Mohit Khera

Testosterone Replacement Therapy Following Radical Prostatectomy

INTRODUCTION Controversy exists regarding testosterone replacement therapy (TRT) in men following radical prostatectomy (RP). Many clinicians are hesitant to offer patients TRT after an RP, out of concern that the increased androgen levels may promote tumor progression or recurrence from residual tumor. Recently, several small studies have demonstrated the use of TRT in men following an RP and have shown an improvement in serum testosterone levels with no increase in prostate-specific antigen (PSA) values. AIMS The aim of this article is to assess changes in PSA and testosterone values in hypogonadal patients on TRT after RP and also to evaluate the impact of pathologic Gleason grade on ultimate PSA values. METHODS All hypogonadal men who were treated with TRT by members of our department following RP were retrospectively reviewed. PSA values before RP, after RP, and after TRT were evaluated. Serum testosterone levels before and after TRT were also examined. Only patients with undetectable PSA values and negative surgical margins on pathologic specimen were offered TRT and included in the study. MAIN OUTCOME MEASURES Main outcome measures were changes in PSA and testosterone values after initiation of TRT. RESULTS Fifty-seven men, ages 53-83 years (mean 64), were identified as having initiated TRT following RP. Men received TRT for an average of 36 months following RP (range 1-136 months). Patients were followed an average of 13 months after initiation of TRT (range 1-99 months). The mean testosterone values rose from 255 ng/dL before TRT to 459 ng/dL after TRT (P < 0.001). There was no increase in PSA values after initiation of TRT and thus no patient had a biochemical PSA recurrence. CONCLUSION TRT is effective in improving testosterone levels, without increasing PSA values, in hypogonadal men who have undergone RP.

A New Era of Testosterone and Prostate Cancer: From Physiology to Clinical Implications

CONTEXT Decades-old beliefs regarding androgens and prostate cancer (PCa) have undergone dramatic shifts in light of modern evidence and new theoretical constructs, but considerable confusion remains on this topic, particularly with regard to the use of testosterone therapy in men with any history of PCa. OBJECTIVE To review current literature regarding the relationship of serum testosterone on PCa and in particular the effect of testosterone therapy on PCa progression and recurrence. EVIDENCE ACQUISITION A Medline search was conducted to identify all original and review articles assessing the effect of androgens on the prostate and the use of testosterone in men with a history of treated and untreated PCa. EVIDENCE SYNTHESIS Contrary to traditional teaching, high endogenous serum testosterone does not increase the risk of developing PCa, and low serum testosterone does not protect against PCa. Although limited in size and duration, current studies similarly fail to indicate any increased risk of PCa in men receiving testosterone therapy. These results indicate a finite ability of androgens to stimulate PCa growth (the saturation model). A majority of studies demonstrate an association between low serum testosterone and poor prognostic features of PCa, including high-grade disease, advanced pathologic stage, and increased risk of biochemical recurrence following radical prostatectomy. The prostate-specific antigen-to-testosterone ratio predicted PCa risk in several biopsy studies. Multiple reports of testosterone therapy in men after treatment for localized PCa have shown low or absent recurrence rates. Some men with untreated PCa have received testosterone therapy without evidence for PCa progression. CONCLUSIONS The long-held belief that PCa risk is related to high serum androgen concentrations can no longer be supported. Current evidence indicates that maximal androgen-stimulated PCa growth is achieved at relatively low serum testosterone concentrations. It may therefore be reasonable to consider testosterone therapy in selected men with PCa and symptomatic hypogonadism.

Testosterone Replacement Therapy in Patients with Prostate Cancer After Radical Prostatectomy

PURPOSE Testosterone replacement therapy in men with prostate cancer is controversial, with concern that testosterone can stimulate cancer growth. We evaluated the safety and efficacy of testosterone in hypogonadal men with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS We performed a review of 103 hypogonadal men with prostate cancer treated with testosterone after prostatectomy (treatment group) and 49 nonhypogonadal men with cancer treated with prostatectomy (reference group). There were 77 men with low/intermediate (nonhigh) risk cancer and 26 with high risk cancer included in the analysis. All men were treated with transdermal testosterone, and serum hormone, hemoglobin, hematocrit and prostate specific antigen were evaluated for more than 36 months. RESULTS Median (IQR) patient age in the treatment group was 61.0 years (55.0-67.0), and initial laboratory results included testosterone 261.0 ng/dl (213.0-302.0), prostate specific antigen 0.004 ng/ml (0.002-0.007), hemoglobin 14.7 gm/dl (13.3-15.5) and hematocrit 45.2% (40.4-46.1). Median followup was 27.5 months, at which time a significant increase in testosterone was observed in the treatment group. A significant increase in prostate specific antigen was observed in the high risk and nonhigh risk treatment groups with no increase in the reference group. Overall 4 and 8 cases of cancer recurrence were observed in treatment and reference groups, respectively. CONCLUSIONS Thus, testosterone therapy is effective and, while followed by an increase in prostate specific antigen, does not appear to increase cancer recurrence rates, even in men with high risk prostate cancer. However, given the retrospective nature of this and prior studies, testosterone therapy in men with history of prostate cancer should be performed with a vigorous surveillance protocol.

