1 Department of Diabetes and Endocrinology, University College Hospitals, Mortimer Street, London W1N 8AA, 2 Centre for Neuroendocrinology, Royal Free and University College Medical School, Pond Street, London NW3 2QG, 3 Department of Histopathology, Royal Free Hospital, Pond Street, London NW3 2QG and 4 University Department of Obstetrics and Gynaecology, Royal Free and University College Medical School, Pond Street, London NW3 2QG, UK
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Abstract |
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Key words: cetrorelix/GnRH antagonist/hyperandrogenaemia/ovarian tumour/virilization
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Introduction |
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We describe a case of virilization in a post-menopausal woman with high androgen, estradiol and gonadotrophin levels. Radiological localization of an ovarian tumour, by ultrasound and computerized tomography (CT) proved unsuccessful. The tumour was localized by ovarian vein catheterisation and shown to be gonadotrophin dependent with the aid of a cetrorelix suppression test. Cetrorelix (Asta Medica, Germany), a decapeptide with a sequence derived from GnRH, is a rapidly acting GnRH antagonist which suppresses gonadotrophin production rapidly. In humans the terminal half-lives after i.v. and s.c. administration are 89 h and 2440 h respectively. In our patient the plasma levels of testosterone, estradiol, FSH and LH all dropped within 3 h of administration, proving that the increased steroid hormone synthesis was of ovarian origin and gonadotrophin dependent.
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Case report |
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Initial investigations showed a total testosterone of 10.7 nmol/l (normal <2.9), androstenedione of 7.2 nmol/l (3.514), FSH of 34.7 U/l (37125), LH of 19.9 IU/l (10.542), dihydroepiandrosterone sulphate (DHEAS) of 1.9 µmol/l (0.911.6) and estradiol of 392 pmol/l (post-menopausal <50). During a low dose dexamethasone suppression test, the plasma cortisol suppressed to <20 nmol/l but the total testosterone remained elevated at 15.2 nmol/l, confirming the non-adrenocorticotrophic hormone dependency of the hyperandrogenic state. A pelvic ultrasound examination noted the endometrial thickness to be 6.9 mm (usually atrophic and <5 mm in the post-menopausal state). The ovaries and uterus were otherwise normal. A CT scan of the pelvis and adrenal gland was normal, giving no clue as to the origin of the hyperandrogenism.
Adrenal and ovarian vein sampling was performed. The results are summarized in Table I and Figure 1
, which clearly demonstrate an increase in testosterone and estradiol production from the right ovarian vein, consistent with the presence of a right ovarian testosterone- and estradiol-secreting tumour. We wished to ascertain whether ovarian hormone synthesis might be gonadotrophin dependent or autonomous and for the first time in the literature, report the acute effect of a GnRH antagonist using cetrorelix. Cetrorelix is a fast acting GnRH antagonist, which suppresses gonadotrophin secretion shortly after administration. Testosterone, FSH and LH were collected over a 24 h period following the administration of cetrorelix 0.5 mg at baseline and 6 h. Control samples were taken over a 24 h period prior to the test. The results are illustrated in Figure 2
. These show that plasma testosterone was suppressed from 8 nmol/l to 2.3 nmol/l, along with the expected decrease in LH and FSH concentration.
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The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Both ovaries were of normal size. Histology of the right ovary showed a 12 mm firm parenchymal nodule with a homogeneous pale yellow cut surface. Microscopic examination showed this to be a solid lesion, well demarcated from the surrounding stroma, composed of nests of cells with pale vesicular cytoplasm. There were no features of cellular hyperplasia. Reinke crystalloids were not identified. Occasional mitoses were noted, but no other sinister features such as nuclear atypia or haemorrhage. Immunostaining for inhibin was positive. These features are in keeping with an ovarian steroid cell tumour. No further sub-classification could be made. Examination of the endometrium showed evidence of simple cystic hyperplasia, presumably resulting from the continued estrogen exposure. Immunohistochemistry of the right ovary and endometrium did not show the presence of GnRH receptors. The left ovary was normal.
Three months post-surgery the patient was asymptomatic and repeat endocrinology had returned to normal (Table II). Of note, both LH and FSH were found to have further increased to the levels usually seen in a post-menopausal woman, demonstrating that although gonadotrophin dependent, the tumour products and inhibin were exerting a negative feedback action in the pituitary gland.
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Discussion |
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Ovarian steroid cell tumours are usually benign, unilateral tumours characterized by a steroid cell proliferation, located within the ovarian stroma. The small size (usually <1cm) accounts for the poor visualization with ultrasound and CT scanning. In line with previous studies (Kirshner and Jacobs, 1971), selective venous sampling in our case proved to be highly effective in tumour localization with a marked testosterone and estradiol gradient being present in the right ovarian vein. This is, however, an invasive procedure with the risk of haemorrhage. This procedure is operator dependent and is also dependent on reliable anatomy.
Eight case reports of gonadotrophin dependent tumours have been previously described (Givens et al., 1975; Lamberts et al., 1982
; Drife et al., 1987
; Paraskevas and Scully, 1989
; Pascale et al., 1994
; Chico et al., 1995
; Marcondes et al., 1997
; Picon et al., 2000
). These consisted of four Leydig cell tumours, one granulosa cell tumour, two hilus cell tumours and one stromal luteoma. This gonadotrophin dependency appears to be related to a high LH receptor expression seen in some tumours (Gutierrez et al., 1983
). In five of these cases, the tumour was 1 cm in size and six cases were post-menopausal. All of these showed suppression of testosterone levels with administration of i.m. GnRH analogues over a period of 2 weeks. In our case, cetrorelix induced suppression of testosterone and gonadotrophin levels within 6 h demonstrating this approach as a safe and rapid diagnostic procedure, which could be performed in an outpatient setting.
There have also been reports of GnRH analogues reducing androgen production in ovarian tumours, where patients (in the reproductive years) had normal levels of gonadotrophins. It has been proposed that, in these cases, GnRH analogues may have a direct effect on the ovarian tumour. These effects have been observed in vitro and appear to be related to inhibition of cellular steroidogenesis by antagonism of the GnRH receptor in ovarian tumour cells (Lamberts et al., 1982; Gutierrez et al., 1983
; Latouche et al., 1989
). Caution is needed as androgen secretion by adrenal tumours may occasionally be under gonadotrophin control (Werk et al., 1973
; Leinonen et al., 1991
) as opposed to being autonomous. Such adrenal tumours are LH dependent and will be suppressed by GnRH analogues. Also, poorly differentiated ovarian androgen secreting tumours may be partially or not at all suppressed by GnRH analogues (McLellan et al., 1990
). However in the case we describe it is clear that their action is to decrease gonadotrophin levels and subsequent ovarian steroid hormone synthesis.
In conclusion, cetrorelix may offer a useful diagnostic test and therapeutic option for gonadotrophin dependent ovarian androgen-producing tumours. Localization is best achieved with venous sampling, but in centres where this facility may not be available and where radiological imaging is inconclusive, a cetrorelix suppression test may point to an ovarian cause of hyperandrogenaemia. Moreover, in patients in whom surgery is contraindicated, the identification of gonadotrophin dependency may allow a medical form of therapy using longer-lasting GnRH antagonists.
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Notes |
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References |
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Submitted on December 12, 2001; accepted on February 11, 2002.