Human Reproduction Vol.21, No.10 pp. 2601–2605, 2006
doi:10.1093/humrep/del224
Advance Access publication June 13, 2006.
Virilization due to ovarian androgen hypersecretion
in a patient with ectopic adrenocorticotrophic hormone
secretion caused by a carcinoid tumour: Case Report
R.T.Netea-Maier1,5, W.-A.Nieuwlaat1, C.G.J.Sweep2, P.Wesseling3, L.Massuger4
and A.R.M.M.Hermus1
1
Department of Endocrinology, 2Department of Chemical Endocrinology, 3Department of Pathology and 4Department of Obstetrics
and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
5
To whom correspondence should be addressed at: Department of Endocrinology, Radboud University Nijmegen Medical Centre,
Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands. E-mail: [email protected]
A 52-year-old woman presented with symptoms of virilization, which had been ongoing for 5 months. At the age of 34
years, she had a large abdominal carcinoid tumour removed. Twelve years later, she presented with Cushing’s syndrome
due to ectopic adrenocorticotrophic hormone (ACTH) production by carcinoid metastases localized in the right parametrium, fornix posterior and right diaphragm. Debulking laparotomy was performed followed by remission of hypercortisolism. Relapse of hypercortisolism followed 3 years later, and a second debulking laparotomy was performed including
resection of the right ovary. In the following year, relapses of hypercortisolism were observed until bilateral adrenalectomy
was performed. Laboratory evaluation revealed elevated serum levels of testosterone (23.0 nmol/l), androstenedione and
17-hydroxyprogesterone, and a serum estradiol (E2) level in the premenopausal range. The computerized tomography
(CT) of the abdomen showed a large pelvic mass on the left side of the uterus without a recognizable left ovary. Treatment
with a GnRH agonist (goserelin, 3.6 mg s.c., monthly) was initiated, resulting in normalization of the androgen levels. One
year later, obstruction of the right ureter occurred due to progression of the pelvic metastases, thus a third debulking
laparotomy with resection of the pelvic metastases including the left ovary was performed. The microscopic examination of
the removed pelvic mass showed malignant carcinoid tissue with focal remnants of atrophic ovarian tissue. Two years after
surgery, serum androgen levels are undetectable. We hypothesize that the high levels of ACTH at the site of the left ovary
have induced androgen hypersecretion by steroid-producing cells in the ovary of our patient.
Key words: carcinoid/ectopic ACTH syndrome/virilization
Introduction
Ovarian androgen hypersecretion is a rare cause of virilization in
post-menopausal women (Lobo, 1991). In most cases, the secretion
of androgens is responsive to gonadotrophin stimulation (Pascale
et al., 1994). The association of ovarian hyperandrogenism with
increased adrenocorticotrophic hormone (ACTH) production is
extremely rare. We report a unique case of a patient presenting
with gonadotrophin-sensitive excessive androgen production 2
years after bilateral adrenalectomy because of Cushing’s syndrome caused by an ACTH-producing malignant carcinoid
tumour. We discuss the differential diagnosis of the hyperandrogenism in this patient and possible explanations for the association
of ovarian androgen hypersecretion and ectopic ACTH secretion.
Case report
A 52-year-old woman presented at our outpatient clinic in
September 2001 with signs of virilization. She had had these
complaints for 5 months. Her family history revealed no endocrine tumours. The patient had been previously examined in
our clinic in 1983, at the age of 34 years, when she presented
complaining of tiredness. The physical examination at that
time revealed a large abdominal mass, and the patient underwent an exploratory laparotomy. A 7 × 3 × 4 cm tumour was
found, located at the top of the appendix. Because of its infiltrative growth into all layers of the appendicular wall, the
tumour was considered as originating from the appendix. However, the tumour additionally showed extensive infiltration into
periappendicular and mesenterial fat and extended into the
muscularis layer of the duodenal well as into the pancreas. The
tumour was surgically removed, together with 14 regional
lymph nodes of which two contained metastatic tumours. Electron microscopic examination revealed round and oval secretory granules in many tumour cells, indicating a carcinoid
tumour. The patient was well until 12 years, after which she
presented with new complaints of periorbital and leg oedema,
© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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R.T.Netea-Maier et al.
pericardial effusion and hypokalaemia (2.2 mmol/l). She had a
normal blood pressure of 112/70 mmHg. Keeping in mind her
medical history, a suspicion of Cushing’s syndrome was
raised. The following investigations confirmed this diagnosis.