Varicocele repair in patients with nonobstructive azoospermia: a meta-analysis.

PURPOSE Multiple small case series have reported sperm in the ejaculate and spontaneous pregnancies in patients with nonobstructive azoospermia after varicocele repair. We hypothesized that men with favorable testicular histopathology on testis biopsy such as maturation arrest or hypospermatogenesis would have a higher probability of success than those with more ablative pathology, eg Sertoli-cell-only. MATERIALS AND METHODS A review of the literature on varicocele repair in patients with nonobstructive azoospermia was performed and 11 publications from the previous 20 years were evaluated. Histopathological data were presented in 8 publications, and were categorized as Sertoli-cell-only, maturation arrest and hypospermatogenesis. Maturation arrest was further differentiated by 4 publications. Early maturation arrest was defined as maturation ending at the secondary spermatocyte and late maturation arrest was defined as maturation ending at the spermatid without spermatozoa present. Success after repair was defined as having sperm in the ejaculate or spontaneous pregnancy. RESULTS A total of 233 patients were analyzed. After varicocele repair 91 (39.1%) patients had motile sperm in the ejaculate and 14 spontaneous pregnancies were reported. Success rates in patients with maturation arrest (42.1%) or hypospermatogenesis (54.5%) were significantly higher than in those with Sertoli-cell-only (11.3%, p <0.001 in both groups). Patients with late maturation arrest had a higher probability of success (45.8%) than those with early maturation arrest (0%, p = 0.007). CONCLUSIONS Infertile men with nonobstructive azoospermia can have improvement in semen analysis and achieve spontaneous pregnancy after repair of clinical varicoceles. This meta-analysis demonstrates that men with late maturation arrest and hypospermatogenesis have a higher probability of success and, therefore, histopathology should be considered before varicocele repair in men with nonobstructive azoospermia.

Improved Sexual Function with Testosterone Replacement Therapy in Hypogonadal Men: Real-World Data from the Testim Registry in the United States (TRiUS)

INTRODUCTION Up to 30% of erectile dysfunction (ED) patients treated with phosphodiesterase type 5 (PDE5) inhibitors do not show improved sexual function, which may be due in part to low serum testosterone. Hypogonadal patients already receiving testosterone replacement therapy (TRT) likewise can still suffer from symptoms of sexual dysfunction. In these patient populations, augmenting with, or switching, TRT treatment may improve sexual function. AIM To determine if 12-month treatment with a testosterone gel improves sexual function in hypogonadal men, as measured by the Brief Male Sexual Function Inventory (BMSFI), and in subgroups defined by low testosterone, PDE5 inhibitor use, and prior TRT. METHODS The Testim Registry in the United States (TRiUS) was a large (N = 849) multicenter registry of hypogonadal men treated with Testim (testosterone 1%) topical gel and followed for 12 months. MAIN OUTCOME MEASURES Data collected at suggested visits (baseline; 1, 3, 6, and 12 months) included total testosterone (TT), free testosterone (FT), BMSFI scores, physical exam, and body measurements. RESULTS TRiUS had 271 patients with baseline testosterone and BMSFI measurements. At 12 months of TRT, TT and FT levels significantly increased from baseline (P < 0.001), with mean ± standard deviation final TT = 17.37 ± 8.61 nmol/L (500.6 ± 248.2 ng/dL) and FT = 240.1 ± 296.0 pmol/L (69.2 ± 85.3 pg/mL). The mean total BMSFI score significantly increased from baseline at 12 months (27.4 ± 10.3 to 33.8 ± 9.8, P < 0.001) and at each visit in all domains (sex drive/libido, erectile function, ejaculatory function, level of bother), overall and for all subgroups. Regression analysis indicated that increased total BMSFI score was significantly associated with increased TT levels at 6 months. CONCLUSIONS In hypogonadal patients, 12-month administration of topical testosterone gel resulted in increased TT and FT levels and significantly improved sexual function. All subgroups studied, including men taking PDE5 inhibitors for ED and those previously on TRT, demonstrated significant improvement in sexual function from baseline scores.

