Full text of DOI:10.1007/BF03343904

J. Endocrinol. Invest. 24: 622-627, 2001
CASE REPORT
Testosterone-secreting gonadotropin-responsive adrenal
adenoma and its treatment with the antiandrogen flutamide
F.A. László*, S. Tóth*, J. Kocsis**, I. Pávó ***, and M. Szécsi***
*City Hospital, Kiskunfélegyháza; **Semmelweis Hospital, Kiskunhalas; ***Endocrine Unit and Research
Laboratory, University of Sciences, Szeged, Hungary
ABSTRACT. A 55-year-old woman with virilization
had an appreciably elevated testosterone level,
which was not suppressed by dexamethasone, but
was increased by stimulation with human chorion-
ic gonadotropin (hCG). Ultrasonography and com-
puted tomography revealed an adenoma 2.5-3.0
cm in diameter in the right adrenal gland. The pa-
tient was treated with the antiandrogen flutamide
in a daily dose of 500 mg for 4 months. A substan-
tial regression of her hirsutism was observed during
flutamide administration, but the serum testoste-
rone level remained high. Right adrenalectomy was
performed. Histologically, the tumor proved to be
an adrenocortical adenoma of zona reticularis type.
The adenoma tissue contained specific hCG recep-
tors (187 fmol/g). The steroid concentration in the
tumor tissue was examined by means of high pres-
sure liquid chromatography-radioimmunoassay
(HPLC-RIA). A significantly increased testosterone
content was detected, and the levels of its precur-
sors, androstenedione and dehydroepiandrostero-
ne, were also elevated. Following adrenalectomy,
serum testosterone concentration decreased to the
normal level. The mechanism of the inappropriate
regulation in the testosterone production of the
adrenal tumor has not been fully elucidated.
(J. Endocrinol. Invest. 24: 622-627, 2001)
©2001, Editrice Kurtis
INTRODUCTION
We report here a post-menopausal woman virilized
by an adrenocortical adenoma with hCG-respon-
sive testosterone secretion, in whom we studied
the hormonal contents and hCG binding capacity of
the tumor and the effect of the antiandrogen flu-
tamide on the androgen steroid production.
A testosterone-secreting adrenocortical adenoma
with pure virilization is a rare disease in the adult
female (1, 2). The tumor tissue, which synthesizes
sexual steroid hormones, is generally independent
of trophic hormone control from a functional aspect
(3, 4). This feature of the autonomous adrenal ade-
nomas is extremely useful in the clinical differenti-
ation of virilizing disorders caused by tumors and
adrenocortical hyperplasias. In a few cases, how-
ever, these tumors have responded to human chori-
onic gonadotropin (hCG) by increasing testosterone
production (5-11). The functional basis for the un-
usual character of the testosterone-secreting go-
nadotropin-responsive adrenocortical adenoma is
conjectural. The exact mechanism of the gonado-
tropin sensitivity of the adrenal adenomas has not
yet been explained.
MATERIALS AND METHODS
Case report
A 55-year-old woman was referred to the Kiskunfé-
legyháza hospital in May 1996 because of viriliza-
tion. At the age of 22 and 25, she had given birth to
a daughter and a son, respectively, without com-
plications. Her menstrual cycles had been regular
until the age of 40 years. Fifteen years before her
admission, her uterus was removed due to an ex-
tensive myomatous disorder of the uterus; the ova-
ries remained intact. During the last 2 years, she
had gradually developed extensive hirsutism and a
deepening of her voice. Hypertension had been
present for 7 years, for which she received β-block-
ers, captopril and diuretics.
Key-words: Adrenal adenoma, testosterone secretion, hCG-dependen-
cy, flutamide treatment, hCG-binding.
Correspondence: Dr. Ferenc A. László, City Hospital, Kiskunfélegyháza,
Fadrusz J. u. 4., Kiskunfélegyháza, H-6100, Hungary.
Gynecological examination revealed clitoromegaly,
transabdominal hysterectomy and slightly atroph-
Accepted January 12, 2001.
622

F.A. László, S. Tóth, J. Kocsis, et al.
ic ovaries. The patient was moderately obese; her
blood pressure was 140/90 mmHg (during antihy-
pertensive treatment). The voice was moderately
deep and the hair growth, especially on the face,
was pronounced, as assessed on the basis of the
description by Ferriman et al. (12). Routine labora-
tory studies, including urine protein and sugar,
blood analysis, glucose tolerance, liver and kidney
functions, serum lipids and electrolytes, gave nor-
mal results.
origin for the tumor, mainly resembling zona retic-
ularis cells. The major part of the adenoma was
used for determination of the steroid content and
hCG receptors of the tumor tissue.