Both the serum cortisol and plasma ACTH concentrations were
increased, ranging from 560 up to 1470 nmol/l for cortisol (reference level 190–550 nmol/l at 0900 hours) and from 10.6 up
to 62 pmol/l for ACTH (reference level 2.2–13.2 pmol/l at
0900 hours), with no circadian rhythm. The urinary cortisol
excretion was increased, amounting to 2250 nmol/24 h (reference level <240 nmol/24 h). There was no overnight suppression of ACTH and cortisol after administration of 1 mg
dexamethasone. Absence of an increase of ACTH and cortisol
concentrations after administration of 100 μg of human corticotrophin-releasing hormone (CRH) (Newell-Price et al.,
2002) and absence of a decrease of ACTH and cortisol concentrations after administration of high-dose dexamethasone
(Liddle, 1960) suggested ectopic ACTH production presumably due to a recurrence of the carcinoid tumour. A computerized tomography (CT) scan and an octreotide scintigraphy
showed a lesion suspect for metastatic disease between
the right lobe of the liver and the diaphragm and possibly a
second lesion just above the bladder. The patient underwent a
second laparotomy. Metastases of the carcinoid tumour were
removed from the right diaphragm, the peritoneum, the right
parametrium and the posterior fornix including the posterior
wall of the vagina, followed by remission of the symptoms.
Cyclic relapses of Cushing’s syndrome followed 3 years later
(February and June 1998), and the patient underwent a third
laparotomy (October 1998) with resection of metastatic tissue
from the diaphragm and removal of her right ovary that had
been almost entirely replaced by tumour tissue with a maximal
diameter of 5 cm (Figure 1). Two months later, a new exacerbation of Cushing’s syndrome occurred. Because it was not
possible to find new localizations of the carcinoid tumour by
imaging procedures, the patient was treated with octreotide (30
mg monthly i.m. injections of Sandostatine LAR®). Nevertheless, this failed to control the hypercortisolism, and the patient
had two relapses of Cushing’s syndrome during this treatment
(April and September 1999). For this reason, it was finally
decided to perform a bilateral adrenalectomy (November
1999), which resulted in remission of Cushing’s syndrome.
Histological examination of the removed adrenals showed nodular hyperplasia of the zona fasciculata of the cortex, probably
secondary to prolonged exposure to ACTH stimulation. One
year before the bilateral adrenalectomy (June 1998), the patient
had become post-menopausal [serum estradiol (E2) 77 pmol/l,
serum LH 67.9 U/l and serum FSH 36.8 U/l]. During the next 2
years, the patient did not have any new complaints until she
presented with symptoms of virilization. At that time, she used
as medication cortisone acetate 37.5 mg daily, fludrocortisone
0.0625 mg daily and vitamin B12 1 mg monthly i.m.
Figure 1. Carcinoid tumour in the right ovary resected in 1998. The upper part of this figure (haematoxylin and eosin staining, original magnification ×25) shows extensive localization of carcinoid tumour with a trabecular growth pattern, whereas pre-existent ovarian stroma with a corpus
albicans (asterisk) is present in the lower left-hand corner. The inset (original magnification ×200) shows intense immunohistochemical staining
of the tumour cells (but not of the surrounding ovarian stroma) for chromogranin, corroborating the neuroendocrine differentiation of the tumour
cells.
