Contributed by Dane C. Olevian, M.D. and Octavia Peck-Palmer, Ph.D.FINAL DIAGNOSIS
Pituitary hCG production.
DISCUSSION
HCG in Normal Human Physiology
Human chorionic gonadotropin (hCG) is a hetero-dimeric glycoprotein hormone consisting of a unique 145 amino acid beta subunit and a 92 amino acid alpha subunit that is identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). Carbo-hydrate side chains comprise 25-40% of the molecular weight of hCG. The 2 most common forms of hCG synthesized by cells are regular hCG and hyperglycosylated hCH (hCG-H), which contains more sugar residues [1].
Gestational trophoblastic tissue is the principle source of hCG. Shortly after implantation of a fertilized ovum into the myometrium, the syncytiotrophoblast begins to secrete hCG, which maintains progesterone production by the corpus luteum until placental production is established, usually by 6 weeks of gestation. Healthy, non-pregnant individuals have low to undetectable hCG levels (generally <5 mIU/ml). During a normal pregnancy, however, hCG levels rise to approximately 50 mIU/ml within 1 week of conception, and double every 1.5 to 3 days for the first 6 weeks. Levels continue to rise at a slower rate until the end of the first trimester, with peak levels reaching 27,300 to 233,000 mIU/ml [1]. HCG is thus a reliable laboratory marker for pregnancy.
Although normal pregnancy is the principle cause for a rise in circulating hCG levels, other situations will result in hCG detection in the serum. These include false-positive test results, neoplastic processes such as gestational trophoblastic disease, and production of hCG by the pituitary gland.
False-Positive hCG Due to Interfering Antibodies
There are numerous reports in the literature of false-positive hCG due to endogenous interfering anti-bodies, including human anti-animal antibodies (HAAA) and heterophile antibodies. HAAAs recognize a specific antigen and may arise after therapeutic antibody administration or environmental exposure to animal antigens. Heterophile antibodies display non-specific interactions with a multitude of antigens and interfere with immunoassays by cross-linking the capture and signal antibodies, leading to false-positive results.
Several approaches exist for identifying interfering antibodies, including detection of hCG in urine, use of different hCG analytical methods, and use of non-specific blocking agents. Confirming the presence of hCG in urine is a simple approach to identifying an interfering antibody, since the high molecular weight of such antibodies prevents renal filtration and urinary excretion. However, this is not practical for very low serum hCG concentrations, because the urine concentration may not reach the detection limits of some qualitative point-of-care tests.
Interfering antibodies can potentially be identified by employing an alternate hCG detection method, since the interference is often eliminated by methods that use different antibodies and reagents. Finally, commercially available non-specific blocking agents like purified animal immunoglobulin can be added to the assay to saturate the heterophile antibodies and prevent their interference with the assay [2].
HCG Production in Gestational Trophoblastic Disease and Non-Gestational Malignancies
Gestational trophoblastic disease (GTD) refers to a group of histologically distinct disorders that arise from placental trophoblastic tissue. This includes complete and partial hydatidiform mole, invasive mole, choriocarcinoma, and placental site tropho-blastic tumor. During active disease states, each of these entities is associated with very high levels of hCG production, ranging from an average serum level of 49,000 mIU/ml in partial moles, up to 100,000 mIU/ml in complete moles, and greater than 600,000 mIU/ml in choriocarcinomas [1]. Patients who have both a history of GTD and persistently low but elevated hCG in the absence of radiologic evidence of GTD are considered to have quiescent GTD (Q-GTD) by some authorities, but this classification is not widely accepted [3]. The serum hCG concentration in these patients tends to persist for 3 or more months at low concentrations (<100 mIU/ml) and remains stable over time. In some patients, however, hCG concentrations have been shown to increase after a protracted period of quiescence, suggesting a return to active GTD that is responsive to treatment. It is therefore hypothesized that the hCG of Q-GTD is elaborated by slow-growing non-invasive syncytiotrophoblasts and that Q-GTD is a premalignant syndrome that can progress to invasive and metastatic disease [2].
During pathologic hCG production, the highly coordinated secretion of alpha and beta subunits may become impaired, resulting in disproportionate quantities of free alpha subunits, or more frequently, free beta subunits. Thus, laboratory assays that detect both intact hCG and free beta hCG are more sensitive for detecting hCG-producing tumors. Furthermore, although regular hCG is mostly produced by syncytotiotrophoblasts, hyperglycosylated hCG (hCG-H) is predominately secreted by the more invasive cytotrophoblast cells. Therefore, laboratory detection of hCG-H may serve as an effective marker of invasive GTD [1].
