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Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario M5G 1X5, Canada, and Department of Laboratory Medicine and Pathobiology, University of Toronto, 100 College St., Toronto, Ontario M5G 1L5, Canada.
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Department of Endocrinology, Division of Andrology,
Hospital Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, The
Netherlands.
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Louisiana State University Medical Center, Department of
Medicine, 1501 Kings Hwy., Shreveport, LA 71130-393.
a Address correspondence to this author at: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario M5G 1X5, Canada. Fax 416-586-8628; e-mail ediamandis{at}mtsinai.on.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: We measured serum and urinary PSA and hK2 before, and 4 and 12 months post testosterone treatment by immunofluorometric methods in 32 female-to-male transsexuals.
Results: Mean serum PSA increased from 1.1 ng/L to 11.1 ng/L and then to 22 ng/L by 4 and 12 months post treatment, respectively; the corresponding mean values in urine were 17, 1420, and 18 130 ng/L, respectively. Serum hK2, another kallikrein closely related to PSA, remained undetectable at the three time points. However, urinary hK2 concentration rose from below the detection limit (<6 ng/L) before treatment to 18 and 179 ng/L by the 4th and the 12th month of treatment, respectively. All changes were statistically significant (P <0.001) at 4 months.
Conclusions: Testosterone administration increases serum and urinary PSA and urinary hK2 in women. These measurements may be useful as indicators of androgenic stimulation in women.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Androgens down-regulate androgen receptor gene expression in vitro (17)(19). Long-term administration of androgens in vivo produces self-limited androgen receptor-dependent transactivation, without significant changes in androgen receptor concentrations. This most probably reflects posttranslational control of androgen receptor activity (18).
Testosterone is present in females, although at only 5–10% of the concentrations found in males (20). In women, androgens affect sexual as well as cognitive function, mood, and general well-being (21), and they are used for female-to-male transsexuals to help the assumption of male secondary sexual characteristics.
In this study, we monitored PSA responses in urine and serum, as well as hK2 response in urine, obtained from female-to-male transsexuals undergoing long-term androgenizing treatment with testosterone. We also attempted to correlate PSA and hK2 concentrations to those of testosterone and other hormones and biomarkers directly or indirectly affected by the administered androgen.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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immunological assays
PSA was measured in undiluted serum and in urine initially diluted
1:10 in a 60 g/L bovine serum albumin solution, pH 7.40, using a
one-step time-resolved fluorometric immunoassay (22). Urine
samples with results below the detection limit (1 ng/L) were reanalyzed
without prior dilution.
hK2 was measured in undiluted serum and urine using a two-step time-resolved immunofluorometric assay with a detection limit of 6 ng/L (23).
A competitive chemiluminescence immunoassay was used to determine serum
free thyroxine (in pmol/L; ACS:180 System; Chiron Diagnostics).
RIAs were used to measure serum testosterone (Coat-A-Count; DPC), serum
5
-dihydrotestosterone (DHT, in nmol/L) after oxidation and
extraction (Intertech), and serum thyrotropin (in mIU/L;
ACS:180). Immunochemiluminogenic assays were used to assess serum
luteinizing hormone (LH) and serum follicle-stimulating hormone (FSH),
both in IU/L (Amerlite; Amersham). IRMAs were used to assess
serum sex hormone-binding globulin (in nmol/L; Orion Diagnostica), and
serum growth hormone (GH, in µg/L; GH color; Sorin Biomedica).
statistical analysis
Because the distribution of all measured variables was nongaussian
(Z-score), statistical analyses were performed using
nonparametric tests. Associations were examined at pretreatment, 4
month post treatment, and where applicable, at 12 months post treatment
using Spearman correlation and Wilcoxon signed-ranks test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A, mean PSA in serum increased from almost undetectable
concentrations to 11 ng/L by the 4th month of steroidal treatment
(P <0.001) and to 22 ng/L by the 12th month of treatment.
Similarly, urinary PSA increased dramatically in response to
testosterone treatment, from 17 ng/L to 1420 ng/L by the end of the 4th
month of therapy, and to 18 130 ng/L by the end of the treatment
period (P <0.001; Fig. 1B
). hK2 could not be detected in
female serum but was readily detectable in urine. Urinary hK2 increased
from a mean of <6 ng/L prior to treatment to 18 ng/L at 4 months of
treatment (P <0.001) and 179 ng/L at 12 months
(P <0.001; Fig. 1C
). Mean serum DHT increased from 0.7
nmol/L to 2.3 nmol/L at 4 months, and to 3.5 nmol/L at 12 months.
