Ovarian Leydig cell tumor and postmenopausal hirsutism with signs of virilisation

Abstract

A 71-year-old woman was referred to the endocrinology clinic to investigate postmenopausal hirsutism with 10 years of evolution. She had history of regular menses and menopause with 50 years old. Physical examination showed a male pattern facies, deepening of the voice, androgenic alopecia and hirsutism with a score of 23 according to the modified Ferriman-Gallwey scale. Testosterone and androstenedione were increased. Transvaginal ultrasound, abdominal and pelvic CT showed uterine fibroids with no pathological findings in the adrenals or ovaries. Since she had postmenopausal vaginal bleeding, uterine fibroids and suspicion of an ovarian source for her hyperandrogenism, total hysterectomy and bilateral oophorectomy were performed. Histopathological diagnosis was a Leydig cell tumour located in left ovary and endometrial carcinoma. Improvement of hirsutism was started to notice 1 month after the surgery and she was referred to the oncology clinic for adjuvant treatment.

Background

Hirsutism is defined as the presence of excessive terminal (coarse) hair in androgen-dependent areas of the female body and commonly results from relatively benign functional disorders.^{1 2} However, sometimes it is the presentation of a more severe disorder and the first manifestation of a condition that will ultimately lead to virilisation, if left untreated.

Virilisation includes the combination of severe hirsutism with male pattern balding, anabolic appearence, deepening of the voice and clitoromegaly.^{3 4} This disorder must be approached cautiously by practitioners due to the negative psychological impact; it can have on the patient but also because it can be a manifestation of life-threatening tumours (ovarian and adrenal malignancies).⁵

This report describes the evaluation, differential diagnoses and follow-up of a woman with long-standing hirsutism, signs of virilisation and a diagnostic hypothesis of ovarian tumorous cause for her hyperandrogenism although with negative imaging studies. After surgical therapy, a rare ovarian Leydig cell tumour in concomitance with an endometrial adenocarcinoma was found.

Case presentation

A 71-years-old woman, retired secretary, with a personal history of arterial hypertension since 63 years old, dyslipidaemia, uterine fibroids and depressive syndrome under therapy with losartan 100 mg one time aday, hydrochlorothiazide 12.5 mg one time a day, lercanidipine 10 mg one time a day, simvastatin 40 mg one time a day, ezetimibe 10 mg one time a day, amitriptyline 75 mg one time a day and alprazolam 1 mg one time a day. She was referred to the endocrinology outpatient clinic due to postmenopausal hirsutism with progressive worsening in the last 10 years. She reported menarche at 13, regular menses, a single pregnancy without complications, menopause at 50 without vasomotor symptoms and without hormone replacement therapy. She denied using vitamins or any others supplements, using or contacting with steroids compounds and smoking. From the family history, she referred to a sister with breast cancer.

On anamnesis, the patient reported being preoccupied with hirsutism signs, especially with the facial hair that disturbed her daily life; however, only in the previous year did she expose this problem to her general practitioner. The patient had noticed an increase in body hair since her 60s. She also described postmenopausal vaginal bleeding related to uterine fibroids, but she denied follow-up consultation in gynaecology. Changes in libido and clitoromegaly were denied.

On physical examination, the patient had a good general condition, male-type facies, deepening of the voice, normal weight (body mass index of 23.7 kg/m²), with elevated blood pressure (166/90 mm Hg), androgenic alopecia, male pattern of coarse hair distribution on the face, chest, abdomen, thighs and arms (score 23 on the modified Ferriman-Gallwey scale). She had no acne, no acantosis nigricans, cervical hump, stretch marks or abnormal growth of the extremities. There were no palpable abdominal or pelvic masses.

Investigations

The laboratory evaluation showed erythrocytosis, high levels of testosterone and increased delta-4-andostenedione (table 1). The hepatic, renal and electrolyte profile, thyroid function, prolactin, urinary free cortisol, 3α-androstanediol glucuronide, 17-hydroxyprogesterone and dehydroepiandrosterone sulfate (DHEA-S) were within the normal range.

