High Estradiol Levels During Postmenopause – Pitfalls in Laboratory Analysis

 

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Abstract

A 54-year-old woman was admitted with a result of high serum estradiol levels (> 4300 pg/ml) and typical postmenopausal symptoms. She had a history of an adnexectomy (normal histopathology) due to the elevated estradiol levels. After surgery, estradiol levels were as high as before. Analyzing the anti-mullerian hormone (AMH), inhibin B, DHEA-S and estrone, typical postmenopausal levels were found. Serum estradiol levels were controlled several times with rabbit-derived polyclonal as well as monoclonal antibodies to optimize the selectivity of the test system. Secondary, a radioimmunoassay was performed to exclude interferences of the detection system where lower, but still elevated estradiol levels (186 pg/ml) were found. Hypothesizing that our patient underwent a cross reaction with irregular antibodies, a control was done using sheep-derived antibodies, which proved a postmenopausal hormone level (estradiol level < 5 pg/ml). This result was confirmed using a fluorescence enzyme immunoassay (FEIA) revealing high levels of irregular antibodies (> 200 mg/l; reference < 30 mg/l). This case depicts the pitfalls of estradiol measurement detecting false elevated estradiol levels in a postmenopausal woman.

Zusammenfassung

Eine 54-jährige Patientin (167 cm, 60 kg) stellte sich mit klimakterischer Beschwerdesymptomatik (Hitzewallungen, Schlafstörungen) bei der behandelnden Gynäkologin vor. Im Rahmen der Diagnostik erfolgte eine Laborkontrolle, die einen deutlich erhöhten Estradiolwert (> 4300 pg/ml) zeigte. Da eine Estradiolproduktion im Rahmen einer Neoplasie vermutet wurde, wurde die Patientin zur operativen Abklärung in ein peripheres Krankenhaus eingewiesen und erhielt eine beidseitige Adnexektomie mit nachfolgend unauffälligem histopathologischen Ergebnis. In der postoperativen Kontrolle zeigte sich der Estradiolwert erneut deutlich erhöht. Die übrigen Hormonwerte entsprachen einem unauffälligen postmenopausalen Befund. Zur Optimierung der Sensitivität des Labortests wurde zunächst ein monoklonaler Antikörper eingesetzt. Auch eine Analyse mittels Radioimmunoassay ergab bereits niedrigere, dennoch weiterhin erhöhte Werte (186 pg/ml). In der Annahme, dass möglicherweise eine Kreuzreaktivität gegen irreguläre Antikörper vorliegen könnte, wurde eine Kontrolle mit Schafsantikörpern durchgeführt, die nun einen typisch postmenopausalen Estradiolspiegel ergaben (< 5 pg/ml). Ein Fluoreszenz-Enzym-Immunoassay konnte in der Tat das Vorliegen irregulärer Antikörper bestätigen (> 200 mg/l; Referenz < 30 mg/l). In diesem Fallbericht werden somit mögliche Fehlerquellen der Estradiolmessung bei postmenopausalen Frauen aufgezeigt.