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Before treatment, no correlation of FSH and/or LH with either PSA or
hK2 was apparent. At 4 months of treatment, however, urinary PSA
correlated weakly with LH and FSH. FSH correlated with LH
(r = 0.639; P <0.0001) at 4 months of
treatment, as well as at 12 months post treatment (r =
0.858; P = 0.001). After 4 months of testosterone
therapy, serum PSA was found to correlate negatively with serum
testosterone and positively with insulin, whereas urinary PSA
correlated with urinary hK2 (Table 1
). By the 12th month of treatment, serum PSA had no noteworthy
correlations with any of the variables tested. However, at 12 months of
treatment, the correlation between urinary hK2 and PSA was better
(r = 0.723; P = 0.003) compared with
the correlation at 4 months post treatment for the same set of subjects
(Table 1
). Other associations relevant to our study included the
expected correlation between testosterone and DHT at 4 months
(r = 0.719; P = 0.004) and at 12 months
of treatment (r = 0.802; P = 0.001). As
expected, testosterone and DHT significantly increased after
testosterone administration; LH, FSH, sex hormone-binding globulin, and
thyroxine decreased, whereas GH and thyrotropin showed no significant
change (data not shown). We also noted a negative correlation of
urinary hK2 with body mass index (r = -0.692;
P = 0.006) and with serum insulin (r =
-0.681; P = 0.007).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Increased urinary PSA could not have originated by clearance from plasma alone, based on calculations of fractional clearances (data not shown). Thus, the source of PSA in urine may be different from that of PSA in serum. Interestingly, in a previous case study of a woman with carcinoma of the Skene gland, serum PSA was 5900 ng/L before surgery; after surgery, serum PSA became undetectable (24). This case report points out that under normal circumstances, the Skene gland does not contribute significantly to serum PSA concentrations as was also confirmed in males (25). Relying on our previous studies of PSA and hK2 in breast tumor tissues and nipple aspirate fluid (3)(4)(26)(27), we suggest that the source of PSA in serum may be the female breast. We propose that PSA production is under androgenic control in breast tissue as well as in the Skene gland. The latter is the most likely source of both PSA and hK2 in urine.
The increased urinary hK2 in response testosterone administration suggests that hK2 is under androgenic control. The good correlation between urinary PSA and hK2 supports the notion that hK2 arises from the same source as PSA. Furthermore, the fact that PSA itself is known to be activated by hK2 provides a physiological rationale for their coexpression (12)(13).
Serum LH concentrations are known to be lower in testosterone-treated female-to-male transsexuals than in controls (28). According to our data, LH and FSH decreased, and this decrease can be accounted for by testosterone-induced negative feedback at the hypothalamo-pituitary level (29)(30). Interestingly, hK2 in urine correlated negatively with body mass index and with serum insulin. The expected increase in DHT concentration was also appreciable, considering the fact that male serum DHT values usually are ~2 nmol/L. Testosterone also had a good correlation with GH, which may be explained by the fact that, at least in males, androgen affects GH release into the circulation (20).
It should be noted that androgen is not the sole physiological up-regulator of the PSA and hK2 genes. In vitro studies (14)(16) and in vivo data (6)(31)(32) clearly demonstrate up-regulation of these genes by progestins. Our study demonstrates, for the first time in vivo, that testosterone can up-regulate quite significantly the PSA and hK2 genes in target tissues and mediate serum and urinary PSA increases post treatment. This finding gives credence to previous reports of increased serum PSA in patients with hyperandrogenic syndromes (7)(8). The target tissues have not yet been identified. Likely, both urinary PSA and hK2 are produced by the periurethral and paraurethral glands and then secreted into the urine. It will be worthwhile to examine whether urinary PSA and hK2 have any value as biochemical indicators of hyperandrogenism in women. This possibility is now under investigation.
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Footnotes |
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-dihydrotestosterone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; and GH, growth hormone. 
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References |
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The following articles in journals at HighWire Press have cited this article:
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  M. H. Slagter, L. J.G. Gooren, A. Scorilas, C. D. Petraki, and E. P. Diamandis Effects of Long-term Androgen Administration on Breast Tissue of Female-to-Male Transsexuals J. Histochem. Cytochem., August 1, 2006; 54(8): 905 - 910. [Abstract] [Full Text] [PDF]
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 M. H. Slagter, A. Scorilas, L. J.G. Gooren, W. de Ronde, A. Soosaipillai, E. J. Giltay, M. Paliouras, and E. P. Diamandis Effect of Testosterone Administration on Serum and Urine Kallikrein Concentrations in Female-to-Male Transsexuals Clin. Chem., August 1, 2006; 52(8): 1546 - 1551. [Abstract] [Full Text] [PDF]
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M. H. Slagter, L. J.G. Gooren, W. de Ronde, A. Soosaipillai, A. Scorilas, E. J. Giltay, M. Paliouras, and E. P. Diamandis Serum and Urine Tissue Kallikrein Concentrations in Male-to-Female Transsexuals Treated with Antiandrogens and Estrogens Clin. Chem., July 1, 2006; 52(7): 1356 - 1365. [Abstract] [Full Text] [PDF]
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 C. V. Obiezu, A. Scorilas, A. Magklara, M. H. Thornton, C. Y. Wang, F. Z. Stanczyk, and E. P. Diamandis Prostate-Specific Antigen and Human Glandular Kallikrein 2 Are Markedly Elevated in Urine of Patients with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1558 - 1561. [Abstract] [Full Text]
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