Gynaecomastia caused by a feminizing adrenal tumour

Abstract

Gynaecomastia is a common finding which typically appears during puberty in boys and in elderly males. At these times, gynaecomastia is likely to be due to physiological hormonal fluctuations, although there are a number of other causes including medications which must also be considered. We present a case of a 52-year-old male with gynaecomastia, hypogonadotropic hypogonadism and hyperoestrogenaemia. MRI of the adrenals confirmed the presence of an adrenocortical carcinoma, which after preoperative hormone workup was diagnosed as a feminizing adrenal tumour. The lesion was excised, and adjunct Mitotane therapy was commenced. Hyperoestrogenaemia is often secondary to exogenous testosterone administration; however, in the presence of hypogonadotropic hypogonadism, other sources of oestrogen should be sought. This case highlights a rare, but nonetheless important cause of gynaecomastia.

Introduction

Raised oestradiol in men is becoming an increasingly common observation in primary care. Causes include obesity, excess alcohol consumption, tumours, hyperthyroidism and some medications. ¹ Abuse of anabolic steroids, where excess testosterone is converted to oestradiol by aromatase enzymes, and cross-sex hormonal therapy used in patients with gender dysphoria are likely also contributing to this finding.

Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7–2.0 cases/million/year. ² Women are more frequently affected than men, with biphasic incidence in the first and fifth decades of life. The majority of patients (40–60%) present with steroid hormone excess (glucocorticoids, mineralocorticoids, androgens) or abdominal mass effects (30%); however. approximately one in five patients with ACC are asymptomatic at diagnosis and detected incidentally. ³ The European Network for the Study of Adrenal Tumors has issued guidance on preoperative hormonal assessment of patients with ACC. ⁴ In male patients where the ACC solely secretes oestradiol, the term feminizing adrenal tumours has been coined. Evidence show these account for less than 1% of all ACCs. ²

We report a case of oestrogen-secreting tumour which presented with features of androgen deficiency.

Case report

A 52-year-old male presented to his doctor with recent onset gynaecomastia, lack of libido and erectile dysfunction. He normally worked out at the gym several times per week but reported a recent lack of energy and an ‘unusual dizzy feeling’ after exercise. Medical history and current medications were unremarkable. Hypogonadotropic hypogonadism was confirmed by a low testosterone (0.7 nmol/L [Reference interval (RI) 8.0–30.0 nmol/L]) and inappropriately low/normal gonadotropins; Luteinising hormone (LH) (1.2 IU/L [RI 1.0–9.0 IU/L]) and Follicular stimulating hormone (FSH) (<0.1 IU/L [RI 1.0–9.0 IU/L]). Testosterone was measured by Liquid chromatography Tandem mass spectrometry (LC-MS/MS) and gonadotropins by immunoassay on the Siemens Centaur (Munich, Germany). Other investigations including prolactin and Thyroid function tests (TFTs) were within reference intervals. The reporting Biochemist recommended oestradiol analysis; this was cascaded to the initial sample and revealed significantly elevated levels (932 pmol/L [RI <150 pmol/L]).

Following discovery of hyperoestrogenaemia, the patient was referred to the regional endocrinology department where repeat bloods confirmed these findings. Oestradiol had initially been measured by immunoassay, a technique known to be subject to assay interference. Positive interference was excluded by in-house radioimmunoassay following ether extraction which confirmed the markedly elevated oestradiol (484 pmol/L [RI <150 pmol/L]). Imaging of the adrenal glands by MRI demonstrated a well circumscribed supra renal mass on the right side, which appeared to be arising from the adrenal gland. It measured approximately 8 cm × 8 cm. Intratumoural haemorrhage was noted with the absence of invasion of adjacent structures. Other investigations were within reference intervals, including full blood count, renal, liver and thyroid function and random cortisol; serum human chorionic gonadotropin (hCG) was undetectable, and the blood pressure was normal. computerised tomography (CT) of the abdomen, pelvis and thorax excluded distant metastasis. As recommended by the European Network for the Study of Adrenal Tumors, a full preoperative hormone assessment was conducted including plasma metanephrines and an overnight dexamethasone suppression test; these and other androgens including Dehydroepiandrosterone sulphate, androstenedione and 17OH-progesterone were all within reference intervals. There was no derangement of the patient’s renin angiotensin pathway, confirming normal mineralocorticoid production.

