Hyperthyroidism and human chorionic gonadotrophin production in gestational trophoblastic disease L Walkington,1 J Webster,2 B W Hancock,1 J Everard,1 and R E Coleman1,* Discussion. Subclinical hyperthyroidism is well documented in pregnancy, but clinical manifestations are uncommon. At the time of peak HCG levels in normal pregnancy, serum TSH falls and bears a mirror image to the HCG peak. This fall in TSH suggests that it is HCG that causes increased secretion of T3 and T4 (Hershman, 2004). When there are clinical features of thyrotoxicosis, as in some cases of hyperemesis gravidum, anti-thyroid treatment may be given, but is rarely required beyond 22 weeks gestation. Human chorionic gonadotrophin is a glycoprotein composed of α and β subunits. The α subunit is almost identical to that found in TSH, luteinising hormone (LH) and follicle-stimulating hormone (Hershman, 2004). The subunit consists of a 92-amino-acid chain containing two nitrogen-linked oligosaccharide side chains. In vitro testing has shown low-affinity cross-reactivity between these hormones (Vaitukaitis, 1977; Hershman, 2004). The HCG subunits all target one or more of the G-protein-coupled seven transmembrane receptors, and have a high degree of homology in their transmembrane domains (Vassart and Dumont, 1992). The LH/HCG receptors share 45% homology with the TSH receptor (Nagayama and Rapoport, 1992; Kohn et al, 1995). Hyperthyroidism (defined as a suppressed TSH with raised FT3 or FT4) is more common in trophoblastic disease than normal pregnancy. It is thought that the HCG produced in woman with GTD has enhanced thyrotrophic activity compared with HCG in normal pregnancy. This is supported by the observation that cAMP production is increased more by HCG associated with GTD when transfected with human TSH-R on Chinese hamster ovary cells (Kato et al, 2004). When compared with human TSH, studies using cAMP have identified the potency of purified HCG to be 0.72μU per UHCG (Hershman et al, 1998). This low potency of HCG for TSH receptors is reflected clinically when hyperthyroidism is seen in GTN because clinical manifestation occurs only in the context of very high levels of HCG. Previous case studies have indicated that serum levels of HCG of >100000mIUl–1 are usually needed to produce clinical evidence of thyrotoxicosis (Odell et al, 1963; Morley et al, 1976; Anderson et al, 1979; Norman et al, 1981; Soutter et al, 1981). In our patient cohort, three cases had serum HCG in excess of 1 million at presentation. In case 4, it is likely that her serum HCG had begun to fall rapidly following spontaneous passage of the molar tissue, and had the serum HCG been checked when her hyperthyroidism was diagnosed, the HCG may have been much higher. The level of thyroid stimulation is directly proportional to HCG concentration. Therefore, the severity of clinical hyperthyroidism also reflects the HCG level. Human chorionic gonadotrophin thyrotropic activity may also be influenced by metabolism of HCG molecule; deglycosylation and/or desialylation of HCG may enhance its thyrotropic properties (Norman et al, 1981). In the United Kingdom, the co-ordinated and centralised management of GTN means that patients usually present early and as such very high levels of HCG are unusual, and thus hyperthyroidism, especially in a clinically overt form, is rare. This may not be the case in healthcare systems, which do not enable early diagnosis. The largest case series of women with GTD and thyroid disease comes from Africa. In 27 patients with GTD, more than half (15 out of 27) were biochemically hyperthyroid (8 choriocarcinoma and 7 hydatidiform mole) at presentation. Of these, 60% were clinically thyrotoxic and one developed acute pulmonary oedema with associated heart failure. The patients were all euthyroid once HCG fell to
Posted on: Sun, 16 Mar 2014 12:49:42 +0000
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