

68.

Loeb

, Folkvaljon

, Damber

, et al. Testosterone replacement therapy and risk of favorable and aggressive prostate cancer. J Clin Oncol, 2017; 35(13):1430–1436; DOI: 10.1200/JCO.2016.69.5304.

69.

Wynia

, Lee

, Taneja

, et al. Testosterone replacement therapy in patients with prostate cancer after prostatectomy: A 5-year single center experience. J Urol, 2014; 191(4S);E527–E528; DOI: 10.1016/j.juro.2014.02.1477.

The Role of Post-Radical Prostatectomy Testosterone Therapy in Erectile Function Recovery

Abstract

Introduction

Materials and Methods

Literature review and identification of relevant studies

Selection of studies

Results

Testosterone and EF

Endogenous testosterone levels and EF

Exogenous testosterone and EF

Testosterone and PC

Testosterone following RP

Testosterone for EF recovery after prostatectomy

Clinical Application and Patient Considerations

Conclusion

Footnotes

Authors' Contributions

Author Disclosure Statement

Funding Information

Abbreviations Used

References