Testosterone and Prostate Cancer – OK or not?

Dr Weeks’ Comment:

Dr. Morgentaler  on  Prostate Cancer and Testosterone

ReviewEur Urol. 2016 May;69(5):894-903. doi: 10.1016/j.eururo.2015.12.005. Epub 2015 Dec 21.Testosterone Therapy in Men With Prostate CancerAlan L Kaplan  1 , Jim C Hu  2 , Abraham Morgentaler  3 , John P Mulhall  4 , Claude C Schulman  5 , Francesco Montorsi  6Affiliations expandPMID: 26719015 PMCID: PMC5000551 DOI:10.1016/j.eururo.2015.12.005Free PMC articleAbstractContext: The use of testosterone therapy in men with prostate cancer was previously contraindicated, although recent data challenge this axiom. Over the past 2 decades, there has been a dramatic paradigm shift in beliefs, attitude, and treatment of testosterone deficiency in men with prostate cancer.Conclusions: An improved understanding of the negative effects of testosterone deficiency on health and health-related quality of life-and the ability of testosterone therapy to mitigate these effects-has triggered a re-evaluation of the role testosterone plays in prostate cancer. An important paradigm shift has occurred within the field, in which testosterone therapy may now be regarded as a viable option for selected men with prostate cancer suffering from testosterone deficiency.Patient summary: In this article, we review and summarize the existing literature surrounding the use of testosterone therapy in men with prostate cancer. Historically, testosterone was contraindicated in men with a history of prostate cancer. We show that this contraindication is unfounded and, with careful monitoring, its use is safe in that regard. 

 2ReviewJ Sex Med. 2011 Apr;8(4):946-55. doi: 10.1111/j.1743-6109.2011.02233.x.Is testosterone a friend or a foe of the prostate?Emmanuele A Jannini  1 , Giovanni L GravinaAbraham MorgentalerAlvaro MoralesLuca IncrocciWayne J G HellstromAffiliations expandPMID: 21457469 DOI: 10.1111/j.1743-6109.2011.02233.xErratum inJ Sex Med. 2011 May;8(5):1552. Mortengaler, Abraham [corrected to Morgentaler, Abraham]AbstractIntroduction: Is there any unequivocal evidence that testosterone (T) can stimulate growth and aggravate symptoms in men with locally advanced and metastatic prostate cancer (PCa)? This is not a controversial point: the answer is yes. However, this evidence does not imply that PCa is a result of T or therapy with T (TTh) of hypogonadal men. Furthermore, currently adequately powered and optimally designed long-term prostate disease data are not available to determine if there is an additional risk from normal T values in cured patients for PCa.Conclusions: It is evident that the issue is still controversial and much more research is needed. However, the available data suggest to the expert in sexual medicine that TTh can be cautiously considered in selected hypogonadal men previously treated for curative intent of low-risk PCa and without evidence of active disease. 

3Review. 2016 Mar;89:27-32. doi: 10.1016/j.urology.2015.11.034. Epub 2015 Dec 9.Controversies and Advances With Testosterone Therapy: A 40-Year PerspectiveAbraham Morgentaler  1Affiliations expandPMID: 26683750 DOI: 10.1016/j.urology.2015.11.034AbstractTestosterone therapy (TTh) has become highly controversial. There are important health consequences of testosterone deficiency, and meaningful benefits with treatment. There is level 1 evidence that TTh improves sexual function and desire, body composition, and bone density. Concerns regarding cardiovascular risk were based on two deeply flawed retrospective studies and are contradicted by dozens of studies showing cardiovascular benefits of TTh or higher endogenous testosterone, including placebo-controlled studies in men with known heart disease (angina, heart failure). Prostate cancer should no longer be considered a risk of TTh.Testosterone is neither scourge nor panacea–it is just good medicine.  

4Eur Urol. 2014 Jan;65(1):115-23. doi: 10.1016/j.eururo.2013.08.015. Epub 2013 Aug 16.A new era of testosterone and prostate cancer: from physiology to clinical implicationsMohit Khera  1 , David CrawfordAlvaro MoralesAndrea SaloniaAbraham MorgentalerAffiliations expandPMID: 24011426 DOI: 10.1016/j.eururo.2013.08.015AbstractContext: 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.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. 

5 ReviewSex Med Rev. 2019 Oct;7(4):636-649. doi: 10.1016/j.sxmr.2019.06.003. Epub 2019 Jul 24.Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual MedicineAbraham Morgentaler  1 , Abdulmaged Traish  2 , Geoffrey Hackett  3 , T Hugh Jones  4 , Ranjith Ramasamy  5Affiliations expandPMID: 31351915 DOI: 10.1016/j.sxmr.2019.06.003 Introduction: The International Consultation for Sexual Medicine met in Lisbon in 2018 to review updated recommendations regarding testosterone deficiency (TD) and its treatment.Results: The terms “testosterone deficiency” (TD) and “testosterone therapy” (TTh) were endorsed over numerous competing terms. The wide interindividual variability of sex hormone binding globulin concentrations influences the interpretation of total T concentrations. Symptoms of T deficiency more closely follow free T than total T concentrations. Symptomatic men with total T <350 ng/dL or free T <65-100 pg/mL may reasonably undergo a trial of T therapy. An empirical 6-month trial of TTh may be considered in men with strongly suggestive symptoms and values above these thresholds. Morning blood testing is indicated in men <40 years of age. Men >40 years may undergo initial afternoon testing, as long as confirmatory morning blood tests are later obtained. High-level evidence demonstrates TTh in men with TD improves sexual desire and erectile function. The weight of evidence indicates that TTh is not associated with increased risk of prostate cancer, cardiovascular events, or worsening lower urinary tract symptoms. Bone density and anemia are improved with TTh. Obesity and type 2 diabetes are associated with TD, and TTh provides consistent improvement in metabolic parameters. Multiple safe and effective therapeutic options are available to treat men with TD. Conclusions: Treatment of TD offers multiple benefits for sexual symptoms as well as for general health, without compelling evidence for increased risk of prostate cancer or cardiovascular events. Morgentaler A, Traish A, Hackett G, et al. Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine. Sex Med Rev 2019;7:636-649. 