Testosterone Replacement Therapy in the Setting of Prostate Cancer Treated With Radiation

A lack of consensus and few data support testosterone replacement therapy (TRT) in hypogonadal men who have been treated for prostate cancer (CaP), particularly those who have received radiation therapy. We performed retrospective review of 13 hypogonadal men with CaP, treated with brachytherapy or external beam radiotherapy who were subsequently treated with testosterone (T) between 2006 and 2011. Serum T, free T (FT), estrogen (E), sex hormone-binding globulin (SHBG), prostate-specific antigen (PSA), hemoglobin (Hgb) and hematocrit (Hct) values were evaluated approximately every 3 months after TRT initiation up to 67 months of follow-up. Prostate biopsies demonstrated four men with Gleason (Gl) 6, 7 with Gl 7 and 2 with Gl 8 disease. Median (interquartile range) age at TRT initiation was 68.0 (62.0–77.0) years, initial T 178.0 (88.0–263.5) ng dl−1, FT 10.1 (5.7–15.0) pg ml−1 and PSA 0.30 (0.06–0.95) ng ml−1. Median follow-up after TRT initiation was 29.7 months (range 2.3–67.3 months). At median follow-up, a significant increase in mean T (368.0 (281.3–591.0) ng dl−1, P=0.012) and SHBG were observed, with no significant increases in Hgb, Hct, E, FT, or PSA (0.66 (0.16–1.35) ng ml−1, P=0.345). No significant increases in PSA or CaP recurrences were observed at any follow-up interval. TRT in the setting of CaP after treatment with radiation therapy results in a rise in serum T levels and improvement in hypogonadal symptoms without evidence of CaP recurrence or progression.

Effect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: data from the Testim Registry in the US (TRiUS)

BackgroundRecent evidence suggests that there may be a bidirectional, physiological link between hypogonadism and metabolic syndrome (MetS), and testosterone replacement therapy (TRT) has been shown to improve some symptoms of MetS in small patient populations. We examined the effect of 12 months of TRT on MetS components in a large cohort of hypogonadal men.MethodsData were obtained from TRiUS (Testim® Registry in the United States), a 12-month, multicenter, prospective observational registry (N = 849) of hypogonadal men prescribed Testim 1% testosterone gel (5-10 g/day). Data analyzed included age, total testosterone (TT), free testosterone (FT), sex hormone-binding globulin (SHBG), and MetS components: waist circumference, blood pressure, fasting blood glucose, plasma triglycerides, and HDL cholesterol.ResultsOf evaluable patients (581/849) at baseline, 37% were MetS+ (n = 213) and 63% were MetS- (n = 368). MetS+ patients had significantly lower TT (p < 0.0001) and SHBG (p = 0.01) levels. Patients with the lowest quartile TT levels (<206 ng/dL [<7.1 nmol/L]) had a significantly increased risk of MetS+ classification vs those with highest quartile TT levels (≥331 ng/dL [≥11.5 nmol/L]) (odds ratio 2.66; 95% CI, 1.60 to 4.43). After 12 months of TRT, TT levels significantly increased in all patients (p < 0.005). Despite having similar TT levels after TRT, only MetS+ patients demonstrated significant decreases in waist circumference, fasting blood glucose levels, and blood pressure; lowest TT quartile patients demonstrated significant decreases in waist circumference and fasting blood glucose. Neither HDL cholesterol nor triglyceride levels changed significantly in either patient population.ConclusionHypogonadal MetS+ patients were more likely than their MetS- counterparts to have lower baseline TT levels and present with more comorbid conditions. MetS+ patients and those in the lowest TT quartile showed improvement in some metabolic syndrome components after 12 months of TRT. While it is currently unclear if further cardiometabolic benefit can be seen with longer TRT use in this population, testing for low testosterone may be warranted in MetS+ men with hypogonadal symptoms.

The effect of testosterone supplementation on depression symptoms in hypogonadal men from the Testim Registry in the US (TRiUS)

