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Estimating the Contribution of the Prostate to Blood Dihydrotestosterone

Department of Endocrinology/Andrology, Vrije Universiteit University Medical Center (A.W.F.T.T., L.J.G.), 1007 MB Amsterdam, The Netherlands; and Department of Andrology, Concord Hospital and ANZAC Research Institute, University of Sydney (S.K., M.J., D.J.H.), Sydney, New South Wales 2139, Australia

Address all correspondence and requests for reprints to: Prof. D. J. Handelsman, ANZAC Research Institute, Sydney, New South Wales 2139, Australia. E-mail: djh{at}anzac.edu.au.

	Abstract

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The prostate strongly expresses type 2 5-reductase, which avidly converts on entry most testosterone (T) to 5-dihydrotestosterone (DHT). However, the quantitative contribution of the prostate to blood DHT is uncertain. We evaluated prostatic contribution to blood DHT by comparing the blood DHT concentrations in androgen-deficient patients with or without a prostate while they were receiving standard dose of T replacement. Androgen-deficient males (ADM) and female to male (F2M) transsexuals were studied in 2 centers, with both groups receiving either testosterone ester injections (250 mg mixed T esters) every 1 wk (Amsterdam) or 800 mg subdermal T implantation (Sydney). Among 39 Dutch patients, F2M (n = 21) were younger and smaller in physique than ADM (n = 18). One week (±1 d) after an injection, plasma DHT concentrations were 1.6 ± 0.2 (F2M) vs. 1.4 ± 0.2 (ADM) nmol/liter (P = 0.47), but the postinjection time interval to blood sampling was shorter in F2M (5.9 ± 0.4 vs. 7.2 ± 0.3 d; P = 0.01). Covariance adjustment for time since last injection, age, and physique did not change the lack of significant difference in postinjection plasma DHT concentration. The rapid and wide excursions in plasma T concentrations after an im T ester injection make the timing of blood sampling critical. To remove confounding by this variable, the experiment was repeated at a second site in similar patients, but using a depot T that achieves steady-state delivery for prolonged periods. Among 29 Australian patients, before and 1 month after subdermal implantation of 800 mg T, plasma DHT concentrations were not significantly different between groups [F2M, 1.1 ± 0.1 (n = 14); ADM, 1.3 ± 0.1 (n = 15); P = 0.28]. Correction for covariates, including age, height, weight, body surface area, and body mass index, did not influence the lack of significant difference between treated groups. As both modes of T administration yielded similar plasma DHT concentrations regardless of the presence of a prostate, this study indicates that the normal human prostate is not a major contributor to circulating blood DHT concentrations.

	Introduction

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DIHYDROTESTOSTERONE, THE MOST potent natural androgen, is formed exclusively through 5-reduction of testosterone (T) by the enzyme 5-reductase. This enzyme has two forms produced by distinct, homologous genes, with type 1 5-reductase expressed in liver, skin, and brain, whereas type 2 5-reductase is characteristically expressed strongly in the prostate and at lower levels in skin and liver (1). The functional predominance of prostatic expression type 2 5 reductase made it feasible to develop a prostate-targeted 5-reductase inhibitor, finasteride (2), with the organ specificity based largely on strong expression of the type 2 enzyme in the prostate. Circulating DHT levels are approximately 10% of the blood T levels, mostly arising from nongonadal tissues that express 5-reductase. The testis expresses type 1 5-reductase (3), but at relatively low levels, so that the testis secretes quantitatively minimal DHT into the bloodstream.

Peripheral circulating DHT concentrations (or the ratio of DHT to T) could in theory be considered an estimate of 5-reductase activity in androgen target organs that strongly express 5-reductase. As the classical androgen target organ, the prostate expresses not only high levels of the androgen receptor (4), but also type 2 5-reductase so that more than 95% of T entering the prostate is converted to DHT (5). Two different approaches have supported the contention that prostatic conversion of T to DHT may contribute significantly to circulating DHT levels. One approach involves estimating the effects of type 2 5-reductase from specific enzyme inhibition. A pharmacokinetic-pharmacodynamic study modeling DHT turnover in the presence of two irreversible inhibitors of 5-reductase, one selective for type 2 (finasteride) and the other a dual inhibitor of both types 1 and 2 (GI198745), estimated that about 80% of circulating DHT was formed by type 2 5-reductase (6). This is consistent with finasteride treatment reducing circulating DHT by 60% (7). The other approach is to estimate blood DHT after prostatectomy. A study of 63 men before and 1 yr after total prostatectomy for biopsy-identified local prostate cancer showed a persistent decrease in circulating DHT together with increased T, producing a lowering of the DHT/T ratio (8). By contrast, a smaller study of 28 men before and after retropubic prostatectomy for benign prostatic hypertrophy showed that DHT levels were lowered after surgery and took longer than T to return to the presurgical baseline (9). The latter study, however, involved only partial prostatectomy, and similar observations with minimal changes in blood DHT have been reported after partial prostatectomy (10, 11). We have undertaken a novel approach to estimate the contribution of the prostate to circulating DHT levels by examining the influence of the presence of a prostate on blood DHT concentrations. We compared blood DHT concentrations in two groups of androgen-deficient subjects receiving the same dose of exogenous T. One group consisted of female to male transsexuals (F2M) who had no prostate, and the other was comprised of androgen-deficient men (ADM) who had a prostate. If the prostate releases substantial DHT into the bloodstream, those with a prostate should have higher circulating DHT levels than those without, and, in principle, the discrepancy might estimate the quantitative contribution of the prostate to circulating DHT. Conversely, if DHT levels did not differ, the prostate makes an insignificant contribution to circulating DHT.