6 ReviewSex Med Rev. 2020 Apr;8(2):286-296. doi: 10.1016/j.sxmr.2018.03.002. Epub 2018 Apr 13.The History of Testosterone and the Evolution of its Therapeutic PotentialAbraham Morgentaler  1 , Abdulmaged Traish  2Affiliations expandPMID: 29661690 DOI: 10.1016/j.sxmr.2018.03.002AbstractIntroduction: Testosterone therapy has been controversial since its synthesis in the 1930s to the present day. Testosterone’s history provides depth and context for current controversies.Aim: To review the history of testosterone therapy from its initial synthesis in the 1930s to the modern day.Results: By the 1940s there was already a fascinating literature that described the many symptomatic benefits of testosterone therapy that are recognized today. Numerous early reports suggested testosterone therapy improved angina pectoris and peripheral vascular disease. The assertion by Huggins and Hodges (Cancer Res 1941;1:293-297) in 1941 that testosterone activated prostate cancer (PCa) cast a pall for the next 70 years. The introduction of the radioimmunoassay in the 1970s shifted the diagnosis of testosterone deficiency from signs and symptoms to an undue emphasis on blood test results. The fear of PCa was the primary obstacle to the adoption of testosterone therapy for decades. Prescription rates increased as accumulated evidence showed testosterone therapy was not associated with increased PCa risks. The observation that androgenic stimulation of PCa reaches a maximum at relatively low testosterone concentrations-the saturation model-provided the theoretical framework for understanding the relation between androgens and PCa and led to multiple case series documenting reassuring results of testosterone therapy in men with PCa. Recent concerns regarding cardiovascular risks also have diminished because new evidence suggests testosterone therapy might actually be cardioprotective. In 2016 the Testosterone Trials provided high-quality evidence of multiple benefits of testosterone therapy, nearly all of which had been recognized by clinicians by 1940.Conclusions: If the past has any lessons for the future, it is likely that research will continue to demonstrate health benefits of testosterone therapy, while it remains one of the most controversial topics in medicine.  Morgentaler A, Traish A. The History of Testosterone and the Evolution of its Therapeutic Potential. Sex Med Rev 2020;8:286-296. 

7 Eur Urol Focus. 2017 Oct;3(4-5):316-318. doi: 10.1016/j.euf.2017.09.007. Epub 2017 Oct 5.Testosterone Therapy in a Man with Intermediate-risk Prostate Cancer: ProAbraham Morgentaler  1Affiliations expandPMID: 28988938 DOI: 10.1016/j.euf.2017.09.007AbstractThe original prohibition of testosterone therapy for men with prostate cancer was based on outdated concepts developed more than 70 yr ago. Current evidence, although limited, provides consistently reassuring results that testosterone therapy may be reasonably offered to many men with prostate cancer. These men may experience valuable benefits in quality of life if they suffer from symptoms of testosterone deficiency (hypogonadism). 

8 ReviewExpert Opin Drug Saf. 2019 Nov;18(11):1065-1076. doi: 10.1080/14740338.2019.1666103. Epub 2019 Sep 18.Safety of testosterone therapy in men with prostate cancerAbraham Morgentaler  1 , Monica Caliber  2Affiliations expandPMID: 31495240 DOI: 10.1080/14740338.2019.1666103AbstractIntroduction: The use of testosterone therapy (TTh) in men with prostate cancer (PCa) is relatively new, and controversial, due to the longstanding maxim that TTh is contraindicated in men with PCa. Scientific advances have prompted a reevaluation of the potential role for TTh in men with PCa, particularly as TTh has been shown to provide important symptomatic and general health benefits to men with testosterone deficiency (TD), including many men with PCa who may expect to live 30-50 years after diagnosis. Areas covered: This review outlines the historical underpinnings of the historical belief that TTh ‘fuels’ PCa and the experimental and clinical studies that have radically altered this view, including description of the saturation model. The authors review studies of TTh in men with PCa following radical prostatectomy and radiation therapy, in men on active surveillance, and in men with advanced or metastatic PCa. Expert opinionTTh provides important symptomatic and overall health benefits for men with PCa who have TD. Although more safety studies are needed, TTh is a reasonable therapeutic option for men with low-risk PCa after surgery or radiation. Data in men on active surveillance are limited, but initial reports are reassuring.  

9 Review Am J Med. 2011 Jul;124(7):578-87. doi: 10.1016/j.amjmed.2010.12.027.Testosterone deficiencyAbdulmaged M Traish  1 , Martin M MinerAbraham MorgentalerMichael ZitzmannAffiliations expandPMID: 21683825 DOI: 10.1016/j.amjmed.2010.12.027AbstractTestosterone deficiency (TD) afflicts approximately 30% of men aged 40-79 years, with an increase in prevalence strongly associated with aging and common medical conditions including obesity, diabetes, and hypertension. A strong relationship is noted between TD and metabolic syndrome, although the relationship is not certain to be causal. Repletion of testosterone (T) in T-deficient men with these comorbidities may indeed reverse or delay their progression. While T repletion has been largely thought of in a sexual realm, we discuss its potential role in general men’s health concerns: metabolic, body composition, and all-cause mortality through the use of a single clinical vignette. This review examines a host of studies, with practical recommendations for diagnosis of TD and T repletion in middle-aged and older men, including an analysis of treatment modalities and areas of concerns and uncertainty.   