Table 1.

Laboratory data before and after surgery (total hysterectomy and bilateral oophorectomy)

	Before surgery	3 months after surgery	Reference ranges (postmenopausal women)
Haemoglobin, g/dL	16.0	14.3	(12.0–15.0)
Haematocrit, %	46.8	40.8	(36.0–46.0)
Total testosterone, ng/dL	380	15	(2.9–40.8)
Delta-4-andostenedione, ng/mL	4.3	1.4	(0.3–3.3)
Estradiol, pg/mL	40.1	5.0	(<138.0)
FSH, U/L	30.4	62.5	(25.8–135.0)
LH, U/L	30.7	48.8	(7.7–59.0)
CEA, ng/mL	2.60	<1.80	(<5.0)
CA 19.9, U/mL	25.8	25.1	(<37.0)
CA 125, U/mL	19.1	10.5	(<35.0)

CA, cancer antigen; CEA, carcinoembryonic antigen; FSH, follicle stimulating hormone; LH, luteinising hormone.

Regarding imaging studies, pelvic ultrasound via transvaginal exhibited uterus enlarged by several intramural fibroids, the largest with a 7 cm larger diameter, without adnexal masses or free fluid collections. The abdominal and pelvic CT showed unremarkable adrenals, uterus with fibroids and absence of abnormal masses in adnexal topography.

Taking into account the patients family history, she underwent a breast ultrasound and mammography that showed calcifications with benign characteristics and without evidence of nodules or other suspicious characteristics (BIRADS 2).

Differential diagnosis

The aetiological diagnosis of clinical hyperandrogenism in the postmenopausal period is challenging and it is based mainly on clinical aspects, being categorised into non tumorous and tumorous causes.^{3 6}

Manifestations of hyperandrogenism such as mild hirsutism can occur during the menopausal transition as part of the normal ageing process; however, signs of severe hirsutism and virilisation are a rare condition after menopause and needs careful evaluation.^3–5 The total testosterone value can help identify the aetiology, although there are no well-defined cut-offs. Some data suggest that total testosterone values above 100–140 ng/dL with clinical signs of hyperandrogenism, virilisation and exclusion of exogenous causes may be indicative of ovarian or adrenal androgen-producing tumours.^{3 6} Values below this level may translate to non tumorous hyperandrogenism.^3–5

Non tumorous causes of hyperanrogenism includes the polycystic ovarian syndrome, congenital adrenal hyperplasia, ovarian hyperthecosis, Cushing’s syndrome, acromegaly, iatrogenic hyperandrogenism, obesity and states of insulin resistance.^3–6

Adrenal tumours comprises androgen-secreting adenomas or carcinomas, which can also secrete other hormones such as glucocorticoids and sometimes estrogens.^{4 7} These are rare tumours, highly suggestive of malignancy, usually associated with increased levels of DHEA-S and typically large (more than 8–10 cm).^{5 6}

Ovarian tumours includes Sertoli-Leydig cell tumours, granulosa-theca cell tumours and hilus-cell tumours (or Leydig cells). These tumours are relative rare, comprise 5%–8% of all ovarian neoplasms and may produce testosterone and/or other androgens with or without oestrogens.³

In postmenopausal women, the ovarian causes of virilisation are more common than adrenal ones.^{4 6} In our clinical case, there were signs of virilisation, elevated testosterone (more than nine times) and androstenedione, with DHEA-S and 17-OHP values within the reference values, which made us suspect an ovarian tumorous source of androgens, although the imaging study was negative.

Treatment

On the first visit, after the exclusion of iatrogenesis, eflornithine topical cream (Vaniqa) was prescribed, with a successful decrease in the amount of facial hair after 3 months of use. After excluding other endocrinopathies and given the strong suspicion of an androgen ovarian source along with uterine fibroids and vaginal blood loss, the patient was referred to the gynaecology department. A multidisciplinary discussion was carried out and a total hysterectomy plus bilateral oophorectomy was decided with the patient’s consent.

