The Masquerading, Masculinizing Tumor: A Case Report and Review of the Literature

Abstract

Androgen-producing tumors in women are rare neoplasms that can cause secondary virilizing characteristics. Of patients presenting with symptoms of hyperandrogenism, these tumors are found in ∼0.2% of cases. Androgen-producing tumors can arise from the ovary or the adrenal gland. Those arising from the ovary are rare, accounting for <5% of all ovarian tumors. This case presents a hilar Leydig cell tumor of the ovary, which resulted in secondary virilization of a 45-year-old female 2 months after cessation of combined oral contraceptives (COC). Laboratory findings showed markedly elevated total and free testosterone concentrations with normal dehydroepiandrosterone sulfate, however neither pelvic ultrasound nor magnetic resonance imaging demonstrated any masses. Venous sampling under fluoroscopy revealed supraphysiologic testosterone concentrations from the right ovarian vein suggesting the source. The patient underwent bilateral salpingo-oophorectomy revealing a 1.3 cm hilar cell tumor of the right ovary. This article reviews the clinical features, diagnosis, and treatment of hilar Leydig cell tumors and describes the long-term complications of supraphysiologic testosterone levels. As the tumor presented after cessation of COC, we also review the mechanisms by which COC might suppress supraphysiologic androgen levels and mask the secondary virilizing effects of androgen-producing tumors.

Introduction

Androgen-producing tumors in women are rare neoplasms that can cause rapidly progressive symptoms of virilization.¹ In women, these tumors can originate in the ovaries or the adrenal glands.² Those originating from the ovary are exceptionally rare, accounting for <5% of all ovarian tumors.¹ A Leydig cell tumor is a type of pure stromal tumor, originating from ovarian sex cord stroma. They are classified into two types, nonhilar originating in the parenchyma or hilar originating in the hilus of the ovary.³ Leydig cell tumors are a type of androgen-producing tumor that secretes testosterone. Circulating total and free testosterone levels greater than three to four times above the physiologic level are commonly seen.⁴ Supraphysiologic levels of testosterone result in symptoms of virilization, including hirsutism, clitoral enlargement, voice deepening, weight gain, and menstrual irregularity. Over 80% of Leydig cell tumors lead to symptoms of virilization.⁵

In adult women, testosterone is produced by the ovaries and adrenal glands and through indirect conversion from androgen precursors in peripheral tissue, including muscle, fat, and skin.⁶ Testosterone is bioavailable to the tissues of the body when it is in free form or bound to albumin, and is biologically inactive when bound to the carrier protein sex hormone-binding globulin (SHBG). Testosterone levels in women naturally decline with age, with the steepest decline in the early reproductive years, plateauing in midlife, and slightly increasing beyond 65 years of age.⁷ Elevated testosterone levels can be seen in several disorders such as polycystic ovarian syndrome, and medications can impact levels of testosterone, such as by increasing SHBG levels leading to a decrease in free testosterone.⁸ Exogenous testosterone is also used as treatment for low libido and sexual dysfunction in women.⁹ Elevated levels of endogenous and exogenous testosterone are associated with a myriad of metabolic and cardiovascular adverse effects.^10–13

This article describes a 45-year-old woman who presented with virilizing symptoms shortly after discontinuing combined oral contraceptives (COC) and was ultimately diagnosed with a rare hilar Leydig cell tumor of the ovary. After surgical removal of the tumor, she continued to have polycythemia and hypertriglyceridemia despite normal testosterone levels. We review hilar Leydig cell tumors and the long-term complications of elevated testosterone levels, thereby highlighting the potential long-term sequelae of these tumors. We also hypothesize whether COC can suppress supraphysiologic levels of androgens produced by androgen-producing tumors and mask their secondary virilizing effects.

Case Report

A 45-year-old premenopausal female (gravida 1, para 0) presented with rapidly progressive symptoms of virilization over an 8-week period. Symptoms included facial hair growth, voice deepening, weight gain, labile mood, and an enlarging clitoris. Her symptoms started 2 months after discontinuing a 10-year use of the COC Ethinyl Estradiol/Norethindrone Acetate 20 mcg/1 mg. She discontinued the medication after a diagnosis of breast cancer. Medical history was significant for a multinodular goiter (status post thyroidectomy) and left breast ductal carcinoma in situ and lobular carcinoma in situ (estrogen receptor and progesterone receptor negative), for which she underwent left breast lumpectomy and radiation 1 month before symptom onset. Her family history is negative for breast or ovarian cancer, and multigene testing identified no pathogenetic mutations.

