Full text of DOI:10.1007/BF03345504

J. Endocrinol. Invest. 25: RC29-RC31, 2002
RAPID COMMUNICATION
Prostate-specific antigen is increased in female patients with
Cushing’s disease
L. Manetti*, I. Lupi*, F. Bogazzi*, G. Pellegrini**, A. Precisi**, L. Grasso*, C. Nencetti*, M. Gasperi*,
and E. Martino*
*Department of Endocrinology and Metabolism, University of Pisa, **Clinical Chemistry Laboratory, Azienda Ospedaliera
Pisana, Pisa, Italy
ABSTRACT. Prostate-specific antigen (PSA) is a serine protease with chymotripsine-like enzymatic
activity, produced primarily by the prostate gland. It is widely used as a marker of androgen sensi-
tive-prostate cancer. Likewise, women with androgen-dependent hirsutism have increased serum
PSA levels. The aim of the present study was to investigate whether female patients with Cushing’s
disease had increased serum PSA concentrations. We studied 22 patients with active Cushing’s dis-
ease. Twelve out of 22 patients were also evaluated after remission of the disease. Forty normal wom-
en with no signs of hirsutism served as controls. Mean serum PSA levels were higher in patients with
active Cushing’s disease than controls (p=0.005). Mean serum PSA levels decreased after remission of
the disease (33.7 63.3 pg/ml vs 2.2 3.0 pg/ml, p<0.002, in active and cured patients, respectively). All
patients with high serum PSA levels had a normalization of this parameter after the disease was cured.
Serum T, DHEAS and Δ4 concentrations decreased after the remission of Cushing’s disease. A posi-
tive correlation was found between serum PSA and T values (r=0.6, p<0.05). In conclusion, elevated
serum PSA values are markers of androgen activity in female with Cushing’s disease and their nor-
malization may represent an additional index of remission of the disease.
(J. Endocrinol. Invest. 25: RC29-RC31, 2002)
©2002, Editrice Kurtis
INTRODUCTION
tion of female patients with Cushing’s syndrome presents
signs of hyperandrogenism (acne, amenorrhoea and hir-
sutism), the aim of the present study was to evaluate
whether female patients with Cushing’s disease have in-
creased serum total PSA levels.
Prostate-specific antigen (PSA) is a 33-kDa serine pro-
tease with chymotrypsin-like enzymatic activity (1). PSA
is produced primarily by the prostate gland and is de-
tectable in serum and seminal plasma; in addition, PSA is
a specific serum marker for the diagnosis and follow-up of
prostate cancer (2). Recently, the development of an ul-
trasensitive assay has allowed the detection of serum to-
tal PSA in a significant number of females with hirsutism
(3-6), indicating that this protein may be a marker of hy-
perandrogenism. Further studies have reported the ex-
pression of PSA in various female tissues and fluids, such
as breast, ovary, endometrium, milk, amniotic and breast
cyst fluid (7). PSA gene expression and protein produc-
tion appear to be up-regulated by androgens, glucocorti-
coids and progestins (8, 9). Since, a significant propor-
SUBJECTS AND METHODS
Subjects
Twenty-two women with active ACTH-dependent
Cushing’s disease (mean age SD 40 11 yr, range 18-59
yr) were enrolled in the study. A longitudinal study was
conducted in 12 (mean age 40 14 yr, range 18-59 yr) pa-
tients out of 22 (CD Long); these patients were evaluat-
ed during the activity of disease (CD-Act,) and in remis-
sion (CD-Rem) 1-3 yr after transsphenoidal adenomec-
tomy (no.=9) or with the addition of radiotherapy and
bilateral adrenalectomy (no.=3). Forty normal women
(mean age 40 13 yr, range 17-66 yr) matched for age and
with no signs of hirsutism served as controls (Controls).
Neither the patients nor controls had taken contracep-
tive pills or transdermal estrogen during the study peri-
od. Diagnosis of Cushing’s disease and the definition of
remission were based on standard clinical and laborato-
ry criteria (10).
Key-words: PSA, Cushing, cortisol, hyperandrogenism, T, DHEAS, ꢀ4.
Correspondence: Prof. Enio Martino, Dipartimento di Endocrinologia,
Università di Pisa, Ospedale di Cisanello, via Paradisa, 2, 56124 Pisa, Italia.
E-mail: emartino@endoc.med.unipi.it
Accepted June 17, 2002.
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L. Manetti, I. Lupi, F. Bogazzi, et al.
Assays
250
200
150
100
50
Serum total PSA was measured by an ultrasensitive chemi-
luminescent enzyme immunoassay (Immulite Third Gene-
ration PSA, Diagnostic Products Corp., Los Angeles, CA,
USA) with a sensitivity of 3 pg/ml. All serum samples were
analyzed in duplicate in a single run; the intra-assay coeffi-
cient of variation was <10%. Commercial kits were used
for serum T (n.v. 0.1-1.0 ng/ml) (DiaSorin, Saluggia, Italy),
DHEAS (n.v. 350-4300 ng/ml) (Immulite, Diagnostic
Products Corp., Los Angeles, CA, USA), ꢀ4 (n.v. 0.4-3.0
ng/ml) (DiaSorin Inc., Stillwater, MN, USA), cortisol (n.v.