Objective: To determine the effect of long-term testosterone replacement therapy (TRT) on depression symptoms in hypogonadal men. Methods: Data were from TRiUS, a multicenter, 12-month observational registry (N = 849) of hypogonadal men prescribed 1% testosterone gel. Measures including total testosterone (TT) were assessed at baseline and months 3, 6, and 12. Depression symptoms were measured with Patient Health Questionnaire-9 (PHQ-9), a validated self-report questionnaire. A PHQ-9 score decrease of ≥5 represents clinical improvement. Results PHQ-9 scores were available for 762/849 TRiUS participants at baseline. Overall, 92.4% (704/762) demonstrated some level of depressive symptoms, with 17.3% (132/762) having moderately severe (score 15–19) to severe (score 20–27) symptoms. Subcohorts with significantly (p ≤ 0.03) more moderately severe to severe symptoms were: <60 years old, TT levels <250 ng/dl (<8.68 nmol/l), HIV/AIDS-positive, or used antidepressants or opioids. TT levels and PHQ-9 scores improved significantly (p < 0.01) by 3 months of TRT. At 12 months PHQ-9 scores showed a clinically meaningful mean improvement of 5.62 points, patients with moderately severe to severe symptoms decreased from 17.3% to 2.1% (5/233), and subcohorts, including those defined by age (<60 years) and antidepressant use, had improved PHQ-9 scores ≥5. Conclusion: TRT may reduce depression symptoms in hypogonadal men, including middle-aged men and those using antidepressants.

Changes in Prostate Specific Antigen in Hypogonadal Men After 12 Months of Testosterone Replacement Therapy: Support for the Prostate Saturation Theory

PURPOSE We measured prostate specific antigen after 12 months of testosterone replacement therapy in hypogonadal men. MATERIALS AND METHODS Data were collected from the TRiUS (Testim® Registry in the United States), an observational registry of hypogonadal men on testosterone replacement therapy (849). Participants were Testim naïve, had no prostate cancer and received 5 to 10 gm Testim 1% (testosterone gel) daily. RESULTS A total of 451 patients with prostate specific antigen and total testosterone values were divided into group A (197 with total testosterone less than 250 ng/dl) and group B (254 with total testosterone 250 ng/dl or greater). The groups differed significantly in free testosterone and sex hormone-binding globulin, but not in age or prostate specific antigen. In group A but not group B prostate specific antigen correlated significantly with total testosterone (r=0.20, p=0.005), free testosterone (r=0.22, p=0.03) and sex hormone-binding globulin (r=0.59, p=0.002) at baseline. After 12 months of testosterone replacement therapy, increase in total testosterone (mean±SD) was statistically significant in group A (+326±295 ng/dl, p<0.001; final total testosterone 516±28 ng/dl) and group B (+154±217 ng/dl, p<0.001; final total testosterone 513±20 ng/dl). After 12 months of testosterone replacement therapy, increase in prostate specific antigen was statistically significant in group A (+0.19±0.61 ng/ml, p=0.02; final prostate specific antigen 1.26±0.96 ng/ml) but not in group B (+0.28±1.18 ng/ml, p=0.06; final prostate specific antigen 1.55±1.72 ng/ml). The average percent prostate specific antigen increase from baseline was higher in group A (21.9%) than in group B (14.1%). Overall the greatest prostate specific antigen was observed after 1 month of treatment and decreased thereafter. CONCLUSIONS Patients with baseline total testosterone less than 250 ng/dl were more likely to have an increased prostate specific antigen after testosterone replacement therapy than those with baseline total testosterone 250 ng/dl or greater, supporting the prostate saturation hypothesis. Clinicians should be aware that severely hypogonadal patients may experience increased prostate specific antigen after testosterone replacement therapy.

Androgens and Erectile Function: A Case for Early Androgen Use in Postprostatectomy Hypogonadal Men

INTRODUCTION Erectile dysfunction affects up to 80% of men following a radical prostatectomy (RP) and is a common concern for these patients. Currently, hypogonadal men are not treated with testosterone after a RP for fear of stimulating dormant prostate cancer cells even though there is little evidence to support this hesitancy. There is data, however, to support the use of testosterone to aid in faster and better recovery of erections following RP. AIMS The aim of this article is to explore the relationship between testosterone replacement therapy (TRT) and erectile preservation following RP. MAIN OUTCOME MEASURES The results of findings in the literature on the association between testosterone and its role in preserving erectile function, particularly in men following RP. METHODS This article reviews and evaluates the literature that demonstrates the role of testosterone in obtaining erections and preserving erectile function. Additional articles were reviewed to assess the role of testosterone in erectile preservation following RP. RESULTS This review demonstrates that testosterone does play a role in erectile function, particularly for men who have undergone a RP. Testosterone has been shown to have an effect on nitric oxide synthase release, phosphodiesterase type 5 expression and activity, and in cavernosal nerve function, and to contribute to venoocclusive disease in the penis. All of these effects are of particular importance to men attempting to preserve erectile function following RP. CONCLUSION While the relationship between TRT and improvement in erectile function has been well established, the role of testosterone in men following RP may be of even greater significance. However, further studies are needed to assess the true safety of TRT following RP.