10 Review Urol Clin North Am. 2016 May;43(2):209-16. doi: 10.1016/j.ucl.2016.01.007.Testosterone Therapy and Prostate CancerEmily Davidson  1 , Abraham Morgentaler  2Affiliations expandPMID: 27132578 DOI: 10.1016/j.ucl.2016.01.007AbstractChanges in understanding regarding the relationship of androgens and prostate cancer have led to changes in the use of testosterone therapy. The evidence supports a finite ability of androgens to stimulate prostate cancer growth, with a maximum achieved at low testosterone concentrations, called the saturation model. The saturation point corresponds with maximal androgenic stimulation at 250 ng/dL. Evidence is reviewed herein regarding the relationship of testosterone to prostate cancer and the relatively new practice of offering testosterone therapy to men with a history of prostate cancer. Although no prospective controlled trials have been performed, results have been reassuring.  

11 J Sex Med. 2008 Aug;5(8):1834-40. doi: 10.1111/j.1743-6109.2008.00889.x. Epub 2008 Jun 10.Guilt by association: a historical perspective on Huggins, testosterone therapy, and prostate cancerAbraham Morgentaler  1Affiliations expandPMID: 18547385 DOI: 10.1111/j.1743-6109.2008.00889.xAbstractIntroduction: A long-standing belief is that higher testosterone (T) will increase the risk of prostate cancer (PCa), yet recent studies do not support this view.Aim: To identify the key historical and scientific events leading to the establishment and persistence of the belief in a T-dependent model of PCa growth, despite evidence to the contrary.Conclusions: The fear that higher T will increase PCa growth stems from a theory of T-dependent PCa growth that originated with observations in a special population (castrated men) that is not particularly relevant to T therapy in hypogonadal men. The negative view of T with regard to PCa should be recognized for what it is–guilt by association.

12 Review Eur Urol. 2009 Jul;56(1):48-56. doi: 10.1016/j.eururo.2009.03.088. Epub 2009 Apr 8.Testosterone and prostate cancer: revisiting old paradigmsHendrik Isbarn  1 , Jehonathan H PinthusLeonard S MarksFrancesco MontorsiAlvaro MoralesAbraham MorgentalerClaude SchulmanAffiliations expandPMID: 19375844 DOI: 10.1016/j.eururo.2009.03.088AbstractContext: 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.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.  

13 Review Eur Urol. 2006 Nov;50(5):935-9. doi: 10.1016/j.eururo.2006.06.034. Epub 2006 Jul 27.Testosterone and prostate cancer: an historical perspective on a modern mythAbraham Morgentaler  1Affiliations expandPMID: 16875775 DOI: 10.1016/j.eururo.2006.06.034AbstractObjectives: To review the historical origins and current evidence for the belief that testosterone (T) causes prostate cancer (pCA) growth.Conclusions: This historical perspective reveals that there is not now-nor has there ever been-a scientific basis for the belief that T causes pCA to grow. Discarding this modern myth will allow exploration of alternative hypotheses regarding the relationship of T and pCA that may be clinically and scientifically rewarding. 

14 Revie wJ Urol. 2013 Jan;189(1 Suppl):S26-33. doi: 10.1016/j.juro.2012.11.028.Testosterone therapy in men with prostate cancer: scientific and ethical considerationsAbraham Morgentaler  1Affiliations expandPMID: 23234627 DOI: 10.1016/j.juro.2012.11.028 Abstract Conclusions: Although no controlled studies have been performed to date to document the safety of testosterone therapy in men with prostate cancer, the limited available evidence suggests that such treatment may not pose an undue risk of prostate cancer recurrence or progression.  

15 Review J Clin Med. 2018 Dec 14;7(12):549. doi: 10.3390/jcm7120549.Do Androgens Modulate the Pathophysiological Pathways of Inflammation? Appraising the Contemporary EvidenceAbdulmaged Traish  1 , Jose Bolanos  2 , Sunil Nair  3 , Farid Saad  4   5 , Abraham Morgentaler  6Affiliations expandPMID: 30558178 PMCID: PMC6306858 DOI:10.3390/jcm7120549Free PMC articleAbstractThe role of testosterone in the pathophysiology of inflammation is of critical clinical importance; however, no universal mechanism(s) has been advanced to explain the complex and interwoven pathways of androgens in the attenuation of the inflammatory processes. PubMed and EMBASE searches were performed, including the following key words: “testosterone”, “androgens”, “inflammatory cytokines”, “inflammatory biomarkers” with focus on clinical studies as well as basic scientific studies in human and animal models. Significant benefits of testosterone therapy in ameliorating or attenuating the symptoms of several chronic inflammatory diseases were reported. Because anti-tumor necrosis factor therapy is the mainstay for the treatment of moderate-to-severe inflammatory bowel disease; including Crohn’s disease and ulcerative colitis, and because testosterone therapy in hypogonadal men with chronic inflammatory conditions reduce tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6, we suggest that testosterone therapy attenuates the inflammatory process and reduces the burden of disease by mechanisms inhibiting inflammatory cytokine expression and function. Mechanistically, androgens regulate the expression and function of inflammatory cytokines, including TNF-α, IL-1β, IL-6, and CRP (C-reactive protein). Here, we suggest that testosterone regulates multiple and overlapping cellular and molecular pathways involving a host of immune cells and biochemical factors that converge to contribute to attenuation of the inflammatory process.  

