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Adrenocorticotropic Hormone is Involved in Regulation ofAndrogen Synthesis in Men Receiving Androgen DeprivationTherapy for Localized Prostate Cancer
Itsuhiro Takizawa, Noboru Hara,* Tsutomu Nishiyama, Etsuko Isahaya,Tatsuhiko Hoshii and Kota TakahashiFrom the Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medicaland Dental Sciences, Niigata University, Niigata, Japan
Purpose: We elucidated the regulatory mechanism of adrenal androgen synthe-sis and examined the influence of pituitary-adrenal axis activity on prostatespecific antigen during androgen deprivation therapy.Materials and Methods: A total of 72 patients with localized prostate cancerwere prospectively studied based on blood samples before and after androgendeprivation therapy for 6 months. Serum pituitary hormones, androgens andprostate specific antigen were measured using highly sensitive assays.Results: After androgen deprivation therapy serum levels of luteinizing hormone,follicle-stimulating hormone, testosterone, dehydroepiandrosterone sulfate, andro-stenedione and prostate specific antigen decreased compared with those at thebaseline (all values p �0.001). No difference was noted between serum levels beforeand after androgen deprivation therapy in growth hormone (p � 0.098) and adre-nocorticotropic hormone (p � 0.101). Each serum level of luteinizing hormone,follicle-stimulating hormone and growth hormone after androgen deprivation ther-apy was not correlated with the serum levels of androgens or prostate specificantigen. The serum adrenocorticotropic hormone level after androgen deprivationtherapy was correlated with the serum levels of testosterone (p � 0.002), dehydro-epiandrosterone sulfate (p � 0.002), androstenedione (p � 0.006) and prostatespecific antigen (p �0.001). Serum dehydroepiandrosterone sulfate and andro-stenedione levels were also correlated with serum prostate specific antigen (p �0.001and p � 0.002, respectively).Conclusions: In patients treated with androgen deprivation therapy the pi-tuitary-adrenal axis mediated by adrenocorticotropic hormone has a centralrole in the regulation of androgen synthesis. Serum adrenocorticotropic hor-mone and adrenal androgen concentrations were correlated with the post-treatment prostate specific antigen. Adrenocorticotropic hormone mediatedandrogen synthesis is a potential target for advanced androgen deprivationtherapy.
Key Words: adrenocorticotropic hormone, androgens, pituitary-adrenal
Abbreviations
and Acronyms
ACTH � adrenocorticotropichormone
ADT � androgen deprivationtherapy
DHEA-S � dehydroepiandrosteronesulfate
DHT � dihydrotestosterone
FSH � follicle-stimulatinghormone
GH � growth hormone
GnRH � gonadotropin-releasinghormone
LH � luteinizing hormone
PSA � prostate specific antigen
rs � Spearman’s rank correlationcoefficient
Submitted for publication February 7, 2010.Study received ethics committee approval.Nothing to disclose.* Correspondence: Asahimachi 1, Niigata
951-8510, Japan (telephone: �81 25 227 2287;FAX: �81 25 227 0784; e-mail: [email protected] or [email protected]).
Editor’s Note: This article is the
fourth of 5 published in this issue
for which category 1 CME credits
can be earned. Instructions for
obtaining credits are given with
system, prostatic neoplasmstopic see page 2172.
IN 1941 Huggins and Hodges reportedthat metastatic prostate cancer re-sponded favorably to castration orthe administration of estrogenic hor-
mones.1 Since the initial report of the0022-5347/10/1845-1971/0THE JOURNAL OF UROLOGY®
© 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RES
androgen dependency of prostate can-cer, ADT has evolved with the adventof GnRH agonists and has become thetherapeutic standard for advanced
prostate cancer.2,3 However, severalVol. 184, 1971-1976, November 2010Printed in U.S.A.
EARCH, INC. DOI:10.1016/j.juro.2010.06.115
the questions on pages 2220 and
2221.
