The Iranian Journal of Obstetrics, Gynecology and Infertility

The Iranian Journal of Obstetrics, Gynecology and Infertility

The Role of Leptin as a Biomarker and Therapeutic Target in Gestational Trophoblastic Diseases and Progression to Gestational Trophoblastic Neoplasia: A Narrative Review

Document Type : Review Article

Authors
Neda Ataei Azimi 1
Amir Avan 2
Fahimeh Afzaljavan 3
Marjaneh Farazestanian 4
1 Resident, Department of Obstetrics and Gynecology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
2 Professor, Department of Medical Genetics, Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
3 PhD in Molecular Medicine, Department of Obstetrics and Gynecology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
4 Associate Professor, Department of Obstetrics and Gynecology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
10.22038/ijogi.2026.92702.6598
Abstract
Gestational trophoblastic diseases (GTDs) include disorders resulting from abnormal trophoblast proliferation, such as hydatidiform moles, invasive moles, and choriocarcinoma. These disorders are often associated with genetic abnormalities and carry risks of malignant transformation, metastasis, and recurrence. The aim of this study is to review the available evidence on the role of leptin as a biomarker and potential therapeutic target in GTD and the progression to malignancy. Beyond its role in energy homeostasis, leptin (the product of the LEP gene) participates in placental physiology, including implantation, invasion, proliferation, angiogenesis, and trophoblast survival. Immunohistochemical and RT-PCR studies have reported increased expression of leptin and its receptor (Ob-R) in complete and partial hydatidiform moles, choriocarcinoma, and placental-site trophoblastic tumors compared with normal placenta, with stronger cytoplasmic staining in cytotrophoblasts. Leptin expression is influenced by hCG, hypoxia, MAPK, cAMP/PKA, and PI3K/Akt signaling, as well as epigenetic mechanisms such as LEP promoter methylation. Cellular studies indicate that leptin can promote trophoblast proliferation, reduces apoptosis, and facilitates cell-cycle progression; also, interaction with Siglec-6 may further enhance invasion and cell survival. However, direct serum evidence in GTD remains limited, and leptin should currently be considered a complementary research biomarker alongside, rather than a replacement for, hCG. Therapeutically, targeting leptin/Ob-R signaling, MAPK/PI3K pathways or the leptin-Siglec-6 interaction may inhibit trophoblastic growth and invasion in preclinical models, but clinical application of these approaches requires human studies, standardization of assessment methods, and safety evaluation.
Keywords
Biomarkers
Epigenetic Regulation
Gestational Trophoblastic Disease
Leptin
Leptin Receptor
Malignant Transformation
Subjects
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The Iranian Journal of Obstetrics, Gynecology and Infertility
Volume 29, Issue 4
June 2026
Pages 86-98