Abraham Morgentaler

IS LOW SERUM FREE TESTOSTERONE A MARKER FOR HIGH GRADE PROSTATE CANCER

PURPOSE The association of free and total testosterone with prostate cancer is incompletely understood. We investigated the relationship of serum free and total testosterone to the clinical and pathological characteristics of prostate cancer. MATERIALS AND METHODS We retrospectively reviewed the clinical records of 117 consecutive patients treated by 1 physician and diagnosed with prostate cancer at our medical center between 1994 and 1997. Low free and total testosterone levels were defined as 1.5 or less and 300 ng./dl., respectively. RESULTS After evaluating all 117 patients we noted no correlation of free and total testosterone with prostate specific antigen, patient age, prostatic volume, percent of positive biopsies, biopsy Gleason score or clinical stage. However, in patients with low versus normal free testosterone there were an increased mean percent of biopsies that showed cancer (43% versus 22%, p = 0.013) and an increased incidence of a biopsy Gleason score of 8 or greater (7 of 64 versus 0 of 48, p = 0.025). Of the 117 patients 57 underwent radical retropubic prostatectomy. In those with low versus normal free testosterone an increased mean percent of biopsies demonstrated cancer (47% versus 28%, p = 0.018). Pathological evaluation revealed stage pT2ab, pT2c, pT3 and pT4 disease, respectively, in 31%, 64%, 8% and 0% of patients with low and in 40%, 40.6%, 12.5% and 6.2% in those with normal free testosterone (p>0.05). CONCLUSIONS In our study patients with prostate cancer and low free testosterone had more extensive disease. In addition, all men with a biopsy Gleason score of 8 or greater had low serum free testosterone. This finding suggests that low serum free testosterone may be a marker for more aggressive disease.

Shifting the Paradigm of Testosterone and Prostate Cancer: The Saturation Model and the Limits of Androgen-Dependent Growth

CONTEXT The traditional belief that prostate cancer (PCa) growth is dependent on serum testosterone (T) level has been challenged by recent negative studies in noncastrated men. OBJECTIVE To provide an improved framework for understanding the relationship of PCa to serum T level that is consistent with current evidence and is based on established biochemical principles of androgen action within the prostate. EVIDENCE ACQUISITION A literature search was performed of publications dating from 1941 to 2008 that addressed experimental and clinical effects of androgens on prostate growth. Review of studies investigating the prostatic effects of manipulation of androgen concentrations in human and animal studies, and in PCa cell lines. EVIDENCE SYNTHESIS Prostate growth is exquisitely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels. This pattern is consistent with the observation that androgens exert their prostatic effects primarily via binding to the androgen receptor (AR), and that maximal androgen-AR binding is achieved at serum T concentrations well below the physiologic range. A Saturation Model is proposed that accounts for the seemingly contradictory results in human PCa studies. Changes in serum T concentrations below the point of maximal androgen-AR binding will elicit substantial changes in PCa growth, as seen with castration, or with T administration to previously castrated men. In contrast, once maximal androgen-AR binding is reached the presence of additional androgen produces little further effect. CONCLUSIONS The evidence clearly indicates that there is a limit to the ability of androgens to stimulate PCa growth. A Saturation Model based on androgen-AR binding provides a satisfactory conceptual framework to account for the dramatic effects seen with castration as well as the minor impact of T administration in noncastrated men.

Endocrine aspects of male sexual dysfunctions

INTRODUCTION Endocrine disorders may adversely affect mens sexual function. AIM To provide recommendations based on best evidence for diagnosis and treatment of endocrine-related male sexual dysfunctions. METHODS The Endocrine Aspects of Male Sexual Dysfunctions Committee, including 11 members from eight countries and four continents, collaborated with the Endocrine subcommittee of the Standards Committee of the International Society for Sexual Medicine. Medical literature was reviewed in detail, followed by extensive internal committee discussion over 2 years, then public presentation and discussion with the other experts before finalizing the report. MAIN OUTCOME MEASURE Recommendations based on grading of evidence-base medical literature and interactive discussion. RESULTS From animal studies, it is derived that testosterone modulates mechanisms involved in erectile machinery, including expression of enzymes that both initiate and terminate erection. In addition, testosterone is essential for sexual motivation. Whether these findings could be extrapolated to human erections is unclear. Testosterone plays a broad role in mens overall health. Recent studies have established strong associations between low testosterone and metabolic and cardiovascular imbalances. In some studies, low testosterone decreased longevity; however, longitudinal studies do not support the predictive value of low testosterone for further cardiovascular events. The article proposes a standardized process for diagnosis and treatment of endocrine-related male sexual dysfunctions, updating the knowledge on testosterone and prostate safety. There is no compelling evidence that testosterone treatment causes prostate cancer or its progression in men without severe testosterone deficiency (TD). The possible roles of prolactin and thyroid hormones are also examined. CONCLUSIONS Men with erectile dysfunction, hypoactive sexual desire and retarded ejaculation, as well as those with visceral obesity and metabolic diseases, should be screened for TD and treated. Prospective interventional studies are required before screening for TD in more conditions, including cardiovascular diseases, and considering correction as preventive medicine as much data suggests.

Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men

Abstract Hypogonadism or Testosterone Deficiency (TD) in adult men as defined by low levels of serum testosterone accompanied by characteristic symptoms and/or signs as detailed further on can be found in long-recognized clinical entities such as Klinefelter syndrome, Kallmann syndrome, pituitary or testicular disorders, as well as in men with idiopathic, metabolic or iatrogenic conditions that result in testosterone deficiency. These recommendations do not encompass the full range of pathologies leading to hypogonadism (testosterone deficiency), but instead focus on the clinical spectrum of hypogonadism related to metabolic and idiopathic disorders that contribute to the majority of cases that occur in adult men.

Management of the impacted ureteral calculus.

The management of 42 impacted ureteral calculi is reviewed. Impacted stones were defined by the inability to pass a guide wire or catheter on initial attempts. Stones were impacted in the upper ureter in 10 patients, mid ureter in 11 and lower ureter in 21. Upper ureteral stones were treated in 8 patients by extracorporeal shock wave lithotripsy after disimpaction by laser or other techniques. Mid ureteral stones were treated by laser alone in 7 patients and by extracorporeal shock wave lithotripsy after disimpaction in 4. Lower stones were treated by laser in 17 patients and ultrasound in 2. Complications included 3 major and 5 minor perforations, and 4 false passages. Treatment was successful without an open operation in 40 of 42 patients (95%). Our current approach to impacted ureteral calculi involves passing a rigid ureteroscope to the stone, with disimpaction performed by laser fragmentation or other dislodgement maneuvers. Proximal stones or large fragments then are treated by extracorporeal shock wave lithotripsy. Mid ureteral stones are treated similarly, unless they are so fragile that in situ fragmentation may be completed easily. Lower ureteral stones are fragmented in situ, with hard fragments extracted by basket. Alternative treatments for impacted calculi at all levels include unstented in situ extracorporeal shock wave lithotripsy, antegrade ureteroscopy and, finally, an operation.

MECHANICAL RELIABILITY AND SAFETY OF, AND PATIENT SATISFACTION WITH THE AMBICOR INFLATABLE PENILE PROSTHESIS: RESULTS OF A 2 CENTER STUDY

PURPOSE We reviewed the experience with the 2-piece Ambicor penile prosthesis (American Medical Systems, Minnetonka, Minnesota) at 2 medical centers to investigate its mechanical reliability and complication rates as well as patient and partner satisfaction with the device. MATERIALS AND METHODS From 1995 through 1999, 131 men underwent implantation of an Ambicor penile prosthesis at 2 medical centers. We performed a 3-part study consisting of a retrospective clinical record review, mailed patient and partner questionnaire, and mailed modified patient and partner Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire. Mean followup was 43.4 months (range 12 to 73). RESULTS All 131 men had a history consistent with an organic etiology of erectile dysfunction, including vascular disease in 62%, radical retropubic prostatectomy in 17%, Peyronies disease in 15%, neophallus construction in 4% and radical pelvic surgery in 2%. Mean patient age was 56.8 years (range 22 to 76) at implantation. Overall there were complications in 10 cases (7.6%), including infection, hematoma and mechanical failure in 6 (4.6%), 1 (0.7%) and 3 (2.3%), respectively. A total of 112 men (85%) and 91 partners completed the questionnaire. All patient respondents still had an Ambicor prosthesis implanted and 96.4% had erection suitable for coitus. Overall patient and partner satisfaction was 96.4% and 91.2%, respectively. Of the respondents 92.9% of patients and 90.1% of partners would recommend the device to others. Of the 85 men (65%) and 46 partners who completed the modified Erectile Dysfunction Inventory of Treatment Satisfaction survey 90.6% and 82.6%, respectively, were satisfied or very satisfied overall with the penile prosthesis. CONCLUSIONS The Ambicor penile prosthesis is associated with a low complication rate and reliable mechanical function. High satisfaction was reported by patients and partners.