16 Review Asian J Androl. Mar-Apr 2015;17(2):206-11. doi: 10.4103/1008-682X.148067.Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendationsAbraham Morgentaler 3rd  1 , William P ConnersAffiliations expandPMID: 25652633 PMCID: PMC4650486 DOI: 10.4103/1008-682X.148067 Free PMC article Abstract For several decades any diagnosis of prostate cancer (PCa) has been considered an absolute contraindication to the use of testosterone (T) therapy in men. Yet this prohibition against T therapy has undergone recent re-examination with refinement of our understanding of the biology of androgens and PCa, and increased appreciation of the benefits of T therapy. A reassuringly low rate of negative outcomes has been reported with T therapy after radical prostatectomy (RP), radiation treatments, and in men on active surveillance. Although the number of these published reports are few and the total number of treated men is low, these experiences do provide a basis for consideration of T therapy in selected men with PCa. For clinicians considering offering this treatment, we recommend first selecting patients with low grade cancers and undetectable prostate-specific antigen following RP. Further research is required to define the safety of T therapy in men with PCa. However, many patients symptomatic from T deficiency are willing to accept the potential risk of PCa progression or recurrence in return for the opportunity to live a fuller and happier life with T therapy. 

17 Review J Urol. 2009 Mar;181(3):972-9. doi: 10.1016/j.juro.2008.11.031. Epub 2009 Jan 16.Testosterone therapy in men with prostate cancer: scientific and ethical considerationsAbraham Morgentaler  1Affiliations expandPMID: 19150547 DOI: 10.1016/j.juro.2008.11.031AbstractPurpose: Pertinent literature regarding the potential use of testosterone therapy in men with prostate cancer is reviewed and synthesized.Conclusions: Although no controlled studies have been performed to date to document the safety of testosterone therapy in men with prostate cancer, the limited available evidence suggests that such treatment may not pose an undue risk of prostate cancer recurrence or progression.  

18 Review ScientificWorldJournal. 2009 Jul 27;9:685-90. doi: 10.1100/tsw.2009.80.Rapidly shifting concepts regarding androgens and prostate cancerAbraham Morgentaler  1Affiliations expandPMID: 19649507 PMCID: PMC5823199 DOI:10.1100/tsw.2009.80Free PMC articleAbstractThere has been a recent dramatic shift in our understanding of the relationship between androgens and prostate cancer (PCa). Whereas for several decades it had been assumed that higher serum testosterone (T) concentrations would lead to ever-greater PCa growth, current literature indicates that PCa growth is unaffected by changes in serum T throughout most of the naturally occurring range. A Saturation Model has been proposed to explain how prostate tissue can be exquisitely sensitive to changes in serum T at the very low end of the concentration range, but appears indifferent to such changes above the near-castrate range. This has special applicability to T-deficient men, since this means that T therapy may not be nearly as risky as once assumed. Indeed, one of the more interesting changes over the last several years has been the growing acceptance of the use of T therapy in men with a prior history of PCa, with early data indicating minimal risk of cancer recurrence or progression. Provocative new evidence suggests that it is not high serum T that is problematic for PCa, but low serum T that is associated with worrisome cancer features and outcomes, such as high Gleason score, advanced stage of presentation, and increased risk of biochemical recurrence after surgery. It will be interesting to see what changes will occur in this rapidly changing field over the next several years. 

19 Review Urol Clin North Am. 2011 May;38(2):119-24. doi: 10.1016/j.ucl.2011.02.002. Epub 2011 Apr 13.Testosterone and prostate cancer: what are the risks for middle-aged men?Abraham Morgentaler  1Affiliations expandPMID: 21621078 DOI: 10.1016/j.ucl.2011.02.002AbstractWith increased recognition of the benefits of testosterone (T) therapy for middle-aged men, there has been a concomitant reexamination of the historical fear that raising T will result in more prostate cancer (PCa). Studies have failed to show increased risk of PCa in men with higher serum T, and supraphysiologic T fails to increase prostate volume or prostate-specific antigen in healthy men. This apparent paradox is explained by the Saturation Model, which posits a finite capacity of androgen to stimulate PCa growth. Modern studies indicate no increased risk of PCa among men with serum T in the therapeutic range. 

