Bilateral microscopic Leydig cell ovarian tumors in the postmenopausal woman

Abstract

A 64-year-old postmenopausal female patient presented with approximately 5 years of intermittent spotting, progressive hirsutism and significantly increased libido and clitoral hypersensitivity with spontaneous orgasms multiple times a day beginning a few months prior. Initial hormone work-up revealed elevated total serum testosterone, androstenedione and 17-hydroxyprogesterone. Luteinising hormone, follicle stimulating hormone, estradiol, dehydroepiandrosterone-sulfate, thyroid stimulating hormone and prolactin were all within normal limits. Initial suspicions suggested an androgen-secreting tumour, likely in the ovary. The lesion was undetectable on transvaginal ultrasound and abdominal–pelvic CT scan. Laparoscopic bilateral salpingo-oophorectomy was performed to remove the likely source of excess androgens. Visible gross lesions were not observed intraoperatively; however, bilateral Leydig (hilus cell) tumours were confirmed by histopathology. Serum testosterone, androstenedione and 17-hydroxyprogesterone levels were normalised postoperatively within 2 weeks and 1 month, respectively.

Background

Hyperandrogenism in the postmenopausal woman could have several plausible causes, both physiologic and pathologic. As women enter menopause, oestrogen and progesterone levels plummet, while the ovaries continue to produce small amounts of testosterone for as long as 10 years beyond menopause.¹ This physiologic, yet relative increase in androgens is a common source of hirsutism, acne and alopecia in postmenopausal women.² However, other pathologic causes of increased postmenopausal androgens include: polycystic ovarian syndrome, ovarian neoplasm, ovarian hyperthecosis, adrenal neoplasm, Cushing’s syndrome, congenital adrenal hyperplasia, pituitary dysfunction and even exogenous androgen use.^3–5 The severity of clinical hyperandrogenism and degree of serum testosterone elevation dictates the rate and extent of clinical workup.³

Postmenopausal hyperandrogenism, especially with signs of virilisation, is very uncommon and tends to be the result of benign or malignant tumours of the ovaries or adrenal glands.⁶ Virilising ovarian tumours are rare, accounting for less than 5% of all ovarian neoplasms.⁷ Leydig cell tumours belong in this category and are very rare neoplastic derivatives of the ovarian sex cord stromal tissue. They comprise less than 0.1% of ovarian neoplasms and typically have good prognoses.⁸

Case presentation

Our patient was a 64-year-old nulliparous woman who was referred to gynaecology from her primary care physician with complaints of intermittent postmenopausal spotting for approximately 5 years, progressive hirsutism and significantly increased libido. She has a medical history including multinodular thyroid goitre, irritable bowel syndrome, cervical spinal stenosis and osteoarthritis. She had a cholecystectomy in 2000. This patient currently takes a probiotic, loperamide as needed for diarrhoea, Acetaminophen 500 mg as needed for pain and vitamin D and calcium supplements. She was adopted and has no knowledge of her family medical history. This patient lives alone and is not sexually active. She smokes ½ pack-per day of cigarettes and denies alcohol or drug use.

Physical examination revealed a body mass index of 26 and signs of mild hirsutism primarily of the face and chin and mild alopecia. The patient states that she has been shaving the coarse hair on her face. Gynaecological examination revealed a prominent clitoris (not tense or enlarged), no cervical motion tenderness, normal uterus and no palpable adnexal masses.

Investigations

At her gynaecology consultation appointment, this patient had already received an endocrine work-up. Biochemical investigation revealed hyperandrogenism, with markedly increased total serum testosterone (234 ng/dL, reference 8–60 ng/dL), androstenedione (385 ng/dL, reference 30–200 ng/dL) and 17-hydroxyprogesterone (115 ng/dL, reference<51 ng/dL). Luteinising hormone, follicle stimulating hormone (FSH), estradiol, dehydroepiandrosterone-sulfate (DHEA-S), thyroid stimulating hormone (TSH) and prolactin were all within normal limits. Repeat total serum testosterone (298 ng/dL, reference 8–60 ng/dL) 2 weeks later revealed an additional increase. This patient’s comprehensive lab work-up can be found in table 1.

Table 1.