For another article on a related
www.jurology.com 1971
ADRENOCORTICOTROPIC HORMONE DEPENDENT ANDROGEN SYNTHESIS1972
studies in healthy men or those with prostate cancerrevealed the limitation of currently available ADT.Intraprostatic androgens after conventional ADT re-main at levels insufficient for tumor regression.3–6 Al-though serum testosterone showed a 94% decreaseafter treatment with chemical hypophysectomy, theposttreatment fractions of intraprostatic testosteroneand DHT represent 20% and 30%, respectively.6 Thesesuggested an important role for adrenal androgens aswell as testicular androgens as a source of intracrineandrogen production. Thus, advanced ADT with adre-nal androgen synthesis inhibitors is under trial, egabiraterone acetate, a small molecule inhibitor of cy-tochrome P17 (CYP17), which inhibits key enzymes inintra-adrenal androgen synthesis.7
The secretion of adrenal androgens such asDHEA-S and androstenedione was found to bepartially mediated by ACTH.8 –10 This pathwaywas clarified 40 years ago in several studies usingdexamethasone suppression and ACTH stimulationtests. Other modulators, eg gonadotropins andgrowth hormone, were also reported to be associatedwith the production of adrenal androgens.10,11 Somerecent studies have suggested that blockade of theadrenal androgen pathway is a therapeutic target toovercome the limitation of conventional ADT.12,13 Incontrast the regulatory mechanism of adrenal an-drogen secretion in patients treated with GnRH ago-nists and/or antiandrogens remains unclear, and itsrelevance to PSA during ADT is also unknown. Im-portantly the former concept has not been validatedfor approximately 40 years despite the advent ofhigh precision measurements, and the latter has notbeen studied after the PSA era.
In this study we measured various biochemicalparameters and hormones before and after treat-ment in patients with local or regional prostatecancer using highly sensitive assays. We also ex-amined the mechanism regulating androgens, fo-cusing on the correlation between the pituitaryhormones and androgens. Finally the relationshipbetween the adrenal androgen pathway and PSAwas shown.
MATERIALS AND METHODS
PatientsA total of 72 consecutive patients who were treated withradiotherapy for localized or locally advanced prostatecancer (cT1c–3 N0 M0) at the Department of Urology,Niigata University Hospital, were enrolled betweenMay 2004 and December 2006. Mean patient age atdiagnosis was 69 years (range 54 to 79). Mean PSA atdiagnosis was 17.9 ng/ml (range 5.2 to 100.9) and meanGleason score was 7.2 (range 5 to 9). The patients re-ceived a subcutaneous injection of GnRH agonist gos-erelin acetate (3.6 mg every 4 weeks) and peroral non-
steroidal antiandrogen flutamide (375 mg daily) for 6months before radiotherapy. The study was prospec-tively designed and the procedure for this researchproject was approved by the ethics committee at ourinstitution. Informed consent was obtained from all pa-tients.
Blood Sampling and Analytical MeasurementsIn all patients blood samples were evaluated at baselineand after ADT for 6 months. All blood samples were ob-tained between 11 a.m. and 2 p.m. Hormonal parameterswere quantified by SRL (Tokyo, Japan). PSA and testos-terone were determined using an electrochemilumines-cence immunoassay. Androstenedione and GH were mea-sured by radioimmunoassay. ACTH was determined byimmunoradiometric assay. LH and FSH were measuredby chemiluminescent immunoassay. DHEA-S was quan-tified using the chemiluminescent enzyme immunoas-say. The lower measurement limits of PSA, testoster-one, androstenedione, DHEA-S, LH, FSH, GH andACTH were 0.03 ng/ml, 0.05 ng/ml, 0.1 ng/ml, 2 �g/dl,0.10 mIU/ml, 0.05 mIU/ml, 0.03 ng/ml and 5.0 pg/ml,respectively.
Histopathological DiagnosisAn independent urological pathologist performed his-topathological diagnoses based on biopsy cores from all 72patients. Standardized grading was performed accordingto the Gleason classification system.