The surgery had no complications and the histopathological diagnosis of the ovaries included a Leydig cell tumour in the left ovary with 1 cm in diameter. The immunohistochemistry of these cells showed diffuse positive staining for inhibin A, negative for cytokeratin 7 and positive staining for Ki67 less than 2%. In the uterus was identified a grade 2 endometrioid adenocarcinoma of the endometrium (pT1bNxMx), completely resected. Other findings included multiple leiomyomas, the largest being subserous with 7.5 cm in diameter and several calcifications.

Outcome and follow-up

One month after surgery, the patient reported an improvement in hirsutism signs. When evaluated, 3 months after surgery, the patient was satisfied with resolution of the hirsutism, noticed less hair loss, but maintaining frontal balding (figure 1). On physical examination, a score of 4 on the modified Ferriman-Gallwey scale and blood pressure of 124/76 mm Hg were observed. Laboratory data showed normalisation of haematocrit and decreased value of total testosterone and androstenedione to within reference levels for postmenopausal women (table 1).

Figure 1.

Male pattern balding in a 71-year-old woman presenting with a 10-year progressive history of postmenopausal hirsutism and virilisation.

Due to the incidental diagnosis of the endometrial adenocarcinoma, the patient underwent chest, abominal and pelvic CT scans for tumour staging. No adenopathies or secondary lesions were found and the patient was subsequently referred to an oncology clinic, where she started on adjuvant radiotherapy.

Discussion

The Leydig cell tumour of the ovary is a rare disease (it represents less than 0.1% of all ovarian tumours) which arises from ovarian hilar cells.³ For this reason, specific data on its natural history, prognosis and follow-up are not yet well defined.⁷

Women with this type of tumour had high testosterone levels (between 3 and 25 times above the upper limit of normal). Most reported cases of ovarian Leydig cell tumours were diagnosed in postmenopausal women (mean age of reviewed cases is 69 years (range 60–81)). Most of these tumours were unilateral, relatively small (between 1 and 5 cm) and associated with clinical virilisation in more than half of women. The mean time between the start of the symptoms and histological diagnosis was 5.6 years (range 2–14).3 4 6–11

In our case, the diagnosis was made 10 years after the onset of symptoms and testosterone values were elevated more than 9 times above the upper limit of normal, with a slight increase in androstenedione value. The 17-hydroxyprogesterone and DHEA-S were normal. Serum levels of follicle stimulating hormone (FSH) and luteinising hormone were within the reference range for menopause. Three months after surgery, testosterone values normalised and an increase in FSH value was noted.

Erythrocytosis has been reported in women with androgen-producing tumours, which resolved after surgical removal of the tumour.^7–12 Increased testosterone levels have been associated with secondary erythrocytosis due to its action in stimulating endogenous erythropoietin and in suppressing hepcidin levels.¹³ In our patient, the red blood cell count returned to normal after surgery. These data favoured the relationship between the excess of androgens and erythrocytosis found initially.

In the literature review, a cohort of 22 clinical cases with postmenopausal biochemical hyperandrogenism was evaluated.⁶ In this cohort, alopecia was the most frequent virilisation sign. Three of the eight cases (37.5%) which had an ovarian tumour aetiology had negative imaging studies. In this study, two biological markers (testosterone and FSH) allowed the differentiation between tumour and non-tumour aetiology. Sarfati et al⁶ describe in postmenopausal women with tumour aetiology a positive likelihood ratio of 8.4 for testosterone value greater than or equal to 140 ng/dL and 10.8 for FSH less than or equal to 35 IU/L. In our clinical case, similar testosterone and FSH values were also found. In the same study, DHEA-S values were found above the upper limit of normal only in cases of adrenal carcinoma.⁶ This finding allow, with some degree of confidence, the exclusion of adrenal tumours when DHEA-S value within the reference values and the image is negative for adrenal mass.