She presented for medical evaluation 6 months after virilizing symptoms began. The physical exam revealed normal vital signs, a seven-pound weight gain over 6 months, coarse hair on her lower abdomen, and slight prominence of her clitoris. Initial diagnostic workup revealed elevated total testosterone (396 ng/dL), free testosterone (52.5 pg/mL), follicle-stimulating hormone (35.9 IU/L), and luteinizing hormone (31.5 IU/L). Dehydroepiandrosterone sulfate (DHEA-S, 110 μg/dL) and estradiol (39 pg/mL) were normal. Other notable laboratories included elevated hemoglobin/hematocrit (15.7 g/dL/45.8%), normal high-density lipoprotein (HDL, 50 mg/dL), and elevated low-density lipoprotein (LDL, 142 mg/dL), triglycerides (161 mg/dL), and total cholesterol (224 mg/dL), all of which had been normal 4 years prior (Table 1).

Table 1.

Trends in Serum Markers Pre- and Post-tumor Resection

	June 23, 2015	May 24, 2016	June 14, 2019 (initial presentation)	June 21, 2019 (1 week after initial presentation)	July 9, 2019 (3 weeks after initial presentation)	September 5, 2019 (2 weeks after tumor resection)	December 2, 2019 (15 weeks after tumor resection)	March 2, 2020 (28 weeks after tumor resection)
Free testosterone (pg/mL)	—	—	11.26	52.5	—	1.4	1.9	1.1
Total testosterone (ng/dL)	—	—	333	396	—	12	14	11
Cholesterol (mg/dL)	185	238	224	—	—	260	257	210
HDL (mg/dL)	53	51	50	—	—	76	72	62
LDL (mg/dL)	98	143	142	—	—	152	161	126
Triglycerides (mg/dL)	169	221	161	—	—	182	119	109
Hemoglobin (g/dL)	15	15.1	15.7	—	16.2	16.1	15.7	15.7
Hematocrit (%)	45.2	43.4	45.8	—	46.7	46.8	48.0	47.2

Total testosterone was measured with LC-MS/MS and free testosterone was calculated based on the LC-MS/MS-derived total testosterone and equilibrium dialysis-derived percent free levels.

LC-MS/MS, liquid chromatography–tandem mass spectrometry; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Two weeks after presentation with virilization complaints, a transvaginal and transabdominal pelvic ultrasound was unable to visualize the ovaries but was otherwise reported as normal. A pelvic magnetic resonance imaging (MRI) was then ordered and revealed normal adrenal glands and atrophic ovaries with no masses seen. To locate the source of the elevated testosterone, the patient underwent venous sampling under fluoroscopy of the adrenal, ovarian, inferior vena cava, and external iliac veins. Total testosterone levels were highly elevated from the right ovarian vein (>1500 ng/dL), moderately elevated from the left ovarian vein (534 ng/dL), and normal in the adrenals and iliac veins.

Given the high likelihood of a right ovarian tumor based on venous sampling, laparoscopic bilateral salpingo-oophorectomy was performed 4 weeks later. Estimated blood loss was <10 mL. Final pathology was notable for a 1.3 × 1.0 × 0.7 cm tumor of the right ovary consistent with a benign hilar cell tumor with atrophy and cortical fibrosis (Fig. 1). Two weeks after surgery, she reported improvement in mood stabilization, voice pitch, and a decrease in clitoral size, and her free and total testosterone decreased to 1.4 and 12 ng/dL, respectively. Her hemoglobin/hematocrit remained elevated (16.1 g/dL/46.8%), whereas her LDL and cholesterol were elevated to 152 and 260 mg/dL, respectively. Four months after surgery, her dyslipidemia and polycythemia persisted, and 7 months after surgery her LDL returned to normal range, however, she continued to have an elevated total cholesterol and polycythemia (Table 1).

FIG. 1.

An intraparenchymal nodule measuring 1.3 × 1.0 × 0.7 cm was seen on the right ovary.

Discussion

We present a rare case of a hilar Leydig cell tumor of the ovary that presented with secondary virilizing characteristics 8 weeks after the discontinuation of COC. The tumor was not visualized on pelvic ultrasound or MRI, but its location in the right ovary was suggested by results from selective venous catheterization of the ovarian and adrenal veins for testosterone. Bilateral salpingo-oophorectomy confirmed an androgen-secreting hilar Leydig cell tumor of the right ovary.

Pathology

Androgen-secreting tumors in women can originate from the ovaries or the adrenal glands. Most androgen-secreting tumors that originate from the ovary are sex cord–stromal tumors; however, not all sex cord–stromal tumors secrete androgens. According to the World Health Organization, sex cord–stromal tumors can be classified based on their histologic subtypes, which include pure stromal tumors, pure sex cord tumors, and mixed sex cord–stromal tumor.¹⁴ A Leydig cell tumor is a type of pure stromal tumor that can secrete androgens. They are very rare tumors, accounting for 0.1% of all ovarian tumors.¹⁵ Leydig cell tumors are categorized as either hilar or nonhilar cell tumors, based on whether the tumor arose in the ovarian parenchyma or in the hilus. Nonhilar Leydig cell tumors are extremely rare, with only a few cases reported in the literature, and appear to be benign.