Measurement of adrenal hCG receptors
The hCG binding capacity of the adrenal tumor was
measured as reported earlier (16). Briefly summa-
rized, the method is as follows. The tumor tissue
was homogenized in Dulbecco’s phosphate-buf-
fered saline (pH 7.4) containing 0.1% bovine serum
albumin (PBS-BSA). After centrifugation for 10 min
at 600 g, the supernatant was sedimented for 30
min at 20,000 g. The membrane preparation was
resuspended in PBS-BSA solution and was used for
receptor binding determination. [125I] hCG (New
England Nuclear, Boston, USA) in increasing con-
centrations was added to the membrane suspen-
sions and the mixtures were incubated overnight at
23 C. The bound and free hormone fractions were
separated by centrifugation after 15-fold dilution
of the samples with ice-cold PBS-BSA. Subsequen-
tly the bound radioactivity was measured. Non-spe-
cific binding was determined in the presence of an
excess (50 IU/tube) of unlabelled hCG. The specif-
ic hCG binding was measured by Scatchard me-
thod (17). Following linear regression analysis, the
apparent association constant (Ka) and binding ca-
pacity were determined.
Hormone assays
Serum gonadotropins were assayed with commer-
cially available RIA kits. Serum steroids were deter-
mined by means of specific RIA developed in our
laboratories (13, 14) and performed on the basis of
World Health Organization principles (15).
Dexamethasone suppression and hCG
stimulation tests
Dexamethasone suppression testing was carried
out by the oral administration of 0.5 mg oradexon
(Organon, Oss, The Netherlands) every 6 h for 12
days, followed by 2.0 mg oradexon every 6 h for 3
days, while hCG stimulation testing was performed
by means of intramuscular injections of choriogo-
nin (Richter, Budapest, Hungary) in daily doses of
3000 IU for 3 days. Blood samples were obtained
the next morning.
Antiandrogen treatment with flutamide
Determination of tissue steroids
Because of the virilization and high serum testoste-
rone level, we treated the patient with 2 x 250 mg
flutamide (Fugerel, Schering-Plough, Kenilworth,
USA) daily for 4 months. The liver function was con-
trolled during and after the flutamide treatment;
the results of functional tests remained normal.
Tissue steroid concentrations were determined by
high-pressure liquid chromatography (HPLC)-RIA
methods described previously (18, 19) with some
modifications. In brief, the steroid hormones from
the tumor sample were extracted with ethyl ac-
etate, using ultrasonic homogenization. The sol-
vent was then evaporated off under nitrogen, and
the extract was purified on a 500 mg C18 column
(Supelclean LC-18, Supelco, Bellefonte, USA) with
methanol-water as eluent. Steroids were isolated
by reversed-phase HPLC on a 250x4.0 mm C18
column (Eurospher 100-C18-7; Knauer, Berlin,
Germany) with 55 v/v% methanol-water as eluent.
Fractions were collected and the eluted steroids
were detected via the radioactivity of tritiated
steroids added as internal standards to the tissue
samples before the extraction procedure. Fractions
of isolated steroids were dried and dissolved in the
RIA buffer and the assays were performed as
above. The steroid contents of the tissue sample
were calculated with consideration of the recovery
of the labeled internal standards and the method-
ological background (blank). Results are given in
μg/g wet weight tissue.
Imaging
Ultrasonography and computed tomography re-
vealed a right adrenal tumor, estimated to measure
2.6 x 2.5 x 3.0 cm.
Surgery and histology
In view of the positive imaging finding, surgical in-
tervention was performed. The right adrenal gland
was found to be in contact with an ovoid, encap-
sulated yellow mass, which was removed together
with the adjacent uninvolved, but small right ad-
renal gland. There were no enlarged lymph nodes
in the surrounding tissues. A small part of the tu-
mor was examined histologically, and proved to
consist of acidophilic cells with scant cytoplasmic
pigment. No histologic signs of malignancy were
seen. The histology suggested an adrenocortical
623

Testosterone-secreting adrenal adenoma
RESULTS
Specific hCG binding capacity was detected in the
membrane fraction of the adrenal tumor. Linear re-
gression analysis indicated an equilibrium associa-
tion constant (Ka) of 1.28x10-10 M-1 and a specific
hCG receptor binding capacity of 187 fmol/g of
original adrenal tumor tissue.