	Subjects and Methods

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Patients

F2M transgender and ADM receiving regular androgen replacement therapy according to the local standard treatment were recruited at each study center. In Amsterdam, T treatment was provided by im injections of 250 mg mixed T esters (Sustanon, Organon, Oss, The Netherlands) at 2-wk intervals (12), whereas in Sydney, implantation of 800 mg T (four 200-mg pellets) under the skin of the lateral abdominal wall or over the iliac crest at 4- to 6-month intervals was used (13). Patients with other pituitary hormone deficiencies were treated with appropriate hormone replacement therapies. The relevant local institutional ethics committees approved the studies, and all participants provided written informed consent. Venous blood samples were taken from the anterior cubital fossa, and plasma was stored frozen until assay.

Procedures

Two studies with similar open label design were conducted first in Amsterdam, then in Sydney. In the first study, patients provided a single blood sample, obtained between 0830 and 1400 h, 1 wk (intended 6–8 d) after the patients received an im injection of mixed T esters (250 mg Sustanon). In the second study, blood samples were obtained before and 1 month after subdermal implantation of 800 mg T implants (four 200-mg pellets; Organon). The rationale for the second study was to resolve whether variation in the timing of collection of postinjection blood samples influenced DHT levels. The marked between-subject and day to day variability in plasma T concentrations after im injection of T esters has been well described (14, 15) and might obscure a formal test of the hypothesis.

Assays

All samples were assayed within a single batch per study in the Andrology laboratory, ANZAC Research Institute. LH (specific), FSH, T, estradiol, and SHBG assays were performed using Delfia kits (PerkinElmer, Branchburg, NJ). Within-assay coefficients of variation were 12.4%, 2.6%, 7.5%, 8.1%, and 5.1%, respectively. Plasma DHT was assayed as described previously (16). Briefly, samples (0.1 ml) underwent organic solvent extraction with hexane/ethyl acetate (3:2), with procedural recovery calculated from samples spiked with tritiated DHT tracer. After extraction, the organic fraction was dried overnight and reconstituted with a 1% gelatin PBS buffer. Standards and samples are oxidized by exposure to 0.5% potassium permanganate for 30 min, with oxidation terminated via a second organic extraction. The dried organic extract was reconstituted and assayed using antibody C0457 (Bioquest, North Ryde, Australia) and a liquid chromatography-purified tritiated DHT tracer. These samples were then incubated for 16 h at 4 C, with free and bound steroids separated with dextran T70-coated charcoal. The detection limit was 20 pmol/tube or 0.2 nmol/liter based on a sample volume of 0.1 ml, and the within-assay coefficient of variation was less than 9.5%. The young male eugonadal reference range was 0.8–3.3 nmol/liter (mean DHT, 2.0 nmol/liter) based on a sample of 55 healthy eugonadal men (aged 18–50 yr; no infertility, regular medication, or chronic illness; 2 semen analyses with sperm density >20 million/ml; normal blood LH, FSH, and T). Samples from prepubertal boys or castrated men had blood DHT concentrations below 0.2 nmol/liter.

Data analysis

Differences between groups were analyzed by unpaired t test for between-subject analyses (study 1 and between-group comparisons in study 2), paired t test for within-subject effects (pre- vs. posttreatment effects in study 2), and analysis of covariance as appropriate. Variables with baseline differences [such as age, height, weight, and body surface area (BSA)], number of days since injection, and SHBG were used as covariates. Correlation and regression were performed using linear least squares regression and were confirmed by Spearman rank correlation in the case of violations of bivariate normality. The body mass index (BMI) was calculated as weight (kilograms) divided by the square of height (meters) and BSA according to the Gehan and George formula (17). Statistical analysis was undertaken with SPSS and NCSS software and power estimates with PASS software. All data are presented as the mean and SEM unless stated otherwise.

