Androgen-secreting ovarian tumors represent about 1% of all ovarian neoplasms. Steroid cell tumors (SCT) are among the less common variants, which account for less than 0.1% of all ovarian tumors.
1,2 The SCTs are tumors composed of cells that resemble steroid hormone-secreting cells. The three major categories of SCTs are stromal luteoma, Leydig cell tumors that lack Sertoli cell or stromal component, and steroid cell tumor not otherwise specified (NOS).3,4
In a review of 105 steroid cell tumors of the ovary, stromal luteomas account for about 22% of cases.5 These benign functional neoplasms, first described by Scully in 1964, are believed to be of stromal derivation, originating from luteinized cells or their precursors, or undifferentiated spindle cells of the ovarian stroma.6 About 60% of cases present with estrogenic manifestations, and only 12% of cases are androgenic.1,2 They are usually encountered in postmenopausal women, typically during workup for abnormal bleeding or for virilizing/feminizing symptoms.2,6 Occasionally, they may occur as unsuspected findings during surgery.7 Some reported estrogenic manifestations include endometrial hyperplasia and well-differentiated endometrioid adenocarcinoma.2
A previously reported case of an undifferentiated NOS steroid cell tumor presented with hirsutism, amenorrhea, clitoromegaly, and temporal baldness.8 In our patient’s case, hirsutism was associated with signs of virilization in the form of deepening voice, clitoromegaly, frontal baldness and increased muscularity. In androgen-secreting ovarian tumors, serum testosterone levels are often high, but DHEA-S levels are low. Our patient also had grossly elevated serum testosterone but normal DHEA-S levels. The diagnosis of these rare tumors can be problematic, especially in the case of a small ovarian tumor. These tumors are typically less than 3 cm in diameter, which explains poor visualization with ultrasonography and computerized tomography.4 In previous case reports, selective venous sampling have been shown to be highly effective in tumor localization.9 However, this is an invasive and operator-dependent procedure with the risk of hemorrhage. A few case reports have previously described gonadotropin-dependent stromal luteoma, but these tumors could not be localized with imaging techniques. Testosterone, FSH and LH were markedly inhibited following the administration of a GnRH analogue, suggesting a gonadotropin-dependent, testosterone-secreting ovarian tumor; and implying that a stromal luteoma is not autonomous but is gonadotropin-dependent.10 In our case, computerized tomography incidentally detected a left adnexal mass, which was not clinically palpable; and was subsequently confirmed by transvaginal ultrasonography. A different kind of luteoma can appear in pregnancy. In the Philippines, one case of a maternal pregnancy luteoma responsible for virilization of both newborn and mother was reported, which was not the case in this patient.12
Microscopically, stromal luteomas are composed of round polyhedral cells present in nests that form nodules. Crystalloids of Reinke are conspicuously absent, a distinguishing feature of stromal luteomas from Leydig cell tumors.2 In difficult cases, immunocytochemistry provides diagnostic accuracy. The most useful immunohistochemical marker for their identification is alpha-inhibin, which is positive in most neoplasms in the sex cord-stromal group.4 Stromal hyperthecosis has been found in association with stromal luteomas in the surrounding or contralateral ovary in 90% of cases, a feature not seen in our patient.2,12
In the evaluation of postmenopausal androgen excess, the history and physical examination direct the appropriate laboratory and radiologic evaluation. Testosterone and DHEA-S are the primary hormonal tests that should be measured.13 A testosterone level above 200 ng/dL or DHEA-S level more than 800 ng/mL suggest the need to evaluate for a tumor of the ovary or adrenal. In a study of 478 women (both premenopausal and post-menopausal) with signs and symptoms of hyperandrogenism, 11 had testosterone level above 250 ng/dL. However, only one of these 11 had a tumor. Of the 10 women with DHEA-S level above 600 ng/mL, none had an adrenal tumor.14
Several reports have also more recently confirmed that absolute levels of elevation of these steroid hormones do not clearly differentiate the etiologies. Some have suggested a 2- to 5-day low dose dexamethasone suppression test. Failure to suppress baseline elevation of testosterone or DHEA-S is thought to indicate an ovarian source.15 However, this approach has not been studied among the postmenopausal women.
Pelvic ultrasonography or magnetic resonance imaging (MRI) is useful in women with elevated testosterone levels to evaluate the ovary. The expertise of the ultrasonographer may influence detection, as most tumors are quite small. A CT or MRI of the adrenals is indicated in the evaluation of patients with high DHEA-S, or signs and symptoms and laboratory abnormalities suggestive of adrenal Cushing’s syndrome. Although most patients with isolated elevation of testosterone have an ovarian source of hyperandrogenism, there are rare case reposts of testosterone-secreting adrenal adenomas.16 Thus, imaging the adrenals is useful before proceeding to ovarian surgery.
Data is limited concerning the frequency and severity of androgen excess in the menopause. No data is available concerning long-term effects of altering androgen levels. However, high androgens adversely alter lipid profile with increase LDL, decrease in HDL and increase triglyceride levels.17,18 There have been recent associations reported between levels of advance glycation end-products and testosterone levels in post-menopausal women, independent of insulin resistance. High testosterone and estrogen are both associated with worsening insulin resistance and can worsen hypertension and fluid retention. Recent studies have shown that high testosterone in women correlate with increased risk for breast cancer and cardiac risk.
18,19 In a group of 390 postmenopausal women, 104 of these with history of irregular cycles and hyperandrogenemia had more evidence of coronary artery disease by angiogram, as well as more obesity, metabolic syndrome and diabetes.18,20 This emphasizes the need for thorough evaluation and treatment in postmenopausal women who present with hyperandrogenism. An interdisciplinary approach to management is strongly recommended.
This case highlights the importance of a thorough evaluation in postmenopausal women who present with virilization and hyperandrogenism. The physical manifestations of androgen excess also portend the serious health risks associated with this condition.The cardiometabolic consequences of hyperandrogenemia, particularly due to underlying insulin resistance, leading to diabetes, dyslipidemia and worsening hypertension, should also be evaluated and treated.