20 Review Curr Treat Options Oncol. 2006 Sep;7(5):363-9. doi: 10.1007/s11864-006-0004-y.Testosterone therapy for men at risk for or with history of prostate cancerAbraham Morgentaler  1Affiliations expandPMID: 16904053 DOI: 10.1007/s11864-006-0004-yAbstractSince the early 1940s when Huggins showed that severe reductions in serum testosterone by castration or estrogen therapy caused regression of prostate cancer (PCa), it has been assumed that higher testosterone levels cause enhanced growth of PCa. For this reason, it has been considered taboo to offer testosterone replacement therapy (TRT) to any man with a prior history of PCa, even if all objective evidence suggests he has been cured. The fear has been that higher testosterone levels would “awaken” dormant cells and cause a recurrence. Thus, US Food and Drug Administration-mandated language in all testosterone package inserts states that testosterone is contraindicated in men with a history of, or suspected of having, PCa. Although there is little modern experience with administration of testosterone in men with known history of PCa, there is a varied and extensive literature indicating that TRT does not pose any increased risk of PCa growth in men with or without prior treatment. For instance, the cancer rate in TRT trials is only approximately 1%, similar to detection rates in screening programs, yet biopsy-detectable PCa is found in one of seven hypogonadal men. Moreover, PCa is almost never seen in the peak testosterone years of the early 20s, despite autopsy evidence that men in this age group already harbor microfoci of PCa in substantial numbers. The growing number of PCa survivors who happen to be hypogonadal and request treatment has spurred a change in attitude toward this topic, with increasing numbers of physicians now offering TRT to men who appear cured of their disease. Publications have now reported no prostate-specific antigen (PSA) recurrence with TRT in small numbers of men who had undetectable PSA values after radical prostatectomy. Although still controversial, there appears to be little reason to withhold TRT from men with favorable outcomes after definitive treatment for PCa. Monitoring with PSA and digital rectal examination at regular intervals is recommended. 

21 Case Reports J Sex Med. 2009 Feb;6(2):574-7. doi: 10.1111/j.1743-6109.2008.01066.x.Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancerAbraham Morgentaler  1Affiliations expandPMID: 19215619 DOI: 10.1111/j.1743-6109.2008.01066.xAbstractIntroduction: Testosterone (T) therapy has long been considered contraindicated in men with prostate cancer (PCa). However, the traditional view regarding the relationship of T to PCa has come under new scrutiny, with recent reports suggesting that PCa growth may not be greatly affected by variations in serum T within the near-physiologic range.Results: An 84-year-old man was seen for symptoms of hypogonadism, with serum total T within the normal range at 400 ng/dL, but with a reduced free T of 7.4 pg/mL (radioimmunoassay [RIA], reference range 10.0-55.0). PSA was 8.5 ng/mL, and 8.1 ng/mL when repeated. Prostate biopsy revealed Gleason 6 cancer in both lobes. He refused treatment for PCa, but requested T therapy, which was initiated with T gel after informed consent regarding possible cancer progression. Serum T increased to a mean value of 699 ng/dL and free T to 17.1 pg/mL. PSA declined to a nadir of 5.2 ng/mL at 10 months, increased slightly to 6.2 ng/mL at 21 months, and then declined to 3.8 ng/mL at 24 months after addition of dutasteride for voiding symptoms. No clinical PCa progression was noted.Conclusion: A decline in PSA was noted in a man with untreated PCa who received T therapy for 2 years. This case provides support for the notion that PCa growth may not be adversely affected by changes in serum T beyond the castrate or near-castrate range. 22ReviewCan J Urol. 2006 Feb;13 Suppl 1:40-3.Testosterone replacement therapy and prostate risks: where’s the beef?Abraham Morgentaler  1Affiliations expandPMID: 16526980AbstractIt has been part of the conventional medical wisdom for six decades that higher testosterone in some way increases the risk of prostate cancer. This belief is derived largely from the well-documented regression of prostate cancer in the face of surgical or pharmacological castration. However, there is an absence of scientific data supporting the concept that higher testosterone levels are associated with an increased risk of prostate cancer. Specifically, no increased risk of prostate cancer was noted in 1) clinical trials of testosterone supplementation, 2) longitudinal population-based studies, or 3) in a high-risk population of hypogonadal men receiving testosterone treatment.Moreover, hypogonadal men have a substantial rate of biopsy-detectable prostate cancer, suggesting that low testosterone has no protective effect against development of prostate cancer. These results argue against an increased risk of prostate cancer with testosterone replacement therapy. 

23 Review Front Horm Res. 2009;37:197-203. doi: 10.1159/000176054.Testosterone and prostate safetyA Morgentaler  1 , C SchulmanAffiliations expandPMID: 19011298 DOI: 10.1159/000176054AbstractFor several decades it has been assumed that higher testosterone (T) leads to greater growth of benign and malignant prostate tissue, but this view has come under greater scrutiny over the last several years. Although there are as yet no large-scale, long-term controlled studies of T therapy to provide a definitive assessment of risk, numerous smaller clinical trials as well as population-based longitudinal studies consistently fail to support the historical idea that T therapy poses an increased risk of prostate cancer or exacerbation of symptoms due to benign prostatic hyperplasia. This lack of prostate risk despite increased serum T appears to be explained by data showing that exogenous T does not raise intraprostatic concentrations of T or dihydrotestosterone, suggesting a saturation model. In contrast, there is mounting evidence that low serum T is associated with greater prostate cancer risk, and more worrisome features of prostate cancer. In conclusion, the available evidence strongly suggests that T therapy is safe for the prostate. Given that the population at risk for T deficiency overlaps with the population at risk for prostate cancer, it is strongly recommended that men undergoing T therapy undergo regular monitoring for prostate cancer.

24 Review Eur Urol. 2009 Feb;55(2):310-20. doi: 10.1016/j.eururo.2008.09.024. Epub 2008 Sep 24.Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growthAbraham Morgentaler  1 , Abdulmaged M TraishAffiliations expandPMID: 18838208 DOI: 10.1016/j.eururo.2008.09.024AbstractContext: 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.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. 