Statistical AnalysisThe Wilcoxon signed rank test was used to comparechanges in paired parameters before and after ADT. Thetest was 2-sided and p �0.05 was considered significant.Correlations between pituitary hormone or PSA and otherparameters before and after ADT were analyzed usingSpearman’s rank correlation coefficient analysis (rs). Sta-tistical analyses were calculated and tested using SPSS®software version 15.0.
RESULTS
Adverse Events
Flutamide treatment was discontinued in 28 of 72patients because of adverse effects at 1 month in 6patients, at 2 months in 4, at 3 months in 8, at 4months in 4 and at 5 months in 6. Increased serumtransaminase levels and diarrhea were the causes ofdiscontinuation in 24 and 4 patients, respectively.When transaminase levels increased we immedi-ately discontinued flutamide use to prevent severeliver dysfunction. Transaminase levels recoveredwithin 4 weeks and diarrhea disappeared immedi-ately after the discontinuation of flutamide. All 28patients received GnRH agonist monotherapy forthe remaining treatment period.
Comparison of Serum Pituitary Hormones,
Androgen and PSA Before and After ADT
The comparisons of analytical values before and af-ter ADT are presented in table 1. Of the pituitaryhormones serum LH and FSH decreased after ADT
for 6 months vs baseline (p �0.001 in both). There
ADRENOCORTICOTROPIC HORMONE DEPENDENT ANDROGEN SYNTHESIS 1973
was no difference between the serum levels beforeand after ADT in GH (p � 0.098) and ACTH(p � 0.101). Serum testosterone, DHEA-S, andro-stenedione and PSA decreased significantly afterADT (p �0.001 in all). Serum PSA and LH werereduced to below detectable levels in 14 (19%) and50 (69%) men, respectively. All patients maintainedmeasurable levels of testosterone, androstenedione,DHEA-S, FSH, GH and ACTH.
Correlation of Serum Pituitary Hormones
and Androgen or PSA Before and After ADT
Before ADT we did not note any correlations be-tween serum LH and androgen levels such as tes-tosterone (p � 0.705), DHEA-S (p � 0.068), andro-stenedione (p � 0.770) or PSA (p � 0.374) (table 2).After ADT there was also no correlation betweenserum LH and testosterone, DHEA-S, androstenedi-one or PSA (p � 0.369, p � 0.818, p � 0.697 andp � 0.602, respectively).
Correlations between serum FSH and androgenor PSA before and after ADT are presented in table2. Before ADT serum FSH was inversely correlatedwith serum androstenedione (p � 0.005). After ADTthere was no correlation between serum FSH andandrogen or PSA levels.
Before or after ADT serum GH was not corre-lated with the levels of testosterone (p � 0.689 andp � 0.219, respectively), DHEA-S (p � 0.458 andp � 0.109, respectively), androstenedione (p � 0.427and p � 0.425, respectively) or PSA (p � 0.076 andp � 0.513, respectively).
Table 1. Comparison of serum pituitary hormone, androgenand PSA levels
Mean BeforeADT (SD)
Mean AfterADT (SD) p Value
LH (mIU/ml) 6.51 (5.02) 0.14 (0.55) �0.001FSH (mIU/ml) 12.11 (8.87) 11.06 (4.81) �0.001GH (ng/ml) 1.46 (2.30) 0.94 (0.95) 0.098ACTH (pg/ml) 32.2 (15.5) 29.9 (14.4) 0.101Testosterone (ng/ml) 4.62 (0.15) 0.15 (0.10) �0.001DHEA-S (�g/dl) 133.3 (63.8) 83.4 (51.4) �0.001Androstenedione (ng/ml) 1.6 (0.6) 0.8 (0.4) �0.001PSA (ng/ml) 17.9 (14.0) 0.20 (0.35) �0.001
Table 2. Correlations between serum pituitary hormones and a
Before ADT
LH FSH GH
rs by Testosterone 0.045 �0.120 0.048p Value 0.705 0.316 0.689
rs by DHEA-S �0.216 �0.204 0.090p Value 0.068 0.085 0.458
rs by Androstenedione �0.035 �0.328 0.096p Value 0.770 0.005 0.427
rs by PSA 0.106 0.088 0.212
p Value 0.374 0.462 0.076Correlations between serum ACTH and andro-gen or PSA before/after ADT are presented intable 2. Before ADT we did not observe any corre-lations between the serum levels of ACTH andandrogens such as testosterone (p � 0.574),DHEA-S (p � 0.631), androstenedione (p � 0.729)or PSA (p � 0.535). After ADT serum ACTH wascorrelated with levels of testosterone (rs � 0.367,p � 0.002), DHEA-S (rs � 0.354, p � 0.002), an-drostenedione (rs � 0.321, p � 0.006) and PSA(rs � 0.419, p �0.001, see figure).
