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Annals of Clinical Biochemistry
Gynaecomastia caused by a feminising adrenal tumour
| Journal: | Annals of Clinical Biochemistry |
| Manuscript ID | ACB-18-264.R2 |
| Manuscript Type: | Case Report |
| Date Submitted by the Author: | 19-Sep-2019 |
| Complete List of Authors: | Gibbons, Stephen; St James University Hospital, Specialist Laboratory Medicine |
| Jassam, Nuthar; Harrogate and District NHS Foundation Trust Abbas, Afroze; St James University Hospital, Endocrinology Stuart, Kevin; St James University Hospital, Specialist Laboratory Medicine Fairhurst, April; St James University Hospital, Endocrinology Barth, Julian; Leeds General Infirmary, Clinical Biochemistry; | |
| Keywords: | Endocrinology < Clinical studies |
SCHOLARONE™ Manuscripts
Gynaecomastia caused by a feminising adrenal tumour
Stephen M Gibbons,1 Nuthar Jassam, 2 Afroze Abbas, 3 Kevin Stuart,1 April Fairhurst,1 Julian H Barth1
1. SAS Steroid Centre, Specialist Laboratory Medicine, St James University Hospital, Leeds
2. Biochemistry, Harrogate District Hospital, Harrogate
3. Endocrinology, Saint James University Hospital, Leeds
Address for correspondence
Dr Stephen M Gibbons PhD Specialist Laboratory Medicine Leeds Teaching Hospitals NHS Trust Block 46 St. James’s University Hospital Beckett Street, Leeds LS9 7TF
Tel; 0113 20 64717 Email: Stephen.gibbons@nhs.net
DECLARATIONS:
Competing interests: N/A
Funding: N/A
Ethical approval: N/A
Guarantor: SG Contributorship: SG wrote the article, AF carried out the analytical work, NJ identified the patient, AA managed the patient in clinic and JB/KS reviewd and commented on the final work.
Acknowledgements: N/A
Abstract: 125 words Article: 1265 words
Written consent has been obtained from the patient to allow publication of this manuscript.
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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 pre-operative hormone workup was diagnosed as a feminising adrenal tumour. The lesion was excised and adjunct Mitotane therapy 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. [125 words]
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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 1 in 5 patients with ACC are asymptomatic at diagnosis and detected incidentally.3 The European Network for the Study of Adrenal Tumors has issued guidance on pre-operative hormonal assessment of patients with ACC.4 In male patients where the ACC solely secretes oestradiol, the term feminising adrenal tumors 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. Past medical history and current medications were unremarkable. Hypogonadotropic hypogonadism was confirmed by a low testosterone (0.7 nmol/L [RI 8.0-30.0nmol/L]) and inappropriately low/normal gonadotropins; LH (1.2 IU/L [RI 1.0-9.0IU/L]) and FSH (<0.1 IU/L [RI 1.0-9.0IU/L]). Testosterone was measured by LC- MS/MS and gonadotropins by immunoassay on the Siemens Centaur (Munich, Germany). Other investigations including prolactin and 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 <150pmol/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
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elevated oestradiol (484 pmol/L [RI <150pmol/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 8cm x 8cm. Intra tumoural haemorrhage was noted with 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 hCG was undetectable and the blood pressure was normal. CT of the abdomen, pelvis and thorax excluded distant metastasis. As recommended by the European Network for the Study of Adrenal Tumors a full pre-operative hormone assessment was conducted including plasma metanephrines and an overnight dexamethasone suppression test; these and other androgens including Dehydroepiandrosterone sulphate (DHEAS), 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 the patient had a feminising adrenal tumour. On 1st 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. Post-operative blood tests demonstrated normalisation of oestradiol (151pmol/L [RI <150pmol/L]) and testosterone (19nmol/L [RI 8.0-30.0nmol/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 2 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, 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
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secreting tumour was supported by MRI evidence of an 8cm 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 <150pmol/L]).
Adrenocortical carcinoma is a rare disease with an annual incidence of 0.7-2 per million. Included in this diagnosis are feminising 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 3 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 feminising adrenal tumours report feeling dizzy following exercise. The authors speculate this could be due to oestradiols effect 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 feminising adrenal tumours. Hyperoestrogenaemia in feminising adrenal tumours is thought to develop from peripheral conversion of androstenedione to oestradiol.9 In this case study however, androstenedione levels and other androgens were not elevated, therefore it is hypothesised the tumour was secreting oestradiol directly. As stated in the European Network for the Study of Adrenal Tumors Guidelines, pre-operative hormone assessment must be completed.
Post adrenalectomy the patient reported rapid resolution of symptoms. Unfortunately, histology characterised the tumour as an adrenal cortical carcinoma pT3 which was present at the margins. Adjunct chemotherapy was recommended to minimise 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 (ER) stress, collectively inhibiting hormone production from ACC cells. Data on efficacy in
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treatment of femininsing adrenal tumours is limited, however one study demonstrated >20% of patients experienced long term disease control (>1year) for management of ACC. 10
Conclusion
Although extremely rare, feminising 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 HPTA (Hypothalamus-Pituitary-Testes-Axis) axis. However, the authors suggest 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.
References
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