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Original Studies |
Division of Endocrinology and Metabolic Diseases (C.N., F.T., G.G.S., M.M., R.C., P.M.), University of Verona, I–37126 Verona; Laboratory of Clinical Chemistry (R.D.), Ospedale Maggiore, I-37126 Verona; Laboratory of Clinical Chemistry (A.F.), Ospedale San Bortolo, I-36100 Vicenza, Italy
Address correspondence and requests for reprints to: Dr. Paolo Moghetti, Divisione di Endocrinologia e Malattie del Metabolismo, Ospedale Maggiore, I-37126 Verona, Italy. E-mail: moghetti{at}iol.it
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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To establish the potential for this assay as a biochemical marker of
androgen action in women, we studied 40 hirsute subjects recruited in a
double-blind, placebo-controlled, 6-month trial assessing the effects
of 3 different antiandrogen drugs: spironolactone, flutamide, or
finasteride. In each subject, serum PSA, free
testosterone, and 3
-androstanediol glucuronide were determined at
baseline and at the end of treatments.
At baseline, PSA concentrations were higher in these 40 women than in 19 nonhirsute healthy controls (12.9 ± 1.5 vs. 4.9 ± 0.7 pg/mL, P = 0.03) and significantly correlated with serum free testosterone (r = 0.37, P < 0.005). After treatments, the 29 hirsute subjects given active drugs showed significant reduction of serum PSA levels (7.2 ± 1.4 vs. 14.7 ± 3.0 pg/mL, P = 0.002). This phenomenon was correlated to baseline PSA values. No change was found in the placebo group.
In conclusion, serum PSA is increased in many hirsute women. A 6-month course of antiandrogen treatments with spironolactone, flutamide, or finasteride determines a reduction of PSA levels in these subjects. These results suggest that serum PSA is a biochemical marker of androgen action in tissues of female subjects.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Until a few years ago, PSA was believed to be produced only in man and only in the prostate. However, using a highly sensitive PSA assay, Diamandis et al. recently demonstrated detectable levels of PSA in serum of women as well (3). Subsequent studies identified this protein in many female tissues and fluids, such as breast, ovary, milk, and amniotic fluid (4). However, the source of circulating PSA in women remains to be determined.
Interestingly, a more recent study from the Diamandis group showed
higher circulating levels of PSA in hirsute than in nonhirsute women
(5). In these subjects, serum PSA was positively correlated with serum
3-androstanediol glucuronide (3-AG), a catabolite of
dihydrotestosterone. Based on these findings, these authors proposed
ultrasensitive assay of serum PSA as a potential new marker of androgen
excess.
Data from another group recently confirmed that serum PSA is higher in hirsute than in nonhirsute women (6). Nevertheless, there was considerable overlap between these subjects. Actually, as compared with established biochemical markers of androgen excess, current methods of PSA assay do not seem to improve assessment of hyperandrogenism (7).
At present, there is no reliable marker of androgen activity in androgen-sensitive tissues. If one were available, it would be of great value in clinical practice. To assess whether serum PSA assay may fulfill this role, we measured serum PSA levels in 40 hirsute women, at baseline and after a 6-month course of double-blind, placebo-controlled treatments with 3 different antiandrogens: spironolactone, flutamide, or finasteride.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Forty young women [mean age (±SEM), 20.4 ± 0.5 yr; body mass index, 24.4 ± 0.7 kg/m2] with moderate-severe hirsutism were studied. These subjects were recruited, after giving written informed consent, to participate in a double-blind, placebo-controlled study, designed to compare the clinical efficacy on hirsutism of three different antiandrogen drugs: spironolactone, flutamide, or finasteride.
The characteristics of women included in the study, and the protocol, are described in detail elsewhere (7A ). Briefly, after baseline evaluations, hirsute women were randomly assigned to double-blind, placebo-controlled treatments with spironolactone (100 mg/day), flutamide (250 mg/day), or finasteride (5 mg/day). Drugs were given once daily for 6 months, as a wafer capsule per os.
The diagnosis of hirsutism was made by using the Ferriman and Gallwey scale, as modified by Hatch et al. (8). All hirsute women recruited in the study had a hirsutism score greater than 10. The mean value was 17.2 ± 0.7.
Adrenal enzyme defects, androgen-secreting adrenal or ovarian tumors, Cushing’s syndrome, hyperprolactinemia, and thyroid dysfunction were excluded in all patients. No subjects suffered from any other disease or were taking medication. None of them had been treated with oral contraceptives or antiandrogen drugs in the last year.
The efficacy of treatments on hair growth was estimated both by the modified Ferriman and Gallwey score and by computer-assisted light microscopy measurement of shaft diameters of hairs plucked from the linea alba. Measurements were carried out at baseline and at the end of treatments.
Blood samples for serum PSA and a standard hormonal profile (including
free testosterone and 3-AG) were obtained at baseline and at the end
of treatments, at 0800 h. In one subject, receiving
spironolactone, posttreatment PSA measurement was not carried out
because of lack of an adequate amount of serum. Data regarding serum
free testosterone and 3-AG have been included in the above mentioned
paper.