Hilar Leydig cell tumors are derived from eosinophilic cells similar to those present in the ovarian hilus.⁵ By definition, hilar Leydig cell tumors must contain Reinke crystals, hexagonal eosinophilic crystals, which are present in the cytoplasm of the cell and rarely in the nucleus.⁵ Hilar Leydig cell tumors are generally small (average diameter is 2–3 cm) and unilateral. On gross histologic exam, they appear solid and well circumscribed. They occur primarily in patients over the age of 50, and the majority develop signs of virilization due to hyperproduction of testosterone.¹⁶ Rarely, these tumors secrete estrogen leading to estrogenic manifestations, such as irregular menses or postmenopausal bleeding, or are inactive. Onset is typically <1 year, and the majority of tumors are not malignant.¹⁶

Diagnosis and treatment

The diagnosis of androgen-secreting tumors as a cause of virilization is often made in combination with laboratory and radiographic findings. Total testosterone, free testosterone, DHEA-S, and 17-hydroxyprogesterone levels are obtained to determine whether hyperandrogenism is present, and an isolated elevation of total and free testosterone typically indicates the ovary as the source. Leydig cell tumors can cause testosterone elevations three to four times above the physiologic level.⁴ Imaging is subsequently needed to identify whether any masses are present. Pelvic ultrasound, computerized tomography (CT) scan, MRI, and transvaginal ultrasound with Doppler have all been used with varying degrees of efficacy; however, imaging may often miss these tumors due to their small size and because the tumors are isoechoic to the uterus on ultrasound and isoattenuating on CT scan.⁵ Selective venous catheterization, while not performed routinely, is another diagnostic tool to localize the source of testosterone when imaging is unrevealing. However, because the procedure requires a high level of expertise to perform and the false-positive rate is high, the test is primarily reserved for cases when there is high suspicion for an androgen-secreting ovarian tumor.¹⁷ The procedure has been shown to correctly identify 90% of right-sided ovarian tumors when the ovarian gradient is ≥1.44, but can only correctly identify 66% of left-sided tumors due to anatomic variations in venous drainage and reflux as well as differences in catheterization technique.¹⁸

The definitive treatment of a Leydig cell tumor is surgery. For an older woman who does not desire fertility, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be based on the individual risk versus benefit and for concern of extraovarian spread.¹⁹ In young patients who may desire fertility, a unilateral oophorectomy can be performed with close follow-up of hormone levels postoperatively.⁴ Since most Leydig cell tumors are benign, following surgery only monitoring of hormone levels and the resulting complications of hyperandrogenism is needed. For our patient, a unilateral oophorectomy was offered given she was premenopausal; however, patient preferred to have a bilateral salpingo-oophorectomy without hysterectomy.

Improvements in hirsutism, alopecia, and libido is typically seen within 1 year after removal of the androgen-secreting tumor.^20–22 For patients at high surgical risk or where the origin of hyperandrogenism is unknown, gonadotropin-releasing hormone agonists (GnRH) can be used to treat hyperandrogenism caused by Leydig cell tumors.¹⁵ GnRH agonists bind to GnRH receptors on tumor cells inducing apoptosis and inhibiting androgen secretion; however, due to the increased risk of osteoporosis associated with GnRH agonists, this treatment is generally not recommended for premenopausal women.¹⁵

Long-term sequalae

Given the rarity of androgen-secreting tumors, the long-term complications of these tumors are largely unknown. Since the majority of symptoms of androgen-secreting tumors are secondary to the supraphysiologic levels of testosterone, it may be thought that androgen-secreting tumors have similar effects as exogenous testosterone administration, however, its use in women causes varying testosterone levels and reported effect profiles. Exogenous testosterone is used off-label for treatment of decreased sexual function in women, and in larger doses it is used in trans men for cross-sex hormone therapy. Testosterone can be administered orally or nonorally (e.g., by transdermal through injection, sublingual, or cream) with different side effect profiles. In a systematic review of over 8000 women, both oral and nonoral administration of testosterone was found to be positively associated with weight gain; however, exogenous testosterone taken orally was found to cause elevated LDL and reduced levels of total cholesterol, HDL, and triglycerides, whereas nonoral administration did not produce any lipid abnormalities.¹¹ Both oral and nonoral administration of exogenous testosterone showed no effect on diabetes mellitus or blood pressure and was not associated with cardiovascular events.¹¹ Physiologic to slightly increased doses of exogenous testosterone has not been found to cause elevated hemoglobin levels in women; however, large doses of testosterone used for cross-sex hormone therapy is associated with increased hemoglobin levels.¹⁰