Relationship Between Serum Levels
of Adrenal Androgens and PSA After ADT
To evaluate the influence of DHEA-S and andro-stenedione regulated by ACTH on posttreatmentPSA we analyzed the relevance between the serumlevels of adrenal androgens and PSA after ADT.Serum DHEA-S and androstenedione levels werecorrelated with serum PSA after ADT (rs � 0.459,p �0.001 and rs � 0.354, p � 0.002, respectively).
DISCUSSION
We first verified the central role of the pituitary-adrenal axis in androgen synthesis in men treatedwith a GnRH agonist and antiandrogens. ACTH isassociated with the regulation of androgen synthesisduring ADT. In addition, we elucidated the influenceof the activity of this axis on PSA in men receivingADT.
In the 1970s several studies using the dexameth-asone suppression test revealed the function ofACTH in the regulation of adrenal androgen produc-tion in men.14–16 Although the authors suggestedthat adrenal androgen secretion was in part modu-lated by ACTH, the regulatory mechanism waspoorly defined. In our previous report we failed toshow a correlation between serum ACTH andDHEA-S or androstenedione after ADT with castra-tion and flutamide because of the small number ofpatients and less sensitive measurement modali-ties.4 To our knowledge this study is the first tosuggest associations between serum ACTH and ad-
en or PSA levels
After ADT
ACTH LH FSH GH ACTH
0.068 �0.107 0.012 �0.147 0.3670.574 0.369 0.919 0.219 0.0020.058 �0.028 0.021 �0.190 0.3540.631 0.818 0.860 0.109 0.0020.042 �0.047 0.188 �0.096 0.3210.729 0.697 0.115 0.425 0.0060.075 �0.062 0.135 �0.078 0.419
ndrog
0.535 0.602 0.257 0.513 �0.001
rone (A
ADRENOCORTICOTROPIC HORMONE DEPENDENT ANDROGEN SYNTHESIS1974
renal androgen levels in men treated with a GnRHagonist and antiandrogens.
In our study serum testosterone decreased afterADT due to the low LH level which could not func-tion as a major regulatory hormone for androgensynthesis in the testis. In such an androgen deprivedmilieu adrenal androgens are the major sources ofandrogens synthesized locally in the prostate, andthe consumption of adrenal androgens and theirsupplementation mediated by ACTH may create analtered hormonal milieu where androgenic activitylargely depends on adrenal androgens regulated byACTH. Otherwise it is possible that men receivingADT recover the prepubescent androgen milieu inwhich adrenal androgens regulated by ACTH exertan androgenic function in vivo.17,18 Accordingly it isfeasible that the relationship between ACTH andadrenal androgens emerged through the influence ofADT on the pituitary-testicular axis.
In addition, in our study adrenal androgens in-cluding DHEA-S and androstenedione in the serumlevel decreased after ADT with GnRH analogue plusantiandrogen. Previous studies have shown the in-fluence of nonsteroidal androgen receptor antago-nists such as flutamide and nilutamide on the serum
ACTH(pg/ml)
test
ost
ero
ne
(ng/ml)
ACTH(pg/ml)
An
dro
sten
edio
ne
(ng/ml)
rs=0.367p=0.002
rs=0.321p=0.006
A
C
Correlations between serum ACTH and testoste
level of adrenal androgens.4,19,20 They speculated
that flutamide has an inhibitory effect on humanadrenal microsomal 17�-hydroxylase and 17,20-lyase activities.20 In contrast, it was reported thatnilutamide alone did not suppress serum adrenalandrogen.21 Thus, the mechanism of the decrease ofadrenal androgens in men treated with ADT re-mains unclear.
