Hyperandrogenism due to ovarian Leydig cell tumour presenting with polycythaemia

Background

Polycythaemia or erythrocytosis or polyglobulia refers to an increase in haemoglobin concentration or haematocrit in peripheral blood. It is commonly classified as primary or secondary polycythaemia. Primary polycythaemia is caused by mutations in erythrocyte progenitor cells that result in increased and uncontrolled growth, most commonly in the setting of a myeloproliferative neoplasm. Secondary polycythaemia is most commonly caused by an elevated erythropoietin (EPO) due to hypoxia (eg, smoking or living at high altitude) or autonomous EPO production by various tumours. Occasionally, polycythaemia can be caused by hyperandrogenism, most often as a result of replacement therapy or self-injection with androgens or anabolic steroids.1 Rarely, polycythaemia is encountered in women who present with severe hyperandrogenism by virtue of androgen-secreting tumours. The major androgens in women are testosterone, androstenedione and dehydroepiandrosterone, which are produced in the adrenal glands and ovaries. Androgen levels peak between the ages of 18 and 24 years, significantly decline by 35–40 years of age and remain relatively stable during menopause.2 3 We describe a patient who primarily presented with a polycythaemia that was caused by an excessive androgen production from a pure Leydig cell tumour of the ovary and who remained astonishingly indifferent to progressive virilisation of her body.

Case presentation

A postmenopausal woman in her 60s was referred to our haematology clinic due to polycythaemia. She was previously seen by her general practitioner for a regular check-up which revealed a haemoglobin value vastly above the upper level of normal. The development of plethoric face had been noticed, although not clear for how long. She was a long-time smoker since the age of 18. She did not experience any symptoms of obstructive sleep apnoea syndrome, dyspnoea, chest pain or erythromelalgia. On entering the examination room, characteristic manifestations of hyperandrogenism were noted: alopecia with a male pattern (figure 1), severe hirsutism on the arms, back and torso, and an anabolic appearance with a pronounced muscle mass. Although she always had some degree of hirsutism, it gradually worsened since she entered menopause 10 years ago. Previously, she had a regular menstrual cycle. During the postmenopausal period, the alopecia also gradually developed, which she did not consider to be abnormal nor a cosmetic problem. She was aware of an enlargement of the clitoris. Neither increase of libido nor deepening of voice was perceived and mentioned. She denied use of androgens or anabolic steroids.

Investigations

Haematological investigations showed elevated levels of haemoglobin of 21.3 g/dL (normal range 12.1-16.1 g/dL), haematocrit of 0.67 L/L (normal range 0.35–0.45 L/L) and erythrocytes of 7.4×10¹²/ L (normal range 4–5×10¹²/L). Other blood cell lineages (total leucocytes, leucocyte differentiation and thrombocytes) were within normal ranges. EPO level was normal (9 IU/L; normal range 4–29 IU/L) and JAK2-V617F mutation analysis was negative. These findings pointed to a secondary cause of the polycythaemia, that is, hypoxia or a tumour-associated polycythaemia. Due to physical signs of an androgen excess, endocrine tests (gonadotropins and steroid panel) were requested. Laboratory results showed an impressive increase in total testosterone (64.5 nmol/L; normal range 0.3–2.1 nmol/L) and calculated free testosterone (1.3 nmol/L; normal range 2–37 pmol/L) levels. Oestradiol level was slightly elevated (0.2 nmol/L; normal range 0.04–0.1 nmol/L), while androstenedione and dehydroepiandrosterone sulfate (DHEA-S) remained within normal ranges. Luteinising hormone and follicle stimulating hormone were both suppressed. The combination of very highly elevated testosterone and normal DHEA-S (adrenal originated androgen) levels raised the suspicion of an ovarian pathology. Table 1 shows an overview of the laboratory investigations. Additional radioimaging investigations were requested to assess the abdomen and pelvis for the presence of a pathology concerning either the ovaries or the adrenal glands. CT images showed normal-sized ovaries, with a nodular hyperdense lesion of 2.6 cm in the right ovary and a nodular hyperdense lesion of 1.8 cm in the left ovary (figure 2). The adrenal glands were not enlarged and showed normal CT scans.

The patient was referred to the gynaecology department for further investigation and treatment. Gynaecological examination was unremarkable apart from a clitoromegaly. Transvaginal pelvic ultrasound showed a solid right ovary bordering a unilocular cyst of 1.7 cm, whereas the left ovary was invisible (figure 3).

Differential diagnosis

The differential diagnosis of severe hyperandrogenism with virilisation in a postmenopausal woman consists of neoplastic causes (adrenal or ovarian androgen-secreting neoplasms), ovarian hyperthecosis, or use of anabolic steroids and testosterone supplements. The latter was repeatedly denied by our patient.

The combination of pronounced virilisation, the marked increase in testosterone levels with normal DHEA-S levels, and the normal adrenal and nodular ovarian lesions on CT images militated against an adrenal hyperandrogenism and advocated for an ovarian source, either an androgen-secreting neoplasm or an ovarian hyperthecosis.

Ovarian hyperthecosis is a non-neoplastic disorder characterised by luteinisation of the ovarian stromal cells and typically presents with a gradual onset of acne, hirsutism and eventually virilisation. Ovarian volume on transvaginal ultrasound is usually increased, which was not the case in our patient.

Ovarian androgen-secreting neoplasms present with severe hyperandrogenism and often rapid progression of virilising symptoms. Testosterone levels are usually higher compared with ovarian hyperthecosis. Pelvic MRI can be used to differentiate these two conditions. In practice, the diagnosis is usually made by the pathologist after surgical removal of the ovary.

Treatment

Because of the possible diagnosis of an ovarian androgen-secreting tumour or an ovarian hyperthecosis, a laparoscopic bilateral oophorectomy was performed. Despite the recommendations on the Dutch guideline for tumours of the ovary, we agreed in our regional tumour board meeting not to perform hysterectomy along with bilateral oophorectomy. The following arguments were decisive: possible benign nature of the lesion, histologically normal and no thickened endometrium on ultrasound, and preference for a less invasive surgery.

During laparoscopy mildly enlarged ovaries were seen and there were no macroscopic abnormalities in the peritoneum, uterus or omentum.

Histopathological examination showed a right ovary of 3.8×2.2×2 cm (mean ovarian volume for women 60–69 years of age is 2.1±0.01 cm³ by transvaginal ultrasonography4) with a cyst of 2 cm in size. Microscopy showed closely packed cells with Reinke crystals consistent with Leydig cells, with no prominent mitosis present, and a simple cyst of the ovary (figure 4). The contralateral left ovary showed normal size and morphology. These findings led to the conclusion of Leydig cell tumour of the ovary.

Outcome and follow-up

Six weeks after surgery testosterone and free androgen levels decreased to normal ranges and gonadotropin levels restored to normal postmenopausal levels, and these levels remained within the normal range 20 weeks after surgery. Her hair on the head started to grow again. Haemoglobin and haematocrit levels both decreased and normalised after surgery (table 1).