| Carl
W. Bushong, Ph.D., LMFT Richard A. Martin, Jr., M.D., FACEP Kimberly L. Westwood, CPE, CCE et al. |
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Specialists in the Medical & Psychological Aspects of Transgender Health Care |
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The Effects of Chronic High Dose Androgen or Estrogen Treatment on Human Prostate B. JIN Andrology Unit, Departments of Medicine and Obstetrics and Gynecology, Royal Prince Alfred Hospital, University of Sydney, Sydney; and the Discipline of Reproductive Medicine, University of Newcastle, Newcastle, Australia August 2, 1996 ABSTRACT Prostate development and disease are androgen dependent. However, the nature of hormonal effects on the prostate of healthy young men is not clear. We, therefore, measured prostate size in males chronically exposed to high doses of androgens (AS; habitual anabolic steroid abusers; n = 15) or estrogens (E; male to female transsexuals; n = 11) and compared the results with those in age-matched healthy eugonadal men without known prostate disorders. Prostate size was measured by planimetric ultrasound as cross-sectional areas and maximal dimensions in three orthogonal dimensions with a 7.5-megahertz B-mode sector scanner biplane in a transrectal transducer at 2.5 mm steps from the base to the apex of prostate. Total prostate volume (TPV) was reconstructed from planimetric sections, central prostate volume (CPV) was calculated by the ellipsoidal formula from the appropriate three maximum dimensions, and peripheral prostate volume was determined by the difference between TPV and CPV. Compared with age-matched controls, TPV was normal (-2%) in AS ( P = 0.752) and reduced by 31% in E ( P = 0.002), whereas CPV was increased by 20% in AS ( P = 0.002) and reduced by 46% in E ( P = 0.002), and the ratio of CPV/peripheral prostate volume was increased by 77% in AS ( P < 0.001) and decreased by 33% in E ( P = 0.047). Blood sex hormone-binding globulin was elevated by nearly 500% in E ( P < 0.001), but was reduced by 47% in AS ( P = 0.003). Prostate-specific antigen was normal (-6%) in AS (P = 0.799) and decreased by 86% in E ( P= 0.002). Prostatic acid phosphatase was increased by 26% in AS ( P = 0.007), but was unchanged (-28%) in E ( P = 0.106). Total and free testosterone levels were reduced to castrate levels in E, whereas LH, FSH, and total testosterone levels were significantly reduced in AS. We conclude that in the human prostate of young men, CPV is more hormonally sensitive than TPV, and during high dose treatment, CPV is preferentially increased by chronic androgen treatment and decreased by chronic estrogen treatment. The reduction of TPV by estrogens was less than expected if solely attributable to inhibition of endogenous gonadotropin and testosterone secretion, suggesting that estrogens also have a positive effect on the normal human prostate. The reversibility and long term significance of androgen-induced stimulation of CPV and, in particular, its relationship to the onset and severity of benign prostatic hyperplasia remain to be clarified. ( J Clin Endocrinol Metab 81: 4290-4295, 1996)
THE HORMONAL dependence of the prostate on androgen and estrogen has been well known for decades. During prostatic development, androgens, testosterone, and its 5alpha-dihydrotestosterone metabolite are essential, as indicated by the complete failure of prostatic development in the absence of functional androgen receptors ([1] ) and the vestigial gland that develops in the absence of the prostatic type II 5alpha-reductase enzyme ([2] ). After sexual maturation, both androgens and estrogens are important in maintaining the structure and integrity of the prostate. For example, medical or surgical castration that removes more than 95% of circulating androgens leads to dramatic prostate involution ([3] , [4] ), whereas in men castrated before the fourth decade of life, prostate development is stunted ([5] ) and late-life prostatic diseases are reported not to develop ([6] ). On the other hand, among older men there is little or no relationship between androgens or estrogens in blood or prostatic tissues and the development of prostate diseases ([7] ). Indeed, prostate diseases develop when circulating androgens are falling and estrogens rising, and presumably the predominant hormonal. Subjects and MethodsSubjectsAnabolic steroid (AS) abusers over 18 yr of age without known prostate disease were recruited by advertisement from sports medicine centers, gymnasia, and a specific Health Department-sanctioned clinic for AS abusers. Male to female transsexuals over 18 yr of age without known prostate disease were recruited from appropriate doctors and through a transgender community support organization. Age-matched eugonadal controls were men participating in an ongoing community-based study surveying age-specific prostate size and shape among healthy Sydney men. The survey of healthy controls excluded men using any exogenous sex steroids or with reproductive or prostatic dysfunction. Volunteers for this study underwent a standardized medical