The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 9 3313-3315
Copyright © 1999 by The Endocrine Society
Breast Tissues in Transsexual Women–A Nonprostatic Source of Androgen Up-Regulated Production of Prostate-Specific Antigen
Victor H. H. Goh
Department of Obstetrics and Gynaecology, National University of
Singapore, National University Hospital, Kent Ridge, Singapore
110794
Address all correspondence and requests for reprints to: Victor Goh, Department of Obstetrics and Gynaecology, National University of Singapore, National University Hospital, Kent Ridge, Singapore 110794; E-mail: obggohhh{at}nus.edu.sg
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Abstract
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The present study made use of the female transsexual model and sought
to evaluate the contributions of the ovarian, endometrial, and breast
tissues to the androgen up-regulated production of prostate specific
antigen (PSA). Serum levels of PSA were significantly raised in female
transsexuals before surgery, after long-term androgen therapy
(mean ± SE = 35.3 ± 6.2 pg/mL) when compared
with female transsexuals before surgery, but with no androgen
therapy (mean ± SE = 1.53 ± 0.25 pg/mL).
In addition, in androngenized female transsexuals, after surgery,
concentrations of PSA (mean ± SE = 14.5 ± 2.8
pg/mL) were significantly lowered compared with androngenized female
transsexuals after surgery, but the levels were, nevertheless,
significantly higher than in normal females. Monthly im injection of
250 mg Sustanon-250 to female transsexuals had raised serum
testosterone levels to within the male range. In five subjects, in whom
serial measurements were taken, serum testosterone levels were greatly
raised 24 h after the testosterone therapy; the mean level
(±SE) was 19.5 ± 2.1 ng/mL. But in spite of these
high testosterone levels, serum PSA levels (mean ± SE
= 2.2 ± 0.9 pg/mL) were not significantly raised. However, after
12 months of androgen therapy, the mean (±SE) PSA level in
these five subjects was 47 ± 11.6 pg/mL and was significantly
higher than the mean level in nonandrogenized female transsexuals. The
present study confirmed that high levels of testosterone were able to
up-regulate PSA production in women. This up-regulation of PSA
production is both a dose- and time-dependent process. Furthermore, the
evidence indicates that breast tissues are possibly a nonprostatic
source of androgen up-regulated production of PSA women.
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Introduction
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RECENT studies have shown that
prostate-specific antigen (PSA) is found in several nonserum tissue
fluids and could be produced by several female tissues, including those
of the breast, ovaries, and endometrium (1, 2, 3). As in men, it is
believed that the production of PSA in females is up-regulated by
androgens (4, 5, 6). Studies have also linked the regulation of PSA to
different phases of the menstrual cycle, especially to the peak
progesterone release during the luteal phase (7, 8). However, the
precise nature of androgen up-regulation of PSA in females remains
unclear (1, 9).
The present study evaluated the effects of the acute and chronic
exposure to high levels of testosterone on the production of PSA in
female transsexuals before and after their sex change surgery. The use
of the transsexual model enabled us to assess the direct effect of high
levels of testosterone on PSA production as well the relative
contributions of the ovarian, endometrial, and breast tissues to serum
PSA levels.
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Materials and Methods
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Informed consent was obtained from two groups of female
transsexuals. A random blood sample was collected from each subject of
the two groups. Group I comprised 48 female transsexuals who had yet to
go through their sex change operation. It was further subdivided into
two groups, Ia (pretreatment) and Ib (androngenized). Group Ia included
the 32 individuals who had not been on any androgen therapy previously,
while Group Ib included those 16 who had undergone androgen therapy
(250 mg Sustanon-250/monthly) for between 4 and 48 months,
according to previously reported hormone replacement regimes (10).
Included in Groups Ia and Ib were 5 presurgery female transsexuals who
were monitored longitudinally. Serum samples were collected before,
24 h after the first im injection of 250 mg Sustanon-250, and 12
months after the initiation of androgen therapy.
Group II (postsurgical) consisted of 15 female transsexuals who had
undergone sex change operations that included reduction mammoplasty,
castration, total hysterectomy, and the construction of a neophallus
(11). They were on testosterone therapy (Sustanon-250, 250 mg/month)
for between 5 and 72 months after their sex change surgery.
Sustanon-250 (Organon, Scotland, UK) is a depot
preparation consisting of a mixture of testosterone esters:
testosterone propionate (30 mg), testosterone phenylpropionate (60 mg),
testosterone isocaproate (60 mg), and testosterone deconoate (100
mg).
Serum PSA levels were measured using the ultrasensitive assay kits from
DSL (Webster, TX). The minimum detection dose was 2 pg/mL. The
interassay coefficients of variation calculated from several sets of
the two internal quality control pools were less than 10%. The sum of
the free and the antichymotrypsin (ACT)-bound fractions constituted the
total immunoreactive PSA (12), and the kits measured the ACT-bound and
free forms of PSA in equimolar concentrations. Serum levels that were
lower than the detection limit of the assay were assigned a value of 1
pg/mL for statistical computations.