85-250 ng/ml) (Immunotech, Marseille, France) and ACTH
(n.v. 9-52 pg/ml) (Nichols Institute Diagn., San Juan Capi-
strano, CA, USA) measurements.
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Serum T (ng/ml)
Fig. 2 - Correlation between serum PSA and T concentrations in patients
with active Cushing’s disease (r=0.6, p<0.05).
Statistical analysis
Baseline values were expressed as mean SD; unpaired and
paired t test and linear regression analysis were used as ap-
propriate; some analyses were performed after log trans-
formation.
tween serum PSA and >T levels was found (r=0.6, p<0.05
and r=0.9, p<0.0001, respectively) (Fig. 2) but not with ꢀ4
and DHEAS concentrations.
DISCUSSION
RESULTS
With the development of a highly sensitive immunofluoro-
metric total PSA assay, elevated serum PSA levels related
with serum androgens concentrations have been reported
in hirsute women (3-6). Subsequent studies identified this
protein in many female tissues such as breast, ovary and
endometrium (7).
Mean serum total PSA concentrations were higher in CD
than controls (26.4 47.4 pg/ml vs 4.8 4.2 pg/ml, p=0.005).
Serum PSA levels ranged <3-14 pg/ml in Controls and <3-
229 pg/ml in CD-Act. Ten out of 22 patients (45%) with
CD had serum PSA values higher than 14 pg/ml.
In the CD-Long group mean serum PSA levels were high-
er in CD-Act than CD-Rem (33.7 63.3 vs 2.2 3.0 pg/ml,
p<0.002). Serum PSA levels were higher than >14 pg/ml in
5/12 (42%) CD-Act patients and normalized after the cure
of disease. The remaining 7 (58%) CD-Act patients had
serum PSA levels into the normal range, which had a further
decrease after remission of the disease (Fig. 1). After the re-
mission a decrease in serum T (1.1 1.1 ng/ml vs 0.2 0.2
ng/ml, p<0.05), DHEAS (2833 2630 ng/ml vs 627 1052
ng/ml, p=0.01) and ꢀ4 (3.0 3.5 ng/ml vs 0.6 0.4 ng/ml,
p=0.01) concentrations was observed.
The results of the present study showed that female pa-
tients with active Cushing’s disease have increased serum
PSA concentrations compared to controls, and that in half
of them serum PSA values are above the normal range. PSA
normalized after the cure of disease in all patients with high
levels at baseline; in the other, with normal PSA values, a
further decrease after remission of CD was observed. At
the same time there was a reduction in serum T, DHEAS
and ꢀ4 levels. Serum PSA concentrations were correlated
with serum T levels both before and after remission of dis-
ease, accordingly with the data by Negri et al. who observed
a concomitant reduction of serum PSA and androgens in
hirsute women (5) after therapy. Furthermore, in vitro stud-
ies using a breast carcinoma cell line indicate that the pro-
duction of PSA is under the control of steroid hormones,
including androgens and progestins (9). The fact that PSA
values are elevated in about 50% of the patients with CD
and that are related to androgens and not to cortisol lev-
els is in keeping with either the androgen-dependent regu-
lation of PSA or to the fact that hyperandrogenism is not
invariably present in all patients with CD.
A positive correlation in CD-Act and CD-Rem patients be-
300
229
150
50
40
30
20
10
0
In conclusion serum total PSA measurement could be con-
sidered a marker of androgen activity in female with
Cushing’s disease. In female patients with active Cushing’s
disease and elevated serum PSA concentrations the mea-
surement of this protein may be considered an additional,
useful parameter of the remission of disease. Further stud-
ies in a large population with Cushing’s disease are neces-
sary to confirm this data.
CD-Act
CD-Rem
Fig. 1 - Serum total PSA levels in patients with Cushing’s disease before
(CD-Act) and after the remission (CD-Rem). The shaded area represents the
range obtained in 40 controls.
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PSA in female patients with Cushing’s disease
ACKNOWLEDGMENTS
5. Negri C., Tosi F., Dorizzi R., et al. Antiandrogen drugs lower
serum prostate-specific antigen (PSA) levels in hirsute subjects:
evidence that serum PSA is a marker of androgen action in wom-
en. J. Clin. Endocrinol. Metab. 2000, 85: 81-84.
This work was supported in part by Grants from the M.I.U.R, Rome
and University of Pisa (Fondi d’Ateneo) to E. Martino.
6. Obiezu C.V., Scorilas A., Magklara A., et al. Prostate-specific anti-
gen and human glandular kallikrein 2 are markedly elevated in
urine of patients with polycistic ovary syndrome. J. Clin.
Endocrinol. Metab. 2001, 86: 1558-1561.
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