history (including drug history) and physical examination (including evaluation of androgenization and testis volume by orchidometry) and provided a blood sample before undergoing the prostate ultrasound. Neither group of steroid users was paid for participation in these studies; some controls received $20 to reimburse travel costs and time taken for the study. This study was approved by the Human Ethics Review Committee of the Central Sydney Area Health Service, and participants were required to provide written informed consent. Participants in this study were not prescribed or provided with any medications by study personnel. Ultrasound measurementProstate ultrasound was performed with a 7.5-megahertz biplanar transrectal transducer (2 cm external diameter) and Opus 1 (Ausonic, Sydney, Australia) ultrasound equipment. The ultrasound transmission gel (Aquasonic, Parker Laboratories, NJ) was applied to the transducer, which was then covered with a disposable rubber sheath. The rubber-covered transducer was lubricated with a water-soluble lubricant (K-Y Jelly, Johnson and Johnson, UK), inserted gently and gradually about 3 cm into the rectum and directed toward the anterior rectal wall to visualize the prostate. Each prostate ultrasound procedure took an average of 10 min (range, 5-15 min). Cross-sectional areas of each slice of the prostate were measured sequentially from base to apex at 2.5-mm intervals using a calibrated stepper device ([8] ). At each step, the two-dimensional sonographic image of the prostate was outlined manually with a track ball, and the image was integrated automatically to give the slice's cross-sectional area with a hardcopy record provided by the video processor (P67E, Mitsubishi, Tokyo, Japan). In addition, the three maximal diameters of the prostate were measured for both total and central areas of the prostate. Subsequently, prostate volume was calculated by reconstruction of all planimetric sections (TPV) as well as from the standard ellipsoidal formula using the three maximal dimensions measured. All prostate ultrasounds and calculations were performed by the same observer (B.J.). For this study we have adopted the terminology of Bosch et al. ([9] ) for the sonographic anatomy of the prostate. Briefly, in addition to the total prostate outline, we also demarcate and measure separately the central hypoechoic volume [also referred to by the same group as the inner zone of the prostate ([10] )]. From this, the central prostate volume (CPV) is calculated, and the peripheral prostate volume (PPV) is calculated as the difference between the CPV and the TPV. The CPV measured in this manner includes the following anatomical areas: the transitional zone, the preprostatic sphincter, and the periurethral glands from the zonal description of McNeal ([11] ). AssaysTotal and free testosterone, LH, FSH, sex hormone-binding globulin (SHBG), and prostate-specific antigen (PSA) were measured by immunoradiometric assays, and prostatic acid phosphatase was determined by autoanalyzer. Data analysisControls were selected from all participants in the ongoing survey of prostate size of healthy eugonadal men (n = 147). They were matched by age (within decade of life), and where excess controls were available, three were randomly selected (without replacement) for each subject in this study from the eligible age-matched pool. Data were expressed as mean and SEM unless otherwise stated and analyzed by unpaired t test, giving exact P values. ResultsAS abusersFifteen AS abusers, aged 20-53 yr, were recruited ( Tables 1 and 2 ). -4At the time of the study, 13 of 15 were currently receiving drug treatment. AS abuse had commenced at a median age of 28 yr (range, 15-53 yr), and they had been using AS in cycles for a median duration of 18 months (range, 1-180 months) at the time of participation in the study. Most (10 of 15) obtained their steroids from doctors; the remainder obtained the drugs from veterinarians (n = 2), a gymnasium (n = 1), a friend (n = 1), or an unknown source (n = 1).
AS abusers were 19% heavier, marginally (2%) taller, and had correspondingly higher body mass index, body surface area, and standardized body weight, but unchanged testis size, compared with age-matched controls. TPV and prostate dimensions were unchanged, but CPV and the ratio of CPV/PPV were increased and PPV decreased compared with those in age-matched eugonadal controls. Similarly, total prostate dimensions were unchanged apart from central anterio-posterior and transverse diameters, which were increased. AS abusers had lower SHBG, LH, FSH, and total and free testosterone concentrations; increased prostatic acid phosphatase levels; and unchanged PSA concentrations compared with those in healthy eugonadal age-matched controls. The duration of AS abuse was inversely correlated with the mean testis size (r = -0.552; P = 0.041), but not with any measure of prostate size. Blood testosterone correlated most strongly (inversely) with the ratio of CPV / PPV ( Table 5 ), but there was no correlation of gonadotropins with any measure of prostate volume.
