Hum. Reprod. Advance Access originally published online on June 13, 2006
Human Reproduction 2006 21(10):2601-2605; doi:10.1093/humrep/del224
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Virilization due to ovarian androgen hypersecretion in a patient with ectopic adrenocorticotrophic hormone secretion caused by a carcinoid tumour: Case Report
1 Department of Endocrinology 2 Department of Chemical Endocrinology 3 Department of Pathology and 4 Department 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: r.netea-maier{at}endo.umcn.nl
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Abstract |
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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
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Introduction |
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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 |
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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 x 3 x 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, 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.
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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 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 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).
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Discussion |
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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 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 adrenal-specific 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 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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