• References

• 1 Labrie F. All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause. J Steroid Biochem Mol Biol 2015; 145: 133-138
  CrossrefPubMedGoogle Scholar
• 2 Pachman DR, Jones JM, Loprinzi CL. Management of menopause-associated vasomotor symptoms: current treatment options, challenges and future directions. Int J Womens Health 2010; 2: 123-135
  PubMedGoogle Scholar
• 3 Kronenberg F. Menopausal hot flashes: a review of physiology and biosociocultural perspective on methods of assessment. J Nutr 2010; 140: 1380S-1385S
  CrossrefPubMedGoogle Scholar
• 4 Adelson KB, Loprinzi CL, Hershman DL. Treatment of hot flushes in breast and prostate cancer. Expert Opin Pharmacother 2005; 6: 1095-1106
  CrossrefPubMedGoogle Scholar
• 5 Berendsen HH. The role of serotonin in hot flushes. Maturitas 2000; 36: 155-164
  CrossrefPubMedGoogle Scholar
• 6 Casper RF, Yen SS. Neuroendocrinology of menopausal flushes: an hypothesis of flush mechanism. Clin Endocrinol (Oxf) 1985; 22: 293-312
  CrossrefPubMedGoogle Scholar
• 7 Overlie I, Moen MH, Holte A et al. Androgens and estrogens in relation to hot flushes during the menopausal transition. Maturitas 2002; 41: 69-77
  CrossrefPubMedGoogle Scholar
• 8 Miller JJ, Valdes jr. R. Approaches to minimizing interference by cross-reacting molecules in immunoassays. Clin Chem 1991; 37: 144-153
  PubMedGoogle Scholar
• 9 Keski-Rahkonen P, Huhtinen K, Desai R et al. LC-MS analysis of estradiol in human serum and endometrial tissue: comparison of electrospray ionization, atmospheric pressure chemical ionization and atmospheric pressure photoionization. J Mass Spectrom 2013; 48: 1050-1058
  CrossrefPubMedGoogle Scholar
• 10 Abraham GE. Solid-phase radioimmunoassay of estradiol-17 beta. J Clin Endocrinol Metab 1969; 29: 866-870
  CrossrefPubMedGoogle Scholar
• 11 Gorovits B, McNally J, Fiorotti C et al. Protein-based matrix interferences in ligand-binding assays. Bioanalysis 2014; 6: 1131-1140
  CrossrefPubMedGoogle Scholar
• 12 Kragstrup TW, Vorup-Jensen T, Deleuran B et al. A simple set of validation steps identifies and removes false results in a sandwich enzyme-linked immunosorbent assay caused by anti-animal IgG antibodies in plasma from arthritis patients. Springerplus 2013; 2: 263
  CrossrefPubMedGoogle Scholar
• 13 Geetha P, Nair MK. Granulosa cell tumours of the ovary. Aust N Z J Obstet Gynaecol 2010; 50: 216-220
  CrossrefPubMedGoogle Scholar
• 14 Guo L, Yang X, Zhu H et al. Sertoli-Leydig cell tumor presenting hyperestrogenism in a postmenopausal woman: a case report and review of the literature. Taiwan J Obstet Gynecol 2012; 51: 620-624
  CrossrefPubMedGoogle Scholar
• 15 Rey RA, Lhomme C, Marcillac I et al. Antimullerian hormone as a serum marker of granulosa cell tumorsof the ovary: comparative study with serum alpha-inhibin and estradiol. Am J Obstet Gynecol 1996; 174: 958-965
  CrossrefPubMedGoogle Scholar
• 16 Joh K, Aizawa S, Ohkawa K et al. Case report of a malignant Brenner tumor with hyperestrogenism. Pathol Int 1995; 45: 75-84
  CrossrefPubMedGoogle Scholar
• 17 Bertagna C, Orth DN. Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 1981; 71: 855-875
  CrossrefPubMedGoogle Scholar
• 18 Sharma DC, Raheja MC, Dorfman RI et al. Studies on a feminizing human adrenal tumour. II. Biosynthesis in vitro of steroid hormones from testosterone-4-14C and androst-4-ene-3,17-dione-4-14C by a feminizing adrenal tumour. Acta Endocrinol (Copenh) 1965; 50: 439-451
  PubMedGoogle Scholar
• 19 deAsis jr. DN, Samaan NA. Feminizing adrenocortical carcinoma with Cushingʼs syndrome and pseudohyperparathyroidism. Arch Intern Med 1978; 138: 301-303
  CrossrefPubMedGoogle Scholar
• 20 Goto T, Murakami O, Sato F et al. Oestrogen producing adrenocortical adenoma: clinical, biochemical and immunohistochemical studies. Clin Endocrinol (Oxf) 1996; 45: 643-648
  CrossrefPubMedGoogle Scholar
• 21 Young J, Bulun SE, Agarwal V et al. Aromatase expression in a feminizing adrenocortical tumor. J Clin Endocrinol Metab 1996; 81: 3173-3176
  CrossrefPubMedGoogle Scholar
• 22 Bouraima H, Lireux B, Mittre H et al. Major hyperestrogenism in a feminizing adrenocortical adenoma despite a moderate overexpression of the aromatase enzyme. Eur J Endocrinol 2003; 148: 457-461
  CrossrefPubMedGoogle Scholar
• 23 Van Thiel DH, Gavaler JS, Slone FL et al. Is feminization in alcoholic men due in part to portal hypertension: a rat model. Gastroenterology 1980; 78: 81-91
  PubMedGoogle Scholar
• 24 Longcope C, Pratt JH, Schneider S et al. Estrogen and androgen dynamics in liver disease. J Endocrinol Invest 1984; 7: 629-634
  CrossrefPubMedGoogle Scholar
• 25 Rempe I, Brezina U, Kersten S et al. Effects of a Fusarium toxin-contaminated maize treated with sodium metabisulphite, methylamine and calcium hydroxide in diets for female piglets. Arch Anim Nutr 2013; 67: 314-329
  CrossrefPubMedGoogle Scholar