Male to female transsexualsAll male to female transsexuals were genetic males using an estrogen preparation continuously for a median of 9 yr (range, 0.25-16 yr). All were using at least one estrogen preparation (conjugated equine estrogens, n = 9; ethinyl estradiol, n = 5; estradiol valerate, n = 2; piperazine estrone sulfate, n = 1), and three were using more than one estrogen. Most also used an antiandrogen (spironolactone, n = 6; cyproterone acetate, n = 6) with or without a progestin (medroxyprogesterone acetate, n = 10). All had marked breast development (gynecomastia), and one also had breast implants. Three transsexuals had prior bilateral orchidectomy, and one had a unilateral orchidectomy. Current intake of alcohol (moderate, n = 1; light, n = 8; nil, n = 5) or tobacco (five smokers, one exsmoker, and eight nonsmokers) was relatively low. Four reported nonspecific urinary symptoms. Transsexuals had similar height, weight, body mass index, and body surface area as age-matched controls ( Tables 3 and 4 ). Among nonorchidectomized subjects, mean testis volume was reduced by 50%. TPV, CPV, PPV, the ratio of CPV / PPV (by 21-46%), and all prostate dimensions (by 10-25%) were significantly reduced compared with those in healthy eugonadal age-matched controls. Blood total and free testosterone levels were reduced to castrate levels, but blood LH and FSH levels remained (inappropriately) similar to those in age-matched eugonadal controls and were not correlated with any measure of prostate volume. Blood SHBG was elevated nearly 500%, whereas PSA was reduced by over 90%, but prostatic acid phosphatase was unchanged. DiscussionThis is the first study to systematically and accurately measure prostate size among AS abusers, a difficult group to study ([12] ). We used planimetric ultrasound, which is recognized as the most accurate and reproducible method to quantitate prostate size and is free of arbitrary geometric assumptions about prostate shape ([13] [14] [15] [16] [17] ). Although total prostate volume and PSA concentrations were unchanged among AS abusers, central prostate volume and the CPV/ PPV ratio were significantly increased. These findings are consistent with previous studies suggesting that the central volume, a sonographic feature that includes (but is not identical with) the transitional zone [a histological demarcation ([11] )] grows faster than the remainder of the prostate among older men ([9] ), is the most hormonally responsive region of the primate prostate ([18] ,[19] ), and is the locus of the initial pathogenic changes in benign prostatic hyperplasia ([11] ). Our findings contradict a single report which claimed that a 49-yr-old bodybuilder had an increase in prostate volume with decreased urine flow rate during a single 7-week cycle
of self-administered multiple AS ([20] ). Given our findings, these anomalous findings presumably reflect undiagnosed underlying prostate disease rather than genuine androgenic effects. A controlled study using a standard androgen replacement therapy dosage showed no change in urinary symptoms, serum PSA, or acid phosphatase concentrations, with a small (12%) rise in prostate volume among middle-aged men administered 160 mg testosterone undecanoate daily for 8 months ([21] ). The latter observation is consistent with an older report of eugonadal men treated with androgens for a median of more than 12 months who developed no more frequent prostate disorders than age-matched untreated controls during follow-up ([22] ). Another study in elderly men (mean age, 67.5 yr) receiving 100 mg testosterone enanthate weekly for 3 months showed no increase in total prostate volume (measured by suprapubic ultrasound), but had a small increase in blood PSA concentrations that persisted after cessation of testosterone administration ([23] ). The most detailed study of prostate volume measurements in men receiving androgens demonstrated that various modalities of androgen replacement therapy increased prostate size to levels comparable with but not higher than those in age-matched eugonadal men ([24] ). This included men receiving testosterone enanthate injections, which repeatedly increase blood testosterone concentrations to supraphysiological levels ([25] ). Another study of five men treated with 200 mg testosterone enanthate weekly for up to 18 months in a male contraceptive study claimed that prostate size increased without a change in PSA or urinary symptoms ([26] ). Although we confirm the unchanged PSA concentrations, an increase in total prostate volume in that study seems unlikely based on our present observations as well as the fact that PSA measurements are usually a reliable marker of total prostate volume. The discrepancy from our findings is probably attributable to the use by Wallace et al. of prostate cross-sectional area, a nonstandard measure that lacks between-study reproducibility as well as any appropriate