Biochemical features pre surgery, 2 weeks post surgery and 2 months post surgery

Hormone	Result		Reference	Units
	Before	After
FSH	92.9	117	25.8–150.3	mIU/mL
LH	42.3	–	10.4–64.6	mIU/mL
Total testosterone	234, 298	21, 18	8–60	ng/dL
Free testosterone	4.77	1.7, 1.0	0.06–0.87	ng/dL
Bioavailable testosterone	42	–	0.8–10.0	ng/dL
17-Hydroxyprogesterone	115	31	<51	ng/dL
Estradiol	33	18	<5–54.7	pg/mL
Androstenedione	385	63	30–200	ng/dL
DHEA-S	110	–	9.7–159	µg/dL
TSH	0.597	0.122	0.358–3.740	µIU/mL
Free T4	1.1	1.2	0.76–1.46	ng/dL
Prolactin	11.8	6.2	1.2–29.9	ng/mL

DHEA-S, dehydroepiandrosterone-sulfate; FSH, follicle stimulating hormone; LH, luteinising hormone; TSH, thyroid stimulating hormone.

Transvaginal ultrasound revealed nabothian cysts present on the cervix and an endometrial thickness of 4 mm. Uterus was 5.7×4.1×2.9 cm, homogenous in echotexture and without masses. There was a small amount of fluid present in the endometrial cavity. Right and left ovaries were 1.8×1.3×1.5 cm and 1.8×2.4×1.4 cm, respectively, with normal colour flow doppler. There was no free fluid in the abdomen. Endometrial biopsy revealed an inactive but weakly proliferative endometrium. There was no evidence of hyperplasia or metaplasia.

The pelvic and abdominal computed axial tomography showed unremarkable adrenal glands, a slightly thickened endometrium, calcified lesions of the inferior right hepatic lobe and unremarkable ovaries.

Differential diagnosis

In the present case, the clitoris was prominent on pelvic examination, but the uterus was of normal size and texture and there was no adnexal fullness or tenderness. She had mild patterns of hirsutism on the face and alopecia, but no deepening of the voice or hoarseness. Significantly high levels of total testosterone (298 ng/dL, reference 8–60 ng/dL) confirmed the presence of a virilising neoplasm. Normal levels of DHEA-S (110 µg/dL, reference 9.7–159 µg/dL) ruled out an adrenal source. In most cases, adrenal tumours present with markedly increased levels of DHEA-S.⁹

Transvaginal ultrasound and abdominopelvic CT were then conducted to further evaluate potential sources of excess androgens. Radiological findings in this case showed unremarkable ovaries and adrenal glands in both imaging studies. There was enough evidence biochemically and radiologically to rule out adrenal neoplasm, so the next step for this postmenopausal woman was bilateral salpingo-oophorectomy for both diagnostic, and ideally therapeutic measures.

Treatment

Bilateral laparoscopic adnexectomy is recommended in postmenopausal women experiencing hyperandrogenism for diagnostic and therapeutic purposes.¹⁰ Bilateral salpingo-oophorectomy was performed without complications in our patient. There were no visible lesions on gross inspection. Right and left ovaries were non-enlarged measuring 2.5×1.6×1.1 cm and 2.4×1.5×1.1 cm, respectively. Endometrial curettage revealed benign quiescent endometrium without evidence of hyperplasia or malignancy. Intraoperative images of the normal-appearing uterus, bilateral ovaries and fallopian tubes are included in figures 1 and 2.

Figure 1.

Laparoscopic view of uterus, bilateral fallopian tubes, and bilateral ovaries. No gross evidence of pathology.

Figure 2.

Laparoscopic images of the left (A) and right (B) ovaries prior to bilateral salpingo-oophorectomy.

Outcome and follow-up

Histopathology reported the presence of bilateral benign Leydig (hilus cell) tumours. There were clear margins in the bilateral ovary excisions. No further therapy was indicated as there were no signs of local tumour spread.

Histological images of this patient’s ovary sections demonstrate normal ovarian stroma and parenchyma (figure 3), stromal (Leydig cell) tumour involving the ovarian parenchyma (figure 4) and increasingly magnified views of the Leydig cell tumour within the ovarian stroma (figure 5A–C). Pure Leydig cell tumours, as in this patient, are described histologically as medium-to-large polygonal Leydig cells with eosinophilic cytoplasm, uniform, round nuclei and central nucleoli (figure 5C). Upwards of 30% of Leydig cell tumours have characteristic rod-shaped cytoplasmic inclusions called Reinke crystalloids; however, these were not present in our patient’s ovarian sections. Pure Leydig cell tumours are almost always benign and primarily produce testosterone.¹¹

Figure 3.

Histological image demonstrating normal ovarian parenchyma and stroma. H&E, ×25.