The steroid concentrations in the tumor tissue are
reported in Table 3. After HPLC isolation, the cor-
tisol concentration was much less than in the normal
adrenal tissue and a very high testosterone level
was detected, but the DHEA and androstenedione
contents of the adenomous tissue were also high.
Unfortunately, the mass of normal adrenal tissue
removed was not sufficient for our HPLC-RIA de-
termination. Thus, we can not directly compare the
steroid concentrations of the normal and tumorous
adrenal tissues. In this respect, we had to take the
normal steroid values for intact adrenal tissue from
the relevant literature (11).
Following flutamide treatment, hirsutism regressed:
the virile hair growth on the trunk area disappeared,
but the facial hair growth persisted. Four months
after the tumor removal, the hair growth had nor-
malized; the total hirsutism scores (12) had de-
creased from 16 to 6.
The serum hormone concentrations before the op-
eration are listed in Table 1. The testosterone lev-
el and the ratio testosterone/SHBG were high. The
FSH and LH concentrations were also increased be-
cause of the post-menopausal state. The other hor-
mone values were in the normal ranges. During the
antiandrogen treatment with flutamide, the serum
testosterone level remained high. Four months af-
ter the surgical intervention, the testosterone level
and the ratio testosterone/SHBG had normalized.
Before the operation, dexamethasone suppression
testing and hCG testing were applied (Table 2).
Following dexamethasone administration (2 or 8
mg/day), the cortisol level decreased by about one-
third. The testosterone concentration remained el-
evated, while the DHEA and DHEAS levels were
unchanged. After 3 days of hCG treatment, the
testosterone level was significantly increased.
DISCUSSION
A 55-year-old post-menopausal woman with viril-
ization had a markedly increased testosterone lev-
el; this was not suppressed by dexamethasone, but
Table 1 - Serum hormone concentrations before surgery, following flutamide treatment and after surgery.
Before operation
After operation
Normal range
Steroids (nmol/l)
Basal
Following flutamide
treatment
467.0
0.32
8.0
Cortisol
371.0
0.38
7.6
286.0
0.26
1.2
150.0-550.0
0.25-0.40
0.9-2.8
Estradiol
Testosterone
DHEA
10.01
220.0
0.7
10.4
370.0
1.2
5.6
7.9-24.8
220.0-650.0
0.6-3.2
DHEAS
120.0
2.0
Progesterone
17α-hydroxyprogesterone
Androstenedione
Androstenediol
Others
3.6
3.2
2.9
1.2-4.2
8.6
10.03
7.1
3.9
1.9-8.9
6.0
0.4
2.4-8.3
FSH (IU/l)
75.5
45.2
76.2
49.4
0.27
50.0
16.0
-
67.8
51.3
0.31
36.2
3.3
30.0-96.0*
28.0-100.0*
0.04-0.47
25.0-65.0
2.0-7.0
LH (IU/l)
PRL (IU/l)
0.24
SHBG (nmol/l)
Testosterone/SHBG (x10-2)
CBG (nmol/l)
Cortisol/CBG (x10-2)
*Post-menopausal level.
42.3
17.9
264.0
140.0
258.0
111.0
250.0-450.0
60.0-122.0
-
624

F.A. László, S. Tóth, J. Kocsis, et al.
Table 2 - Serum steroid concentrations (nmol/l) following dexamethasone suppression and human chorionic gonadotropin (hCG)
administration.
Reference range
Cortisol
150-550
Testosterone
0.9-2.8
DHEA
7.9-24.8
DHEAS
220-650
Basal
357
242
233
348
7.1
6.5
10.6
11.7
10.5
16.2
210
221
218
273
Dexamethasone 2 mg
Dexamethasone 8 mg
hCG
6.2
25.4
was further elevated by stimulation with hCG. Ul-
trasonography and computed tomography re-
vealed an adenoma in the right adrenal gland, and
right adrenalectomy was performed. Histologically,
the tumor proved to be an adrenocortical adenoma
of zona reticularis type. The steroid concentrations
in the tumor tissue were measured by means of
HPLC-RIA. A smaller cortisol concentration was de-
tected and a significantly increased testosterone
content was found, and the concentrations of its
precursors, androstenedione and dehydroepian-
drosterone, were also elevated. These latter two
results and the normalization of the serum testos-
terone level following surgical intervention clearly
prove the origin of the virilization, which was caused
by the autonomous adrenocortical adenoma. Be-
fore the adrenalectomy, we treated the patient with
the non-steroid antiandrogen flutamide: a sub-
stantial regression of her virilization was observed
during the 4-month flutamide treatment, but the
serum testosterone level remained increased.
