Pathophysiology of hyperthyroidism in GTD
This protocol is extracted from research article:
Hyperthyroidism in gestational trophoblastic disease – a literature review
Thyroid Res, Jan 14, 2021; DOI: 10.1186/s13044-021-00092-3

The pathophysiological mechanisms underpinning hyperthyroidism in GTD have been explored by several studies. The hyperthyroid state in GTD cannot be explained by the effects of thyroid stimulating hormone (TSH) or thyroid stimulating antibodies (as in Graves’ disease) alone. In addition, removal of the hydatidiform mole or trophoblastic tumour results in the rapid resolution of hyperthyroidism. These findings point to the trophoblastic tissue as the main source of the thyroid stimulating agent [19].

hCG has thyrotropic activities and plays a central role in mediating hyperthyroidism in GTD [2022]. This is due to “specificity spillover”, where one hormone interacts with the receptor of a different hormone, causing effects that are determined by the type of receptor activated [19]. Several conditions allow this “spillover” to occur. Firstly, hCG and TSH bear structural resemblance. hCG is made up of a heterodimer consisting of two subunits (alpha and beta) joined noncovalently. The alpha subunit of hCG is virtually identical to TSH, while its beta subunit is similar but sufficiently unique to give it its biological properties [23]. The similarities in biological structures between hCG and TSH allow hCG to exert its effects on the TSH receptor on thyroid membranes. Furthermore, the chances of a clinically significant “spillover effect” is increased during pathological states where there is an excess of the hormone, such as in GTD. In normal pregnancies, the affinity of hCG for the TSH receptor and thyrotropic potency of hCG is thought to be sufficiently low for the “spillover effects” to be negligible [19]. In support of this hypothesis, serum levels of hCG closely correlate with levels of thyroid hormone [24]. Importantly, this also suggests that serum hCG levels may predict the severity of clinical hyperthyroidism [11].

Several studies have also demonstrated that hCG secreted by hydatidiform moles and GTN have different biological properties from the hCG in women with normal pregnancies. Yoshimura et al. (1994) [25] found that the hCG isoform produced by hydatidiform moles had significantly greater thyrotropic activity compared to hCG preparations from normal pregnancy.

Kato and colleagues (2004) [26] focused on women who had hCG serum level lower than 100,000 IU/l and compared the frequency of hyperthyroidism between women with normal pregnancy, hydatidiform mole and choriocarcinoma. The authors found that patients with choriocarcinoma had a significantly higher incidence of hyperthyroidism (4/7; 57%) compared to patients with a normal pregnancy (5/28; 17.9%), which confirmed that hCG produced by choriocarcinomas may have altered biological properties. Of note, however, is that patients in the choriocarcinoma group had significantly higher levels of free beta-hCG compared to the normal pregnancy group. While the thyrotropic effect of free beta-hCG in the setting of choriocarcinoma is unclear, this may represent a potential confounder.

These findings corroborate the hypothesis that excessive secretion of a variant hCG molecule may underpin the pathogenesis of hyperthyroidism in GTD.

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