geometric relationship to true total prostate volume. Most recently, Bhasin et al. ([27] ) demonstrated no change in circulating PSA concentrations among men treated with 600 mg testosterone enanthate for 10 weeks. The importance of estrogen effects on the mature human prostate has been known for decades, although these effects are complex ([28] , [29] ). The present study demonstrates that in genetic male transsexuals, chronic administration of high dose estrogens reduces total prostate volume by ~30%, resulting in a mean prostate volume of 19.6 mL. Our findings are consistent with a preliminary report of nine orchidectomized, estrogen-treated, male to female transsexuals, among whom both prostate size and PSA concentrations were low and prostatic acid phosphatase levels were normal ([30] ). Thus, despite a single case report of urinary obstruction in an aging estrogen-ingesting transsexual ([31] ), urinary obstruction due to prostate enlargement is likely to be less common among male to female transsexuals than among eugonadal men of a similar age, consistent with the absence of prostatic problems in the largest retrospective review of medical problems among transsexuals ([32] ). Interestingly, however, prostate volume remains more than 50% higher than the mean prostate volume (12.2 mL) of untreated hypogonadal men of similar age, who subsequently exhibited normal prostate growth when exposed to adequate androgen replacement therapy ([24] ). As the blood testosterone concentrations in our study were fully suppressed to castrate levels, this discrepancy strongly suggests that estrogen alone, in the absence of androgen, has a direct stimulatory effect on the prostate. The most decisive comparison to confirm this supposition would be to quantify prostate size in a control group of long term orchidectomized men with normal prostate glands who were not treated with any sex steroids; such men might have even lower prostate volume than untreated hypogonadal men ([24] ). However, such subjects are not available for study. Our suggestion that chronic estrogen use may not suppress prostate size as effectively as castration provides an interesting reflection on the use of high dose oral estrogens, the first effective medical treatment established for prostate disease ([3] ). Although high dose estrogen therapy is an effective palliative hormonal therapy for advanced prostate cancer due to its gonadotropin-suppressive effects causing androgen withdrawal, experimental studies in cell culture, rodent, canine, and nonhuman primate models have all consistently demonstrated stimulatory, rather than inhibitory, effects of estrogens on prostate growth, development, structure, and/or function. To date, however, there has been little direct evidence in men that the efficacy of the high dose oral estrogen treatments used to induce androgen withdrawal may have been tempered by an opposing direct stimulatory effect. The present study suggests that prolonged use of high dose exogenous androgens causes disproportionate growth of the inner, but not the whole, prostate. This regional expansion occurs in the region known to be the histological origin of benign prostatic hyperplasia, but whether such enlargement as we have observed is reversible and/or has any relationship to the early lesions of BPH is at present unclear. In contrast, prostate cancer most frequently originates in the peripheral (posterior) zones of the prostate, but whether chronic AS abuse alters the risk of prostate cancer ([33] ) remains unknown. Our findings do indicate, however, that among AS abusers, medical monitoring of prostatic effects by digital rectal examination and/or PSA measurements would be inadequate to effectively monitor the effects of androgen, which would require ultrasonographic evaluation of the inner prostate region. These observations pertain to the ingestion of very high doses of multiple androgens, well above the recommended doses characteristic of AS abusers doses. In contrast, current evidence suggests that maintenance of physiological androgen levels, such as during androgen replacement therapy or potentially in androgen supplementation in aging men or hormonal male contraception, is unlikely to induce excessive prostatic effects; however, additional studies of regional sonographic changes in the prostate are needed. Acknowledgments This study was supported by the Medical Foundation of the University of Sydney and the MSD Research Foundation. The authors are grateful to the volunteers, to Dr. A. Millar (Lewisham Sports Medicine Clinic) for referral of patients, and to the staff of the Andrology Unit and Laboratory for their help in conducting this study. References 1. Quigley CA, DeBellis A, Marschke KB, EI-Awady MK, Wilson EM, French FF. 1995 Androgen receptor defects: historical, clinical and molecular perspectives. Endocr Rev. 16:271-321. 