Progestins as a Contributing Factor to Hepatocellular Adenoma: A Case Series and Literature Review

Abstract

Study objectiveTo explore the role of progestins as potential contributing factors for the development of hepatocellular adenoma (HA). MethodsWe describe three cases of adolescents and young adults who developed HA while on norethindrone (NET), and their management. In addition, we provide a comprehensive literature review on the association of progestins and HA. ResultsSince 1983, 16 cases of HA in patients on progestins have been reported. Ten patients were on norethindrone (NET), and five on a prodrug of norethindrone (four on norethindrone acetate (NETA) and one on lynestrenol). One individual had a norgestrel implant. Eight subsequently ceased all hormones: four experienced a size reduction and three had complete resolution of their HA. Among our patients, one ceased NET and instead had a levonorgestrel intrauterine device inserted and another swapped from NET to oral medroxyprogesterone acetate: both experienced complete resolution of their HA. The third ceased NET and underwent a hysterectomy, with size reduction of her HA. ConclusionThese cases and the literature review suggest an association between progestin exposure, in particular NET and its prodrugs, and the development of HA. The pathophysiology is unknown but may include peripheral conversion of NET and NETA to ethinyl estradiol or a specific action of 19-nortestosterone derivatives on hepatocytes, especially those with higher systemic doses compared to the levonorgestrel-IUD. There are no case reports relating to other forms of progestins such as 17-hydroxyprogesterone, which may be important when considering alternative therapeutic options in females requiring effective menstrual management who have comorbidities.