Endogenous testosterone, on the other hand, naturally declines with age, steepest in the reproductive years, and elevated endogenous testosterone levels is seen in certain disease states, such as obesity and polycystic ovarian syndrome. In premenopausal and perimenopausal women, elevated endogenous testosterone is associated with higher body mass index (BMI), waist/hip ratio, and percent body fat in a dose-dependent manner.²³ In menopausal women, elevated endogenous testosterone is positively correlated with BMI, waist circumference, and the development of type 2 diabetes.¹³ It is also associated with increased blood pressure and total cholesterol without significant changes to LDL, HDL, or triglycerides.¹² High levels of endogenous testosterone is also associated with the occurrence of atherosclerotic coronary artery disease even when adjusted for these lifestyle variables and other cardiovascular risk factors.^12,24

Studies show conflicting data regarding the long-term cardiovascular and metabolic complications of supraphysiologic testosterone levels, seen in ovarian hyperthecosis (OH) and androgen-secreting tumors. OH is a disorder characterized by ovarian stromal hyperplasia and cellular luteinization leading to severe hyperandrogenism, and is associated with average total testosterone levels of 170 ng/dL compared with 448 ng/dL seen in androgen-secreting ovarian tumors.²⁵ In one retrospective study of 8 patients with androgen-secreting ovarian tumors and 16 patients with OH, patients with androgen-secreting tumors and OH were found to have higher rates of obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension than the general population at baseline, and no significant difference in the prevalence of these cardiovascular risk factors was seen between the androgen-secreting ovarian tumor and OH groups. However, at 24 months after tumor removal and testosterone level normalization, patients with ovarian tumors and OH were found to have no differences in mean BMI, glycated hemoglobin (HbA1c), or dyslipidemia compared with their baseline.²⁵ Given that higher rates of metabolic syndrome were present at diagnosis that did not resolve with testosterone normalization, it was predicted from this study that the long-term exposure of supraphysiologic levels of testosterone may lead to irreversible effects on fat mass accumulation and insulin resistance. However, in another prospective study of five patients with androgen-secreting ovarian tumors, there were no significant differences in BMI, insulin sensitivity, or lipid abnormalities in patients with androgen-secreting tumors either before or after surgery compared with the general population.²¹ There is also one case report of a patient with a Leydig cell tumor that was diagnosed with diabetes and dyslipidemia at the time of tumor diagnosis, which improved after tumor removal.⁵

Furthermore, studies show that androgen-secreting tumors can cause erythrocytosis, and case reports reveal complications from erythrocytosis such as recurrent pulmonary embolism, deep vein thrombosis, and sleep apnea.^20,22,26 The erythrocytosis typically resolves within 12 months after tumor removal.²¹ Because the long-term metabolic consequences of androgen-secreting tumors has not been well-established and only case reports have documented cardiovascular complications of erythrocytosis, whether hilar Leydig cell tumors lead to increased cardiovascular events in the short- or long-term remains to be elucidated.

Possible role of COC

Our patient presented with symptoms 2 months after cessation of COC, which raises the question of whether COC has an effect on androgen-secreting tumors. COCs are used for their contraceptive effect and as treatment for hyperandrogenism often caused by polycystic ovarian syndrome or nonclassic congenital adrenal hyperplasia. COC reduces androgen levels by suppressing gonadotrophins, increasing SHBG levels, and by decreasing DHEA and DHEA-S concentrations, which is thought to occur through increased serum cortisol levels and suppression of adrenocorticotropic hormone.²⁷ Through these three mechanisms, COC can reduce testosterone levels by up to 50% independent of the COC dose.²⁷ Did our patient's COC mask the excess production of testosterone by her tumor such that the phenotypic effects of hyperandrogenism did not present until after she stopped the COC?

Whether COC has a similar effect on supraphysiologic testosterone levels produced by androgen-secreting tumors is not known. Since GnRH agonists can be used as treatment for androgen-secreting tumors, COC may have a similar effect given their similar mechanisms of action. Although this mechanism has not been proven for supraphysiologic testosterone levels, case reports show that COC administration leads to reduced levels of testosterone in patients with androgen-secreting tumors and another case report which describes an androgen-secreting tumor that presented after COC cessation.^5,28,29 Given that our patient presented with virilization symptoms 2 months after COC cessation, we propose that COC can mask the virilizing effects of androgen-producing tumors by suppressing supraphysiologic levels of testosterone. Androgen-producing Leydig cell tumors are rare and further research is needed to identify their long-term metabolic and cardiovascular impact on women.

Author Disclosure Statement

No competing financial interests exist

Funding Information

This work was supported by the National Heart, Lung, and Blood Institutes K23HL127262.