2. Imperato-McGinley J, Gautier T, Zirinsky K, et al. 1992 Prostate visualization studies in males homozygous and heterozygous for 5-a reductase deficiency. J Clin Endocrinol Metab. 75:1022-1026. 3. Huggins C, Hodges CV. 1941 Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1:293-297. 4. Huggins C, Stevens RA. 1940 The effect of castration on benign hypertrophy of the prostate in man. J Urol. 43:705-714. 5. Wu J, Gu F. 1987 The prostate 41-65 years post castration. Chinese Med J. 100:271-272. 6. Moore RA. 1944 Benign hypertrophy and carcinoma of the prostate. Surgery. 16:152-167. 7. Nomura A, Heilbrun LK, Stemmermann GN, Judd HL. 1988 Prediagnostic serum hormones and the risk of prostate cancer. Cancer Res. 48:3515-3517. 8. Kimura A, Nakamura S, Niizuma M, et al. 1986 Quantitative analysis of ultrasonogram of the prostate. J Clin Ultrasound. 14:501-507. 9. Bosch JLHR, Hop WCJ, Niemer QHJ, Bangma CH, Kirkels WJ, Schroeder FH. 1994 Parameters of prostate volume and shape in a community based population of men 55 to 74 years old. J Urol. 152:1501-1505. 10. Bangma CH, Niemer AQHJ, Grobbee DE, Schroeder FH. 1996 Transrectal ultrasonic volumetry of the prostate: in vivo comparison of different methods. Prostate. 28:107-110. 11. McNeal JE. 1978 Origin and evolution of benign prostatic enlargement. Invest Urol. 15:340-345. 12. Friedl KE. 1990 Reappraisal of health risks associated with use of high doses of oral and injectable androgenic steroids. NIDA Res Monogr. 102:142-177. 13. Styles RA, Neal DE, Powell PH. 1988 Reproducibility of measurement of prostatic volume by ultrasound: comparison of transrectal and transabdominal methods. Eur Urol. 14:266-269. 14. Hendrikx AJM, vanHelvoort-vanDommelen CAM, van Dijk MAAM, Re-inties AGM, Debruyne FMJ. 1989 Ultrasonic determination of prostatic volume: a cadaver study. Urology. 34:123-125. 15. Jones DR, Roberts EE, Griffiths GJ, Parkinson MC, Evans KT, Peeling WB. 1989 Assessment of volume measurement of the prostate using per-rectal ultrasonography. Br J Urol. 64:493-495. 16. Stone NN, Ray PS, Smith JA, et al. 1991 Ultrasound determination of prostate volume: comparison of transrectal (ellipsoid v planimetry) and suprapubic methods. J Endocrinol. 5:251-254. 17. Terris MK, Stamey TA. 1991 Determination of prostate volume by transrectal ultrasound. J Urol. 145:984-987. 18. Habenicht UF, Schwarz K, Neumann F, EI-Etreby MF. 1987 Induction of estrogen-related hyperplastic changes in the prostate of the cynomolgus mon- 19. Habenicht UF, EI-Etreby MF. 1988 The periurethral zone of the prostate of the cynomolgus monkey is the most sensitive prostate part for an estrogenic stimulus. Prostate. 13:305-316. 20. Weymyss-Holden SA, Hamdy FC, Hastie KJ. 1994 Steroid abuse in athletes, prostatic enlargement and bladder outflow obstruction-is there a relationship? Br J Urol. 74:476-478. 21. Holmang S, Marin P, Lindstedt G, Hedlin H. 1993 Effects of long-term oral testosterone undecanoate treatment on prostate volume and serum prostate-specific antigen concentrations in eugonadal middle-aged men. Prostate. 23:99-106. 22. Lesser MA, Vose SN, Dixey GM. 1955 Effects of testosterone propionate on the prostate gland of patients over 45. J Clin Endocrinol Metab. 15:297-300. 23. Tenover JS. 1992 Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 75:1092-1098. 24. Behre HM, Bohmeyer J, Nieschlag E. 1994 Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf). 40:341-349. 25. Behre HM, Oberpenning F, Nieschlag E. 1990 Comparative pharmacokinetics of androgen preparations: application of computer analysis and simulation. In: Nieschlag E, Behre HM, eds. Testosterone: action deficiency substitution. Berlin: Springer-Verlag; 115-135. 26. Wallace EM, Pye SD, Wild SR, Wu FCW. 1993 Prostate-specific antigen and prostate gland size in men receiving exogenous testosterone for male contraception. Int J Androl. I6:35-40. 27. Bhasin S, Storer TW, Berman N, et al. 1996 The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 335:1-7. 28. Santti R, Newbold RR, Makela S, Pylkkanen L, McLachlan JA. 1994 Developmental estrogenisation and prostatic neoplasia. Prostate. 24:67-78. 29. Thomas JA, Keenan EJ. 1994 Effects of estrogens on the prostate. J Androl. 15:97-99. 30. van Kesteren F, Meinhardt W, van der Valk P, Geldof A, Megens J, Gooren L. Effects of estrogens only on the prostate of aging males [Abstract P2-139]. Proc of the 77th Annual Scientific Meet of The Endocrine Soc. 1995. 31. Goodwin WE, Cummings RH. 1984 Squamous metaplasia of the verumon-tanurn with obstruction due to hypertrophy: long-term effects of estrogen on the prostate in an aging male-to-female transsexual. J Urol. 131:553-554. 32. Asscheman H, Gooren LJG, Eklund PLE. 1989 Mortality and morbidity in transsexual patients with cross-gender hormone treatment. Metabolism. 38:869-873. 33. Roberts JT, Essenhigh DM. 1986 Adenocarcinoma of prostate in 40 year old body-builder. Lancet. 2:742.
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