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Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer

Two Years of Testosterone Therapy Associated with Decline
in Prostate-Specific Antigen in a Man with Untreated
Prostate Cancer

Harvard Medical School—Urology, Brookline, MA, USA A B S T R A C T
Introduction. 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.
Aim. This report details the clinical and prostate-specific antigen (PSA) response of a man with untreated PCa
treated with T therapy for 2 years.
Methods. Measurements of serum PSA, total and free T concentrations were obtained at regular intervals at baseline
and following initiation of T therapy.
Main Outcome Measure. Serum PSA during T therapy.
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. Morgentaler A. Two years of testosterone therapy associated with decline in
prostate-specific antigen in a man with untreated prostate cancer. J Sex Med **;**:**–**.

Key Words. Testosterone; Prostate Cancer; Hypogonadism
Introduction
risky as once believed in men with a prior historyof PCa [6]; the biologic effect of T therapy in these F or several decades, there has been general men is uncertain since the absence of PCa recur- agreement that testosterone (T) therapy is rence may simply reflect complete eradication of contraindicated in men with a history of, or suspi- cion of prostate cancer (PCa) due to the fear that This report details the effect of 2 years of T higher serum T would lead to cancer recurrence or therapy in a man with untreated PCa.
progression. However, recent publications havefailed to find a correlation between PCa and serum Case Report
T in noncastrated men [1,2], and there are nowseveral studies that have reported no PCa recur- This is a case report of an 84-year-old male seen rence in men receiving T therapy after definitive for erectile dysfunction and anorgasmia. Despite treatment of localized PCa [3–5]. Although these his age, he continued to work as an attorney and latter reports suggest that T therapy may not be as exercised three times weekly. Treatment with 2008 International Society for Sexual Medicine Figure 1 Prostate-specific
values at baseline (0 months) and for24 months of testosterone therapy inan 84-year-old man after diagnosisof prostate cancer, without treatment.
Dutasteride was added at month 21,but was discontinued after approxi-mately 1 month.
sildenafil 50 mg had been ineffective. Past medical 17.1 pg/mL. From a baseline PSA of 8.1–8.5 ng/ history was notable only for atrial fibrillation, mL, the PSA concentration was 8.7 ng/mL at 2 treated with coumadin. Physical examination months, and then declined to 6.7 ng/mL at 6 revealed normal external genitalia and a moder- months, 5.7 ng/mL at 8 months, and 5.2 ng/mL ately enlarged prostate without tenderness or at 10 months (Figure 1). From that point, it nodularity. Blood tests were notable for total T of increased slightly and was stable at 6.2–6.3 ng/mL 400 ng/dL, but free T was reduced at 7.4 pg/mL for 8 months. At 21 months, dutasteride was added (RIA, reference values 10–55 pg/mL). In addition, for lower urinary tract symptoms, but was discon- PSA was elevated at 8.5 ng/mL, and 8.1 ng/mL tinued 1 month later due to the patient’s reluc- when repeated. Prostate biopsy revealed Gleason 6 tance to take additional medications and a lack of cancer in two of six cores, involving 30% of one perceived benefit. At 24 months, the PSA was core and 5% of the other, at the right and left base, 3.8 ng/mL. Prostate exam remains unchanged, respectively. Prostate volume was 35 cc.
without nodularity or other abnormality. There After discussion, the patient declined treatment was no gynecomastia prior to or following T ther- for his PCa. In addition, the patient requested T apy. Hematocrit was within normal limits at all therapy for his hypogonadism despite being times. The patient has declined follow-up prostate advised that T therapy was considered contraindi- cated in men with PCa, and there was a potentialrisk of disease progression and even death.
Treatment was begun with T gel (Androgel) at Discussion
5 g topically daily, and was titrated up to 10 g daily.
Two months following prostate biopsy, the patient This appears to be the first report of T therapy in developed urinary urgency and was treated with 14 a man with untreated PCa in the PSA era. The days of ciprofloxacin, followed 2 months later by case is noteworthy for what did not occur. Despite an E. coli urinary infection treated successfully the presence of multifocal disease and a moder- with sulfa/trimethoprim. With T therapy, the ately elevated PSA, 2 years of T therapy did not patient experienced improved erection quality and result in clinical or biochemical progression of increased libido, energy, and sense of vigor. Anor- PCa. In fact, serum PSA declined during T gasmia did not resolve. He also uses tadalafil therapy from a baseline of 8.1–8.5 ng/mL to 6.2– 6.3 ng/mL at 21 months (and lower still after addi- Blood tests for total T, free T, and PSA were tion of dutasteride). It is possible this decline obtained approximately every 2–3 months over simply reflected resolution of subclinical inflam- the course of 2 years of treatment. Mean total T mation, although it is interesting to speculate concentration was 699 ng/dL and mean free T whether this decline may have resulted directly Testosterone Therapy and Untreated Prostate Cancer from T therapy itself, based on research indicating greater rate than men who received placebo [15].
that T has antiproliferative activity in the prostate If raising T in hypogonadal men reliably caused PCa to grow more rapidly, one would expect to see Despite the longstanding prohibition against a high rate of PCa in men undergoing T therapy, the use of T therapy in men with a prior history of given the substantial number of men with occult PCa, there are now at least three publications but biopsy detectable cancer in that population.