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Virilization in a patient with an ACTH-producing carcinoid tumour
Table I. Hormone levels (in plasma/serum) at 0900 hours after stopping glucocorticoid and mineralocorticoid
substitution for 24 h, in our patient presenting with symptoms of virilization 3 years after right ovariectomy and
2 years after bilateral adrenalectomy
Reference levels
ACTH (pmol/l)
Cortisol (nmol/l)
Aldosterone (nmol/l)
LH (U/l)d
FSH (U/l)d
Progesterone (nmol/l)d
17-OH progesterone (nmol/l)d
Androstenedione (nmol/l)
DHEA (nmol/l)
DHEA-S (μmol/l)
Testosterone (nmol/l)
Dihydrotestosterone (nmol/l)
Estradiol (pmol/l)d
Basal
2.2–13.2
190–550
0.08–0.69
0.6–16/13–110/0.15–19
3.3–19/5.2–29/1.8–15
<1.3/1.3–12/19–120
0.45–2.1/-/1.1–8.8
3.9–9.6
15–45
4–10
0.5–2.4
0.14–0.76
11–1300/350–1800/
220–1000
65.9
<20
<0.06
8.7
22.5
6.1
22
17
2.2
0.94
20
1.6
160
After dexamethasonea
Before hCGb
After hCGc
33.1
—
—
11.2
28.1
6.5
30
38
4.9
1.6
39
3.5
230
58.9
—
—
5.3
17.4
12
65
68
11
3.4
87
4.7
430
ACTH, adrenocorticotrophic hormone; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone
sulphate.
Dexamethasone was administrated as 0.5 mg every 6 h on 2 consecutive days followed by 2 mg every 6 h for 5
consecutive days. Three daily i.m. injections of 1500 U hCG were administrated in combination with dexamethasone on the last 3 days of the test.
b
After 4 days of dexamethasone administration, as mentioned above, before the first hCG injection.
c
After the third hCG injection.
d
Follicular phase/mid-cycle/luteal phase.
a
On physical examination, she had a BMI of 21 kg/m2 and
was normotensive. Her voice had deepened. She had increased
skin pigmentation. Her skin and hair were oily, and she had
acne on her chest and back. She had hirsutism of her face but
no excessive hair growth elsewhere. She had old scars on her
abdomen but no striae. No abdominal mass was felt. She had
an enlarged clitoris, whereas a normal aspect of the external
genitalia had been documented 1 year earlier. There was no
peripheral oedema. The biochemical test results at that time are
presented in Table I. Besides the elevated serum testosterone
level, elevated serum levels of androstenedione and 17-hydroxyprogesterone were found. Serum dehydroepiandrosterone sulphate (DHEA-S) was low, and plasma cortisol and aldosterone
levels were undetectable (after stopping glucocorticoid and
mineralocorticoid substitution for 24 h) as expected after bilateral adrenalectomy. Surprisingly, the serum levels of E2, LH
and FSH were in the premenopausal range. The CT of the
abdomen showed a large pelvic mass on the left side of the
uterus without a recognizable left ovary (Figure 2). The serum
levels of testosterone, 17-hydroxyprogesterone and androstenedione were not suppressible by dexamethasone (0.5 mg every
6 h during two consecutive days followed by 2 mg every 6 h
during five consecutive days) but were markedly increased
after three daily injections of 1500 U hCG on 3 consecutive
days (Smals et al., 1979), demonstrating gonadotrophin sensitivity of androgen secretion (Table I). Hypersecretion of androgens by the left ovary was presumed. Because of the repetitive
abdominal surgery in the past, another surgical procedure
seemed at that time a less appropriate option. The patient
agreed to start treatment with a GnRH agonist (Zoladex®, goserelin, 3.6 mg s.c., once every month), which normalized the
androgen levels. During 1 year of treatment with goserelin, the
Figure 2. Abdominal computerized tomography (CT) (September
2001) showing a large pelvic mass (indicated by arrows) without a
recognizable left ovary.
patient experienced no side effects, and signs and symptoms of
virilization disappeared. After 1 year’s remission of hyperandrogenism, on GnRH agonist treatment, obstruction of the right
ureter due to progression of the pelvic metastases was diagnosed. The GnRH agonist treatment was stopped, and another
debulking laparotomy with partial resection of the pelvic mass
including resection of the left ovary was performed. The microscopic examination of the removed pelvic mass (diameter 7 cm)
showed carcinoid tissue with focal remnants of atrophic ovarian
tissue. The tumour infiltrated the connective tissue surrounding
the ovary, and lymphatic invasion was present. No evidence
for a stromal cell tumour or stromal cell hyperplasia was found
on histological examination. The tumour cells showed intense
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R.T.Netea-Maier et al.
immunohistochemical staining for chromogranin, synaptophysin and neural cell adhesion molecule (NCAM/CD56), corroborating the neuroendocrine differentiation of the tumour
cells. Two years after surgery, serum androgen levels were
undetectable, and serum LH and FSH returned to post-menopausal levels (LH 24.8 U/l and FSH 36.5 U/l).