After discussion at multiple MDT meetings, it was concluded that the patient had a feminizing adrenal tumour. On 1 May 2018, the patient underwent a right open adrenalectomy. Following surgery, the patient noted a rapid return of libido and improved energy levels, his appetite improved and he gained weight. Gynaecomastia resolved. Postoperative blood tests demonstrated normalization of oestradiol (151 pmol/L [RI <150 pmol/L]) and testosterone (19 nmol/L [RI 8.0–30.0 nmol/L]). Histology indicated an adrenal cortical carcinoma pT3 Nx Ki-67 60% (T3 = tumour growing in adipose surrounding the adrenal gland, Nx = Regional lymph nodes cannot be assessed due to lack of information, Ki-67 = prognostic marker). Tumour cells were also present at the margins. Given these findings, it was recommended adjuvant chemotherapy be offered. The patient was prescribed Mitotane which was scheduled to be taken for two years in addition to bi-annual CT scans. Unfortunately, after a period of remission, the patient relapsed.

Discussion

This 52-year-old male presented to his general practitioner with a relatively recent onset of erectile dysfunction, gynaecomastia, lack of libido and decreased energy levels. Gynaecomastia is an increasingly common finding in men; indeed, between the ages of 50 and 69, around 70% of men are affected. ⁵ As with gynaecomastia, the development of erectile dysfunction in this age group is also prevalent. Given the frequency in this demographic, these findings alone or in combination have a poor positive predictive value for the diagnosis of an endocrinopathy. What may rouse suspicion is when these symptoms develop acutely.

Biochemically, the patient had hyperoestrogenaemia with hypogonadotropic hypogonadism; other pituitary hormones were within reference intervals. A preliminary diagnosis of an oestrogen-secreting tumour was supported by MRI evidence of an 8 cm mass on the right adrenal gland. As oestradiol was originally measured by immunoassay which is prone to both positive and negative interference, confirmation was made using an extraction method. Interference in the assay can be due to cross-reactivity with anabolic steroids and plant lignins as well as physiological interference. ⁶ Indeed, given around 4% of the population have an adrenal incidentaloma which rises to 10% in older patients, raised hormone levels (by immunoassay) plus visual (MRI) evidence should not be used to confirm the presence of a hormone-producing tumour. ⁷ In this case, the extraction method confirmed raised levels, albeit significantly lower than that measured by immunoassay (immunoassay = 932 pmol/L vs. RIA = 484 pmol/L [RI <150 pmol/L]).

ACC is a rare disease with an annual incidence of 0.7–2 per million. Included in this diagnosis are feminizing adrenal tumours, which account for less than 2% of all adrenal neoplasms. A review of the available literature confirmed the rarity with one institute documenting only three cases over a 32-year period. ⁸ A striking yet potentially anecdotal common finding between published cases and the one described here is that patients with feminizing adrenal tumours report feeling dizzy following exercise. The authors speculate that this could be due to the effect of oestradiols on fluid balance and thus swelling around the Eustachian tube or its ability to cause hypoglycaemia. Regardless, when found in combination with the other clinical features described above, it should prompt the physician to consider feminizing adrenal tumours. Hyperoestrogenaemia in feminizing adrenal tumours is thought to develop from peripheral conversion of androstenedione to oestradiol. ⁹ In this case study however, androstenedione concentrations and other androgens were not elevated; therefore, it is hypothesized the tumour was secreting oestradiol directly. As stated in the European Network for the Study of Adrenal Tumors Guidelines, preoperative hormone assessment must be completed.

Post adrenalectomy, the patient reported rapid resolution of symptoms. Unfortunately, histology characterized the tumour as an adrenal cortical carcinoma pT3 which was present at the margins. Adjunct chemotherapy was recommended to minimize the chance of tumour recurrence. Mitotane (Lysodren) is an inhibitor of steroidogenesis used in the treatment of ACC and Cushing's syndrome. Its use is often limited by side-effects including anorexia and nausea (88%), diarrhoea (38%), vomiting (23%), decreased memory and ability to concentrate (50%), rash (23%), arthralgia (19%), leukopenia (7%) and, paradoxically in this case, gynaecomastia (50%). Mitotane inhibits enzymes involved in cholesterol side-chain cleavage (P450scc, CYP11A1) and also rapidly induces endoplasmic reticulum stress, collectively inhibiting hormone production from ACC cells. Data on efficacy in treatment of feminizing adrenal tumours are limited; however, one study demonstrated >20% of patients experienced long-term disease control (>1 year) for the management of ACC. ¹⁰

Conclusion

Although extremely rare, feminizing adrenal tumours can present with gynaecomastia, lack of libido and erectile dysfunction, often with an acute onset. Hypogonadotropic hypogonadism is an increasingly common finding in primary care as a result of increased use of anabolic steroids which suppress the Hypothalamus-Pituitary-Testes-Axis axis. However, the authors suggest that when observed with the myriad of symptoms described, hyperoestrogenaemia should be excluded. Where hyperoestrogenaemia is evident, it is also the authors’ recommendation that raised oestradiol be confirmed by an ether-extraction or LC-MS/MS method to exclude positive assay interference in the immunoassay.