25 Review Endocr Pract. 2008 Oct;14(7):904-11. doi: 10.4158/EP.14.7.904.Does testosterone therapy increase the risk of prostate cancer?Adrian S Dobs  1 , Abraham MorgentalerAffiliations expandPMID: 18996823 DOI: 10.4158/EP.14.7.904AbstractConclusions: Mounting evidence demonstrates that there is a lack of association between testosterone therapy and prostate cancer progression. Testosterone therapy may be prescribed for men for whom it was once not considered. Careful monitoring of patients with hypogonadism who are receiving testosterone therapy is imperative. Well-designed, large-scale prospective clinical trials are necessary to adequately address prostate safety in hypogonadal men receiving testosterone therapy.  

26 Asian J Androl. Jan-Feb 2016;18(1):16-20. doi: 10.4103/1008-682X.160270.Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary resultsRavi Kacker  1 , Mariam HultIgnacio F San FranciscoWilliam P ConnersPablo A RojasWilliam C DewolfAbraham MorgentalerAffiliations expandPMID: 26306850 PMCID: PMC4736350 DOI: 10.4103/1008-682X.160270Free PMC articleAbstractThis report presents our experience with T therapy in a cohort of T-deficient men on active surveillance (AS) for Gleason 3 + 3 and Gleason 3 + 4 prostate cancer (PCa). A retrospective chart review identified 28 men with T deficiency who underwent T therapy (T group) for at least 6 months while on AS for PCa. A comparison group of 96 men on AS for PCa with untreated T deficiency (no-T group) was identified at the same institution. The AS protocol followed a modified Epstein criteria and allowed inclusion of men with a single core of low-volume Gleason 3 + 4 PCa. Mean age was 59.5 and 61.3 years, and mean follow-up was 38.9 and 42.4 months for the T and no-T groups, respectively. Of all 28 men in the T group, 3 (10.7%) men developed an increase in Gleason score while on AS. Of 22 men in the T group with Gleason 3 + 3 disease, 7 (31.8%) men developed biopsy progression including 3 men (13.6%) who developed Gleason 3 + 4 PCa. Of 6 men with Gleason 3 + 4 disease at baseline, 2 (33.3%) men developed an increase in tumor volume, and none developed upgrading beyond Gleason 3 + 4. All 96 men in the no-T group had Gleason 3 + 3 disease at baseline and, 43 (44.7%) developed biopsy progression, including 9 men (9.38%) with upgrading to Gleason 7 (3 + 4). Biopsy progression rates were similar for both groups and historical controls. Biopsy progression in men on AS appears unaffected by T therapy over 3 years. Prospective placebo-controlled trials of T therapy in T-deficient men on AS should be considered given the symptomatic benefits experienced by treated men.  

27 Urol Clin North Am. 2007 Nov;34(4):555-63, vii. doi: 10.1016/j.ucl.2007.08.002.Testosterone replacement therapy and prostate cancerAbraham Morgentaler  1Affiliations expandPMID: 17983895 DOI: 10.1016/j.ucl.2007.08.002AbstractThe long-standing concern that testosterone replacement therapy (TRT) may increase the risk of prostate cancer (PCa) has come under new scrutiny. Arguments used to support this concern lack a scientific basis. The original assertion by Huggins that administration of testosterone (T) caused “enhanced growth” of PCa was based on only a single patient. New evidence suggests that TRT has little, if any, negative impact on the prostate, even in men with a history of PCa. A saturation model is proposed that is consistent with regression of cancer when T is reduced to castrate levels and with lack of observed growth when serum T is increased. 

28 Urology. 2006 Dec;68(6):1263-7. doi: 10.1016/j.urology.2006.08.1058.Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or lessAbraham Morgentaler  1 , Ernani Luis RhodenAffiliations expandPMID: 17169647 DOI: 10.1016/j.urology.2006.08.1058AbstractResults: Cancer was identified in 15.1%. The cancer detection rate was 5.6%, 17.5%, 26.4%, and 36.4% for a PSA level of 1.0 or less, 1.1 to 2.0, 2.1 to 3.0, and 3.1 to 4.0 ng/mL, respectively (P < 0.05). Cancer was detected in 26 (30.2%) of 86 men with a PSA level of 2.0 to 4.0 ng/mL. Cancer was detected in 21% of men with a testosterone level of 250 ng/dL or less compared with 12% of men with a testosterone level greater than 250 ng/dL (P = 0.04). Men with free testosterone levels of 1.0 ng/dL or less had a cancer rate of 20% compared with 12% for men with greater values (P = 0.04). The odds ratio of cancer detection for men in the lowest tertile compared with the highest tertile was 2.15 (95% confidence interval 1.01 to 4.55) for total testosterone and 2.26 (95% confidence interval 1.07 to 4.78) for free testosterone.Conclusions: Prostate cancer was present in more than 1 of 7 hypogonadal men with PSA of 4.0 ng/mL or less. An increased risk of prostate cancer was associated with more severe reductions in testosterone. 

29 Multicenter Study J Urol. 2015 Nov;194(5):1271-6. doi: 10.1016/j.juro.2015.05.084. Epub 2015 May 27.Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate CancerAlexander W Pastuszak  1 , Abhinav Khanna  2 , Niraj Badhiwala  3 , Abraham Morgentaler  4 , Mariam Hult 4 , William P Conners  4 , Michael F Sarosdy  5 , Christopher Yang  6 , Rafael Carrion  6 , Larry I Lipshultz  1 , Mohit Khera  7Affiliations expandPMID: 26025500 DOI: 10.1016/j.juro.2015.05.084AbstractPurpose: Limited literature exists regarding the safety of testosterone therapy in men treated for prostate cancer. We present multi-institutional data on testosterone therapy in hypogonadal men with prostate cancer treated with radiation therapy.Conclusions: Testosterone therapy in men following radiation therapy for prostate cancer was associated with a minor increase in serum prostate specific antigen and a low rate of biochemical recurrence.  