Testosterone and Prostate Cancer: Revisiting Old Paradigms

CONTEXT Androgens are vital for growth and maintenance of the prostate; however, the notion that pathologic prostate growth, benign or malignant, can be stimulated by androgens is a commonly held belief without scientific basis. Therefore, the current prostatic guidelines for testosterone therapy (TT) appear to be overly restrictive and should be reexamined. OBJECTIVE To review the literature addressing the possible relationship between testosterone and prostate cancer (PCa) and to summarize the main aspects of this issue. EVIDENCE ACQUISITION A Medline search was conducted to identify original articles, review articles, and editorials addressing the relationship between testosterone and the risk of PCa development, as well as the impact of TT on PCa development and its natural history in men believed to be cured by surgery or radiation. EVIDENCE SYNTHESIS Serum androgen levels, within a broad range, are not associated with PCa risk. Conversely, at time of PCa diagnosis, low rather than high serum testosterone levels have been found to be associated with advanced or high-grade disease. The available evidence indicates that TT neither increases the risk of PCa diagnosis nor affects the natural history of PCa in men who have undergone definitive treatment without residual disease. These findings can be explained with the saturation model (which states that prostatic homeostasis is maintained by a relatively low level of androgenic stimulation) and with the observation that exogenous testosterone administration does not significantly increase intraprostatic androgen levels in hypogonadal men. It must, however, be recognized that the literature remains limited regarding the effect of TT on PCa risk. Nonetheless, the current European Association of Urology guidelines state that in hypogonadal men who were successfully treated for PCa, TT can be considered after a prudent interval. CONCLUSIONS Although no controlled studies have yet been performed and there is a paucity of long-term data, the available literature strongly suggests that TT neither increases the risk of PCa diagnosis in normal men nor causes cancer recurrence in men who were successfully treated for PCa. Large prospective studies addressing the long-term effect of TT are needed to either refute or corroborate these hypotheses.

Testosterone Therapy in Men With Untreated Prostate Cancer

PURPOSE A history of prostate cancer has been a longstanding contraindication to the use of testosterone therapy due to the belief that higher serum testosterone causes more rapid prostate cancer growth. Recent evidence has called this paradigm into question. In this study we investigate the effect of testosterone therapy in men with untreated prostate cancer. MATERIALS AND METHODS We report the results of prostate biopsies, serum prostate specific antigen and prostate volume in symptomatic testosterone deficient cases receiving testosterone therapy while undergoing active surveillance for prostate cancer. RESULTS A total of 13 symptomatic testosterone deficient men with untreated prostate cancer received testosterone therapy for a median of 2.5 years (range 1.0 to 8.1). Mean age was 58.8 years. Gleason score at initial biopsy was 6 in 12 men and 7 in 1. Mean serum concentration of total testosterone increased from 238 to 664 ng/dl (p <0.001). Mean prostate specific antigen did not change with testosterone therapy (5.5 ± 6.4 vs 3.6 ± 2.6 ng/ml, p = 0.29). Prostate volume was unchanged. Mean number of followup biopsies was 2. No cancer was found in 54% of followup biopsies. Biopsies in 2 men suggested upgrading, and subsequent biopsies in 1 and radical prostatectomy in another indicated no progression. No local prostate cancer progression or distant disease was observed. CONCLUSIONS Testosterone therapy in men with untreated prostate cancer was not associated with prostate cancer progression in the short to medium term. These results are consistent with the saturation model, ie maximal prostate cancer growth is achieved at low androgen concentrations. The longstanding prohibition against testosterone therapy in men with untreated or low risk prostate cancer or treated prostate cancer without evidence of metastatic or recurrent disease merits reevaluation.

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.

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth.

Androgen deprivation therapy reduces prostate cancer (PCa) tumour growth; however, disease relapse often ensues independently of androgen stimulation, producing androgen-refractory tumours with increased invasion, proliferation, and malignancy. Androgens downregulate epidermal growth factor receptor (EGFR) in normal prostate but not in PCa. Thus, loss of EGFR regulation and altered signalling may, in part, explain the transition of prostate tumours from androgen dependent to androgen independent. Studies in animal models, PCa cell lines, and tumour specimens suggest that androgens modulate prostate growth and function through mechanisms that involve ‘cross-talk’ between androgen receptor (AR) and growth factor receptor signalling pathways. The objective of this review is to discuss the paradoxical relationship between androgen regulation of EGFR in normal prostate and PCa. We reviewed the literature from mid-1980s through 2009 to assess the relationship between androgens and EGFR function in modulating the growth of normal prostate and PCa. Loss of androgen regulation of EGFR in PCa may be responsible for increased tumour growth, invasion, and metastasis, with important implications on the clinical management of PCa. We advance the hypothesis that a molecular switch, responsible for downregulating EGFR expression by androgens in the normal prostate, is either lost or modified in PCa.