	Results

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Participants were 21 F2M and 18 ADM patients in Amsterdam and 14 F2M and 15 ADM patients in Sydney, whose characteristics are summarized in Table 1. F2M included 15 who had and 20 who had not undergone ovariectomy. ADM included diagnoses of hypergonadotropic (Klinefelter’s syndrome, n = 8; other testicular failure, n = 9) and hypogonadotropic (isolated, n = 6; panhypopituitarism, n = 10) hypogonadism, with similar distributions at each center. In both centers, F2M were younger, shorter, and lighter than ADM, although the difference in weight and physique (BSA) was not significant in the Sydney center. The degree of adiposity (BMI) did not differ between groups at each center. Within each center, the median time on T treatment did not differ between groups (17 vs. 20 months in Amsterdam and 58 months vs. 45 months in Sydney, respectively).

In study 2, blood samples were taken at similar times after implantation for both groups (Table 3). DHT and T concentrations and the DHT/T ratio were not significantly different between F2M and ADM either before or after T implantation. The DHT/T ratio was lowered to a similar degree in both groups after T administration. Covariance adjustment for between-group differences in age or anthropometric data (height, weight, BMI, and BSA) did not modify the nonsignificance of the between-group comparisons in DHT, T, or DHT/T ratio.

	Discussion

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The present findings suggest that the quantitative contribution of the normal prostate to circulating blood DHT concentrations is negligible. Two studies with the same overall objective and design of comparing genetic males with androgen deficiency (who have a prostate) with androgen-treated genetic females (who do not) gave consistent findings that neither DHT levels nor DHT/T ratios were significantly different between these two groups of T-treated individuals. If the hypothesis that the prostate contributes significant amounts of DHT to blood DHT concentrations were correct, then it would be predicted that after the administration of a standard dose of T, genetic females would produce less DHT than ADM, resulting in lower plasma levels of DHT in F2M. The first study showed no difference in the primary end points, but also had a number of potentially confounding variables, including differences in age and physique (BSA), SHBG concentrations, and, most importantly, time between im injection and blood sampling. Although covariance adjustment to account for such potential effect modifiers did not alter the findings for the primary end points, we undertook an additional study with the intention to control more tightly for intermediary variables such as plasma T concentrations and time since T administration. For this purpose we repeated the study using T pellet implants, which exhibit very stable day to day plasma T concentrations (13), and tightly controlled the time between T administration and blood sampling. Nevertheless, the findings of the second study confirmed those of the first that there was no difference in plasma DHT between groups and, accordingly, in whether a prostate was present. Hence, our hypothesis that the prostate is a major contributor to circulating levels of DHT is effectively refuted. Presumably other androgen target organs, including the skin and liver, must be the major contributors to circulating DHT. As direct measurement of isotope conversion rates suggests that the liver converts very little T to DHT (18), the precise tissue source of most blood DHT remains to be clarified. As it is well known that androgen action on skin (19) and hair (20) evolves slowly during and after puberty, this raises the possibility that the effects of T may not have yet reached a plateau in our study. This seems unlikely, as our study populations had been treated with full doses of T for some years compared with the much slower rise of endogenous androgens during male puberty. Finally, as DHT is metabolized faster in genetic males than females (21), if this were determined by an androgen-insensitive mechanism, a prostatic contribution to blood DHT might have been obscured. Although we cannot exclude this possibility, it seems unlikely, as the metabolic clearance rates of the endogenous androgens T and DHT are governed primarily by blood SHBG concentration (22). However, blood SHBG concentrations are both androgen sensitive and not systematically different between groups in experiment 2, making this possibility unlikely.