30 J Urol. 2000 Mar;163(3):824-7.Is low serum free testosterone a marker for high grade prostate cancer?M A Hoffman  1 , W C DeWolfA MorgentalerAffiliations expandPMID: 10687985AbstractPurpose: 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.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. 

31 BJU Int. 2014 Aug;114(2):229-35. doi: 10.1111/bju.12682. Epub 2014 May 4.Low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillanceIgnacio F San Francisco  1 , Pablo A RojasWilliam C DeWolfAbraham MorgentalerAffiliations expandPMID: 24898919 DOI: 10.1111/bju.12682AbstractConclusions: Free testosterone levels were lower in men with PCa who had reclassification during AS. Men with moderately severe reductions in free testosterone level are at increased risk of disease reclassification. 

32 Practice Guideline J Sex Med. 2017 Mar;14(3):285-296. doi: 10.1016/j.jsxm.2016.11.325.Sexual Rehabilitation After Treatment for Prostate Cancer-Part 1: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015)Andrea Salonia  1 , Ganesh Adaikan  2 , Jacques Buvat  3 , Serge Carrier  4 , Amr El-Meliegy  5 , Kostas Hatzimouratidis  6 , Andrew McCullough  7 , Abraham Morgentaler  8 , Luiz Otavio Torres  9 , Mohit Khera  10Affiliations expandPMID: 28262099 DOI: 10.1016/j.jsxm.2016.11.325AbstractIntroduction: Sexual dysfunction is common in patients after radical prostatectomy (RP) for prostate cancer.Aim: To provide the International Consultation for Sexual Medicine (ICSM) 2015 recommendations concerning prevention and management strategies for post-RP erectile function impairment in terms of preoperative patient characteristics and intraoperative factors that could influence erectile function recovery.Conclusions: This article discusses Recommendations 1 to 5 of the ICSM 2015 committee on sexual rehabilitation after RP. Salonia A, Adaikan G, Buvat J, et al. Sexual Rehabilitation After Treatment for Prostate Cancer-Part 1: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med 2017;14:285-296.

33 J Urol. 2011 Apr;185(4):1256-60. doi: 10.1016/j.juro.2010.11.084. Epub 2011 Feb 22.Testosterone therapy in men with untreated prostate cancerAbraham Morgentaler  1 , Larry I LipshultzRichard BennettMichael SweeneyDesiderio Avila JrMohit KheraAffiliations expandPMID: 21334649 DOI: 10.1016/j.juro.2010.11.084AbstractPurpose: 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.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. 

34 J Urol. 2008 May;179(5):1741-4. doi: 10.1016/j.juro.2008.01.045. Epub 2008 Mar 17.The ratio of serum testosterone-to-prostate specific antigen predicts prostate cancer in hypogonadal menErnani Luis Rhoden  1 , Charles Edison RiednerAbraham MorgentalerAffiliations expandPMID: 18343420 DOI: 10.1016/j.juro.2008.01.045AbstractPurpose: We determined whether the ratio of serum testosterone to prostate specific antigen might provide diagnostic value regarding the risk of prostate cancer in a population of hypogonadal men undergoing prostate biopsy.Conclusions: A low ratio of testosterone to prostate specific antigen is an independent predictor of prostate cancer in hypogonadal men with prostate specific antigen 4.0 ng/ml or less. Ratios less than 1.8 were associated with a greater than 3-fold increase in prostate cancer risk.  

35 JAMA. 1996 Dec 18;276(23):1904-6.Occult prostate cancer in men with low serum testosterone levelsA Morgentaler  1 , C O Bruning 3rdW C DeWolfAffiliations expandPMID: 8968017AbstractConclusions: A high prevalence of biopsy-detectable prostate cancer was identified in men with low total or free testosterone levels despite normal PSA levels and results of digital rectal examination. These data suggest that (1) digital rectal examination and PSA levels are insensitive indicators of prostate cancer in men with low total or free testosterone levels, and (2) PSA levels may be altered by naturally occurring reductions in serum androgen levels.  

36 J Urol. 2003 Nov;170(5):2101-3. doi: 10.1097/01.ju.0000091827.97826.57. Effects of chronic administration of dehydroepiandrosterone on serum testosterone levels and prostatic tissue in ratsErnani Luis Rhoden  1 , Daniel GobbiClaudia Ramos RhodenEduardo MentiAdriane Nial RoeheAntonio HartmannAbraham MorgentalerAffiliations expandPMID: 14532863 DOI: 10.1097/01.ju.0000091827.97826.57AbstractPurpose: We evaluated the effects of chronic administration of dehydroepiandrosterone (DHEA) on serum total testosterone and DHEA sulfate (DHEAS), prostatic weight and histological features in the rat.Results: At the end of the 10-month study period total testosterone levels were higher in the DHEA group compared with controls (2.0 +/- 0.4 vs 0.8 +/- 0.2 mg/dl, p <0.0001) and DHEAS levels were also greater in the treated group compared with placebo (222.1 +/- 41.5 vs 2.0 +/- 0.3 mg/dl, p <0.0001). Weight of the prostate, testis and body did not differ between the groups (p >0.05). No differences between the 2 groups were noted in regard to the degree of hyperplasia, atrophy, a papillary component or the stromal-to-gland ratio (p >0.05).Conclusions: Oral ingestion of DHEA on a chronic basis in the rat increases serum DHEAS and total testosterone without any evident change in prostate weight or histology
1:  Association of low testosterone with changes in non-cardiovascular biomarkers in adult men
Michael Samoszuk, Abraham Morgentaler, Mark de Groot, Wouter van Solinge, Yu Li, Fiona Adair, Imo Hoefer, Saskia Haitjema
Int J Impot Res. 2020; 32(2): 167–175.  Published online 2019 Jan 22. doi: 10.1038/s41443-019-0112-4
PMCID: PMC7066050