Discussion
We report on a patient presenting with gonadotrophin-sensitive
excessive androgen production. The abrupt onset of rapidly
progressive virilization together with the markedly elevated
testosterone levels suggested an androgen-secreting tumour in
this patient. In the past, the patient had already undergone
bilateral adrenalectomy and removal of her right ovary for
treatment of a metastatic carcinoid tumour complicated by
ectopic ACTH secretion. Thus, our assumption was that the
androgen excess originated from her left ovary. What makes
this case intriguing is the association of the hyperandrogenism
with the ACTH-producing malignant carcinoid tumour. To our
knowledge, there are no previous reports of ACTH-producing
malignant carcinoids associated with gonadotrophin-sensitive
hyperandrogenism.
Ectopic ACTH secretion represents approximately 5% of all
causes of Cushing’s syndrome (Wajchenberg et al., 1994; Ilias
et al., 2005; Isidori et al., 2006). It may originate from either
highly malignant carcinomas (approximately 20%) or less
aggressive neuroendocrine tumours (approximately 60%),
most of which are localized in the lung. In 10–17% of the
cases, the source of ACTH production remains unidentified
(Wajchenberg et al., 1994; Ilias et al., 2005; Isidori et al.,
2006). The location of the initial carcinoid tumour in our
patient and its growth pattern in the appendicular wall suggested that the neoplasm originated in the appendix. Appendiceal carcinoids, which account for approximately 20% of all
neuroendocrine tumours of the gastrointestinal tract, are rare
causes of ACTH secretion (Ilias et al., 2005). They are mostly
reported to show, with the exception of the very rare and more
aggressive goblet cell variant, a favourable prognosis (Kloppel
and Anlauf, 2005). Also, several ovarian neoplasms, including
adenocarcinomas, androblastomas, Sertoli cell carcinomas, teratomas, steroid cell tumours and carcinoid tumours, can secrete
ACTH (Sworczak et al., 2002).
Hyperandrogenism of ovarian origin is rare in post-menopausal women. It is caused most often by a small tumour of the
Sertoli or Leydig cells in the stroma (Young and Scully, 1985)
and, less frequently, by diffuse stromal cell hyperplasia (Taylor
et al., 2000). Virilizing granulosa cell tumours have only rarely
been reported in post-menopausal women (Sayegh et al.,
1999). Androgen secretion in the post-menopausal ovary is
reported to be gonadotrophin dependent (Peluso et al., 1976;
Denneforts et al., 1980; Drummond et al., 2002), and there
have been several reports of patients with virilizing ovarian
stromal tumours showing reduced testosterone levels after
being treated with GnRH agonists (Barnes and Ehrmann, 1977;
Kennedy et al., 1987; Efsathiadou and Tsatsoulis, 2001; Wang
et al., 2001; Gherghisan-Galateanu et al., 2003). There are,
however, no data in the literature on the expression of ACTH
2604
receptors neither in the cells of the germinal epithelium nor in
the stromal cells.
Ectopic adrenocortical tissue has been reported as an incidental finding at autopsy or surgery in the region of the uterine
adnexae or kidney region. However, ectopic adrenocortical tissue only rarely has been associated with excessive hormonal
production (Sullivan et al., 2005). We are aware of three case
reports of women with Nelson’s syndrome in whom virilizing
ovarian tumours developed, which histologically resembled
adrenocortical tissue, so called adrenal rest tumours (Verdonk
et al., 1982; Wild et al., 1988). Such ovarian adrenal rest
tumours resemble the testicular adrenal rest tumours of men
with congenital adrenal hyperplasia or Nelson’s syndrome
(Baranetsky et al., 1979). It has been suggested that in these
women with Nelson’s syndrome, the exposure to high ACTH
levels has stimulated ovarian steroid-secreting cells of common adrenogenital origin to produce testosterone. Although the
presence of ACTH receptors and the expression of adrenalspecific steroidogenic enzymes have been shown in an ovarian
non-virilizing adrenal rest tumour (Lin et al., 2000), in none of
the three mentioned cases of virilizing ovarian adrenal rest
tumours, the presence of ACTH receptors has been demonstrated (Verdonk et al., 1982; Wild et al., 1988). In one of
these case reports, Baranetsky et al. (1979) demonstrated
ACTH dependency of androgen hypersecretion by suppression
of both ACTH and testosterone concentrations after administration of high-dose dexamethasone (32 mg daily for 3 days)
and subsequently stimulation of testosterone production after
administration of synthetic ACTH. Also Verdonk et al. (1982)
showed in their case report a significant decrease in both
ACTH and testosterone concentrations after administration of
dexamethasone (20 mg daily for 2 days). In the remaining
reported case (Wild et al., 1988), administration of dexamethasone (8 mg daily for 3 weeks) had no effect on the testosterone
level. There is no mention of gonadotrophin responsiveness in
two of these case reports (Baranetsky et al., 1979; Verdonk
et al., 1982; Wild et al., 1988). Gonadotrophin administration
had no effect on testosterone and ACTH concentrations in the
third case (Lin et al., 2000).