demonstrating a lack of PCa recurrence with T One must be extremely cautious in drawing therapy after definitive PCa treatment. Two conclusions from a single case, yet this report pro- articles have reported no PSA recurrence in a total vides additional evidence that raising serum T in of 17 men, following radical prostatectomy (RRP) men with modest, naturally occurring T deficien- in men with undetectable PSA [3,4]. A third study cies does not necessarily precipitate rapid PCa reported that no cancer recurrence was noted in 31 growth. Whereas there is no dispute that optimal hypogonadal men treated with brachytherapy with growth of PCa requires the presence of androgen, a follow-up of approximately 5 years [5]. These accumulating evidence suggests there is a serum T small studies suggest that normalization of T in concentration at which maximal PCa stimulation men with definitively treated PCa may not be as occurs, and that this saturation point occurs in the near-castrate range [10]. Perhaps the strongest A number of reports prior to 1982 detail the evidence in this regard is the recently published effects of T administration to men with advanced global pooled analysis of 18 longitudinal studies or metastatic PCa. Although T administration in revealing that PCa risk is unrelated to serum castrated men produced reliable and rapid PCa androgen concentrations [2]. As the number of progression, T administration in men without men undergoing surveillance for PCa increases, prior castration was not associated with evident there will be greater demand from patients for progression, as determined by clinical course and treatment of their hypogonadism. A critical acid phosphatase [8,9]. In addressing the benign re-evaluation of traditional concepts regarding the course of noncastrated men with metastatic PCa relationship of T and PCa is warranted.
who received T injections, Fowler and Whitmorepostulated that naturally occurring serum T con- Corresponding Author: Abraham Morgentaler, MD,
centrations provided near-maximal stimulation of Harvard Medical School—Urology, Brookline, MA, PCa, and that additional T was thus without effect USA. Tel: 617-277-5000; Fax: 617-277-5444; E-mail: [8]. That concept is consistent with a saturationmodel for the relationship of T and PCa [10], Conflict of Interest: Consulting, research grants, advisory which in turn reflects the observation that maximal boards and/or lecture honoraria from Auxilium, Solvay, binding of androgen to the androgen receptor occurs experimentally at very low T concentra-tions [11]. Marks et al. also reported that intrapro-static androgen concentrations were unchanged Statement of Authorship
when hypogonadal men received 6 months of T injections [12]. This case involving the patient (a) Conception and Design
appears to be consistent with this literature.
Although it may seem a departure from stan- (b) Acquisition of Data
dard therapy to provide T therapy to an individual with untreated PCa, it must be acknowledged that (c) Analysis and Interpretation of Data
a substantial number of men who receive T therapy consistent with established clinical proto-cols also have PCa, albeit undiagnosed, without evidence that T therapy increases their risk of (a) Drafting the Article
PCa. In one study, prostate biopsy in 345 men with hypogonadism and PSA Յ4.0 ng/mL revealed (b) Revising It for Intellectual Content
PCa in 52 men (15%) [13]. Yet the cancer rate among hypogonadal men in T therapy trials isonly approximately 1% [14], and a recent meta- analysis has failed to show that hypogonadal men (a) Final Approval of the Completed Article
who received T therapy developed PCa at a References
with advanced prostatic carcinoma to exogenous 1 Morgentaler A. Guilt by association: A historical administration of testosterone. Cancer 1967;20: perspective on Huggins, testosterone therapy, and prostate cancer. J Sex Med 2008;5:1834–40.
10 Morgentaler A. Testosterone replacement therapy 2 Endogenous Hormones, Prostate Cancer Collabo- and prostate cancer. Urol Clin N Am 2007;34:555– rative Group, Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate 11 Ho SM, Damassa D, Kwan PW, Seto HS, Leav I.
cancer: a collaborative analysis of 18 prospective Androgen receptor levels and androgen contents in the prostate lobes of intact and testosterone-treated 3 Kaufman JM, Graydon RJ. Androgen replacement Noble rats. J Androl 1985;6:279–90.
after curative radical prostatectomy for prostate 12 Marks LS, Mazer NA, Mostaghel E, Hess DL, cancer in hypogonadal men. J Urol 2004;172:920–2.
Dorey FJ, Epstein JI, Veltri RW, Makarov DV, 4 Agarwal PK, Oefelein MG. Testosterone replace- Partin AW, Bostwick DG, Macairan ML, Nelson ment therapy after primary treatment for prostate PS. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogo- 5 Sarosdy MF. Testosterone replacement for hypogo- nadism: A randomized controlled trial. JAMA nadism after treatment of early prostate cancer with brachytherapy. Cancer 2007;109:536–41.
13 13Morgentaler A, Rhoden EL. Prevalence of pros- 6 Rhoden EL, Averbeck MA, Teloken PE. Androgen tate cancer among hypogonadal men with prostate- replacement in men undergoing treatment for pros- specific antigen of 4.0 ng/mL or less. Urology tate cancer. J Sex Med 2008;5:2202–8.
7 Wu CT, Altuwaijri S, Ricke WA, Huang SP, Yeh S, 14 Rhoden EL, Morgentaler A. Risks of testosterone- Zhang C, Niu Y, Tsai MY, Chang C. Increased replacement therapy and recommendations for prostate cell proliferation and loss of cell differen- monitoring. N Engl J Med 2004;350:482–92.
tiation in mice lacking prostate epithelial androgen 15 Calof OM, Singh AB, Lee ML, Kenny AM, Urban receptor. Proc Natl Acad Sci USA 2007;104:12679– RJ, Tenover JL, Bhasin S. Adverse events associated with testosterone replacement in middle-aged and 8 Fowler JE, Whitmore WF, Jr. The response of older men: A meta-analysis of randomized, placebo- metastatic adenocarcinoma of the prostate to exog- controlled trials. J Gerontol A Biol Sci Med Sci enous testosterone. J Urol 1981;126:372–5.

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