Unusual features of this case were the significantly
increased serum testosterone level induced by the
administration of hCG and the demonstration of the
presence of ectopic hCG receptors in the adrenal
tumor tissue. Many years ago Reifenstein et al. (20)
postulated that adrenal androgen secretion was in-
fluenced by gonadotropin treatment. In stark con-
trast, it was later described that normal healthy
women did not exhibit increases in serum testos-
terone concentrations following gonadotropin ad-
ministration (21, 22), but an elevation may develop
in women with Stein-Leventhal syndrome or idio-
pathic hirsutism (22). Increased 17-ketosteroid ex-
cretion was reported in oophorectomized women
after hCG administration (23-25). Lloyd et al. (26),
however, found no increase in plasma testosterone
concentrations following hCG injections in two
oophorectomized women. In connection with the
hCG responsiveness of testosterone-secreting
adrenal adenoma, many contradictory data are to
be found in the literature on this subject. Increased
serum testosterone levels have been reported in pa-
tients with virilizing adrenal adenoma after hCG
treatment (2, 7, 9, 10). On the other hand, this stim-
ulation test has also yielded negative results in pa-
tients with testosterone-secreting adrenal adenoma
(1, 27).
It is very difficult to explain the mechanism of the in-
appropriate response to hCG and the aberrant reg-
ulation in the testosterone production of the adrenal
tumor. First, it should be mentioned that the adrenal
gland and ovary share a common anlage (28). Ovarian
thecal metaplasia has been reported within the
adrenals of postmenopausal women (29), while a me-
taplasia of embryologically competent mesenchymal
cells is subject to extended stimulation by increased
levels of gonadotropin (30). On the other hand, in ac-
cord with our observation, Leinonen et al. (2) revealed
the presence of hCG receptors in the tissue of testos-
terone-secreting virilizing adrenal adenoma. The char-
acteristics of the hCG-binding sites were similar to
those present in the testosterone-secreting ovarian
androblastoma examined by the same method (31)
and to those in normal human ovaries (32). The pres-
ence of ectopic hCG receptors was suggested by the
tissue culture experiments reported by Leinonen et
al. (2). Steroid hormone secretion was studied in pri-
mary tissue cultures of the virilizing adrenal tumor and
Table 3 - Steroid concentrations in virilizing adrenal tumor tissue.
Steroids
Tumorous adrenal Normal adrenal
tissue
μg/g
wet weight
tissue*
Cortisol
2.37
2.69
0.58
0.17
1.00
1.31
0.49
17.10
0.16
0.27
-
Testosterone
Dehydroepiandrosterone
Progesterone
Androstenedione
Androstenediol
Dihydrotestosterone
*Werk, et al. (1973)
0.14
-
0.36
625

Testosterone-secreting adrenal adenoma
4. Freeman D.A.
the normal adjacent cortex, and the effects of ACTH
and hCG on testosterone production were com-
pared. ACTH increased the testosterone secretion by
the normal adrenocortical cells, but hCG had no ef-
fect on it. In the adenoma tissue culture, however,
both ACTH and hCG stimulations maintained the
testosterone production at the previous level; with-
out such stimulation, the testosterone concentration
in the tissue culture medium decreased. These data
can be compared with the findings of Schorr and Ney
(33), who observed inappropriate trophic hormone
stimulation of adenyl cyclase in experimental tumors
and human endocrine tumors in vitro. The unusual
hCG stimulation does not refer only to the adrenal
sexual steroidogenesis. LH-dependent cortisol or cor-
ticosterone production was recently reported in a
case with ACTH-independent Cushing’s syndrome
(34) and likewise in transgenic mice (35).
In our case, the LH level was high because of the
post-menopausal state, which may have a positive
influence on the testosterone level, as a permanent
gonadotropin stimulus. This finding is in accordance
with recent experimental data showing that inap-
propriate or prolonged elevation of gonadotropins
can induce LH receptors in the adrenal gland (36,
37). It was reported that gonadectomy or the direct
action of LH can trigger adrenocortical tumorigene-
sis in mice transgenic for the mouse inhibin α-sub-
unit promoter/Simian virus 40 T-antigen fusion gene.
A permanent high LH level in itself, however, is not
sufficient to induce a testosterone-secreting LH-de-
pendent adrenal tumor. Other factors may be need-
ed for the development of such a tumor with a spe-
cial hormonal activity. Further observations will be
required to clarify this unusual and interesting hor-
monal regulatory phenomenon.
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