Hyperandrogenism associated with non-functioning ovarian
neoplasia has previously been described (Nezhat et al., 2002).
Because hyperplasia of the adjacent stroma with or without
luteinization has been found on microscopy, this was thought
to be the source of androgen production. Several hypotheses
have been formulated to explain this phenomenon, e.g.
mechanical effect on the stroma similar to that of the expanding follicle and secretion of hormones or growth factors by the
tumour that in turn stimulate the stromal cells to produce
androgens. In addition, because many of these tumours occur
during pregnancy or in the post-menopausal period, the high
hCG concentrations during pregnancy or LH concentrations in
the post-menopausal women may contribute to this process.
No virilizing tumour could be identified in the left ovary
removed from our patient, neither was stromal cell hyperplasia
present. In fact, the ovary tissue was almost entirely replaced
by the large metastasis of the carcinoid tumour. Therefore, a
definitive statement on the histopathological substrate of the
hyperandrogenic status in this patient cannot be made. There is
Virilization in a patient with an ACTH-producing carcinoid tumour
one report of a patient with an androgen-secreting carcinoid
tumour (Tanaka et al., 2002). However, the fact that in our
patient, excess androgen production ceased completely after
the removal of the remaining ovary, despite persistence of the
carcinoid tumour metastases, argues against this possibility.
The gonadotrophin sensitivity of the excess androgen production suggests that the androgens were produced by the stromal
cells in the ovary, which are known to express LH receptors
(Bulun and Adashi, 2003). We hypothesize that the 1-year
treatment with the GnRH agonist has induced regression of a
stromal cell tumour or of stromal cell hyperplasia. Alternatively, because we found no evidence in the literature of stromal cell tumours or hyperplasia that have completely resolved
after treatment with GnRH agonists, the fact that no histopathological evidence for a stromal cell tumour or of stromal
cell hyperplasia in the removed ovary was found could be
explained by the fact that the left ovary had almost completely
disappeared and had been replaced by the progressive carcinoid tumour during the year of treatment with goserelin.
It remains uncertain which factor triggered the excessive
androgen production in our patient. The androgen production
could not be suppressed after administration of high-dose dexamethasone. However, a statement on the ACTH dependency of
the androgen secretion in this patient cannot be made as, unlike
the above mentioned case reports of patients with Nelson’s
tumours (Baranetsky et al., 1979; Verdonk et al., 1982; Wild
et al., 1988), the ACTH level was not reduced at all by the dexamethasone treatment, reflecting the independent ACTH secretory activity of the carcinoid. One might speculate that the
presence of the carcinoid metastasis, due to the close topographic relationship with the ovary, was implicated in the induction of androgen production by the stromal ovary cells. We
hypothesize that a small amount of ACTH receptors are on these
cells that were up-regulated by the high level of ACTH at the
site of the ovary, inducing in turn excess androgen production.
In conclusion, we present a patient with an ovarian metastasis of an ACTH-producing carcinoid and hypothesize that the
high ACTH levels in the left ovary have induced androgen
hypersecretion by steroid-producing cells in the ovary. The
excess androgen production was gonadotrophin sensitive, and
the patient responded to treatment with a GnRH agonist.
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Submitted on February 14, 2006; resubmitted on May 11, 2006; accepted on
May 15, 2006
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