Outside of gestational diseases, pathologic hCG production is also seen in a range of neoplastic diseases, including seminiferous and nonseminiferous testicular tumors, and benign or malignant non-testicular teratomas. Occasionally, other tumors including hepatic, neuroendocrine, breast, ovarian, pancreatic, cervical, and gastric cancers may produce hCG, albeit usually in modest quantities compared to gestational trophoblastic diseases [1].
Pituitary hCG
Aside from its production during pregnancy, gestational trophoblastic disease, and other malignancies, small quantities of hCG are also produced by the gonadotrophs of the anterior pituitary gland in conjunction with the structurally similar luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). The isolation and characterization of hCG from the pituitary was first reported by Birken, et al. in 1996. In vitro biological activity of this pituitary hCG was found to be 50% as active as hCG purified from the urine of pregnant women [7]. Studies have since demonstrated that hCG production by the pituitary increases in menopause, but the precise mechanism by which such production occurs has not been elucidated. Under normal circumstances, sex steroids produced by the ovaries exerts negative feedback on the hypothalamic-pituitary-ovarian axis, resulting in decreased gonadotropin releasing hormone (GnRH) secretion from the hypothalamus and decreased FSH and LH secretion from the pituitary. During perimenopause, the ovarian synthesis of sex steroids begins to decline, reducing negative feedback control on GnRH secretion, which results in increased FSH and LH production. Since GnRH also promotes pituitary release of hCG, it is likely that the peri- and postmenopausal increase in GnRH leads to a mild increase in pituitary hCG production in certain people [2]. The upper limits of normal hCG in older, non-pregnant women are thus proposed in one study to be ? 8.0 mIU/ml during perimenopause (41-55 years) and ?14.0 mIU/ml in menopause (>55 years). The upper limit of hCG in non-pregnant premenopausal women (18-40 years) is regarded as ? 5 mIU/ml [4].
Use of Serum FSH to Identify the Source of hCG
Although mild increases in serum hCG in peri- and postmenopausal women are not unexpected, it is important to identify the source of hCG since perimenopausal women may still become pregnant. Multiple approaches for identifying the hCG source have been described. Prior to menopause, in the setting of declining ovarian function, there is a decrease in circulating levels of sex hormones and concomitant increase in levels of FSH. One study therefore advocates the use of FSH measurements to discriminate between hCG of placental and non-placental origin. The authors demonstrated that for perimenopausal women 41-55 years of age with mildly increased serum hCG concentrations (5.0-14.0 mIU/ml), an FSH cutoff of 45.0 mIU/ml identified hCG of placental origin with 100% sensitivity and 75% specificity. An FSH >45 mIU/ml was never observed when hCG was of placental origin. FSH testing is not needed when hCG <5 mIU/ml, as pregnancy is unlikely. Similarly, FSH testing is not needed for hCG > 14mIU/ml, as these values are consistent with pregnancy unless determined otherwise. These data indicate that quantitative serum FSH measurements can be used to rule out pregnancy and hCG of placental origin in perimenopausal women with mild increase in serum hCG concentrations [5]. In another study, two weeks of estrogen-progesterone therapy was shown to suppress serum hCG concentrations when the hCG was of pituitary origin, likely though induction of a negative feedback response. Consequently, this approach can be used to confirm pituitary hCG production once pregnancy and a placental origin of hCG has been excluded by FSH measurements [6].
Case Resolution
The patient presented in this case is a 56 year old post-menopausal female with persistent low plasma hCG levels (5-7 mIU/ml) measured over a 1 month period. Pregnancy can be excluded as a source of hCG, given she is post menopause, has no radiologic evidence of pregnancy, and has stable, low plasma hCG concentrations. Furthermore, the FSH level of 118.82 mIU/ml supports a non-placental hCG origin. A false positive result due to antibody interference is not likely because a qualitative urine assay was also faintly positive and serum hCG values were consistent across two testing platforms. Quiescent gestational trophoblastic disease is very unlikely given her lack of GTD history or recent pregnancy. Given these findings and her age, the most likely source of hCG is the pituitary gland. Suppression of hCG upon a short course of estrogen and progesterone therapy can be used to confirm a pituitary origin and exclude neoplastic disease.
REFERENCES
Contributed by Dane C. Olevian, M.D. and Octavia Peck-Palmer, Ph.D.
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