Blood SHBG concentrations differed strikingly between the two study centers. This is probably due to the different T treatment regimens employed. This interpretation is supported by the fact that pretreatment blood SHBG concentrations in the Dutch F2M patients (23) were very similar to those observed at the Sydney center before and during the use of T implants, which, by contrast, do not lower blood SHBG concentrations (24, 25). In a crossover study in which 15 hypogonadal men were administered, in random order, oral, injectable, and implantable T, injectable T esters caused marked lowering of blood SHBG reciprocally related to ambient blood T concentrations, whereas Te implants had no effect on blood SHBG concentrations in that (24) or larger pharmacological studies of T implants involving 43 men receiving doses of 600 or 1200 mg (25). A minor decrease in blood SHBG concentrations was observed in another study of 14 men receiving the high (1200 mg) dose (26). This latter discrepancy may be due to the fact that the lowering of blood SHBG is a good marker of supraphysiological hepatic androgen exposure. This supposition is supported by the reciprocal relationship of blood T concentrations and im T ester injections, whereas oral T undecanoate causes a prominent and persistent lowering of blood SHBG concentrations (24). Oral T undecanoate presents a heavy hepatic portal androgen load despite a proportion being absorbed via intestinal lymphatics (27, 28). Similarly, the use of oral stanozolol as a marker of androgen responsiveness in the spectrum of congenital androgen insensitivity syndromes (29, 30, 31) is related to the obligatory first pass hepatic overdosage of any oral androgen. It is very unlikely that between-center differences in SHBG were due to sample storage or assay artifacts, as all SHBG measurements were performed in the same assay at the Sydney center, with unbroken frozen storage for no more than a few months, whereas SHBG is highly stable (32, 33, 34). The lower blood SHBG concentrations in F2M in Amsterdam, but not in Sydney, probably also reflect the different treatment regimens, in that F2M display greater adherence to injection schedules for a treatment they have sought despite difficulties compared with ADM who are less enthusiastic and tolerate injections but are not infrequently late or seek longer interinjections intervals. By contrast, tolerance of implants and adherence to less frequent (6 monthly) and more convenient treatment schedules are greater for patients with implants.

The reduction of T to DHT is governed by 5-reductase, of which there are two isoforms, types 1 and 2 (1). Type 2 5-reductase is highly expressed in the prostate and other genital tissues, arising from embryonic urogenital sinus as well as transiently in skin and scalp after birth (35). Type 1 5-reductase is localized in the skin, whereas the liver contains both types. The regulation of both forms is poorly understood. The effects of endogenous androgen during male puberty and of exogenous androgens during T treatment of hypogonadal men (36) and F2M (12) typically take considerable time (months to years) to develop characteristic effects on skin and appendages, such as acne, facial and body hair, and male pattern baldness (20). This is consistent with androgen stimulating the expression of type 1 5-reductase in the skin and scalp (1) and of type 2 5-reductase in the prostate (37). The present study avoided confounding by variable androgen effects on 5-reductase activity by studying patients already long stabilized on T treatment.

Our findings must be reconciled with previous observations that blood DHT levels are lowered in congenital type 2 5-reductase deficiency (38, 39), that a specific type 2 inhibitor (finasteride) markedly lowers circulating DHT (7), and that a modeling study of type 1 and 2 inhibitors indicates that type 2 isoenzyme contributes approximately 80% of the circulating DHT (6). The present finding of no difference in blood DHT levels between the two studied groups presumably indicates that circulating DHT originates predominantly from reduction of T to DHT by 5-reductase type 1 and/or type 2 isoenzyme located in nonprostatic tissue. Although the prostate strongly expresses type 2 5-reductase, based on our findings it contributes only a small proportion of the net contribution to total body type 2-reductase activity, reflecting the mass of prostate tissue relative to other tissues. Although the effects of finasteride treatment on blood DHT may be exaggerated by the enlarged prostate size, this explanation does not apply to studies involving healthy men and those with biopsy-identified prostate cancer, who are presumed to have normal prostate size. On the other hand, where prostate enlargement is present, it is possible the prostate makes a proportionately larger contribution to blood DHT concentrations. The persistent reduction in DHT and the DHT/T ratio for at least 1 yr after total prostatectomy (8) is harder to reconcile. It is possible that the younger age of our population (meaning that our study group had smaller prostates, less affected by prostatic hyperplasia) may be responsible for this difference. Further studies of blood DHT after total prostatectomy, particularly relating postoperative DHT to prostate size, would be of interest in this context. Previous studies of partial prostatectomy provide only ambiguous evidence in this context due to the variable extent of prostatectomy and reductions in blood DHT (9, 10, 11). Another possibility that cannot be excluded is that androgenic stimulation in the F2M of Skene’s glands [also known as the "female prostate" (40)] may account for the enhanced expression of type 2 5-reductase activity. In conclusion, although most circulating DHT may be derived from type 2 5-reductase, quantitatively this enzymatic reaction occurs predominantly in tissues other than the normal prostate.

	Footnotes

 
Abbreviations: ADM, Androgen-deficient males; BMI, body mass index; BSA, body surface area; DHT, 5-dihydrotestosterone; F2M, female to male; T, testosterone.

Received March 26, 2003.

Accepted July 19, 2003.

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