2:  Testosterone Therapy in Men With Prostate Cancer
Alan L. Kaplan, Jim C. Hu, Abraham Morgentaler, John P. Mulhall, Claude C. Schulman, Francesco Montorsi
Eur Urol. Author manuscript; available in PMC 2017 May 1.Published in final edited form as: Eur Urol. 2016 May; 69(5): 894–903. Published online 2015 Dec 21.  doi: 10.1016/j.eururo.2015.12.005
PMCID: PMC5000551

3:  Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men
Bruno Lunenfeld, George Mskhalaya, Michael Zitzmann, Stefan Arver, Svetlana Kalinchenko, Yuliya Tishova, Abraham Morgentaler
Aging Male. 2015 Mar; 18(1): 5–15.  Published online 2015 Feb 6. doi: 10.3109/13685538.2015.1004049
PMCID: PMC4648196

4:  Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations
Abraham Morgentaler, William P Conners III
Asian J Androl. 2015 Mar-Apr; 17(2): 206–211.  Published online 2015 Jan 27. doi: 10.4103/1008-682X.148067
PMCID: PMC4650486

5:  Testosterone deficiency and cardiovascular mortality
Abraham Morgentaler
Asian J Androl. 2015 Jan-Feb; 17(1): 26–31.  Published online 2014 Nov 18. doi: 10.4103/1008-682X.143248
PMCID: PMC4291871

6:  Rapidly Shifting Concepts Regarding Androgens and Prostate Cancer
Abraham Morgentaler
ScientificWorldJournal. 2009; 9: 685–690.  Published online 2009 Jul 27. doi: 10.1100/tsw.2009.80
PMCID: PMC5823199

7:  International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women
Sharon J. Parish, James A. Simon, Susan R. Davis, Annamaria Giraldi, Irwin Goldstein, Sue W. Goldstein, Noel N. Kim, Sheryl A. Kingsberg, Abraham Morgentaler, Rossella E. Nappi, Kwangsung Park, Cynthia A. Stuenkel, Abdulmaged M. Traish, Linda Vignozzi
J Womens Health (Larchmt)  April 2021; 30(4): 474–491.  Published online 2021 Apr 19. doi: 10.1089/jwh.2021.29037
PMCID: PMC8064950

8:  Letter to the editor: Questioning the evidence behind the Saturation Model for testosterone replacement therapy in prostate cancer
Abraham Morgentaler, Abdulmaged M. Traish
Investig Clin Urol. 2020 Jul; 61(4): 452–454.  Published online 2020 Jun 29. doi: 10.4111/icu.2020.61.4.452
PMCID: PMC7329646

9:  Successful treatment of Post-orgasmic illness syndrome with human chorionic gonadotropin
Jose Bolanos, Abraham Morgentaler
Urol Case Rep. 2020 Mar; 29: 101078.  Published online 2019 Nov 22. doi: 10.1016/j.eucr.2019.101078
PMCID: PMC6889685

10:  Do Androgens Modulate the Pathophysiological Pathways of Inflammation? Appraising the Contemporary Evidence
Abdulmaged Traish, Jose Bolanos, Sunil Nair, Farid Saad, Abraham Morgentaler
J Clin Med. 2018 Dec; 7(12): 549.  Published online 2018 Dec 14. doi: 10.3390/jcm7120549
PMCID: PMC6306858

11:  Nerve growth factor as a new treatment for testosterone deficiency?
Abraham Morgentaler
EBioMedicine. 2018 Oct; 36: 10–11.  Published online 2018 Sep 22. doi: 10.1016/j.ebiom.2018.09.017
PMCID: PMC6197311

12:  Overselling hysteria: The role of the media and medical journals in promoting questionable risks—a case study of the testosterone controversy
Abdulmaged M Traish, Jay C Vance, Abraham Morgentaler
EMBO Rep. 2017 Jan; 18(1): 11–17.  Published online 2016 Dec 5. doi: 10.15252/embr.201643642
PMCID: PMC5210128

13:  Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results
Ravi Kacker, Mariam Hult, Ignacio F San Francisco, William P Conners, Pablo A Rojas, William C Dewolf, Abraham Morgentaler
Asian J Androl. 2016 Jan-Feb; 18(1): 16–20.  Published online 2015 Aug 21. doi: 10.4103/1008-682X.160270
PMCID: PMC4736350

14:  Screening and Monitoring in Men Prescribed Testosterone Therapy in the U.S., 2001–2010
Jacques Baillargeon, Randall J. Urban, Yong-Fang Kuo, Holly M. Holmes, Mukaila A. Raji, Abraham Morgentaler, Bret T. Howrey, Yu-Li Lin, Kenneth J. Ottenbacher
Public Health Rep. 2015 Mar-Apr; 130(2): 143–152.  doi: 10.1177/003335491513000207
PMCID: PMC4315855

15:  Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth
A M Traish, A Morgentaler
Br J Cancer. 2009 Dec 15; 101(12): 1949–1956.  Published online 2009 Nov 3. doi: 10.1038/sj.bjc.6605376
PMCID: PMC2795439

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