Serum testosterone concentrations were measured using both reagents and
method from the World Health Organization Matched Reagent Program (13).
The intra- and interassay coefficients of variation were less than
10%.
The one-way analysis of variances or the nonparamatric Kruskall Wallis
test and paired t test were used for statistical analyses
where appropriate.
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Results
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Serum levels of PSA were significantly raised (P
< 0.0001) in androngenized female transsexuals (Group Ib) when
compared with presurgical, pretreatment female transsexuals (Group Ia;
Table 1
). In addition, after the sex
change operation, which included the total removal of the ovaries and
the womb and most of the breast tissues, the androgen up-regulation of
PSA production was still evident. But serum levels of PSA were
significantly lower when compared with corresponding levels in
pre-operated androngenized female transsexuals of Group Ib (Table 1).
The monthly injection of 250 mg of Sustanon-250 (Organon)
in female transsexuals before (Group Ib) and after (Group II) their sex
change operation had raised serum testosterone levels to within the
male range (2.5–9.7 ng/mL, 14) (Table 1
). The levels of testosterone
after the androgen therapy were not significantly different between
Group Ib and Group II (Table 1).
In the five subjects in whom serial measurements were taken, serum
testosterone levels were greatly raised 24 h after the im
injection of 250 mg Sustanon; the mean level (±SE) was
19.5 ± 2.1 ng/mL and was significantly higher than corresponding
levels in Group Ib. In spite of these high testosterone levels, serum
PSA levels (mean ± SE = 2.2 ± 0.9 pg/mL),
24 h after the im injection of 250 mg Sustanon were not raised and
were not significantly different from corresponding levels in subjects
of Group Ia. However, after 12 months of androgen therapy, the mean
(±SE) PSA levels in these five subjects was 47 ±
11.6 pg/mL and was significantly higher (P = 0.018;
paired t-test) than their corresponding pretestosterone
therapy levels (Fig. 1).
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Figure 1. Mean (±SE) PSA concentrations
in five presurgical subjects before androgen treatment (pretreatment),
24 h after an im injection of 250 mg Sustanon (24 h post), and 12
months after androgen therapy, 250 mg Sustanon, monthly (12 months
post).
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Discussion
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The use of female transsexuals in the present study enabled us to
examine the direct effects of high levels of testosterone on the
production of PSA in women. The results confirmed that PSA production
in women could be up-regulated by exposure to raised testosterone
levels as was suggested by earlier workers (1, 9, 15). Furthermore, the
up-regulation is not just dose- but also time-dependent. Female
transsexuals injected with 250 mg Sustanon 24 h previously, which
raised serum levels of testosterone to more than double those found in
normal men, did not show raised levels of PSA. Those five subjects
monitored longitudinally, as well as the subjects exposed to long-term
high androgen levels in Group Ib, had significantly raised PSA levels.
It must be noted that blood samples from androngenized presurigical
(Groups Ib) and postsurgical (Group II) female transsexuals were
randomly collected without reference to the time when the last im
injection of testosterone was administered. The wide scatter of
testosterone levels noted in these subjects could be accounted for, in
part, by the known uneven releases of testosterone from the depot
preparation over the 4-week intervals. It is important to note that the
current concentration of testosterone was not an index of its effect.
More importantly, it was the duration and dose of the historical
exposure that mattered (16). Therefore, these observations suggested
that exposure to high levels of testosterone for a sufficiently long
duration was required to up-regulate PSA production in women.
The androgen-induced increases in serum levels of PSA in female
transsexuals after the total removal of the ovaries and the womb and
partial removal of breast tissues were still significantly higher than
corresponding levels in pretreatment female transsexuals, although they
were significantly lower than in presurigical androngenized female
transsexuals. These results implied that the remnant breast tissues
left behind after the sex-change operation, including the nipples, were
capable of producing significant amounts of PSA. Therefore, breast
tissues are possibly a nonprostatic source for testosterone
up-regulated production of PSA in women. This suggestion is supported
by an earlier study, which showed that the ovaries and the adrenal are
unlikely sources of PSA (9). In contrast to our study, Breul et
al. (15) found significant differences in urinary levels of PSA,
but not serum PSA between androngenized postsurgery female transsexuals
and 20 females not treated with testosterone. This discrepancy with our
results probably relates to the fact that the ability to up-regulate
PSA production would depend upon the residual amount of breast tissues
left after reduction mammoplasty.
However, the clinical significance of these findings is not clear in
the present study, although several recent studies have implicated the
usefulness of the measurement of PSA in management of women with breast
cancer (17, 18).
In conclusion, the present study confirmed that high levels of
testosterone are able to up-regulate PSA production in women. This
up-regulation of PSA production in women is both a dose- and
time-dependent process. Furthermore, the evidence indicates that breast
tissues are possibly a nonprostatic source of androgen up-regulation of
PSA production in women.
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Acknowledgments
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We would like to acknowledge the financial support from the
National University of Singapore through the department vote and the
technical expertise of Ms. Helen Mok.
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Abstract
Introduction
