Hyperthyroidism in gestational trophoblastic disease – a literature review

Objective Gestational trophoblastic disease (GTD) is a group of pregnancy-related disorders that arise from abnormal proliferation of placental trophoblast. Some patients with GTD develop hyperthyroidism, a rare but potentially life-threatening complication requiring early detection and management. Existing literature on hyperthyroidism in GTD is scant. This review aims to analyse the epidemiology, pathophysiology and management of this phenomenon. Methods A comprehensive search of MEDLINE, EMBASE and Cochrane Library was performed to obtain articles that explored hyperthyroidism in GTD. A total of 405 articles were screened and 228 articles were considered for full-text review. We selected articles that explored epidemiology, pathophysiology and outcomes/management of hyperthyroidism in GTD. Results The pathophysiology of hyperthyroidism in GTD is well-investigated. Placental trophoblastic tissue secretes excessive hCG, which is structurally similar to thyroid stimulating hormone and also has enhanced thyrotropic activity compared to normal hCG. The incidence and prevalence of hyperthyroidism in GTD varies worldwide, with lower rates associated with high uptake of early antenatal screening and early GTD detection. No clear risk factors for hyperthyroidism in GTD were identified. While hyperthyroidism can be definitively managed with surgical evacuation of the uterus, severe complications associated with hyperthyroidism in GTD have been reported, including thyroid storm-induced multi-organ failure, ARDS, and pulmonary hypertension. Conclusion Early detection of GTD is critical to prevent development of hyperthyroidism and its associated complications. Hyperthyroidism should be recognised as an important perioperative consideration for women undergoing surgery for GTD, and requires appropriate management. Future studies should explore risk factors for hyperthyroidism in GTD, which may facilitate earlier identification of high-risk women.

Inflammatory Cytokines Regulate Glycoprotein Subunit β5 of Thyrostimulin through Nuclear Factor-κB

Thyrostimulin is a heterodimeric hormone comprised of two glycoprotein hormone subunits, namely glycoprotein hormone subunit α2 and glycoprotein hormone subunit β5 (GPB5). Immunological studies have revealed that both subunits colocalize in human pituitary corticotroph cells. Although recombinant thyrostimulin protein selectively activates the TSH receptor and has thyrotropic activity in rats, its biological functions have not been clarified. To explore the physiological regulators for the GPB5, the 5′-flanking region of the GPB5 coding sequence up to 3-kb upstream was analyzed by luciferase reporter assays. We found that nuclear factor-κB (NF-κB) markedly activated GPB5 transcription. Disruption of the putative NF-κB-binding motifs in the GPB5 5′-flanking region silenced the GPB5 activation by p65. Chromatin immunoprecipitation assays revealed that recombinant p65 bound to the predicted NF-κB-binding sites. Because NF-κB is known to associate with acute phase inflammatory cytokines, we examined whether TNFα or IL-1β could regulate GPB5. Both these cytokines activated GPB5 transcription by 2- to 3-fold, and their effects were abolished by the addition of MG132, a NF-κB inhibitor. Our results suggest that inflammatory cytokines positively regulate thyrostimulin through NF-κB activation.