Some previous studies supported the significanceof CYP17 inhibition in combination with conven-tional ADT for patients with castration resistantprostate cancer.22 Taplin et al studied men withcastration resistant prostate cancer who receivedcombined ketoconazole, hydrocortisone and dutast-eride therapy, and reported that the PSA responserate (50% or greater decrease) was 56%.23 In theirstudy DHEA-S decreased by 89%, androstenedioneby 56%, testosterone by 66% and DHT decreased tobelow detectable levels compared with those duringtesticular suppression alone. Although median base-line levels and decreases in these androgens werenot statistically different between the respondersand nonresponders in their study, combination ther-apies targeting multiple steps in androgen synthesisare suggested to be promising in current clinical
ACTH(pg/ml)
DH
EA
-S
(g/dl)
ACTH(pg/ml)
PS
A(ng/ml)
rs=0.354p=0.002
rs=0.419p<0.001
), DHEA-S (B), androstenedione (C) or PSA (D)
B
D
practice.
ADRENOCORTICOTROPIC HORMONE DEPENDENT ANDROGEN SYNTHESIS 1975
Our study revealed that the serum ACTH concen-tration was correlated with PSA as well as the an-drogen milieu during ADT. Androgen activity is reg-ulated in the prostate at the pre-receptor level bythe formation and elimination of DHT, the mostbioactive androgen. Several reports revealed thatDHT in the prostate after ADT was supplied by theprecursors of androgens of adrenal origin such asDHEA-S and androstenedione.3,4,24 The presentstudy demonstrated a correlation not only betweenACTH and DHEA-S or androstenedione, but alsobetween these adrenal androgens and PSA. There-fore, for men treated with ADT it is feasible thatACTH has an important role in the androgen de-pendent progression of prostate cancer via theregulation of adrenal androgens. Yet the analysisclarifying the association between ACTH and bio-chemical progression in prostate cancer duringADT, or the significance of ACTH for monitoringthe androgen milieu or disease progression waslimited in this study. To evaluate such an associ-ation and the significance of ACTH in the clinicaloutcome during ADT a longitudinal study is cur-rently under way involving the present patientseries.
Several studies have shown that treatment in-volving glucocorticoids may exert modest anti-pros-
tate activity with administration as single agents.25REFERENCES
intraprostatic androgen concentrations after med- standing mechanisms of re
In particular, low doses of dexamethasone decreaseserum PSA in patients with castration resistantprostate cancer.26,27 Although the exact mechanismbehind the treatment effects is not understood, eganti-inflammatory actions and direct growth inhib-itory effects, our study theoretically supported theidea that dexamethasone, the most potent inhibitorof ACTH secretion, had therapeutic effects via inhi-bition of the pituitary-adrenal axis during ADT.Based on a more detailed understanding of andro-gen metabolism/milieu or regulation, a therapeuticstrategy should be considered and treatments tar-geting the pituitary-adrenal axis are suggested toovercome the limitation of conventional ADT forprostate cancer.
CONCLUSIONS
In the androgen deprived milieu caused by ADTwith GnRH agonists the pituitary-adrenal axishas a critical role in the regulation of androgensynthesis. Serum ACTH and adrenal androgenconcentrations were correlated with posttreat-ment serum PSA, which reflects the disease con-dition. Inhibiting the activity of this axis is sug-gested to be a promising therapeutic target in menin whom treatment efficacy is insufficient with
conventional ADT.1. Huggins C and Hodges CV: Studies on prostatecancer. Effect of castration, estrogen and andro-gen injection on serum phosphatases in meta-static carcinoma of the prostate. Cancer Res1941; 1: 293.
2. Labrie F, Dupont A, Belanger A et al: New hor-monal therapy in prostatic carcinoma: combinedtreatment with an LHRH agonist and an antian-drogen. Clin Invest Med 1982; 5: 267.