According to algorithms suggested by several authors, in the presence of high levels of testosterone compatible with tumorous hyperandrogenism, a transvaginal ultrasound of the ovaries and CT for adrenal glands are important diagnostic tools. Nevertheless, the location of ovarian androgen-producing tumours can be difficult due to their small dimensions, the isoehoic aspect to the uterus on ultrasound and isodense aspect on CT.^3–6 However, if the imaging study is negative, it does not exclude the presence of a tumour, as occurred in ours and in other clinical cases.^{3 10 11} In the instance of negative imaging studies for ovarian lesions and adrenal glands or pitfalls such as non-functioning adrenal adenomas, functional tests such as adrenal and ovarian venous catheterisation, GnRH analogue test and low-dose dexamethasone suppression test can be performed.^{3 4} Nevertheless, these tests are not validated and with a variable success rate (26%–45% for simultaneous ovarian and adrenal venous catheterisation, which should only be performed in centres specialised in this technique).^{3 4 14}

The definitive diagnosis of Leydig cell tumour of the ovary is confirmed histologically after bilateral oopharectomy (standard treatment), but may be unilateral in the case of premenopausal women who intend to preserve their fertility.⁷

On our patient’s first visit, after a detailed clinical history and physical examination that showed severe hirsutism with signs of virilisation and facial hair being a concern, eflornithine topical cream (Vaniqa) was prescribed. This is considered an adjunctive topical treatment in hirsutism and is approved for unwanted facial hair treatment.² After the aetiological study, with a strong suspicion of an ovarian pathological source of androgens (without access to combined adrenal and ovarian venous sampling) and given the presence of uterine fibroids and postmenopausal vaginal bleeding, it was decided to proceed to bilateral salpingoophorectomy plus total hysterectomy recommended in such cases, with the patient’s consent. This made it possible to resolve the condition of severe hirsutism and improve the signs of virilisation with gratification from the patient.

Hyperandrogenism has important implications in the physical and psychological well-being of postmenopausal women and it has been suggested that androgens excess increase the risk for cardiovascular disease, breast cancer and other gynaecological malignancies.^{3 7}

In about 30% of cases these tumours are associated with a hyperestrogenic state along with endometrial hyperplasia, postmenopausal vaginal bleeding and ultimately endometrial adenocarcinoma.7 8 15–17 This hyperestrogenism may be due to tumour secretion, ovarian hyperthecosis and peripheral androgen conversion. In our case, the estradiol value was slightly above what was expected for a postmenopausal woman (<20 pg/mL), although within the reference values of our laboratory.¹⁸

Endometrial adenocarcinoma was an unexpected diagnosis and may be associated with the increased androgen levels and consequent aromatisation to estradiol in postmenopausal women (‘unopposed oestrogen’).^{3 6 19} Allen et al¹⁹ showed that high levels of oestrogen and testosterone were positively associated with an increased risk of endometrial cancer in postmenopausal women. However, no precise data are available concerning long-term effects and malignancy risk of raised androgen levels in women with androgen-producing tumours.

All cases of Leydig cell tumours reported until now have been benign, with an excellent prognosis and remission of symptoms after surgical treatment. In our case, the presence of immunohistochemistry with Ki-67 below 2% (low index) is suggestive of a benign ovarian Leydig cell tumour.^{7 10}

Learning points.

• The development of clinical signs of hyperandrogenism in postmenopausal women should prompt a timely investigation and therapeutic intervention. In these cases, total testosterone, after excluding exogenous causes, represents the best tool to differentiate between tumour and non-tumour hyperandrogenism.

• The aetiological diagnosis of hyperandrogenism is based mainly on clinical and laboratory data, since the imaging studies may not show the androgen-producing lesion.

• In suspected cases of androgen production from an ovarian source, bilateral oopharectomy should be recommended in postmenopausal women.

• The ovarian Leydig cell tumours are rare, so natural history, management and prognosis are not yet well defined.

• There are few data on long-term effects of raised androgen levels in postmenopausal women; however, association with increased cardiovascular risk and malignancy is advocated.