Figure 4.

Histological image demonstrating atretic ovarian follicles forming the corpus albicans, ovarian parenchyma with tumour invasion and the stromal ovarian tumour. H&E, ×25.

Figure 5.

Histological images of increasing magnification depicting ovarian stromal tumour Leydig cells. H&E, ×50 (A), H&E, ×200 (B) and H&E, ×400 (C).

In 2 weeks following surgery, this patient’s total serum testosterone fell to 21 ng/dL from 298 ng/dL (reference 8–60 ng/dL). The increased libido and clitoral hypersensitivity that she had been experiencing had subsided by her 1-month follow-up; however, she returned to her presurgery baseline over the next month. In response to the patient’s concern of symptom return, repeat endocrine work-up was repeated 2 months post surgery. At this time, total testosterone was 18 ng/dL (reference 8–60 ng/dL), free testosterone 1.0 ng/dL (reference 0.06–0.87 ng/dL), FSH 118 mIU/mL (reference 25.8–150.3), estradiol 18 pg/mL (reference <5–54.7 pg/mL), prolactin 6.2 ng/mL (reference 1.2–29.9 ng/mL) and TSH 0.122 µIU/mL (reference 0.358–3.740 µIU/mL). With the exception of free testosterone, these hormones were within normal limits. However, the free testosterone had decreased to 1.0 ng/dL from 1.7 ng/dL since the 2-week follow-up. There was no longer a biochemical explanation for the return of this patient’s symptoms. Our patient is currently awaiting a neurology consult at her request to further work-up the source of her increased libido in terms of clitoral hypersensitivity.

Discussion

The clinical highlight of this case is bothersome hyperandrogenic symptoms prompting this postmenopausal woman to seek help. The rapidly progressive increased libido and mild signs of virilisation raised suspicion of a virilising tumour, either adrenal or ovarian of origin. Physical examination is crucial to evaluate adnexal masses and tenderness as well as for clitoromegaly. Biochemical and radiologic workup are often both necessary for delineating the source of excess androgens to rule out rare, but potentially life-threatening neoplastic causes.

Leydig (hilus) cell tumours are very rare sex cord stromal cell neoplasms that represent less than 0.1% of all ovarian tumours.⁸ These tumours typically present in postmenopausal years⁸ and are more commonly found unilaterally. The unregulated testosterone production of Leydig cell tumours results in hyperandrogenism in women, oftentimes causing hirsutism and virilisation.¹² Leydig cell tumours are often small, and can be less than 1 cm in diameter, theoretically below the range of ultrasound visualisation capabilities.⁸ Transvaginal ultrasound with colour doppler and MRI are important diagnostic tools for identifying morphological changes in the ovary secondary to Leydig cell tumours³ because oftentimes they are small, isoechoic to surrounding tissue on abdominal ultrasound and isodense on CT.^{13 14} Although biochemical workup and imaging studies are standard, they are oftentimes insufficient to confirm diagnosis of Leydig cell tumours. Ovarian and adrenal vein sampling has been conducted in previous cases to confirm the source of excess androgen; however, catheterisation of these vessels has had low success rates of 26%–45%.⁹

Ovarian sex cord stromal tumours, including Leydig cell tumours, have been associated with DICER1 mutations. According to a recent analysis, 36/37 cases of Sertoli-Leydig cell tumours showed tumor-specific or germline DICER1 mutations.¹⁵ DICER1 is a gene that encodes an RNase III endonuclease responsible for cleaving inactive microRNA into active microRNA. Downstream effects of mutated DICER1 involve altered expression of messenger RNA that increases the person’s risk of several types of neoplasms originating in the ovary, cervix, thyroid, kidney, pituitary and lung.¹⁵ This patient had a history of multinodular thyroid goitre, which raises suspicion of DICER1 mutation involvement in this presentation of bilateral Leydig cell ovarian tumour. We have discussed the referral options for genetic testing with the patient and she has declined genetic work-up for DICER1 mutations at this time.

Learning points.

• Rapid onset of hyperandrogenic, virilising symptoms in a postmenopausal woman should raise suspicions of either ovarian or adrenal neoplasm.

• Elevated testosterone levels with concomitant normal levels of dehydroepiandrosterone-sulfate suggest an ovarian source of androgens.

• Negative imaging studies should not rule out ovarian neoplasm.

• Oophorectomy is the definitive diagnostic and therapeutic option in postmenopausal, hyperandrogenic women.