3. Labrie F, Bélanger A, Luu-The V et al: Gonado-tropin-releasing hormone agonists in the treat-ment of prostate cancer. Endocr Rev 2005; 26:361.
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6. Page ST, Lin DW, Mostaghel EA et al: Persistent
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9. Vaitukaitis JL, Dale SL and Melby JC: Role ofACTH in the secretion of free dehydroepiandros-terone and its sulfate ester in man. J Clin Endo-crinol Metab 1969; 29: 1443.
10. Parker LN and Odell WD: Control of adrenalandrogen secretion. Endocr Rev 1980; 1: 392.
11. Parker LN and Odell WD: Evidence for existenceof cortical androgen-stimulating hormone. Am JPhysiol 1979; 236: E616.
12. Harris WP, Mostaghel EA, Nelson PS et al: An-drogen deprivation therapy: progress in under-
sistance and optimiz-
ing androgen depletion. Nat Clin Pract Urol 2009;6: 76.
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14. Sciarra F, Sorcini G, Di Silverio F et al: Plasmatestosterone and androstenedione after orchiec-tomy in prostatic adenocarcinoma. Clin Endo-crinol (Oxf) 1973; 2: 101.
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19. Balzano S, Cappa M, Migliari R et al: The effectof flutamide on basal and ACTH-stimulatedplasma levels of adrenal androgens in patientswith advanced prostate cancer. J Endocrinol In-vest 1988; 11: 693.
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EDITORIAL COMMENT
REFERENCE
22. Reid AH, Attard G, Barrie E et al: CYP17 inhibitionas a hormonal strategy for prostate cancer. NatClin Pract Urol 2008; 5: 610.
23. Taplin ME, Regan MM, Ko YJ et al: Phase II studyof androgen synthesis inhibition with ketocon-azole, hydrocortisone, and dutasteride in asymp-tomatic castration-resistant prostate cancer. ClinCancer Res 2009; 15: 7099.
24. Hammond GL: Endogenous steroid levels in thehuman prostate from birth to old age: a compar-ison of normal and diseased tissues. J Endocrinol
25. Small EJ and Ryan CJ: The case for secondaryhormonal therapies in the chemotherapy age.J Urol 2006; 176: S66.
26. Nishimura K, Nonomura N, Yasunaga Y et al: Lowdoses of oral dexamethasone for hormone-refrac-tory prostate carcinoma. Cancer 2000; 89: 2570.
27. Storlie JA, Buckner JC, Wiseman GA et al: Pros-tate specific antigen levels and clinical responseto low dose dexamethasone for hormone-refrac-tory metastatic prostate carcinoma. Cancer 1995;
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The recent clinical success of abiraterone acetateand other inhibitors of adrenal androgen synthesisin castration resistant prostate cancer highlightsthe role of adrenal androgens in mediating diseaseprogression in a low testosterone environment.1 Re-cently the source of adrenal androgens has beenquestioned due to evidence of intracrine androgenproduction in many tumors, a discovery that callsinto question the contribution of an intact hypotha-lamic-pituitary-adrenal axis.
Takizawa et al prospectively examined the impactof neoadjuvant ADT on the intact hypothalamic-pituitary-adrenal axis in men undergoing ADT plusradiation. The data presented demonstrate an asso-ciation among ACTH, adrenal androgen levels and
mones can activate the androgen receptor or be con-verted intratumorally to DHT and testosterone,their work suggests that an intact hypothalamic-pituitary-adrenal axis may contribute to the devel-opment of castration resistance, perhaps in parallelwith intracrine androgen production (reference 4 inarticle). These findings provide further rationale forthe use of androgen synthesis inhibitors such asabiraterone.
Terence W. Friedlander
Charles J. Ryan
Urologic Oncology ProgramHelen Diller Family Comprehensive Cancer Center
University of California, San Francisco
posttreatment PSA values. Given that adrenal hor- San Francisco, California
1. Ryan CJ, Smith MR, Fong L et al: Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostatecancer who received prior ketoconazole therapy. J Clin Oncol 2010; 28: 1481.
