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Letters to the Editor |
1 Departments of Clinical Chemistry and 2 Oncology, Helsinki University Central Hospital, Helsinki University, Helsinki, Finland
aAddress correspondence to this author at: Ulf-Håkan Stenman, Helsinki University Central Hospital, Biomedicum Helsinki, Rm. A423a, Haartmaninkatu 8, P.O. Box 700, FIN-00029 Helsinki, Finland. Fax 358-9-47171737; e-mail ulf-hakan.stenman{at}hus.fi.
To the Editor:
Alfa-fetoprotein (AFP) and serum human chorionic gonadotropin (hCG) are reliable markers of testicular cancer, and treatment of a relapse is often initiated on the basis of marker increase alone. Slightly increased hCG concentrations have occasionally been misinterpreted to indicate a relapse, leading to inappropriate chemotherapy (1). We describe a seminoma patient in whom a relapse was suspected 10 years after therapy because the patient had increased hCG concentrations found to be caused by hypogonadism-induced pituitary hCG secretion.
A 27-year-old man underwent left radical orchiectomy and adjuvant radiotherapy for stage I testicular seminoma in the early 1990s at Helsinki University Central Hospital. The patient had a preoperative serum hCG of 0.5 IU/L (upper reference limit 0.7 IU/L) and AFP <1 IU/L (upper reference limit 9 IU/L). Atrophy of the nonmalignant testicle was suspected on the basis of preoperative ultrasound findings, but the serum testosterone concentration, 10.2 nmol/L, was within the reference interval (10–38 nmol/L), whereas follicle-stimulating hormone (FSH) concentration was increased, at 28 IU/L (reference interval 1–7 IU/L), suggesting partially compensated hypogonadism. One year later, examinations revealed a subnormal serum testosterone concentration and azoospermia. At this point the patient’s hCG had increased to 3.7 IU/L, FSH to 50 IU/L, and luteinizing hormone (LH) to 20 IU/L (reference interval 1–9 IU/L). Testosterone replacement therapy was administered, but the patient discontinued its use within a few weeks. During the next 2.5 years, when he did not receive replacement therapy, the serum concentration of hCG remained slightly increased. Intramuscular testosterone replacement therapy was reinstituted 3.5 years after surgery, and serum concentrations of hCG, FSH, and LH normalized. Approximately 9 years after surgery, the patient stopped the testosterone medication because of acne. His hCG gradually increased to 4.5 IU/L, and this finding led to suspicion of a tumor relapse. Serum testosterone was 2.9 nmol/L, FSH 62 IU/L, and LH 31 IU/L, indicating hypogonadism. Testosterone therapy was reinstituted and hCG, FSH, and LH concentrations decreased rapidly (Fig. 1
). Follow-up consisting of radiographic imaging, serum tumor marker determinations, and clinical examinations was discontinued a few months later, almost 11 years after primary therapy. Apart from the increasing serum hCG concentration, there were no other signs of relapse during follow-up.
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The pituitary is a source of hCG, and low serum concentrations can be detected with sensitive assays in most healthy men and women (2)(3). hCG concentrations increase with age, and with our assay values up to 10 IU/L can be observed in postmenopausal women (2). This increase is caused by increased pituitary gonadotropin secretion and is suppressed by hormone replacement therapy (3). hCG concentrations also increase in elderly men, but values exceeding 2 IU/L are rare (2). Testicular cancer and its treatment, particularly cytotoxic chemotherapy, may cause gonadal suppression leading to hypogonadism, which is mostly transient (4) and may lead to increased serum concentrations of LH and FSH, which normalize with testosterone replacement therapy (1). Increased hCG immunoreactivity after treatment of testicular cancer has been described previously but was ascribed to cross-reaction of LH in the hCG assay rather than to hCG itself (1). Cross-reaction is not a problem with assays using highly specific monoclonal antibodies. We determined hCG in serum with a highly sensitive time-resolved immunofluorometric assay (PerkinElmer Wallac) (analytical and functional sensitivities 0.27 IU/L and 0.5 IU/L, respectively) with negligible cross-reactivity with LH (2). Thus we determined that the increased serum hCG was caused by pituitary hCG secretion in response to hypogonadism.
With our hCG-assay the upper reference limit in healthy males younger than 50 years is 0.7 IU/L and in men older than 50 years it is 2.1 IU/L (2). In our patient, the hCG concentration exceeded this limit, although it did not exceed 5 IU/L, which is a commonly used decision limit. Concentrations up to 32 IU/L have been observed in postmenopausal, hypogonadal women (5) but not in men, possibly because of a physiological difference between men and women or differences in calibration and broader assay specificity, i.e., detection of hCG and the free beta subunit of hCG together. With other assays, hCG >5 IU/L will most likely be observed in male patients with severe hypogonadism.
The case we describe shows that a moderate increase of serum hCG is a physiological reaction to hypogonadism, which is common in testicular cancer patients because of the disease and may occur in the absence of relapse. To avoid unnecessary and potentially harmful chemotherapy, it is important to remember that moderate increases in hCG in men treated for testicular cancer are not always caused by cancer relapses.
Acknowledgments
Grant/funding support: Finska Läkaresällskapet.
Financial disclosures: None declared.
References
The following articles in journals at HighWire Press have cited this article:
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  C. M. Sturgeon, M. J. Duffy, U.-H. Stenman, H. Lilja, N. Brunner, D. W. Chan, R. Babaian, R. C. Bast Jr., B. Dowell, F. J. Esteva, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers Clin. Chem., December 1, 2008; 54(12): e11 - e79. [Abstract] [Full Text] [PDF]
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A. Lempiainen, U.-H. Stenman, C. Blomqvist, and K. Hotakainen Free {beta}-Subunit of Human Chorionic Gonadotropin in Serum Is a Diagnostically Sensitive Marker of Seminomatous Testicular Cancer Clin. Chem., November 1, 2008; 54(11): 1840 - 1843. [Abstract] [Full Text] [PDF]
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 B. E.P.B. Ballieux, N. I. Weijl, H. Gelderblom, J. van Pelt, and S. Osanto False-Positive Serum Human Chorionic Gonadotropin (hCG) in a Male Patient with a Malignant Germ Cell Tumor of the Testis: A Case Report and Review of the Literature Oncologist, November 1, 2008; 13(11): 1149 - 1154. [Abstract] [Full Text] [PDF]
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U.-H. Stenman Commentary Clin. Chem., January 1, 2008; 54(1): 213 - 214. [Full Text] [PDF]
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