When possible, blood samples were collected in the early follicular phase of the menstrual cycle. The luteal phase was excluded in all subjects by serum progesterone assay.
Nineteen age-matched, nonhirsute, regular-cycling women served as controls for serum PSA and androgen assay.
The study was conducted in accordance with the Declaration of Helsinki on human experimentation and was approved by the institutional ethical committee.
Assays
Serum PSA was measured by an ultrasensitive chemiluminescent enzyme immunoassay (Immulite Third Generation PSA, Diagnostic Products, Los Angeles, CA), with a sensitivity of 3 pg/mL and a mean intraassay coefficient of variation at the lowest range of values of 15%. This sensitivity is substantially lower than those of standard methods for serum PSA assay in males, for which the range is 30–500 pg/mL.
Free testosterone and 3-AG were assayed as previously described
(9).
For each parameter, all samples were run in the same assay, in duplicate.
Statistics
Results were analyzed by Student’s t test for paired
and unpaired data, and ANOVA. All tests of significance were
two-tailed, and P values 
0.05 were considered
significant. Data were expressed as means ±
SEM.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-AG.
Figure 1
shows individual and mean values
of serum PSA, free testosterone, and 3-AG, at baseline and at the
end of the study, in hirsute women, divided according to treatment with
spironolactone, flutamide, finasteride, or placebo.
Pretreatment values of all parameters examined were similar in the four
treatment groups.
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Among these 29 hirsute women, 22 (75.9%) showed reductions in this parameter. This percentage was slightly increased (85.7%) when only women with increased baseline PSA were taken into account.
Interestingly, after treatment, serum PSA concentrations, as compared with baseline values, were decreased in each group given an active drug, though the difference did not reach statistical significance in women given spironolactone (P = 0.08). The percentage of subjects presenting reductions in PSA levels did not show significant differences among treatment groups (67, 90, and 70%, respectively, for the spironolactone, flutamide, and finasteride groups).
Serum 3-AG was significantly decreased in the
finasteride group, consistent with inhibition of
5-reductase activity. On the other hand, no other significant
changes in serum 3-AG and free testosterone levels were found after
treatment in any groups receiving antiandrogen drugs.
No changes were found in PSA, 3-AG, or free testosterone
concentrations in the placebo group.
At baseline, PSA values were positively correlated with serum free
testosterone (r = 0.37, P < 0.005), whereas no
significant relationship was found with 3-AG levels (r = 0.15,
P = 0.33). In women receiving active drugs, changes
after treatments in serum PSA correlated closely with baseline PSA
values (Fig. 2). On the other hand,
changes in PSA concentrations did not correlate with changes in any of
the other endocrine parameters examined (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-AG levels.
The most relevant finding of our study was reduction of PSA levels, by
about 50%, in hirsute women after antiandrogen therapy, regardless of
which antiandrogen drugs were used. Noticeably, drugs examined in the
study interfere with androgen action by different mechanisms. Whereas
spironolactone and flutamide are antagonists of androgen binding to the
androgen receptor (10, 11), finasteride is an inhibitor of
5-reductase, the enzyme that transforms testosterone to its active
metabolite dihydrotestosterone (12). Though the source(s) of serum PSA
in women is (are) still unknown, this observation suggests that this
parameter might reflect androgen action in one or more
androgen-sensitive tissues.
In men with either benign prostatic hyperplasia or prostate cancer who were given finasteride or flutamide, a 20–50% reduction in serum PSA levels was observed (13, 14). Interestingly, in men receiving flutamide for prostate cancer, this phenomenon showed a correlation with baseline PSA concentrations (14). A similar relationship was found in our hirsute women given antiandrogen drugs.
The overlap between serum PSA levels in healthy women and hirsute subjects suggests that PSA assay does not contribute substantial information in the baseline biochemical assessment of androgen-excess conditions. On the other hand, our results support the intriguing hypothesis that ultrasensitive assay of serum PSA might afford us a marker of androgen activity in women. This perspective is of great value because, at present, there is no reliable biochemical marker of the biological action of androgens. Recent data in female-to-male transsexuals, showing increased serum PSA after treatment with high doses of testosterone, are consistent with this hypothesis (15).
In conclusion, ultrasensitive assay of serum PSA shows that this parameter is increased in many hirsute women. A 6-month course of antiandrogen treatment with spironolactone, flutamide, or finasteride determines a reduction of serum PSA levels in these subjects. These results suggest that serum PSA assay in females may be a useful marker of androgen action in androgen-sensitive tissues.
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Acknowledgments |
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Footnotes |
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Received June 1, 1999.
Revised August 23, 1999.
Accepted September 13, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase inhibitor
finasteride in idiopathic hirsutism. J Clin Endocrinol Metab. 79:1115–1121.[Abstract]
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