Hormonal Links between Lipedema and Gynecological Disorders: Therapeutic Roles of Gestrinone and Drospirenone

Abstract

Aims: This study aimed to investigate the pathophysiological mechanisms related to lipedema, starting from the common genetic alteration observed in all cases, which is associated with estradiol receptors (ERα > ERβ). The study explored its connection with normal hormonal fluctuations throughout a woman's life, the effects of xenoestrogens and endocrine disruptors on estradiol metabolism, and, most notably, its strong association with gynecological disorders in many cases. These disorders are linked to increased production of aromatase, 17β-HSD1, and progesterone resistance, with elevated 17β-HSD2 levels, leading to conditions such as adenomyosis, endometriosis, and miomatosis. Based on these findings, the study proposes the potential therapeutic use of progestins, such as gestrinone and drospirenone, as treatment options for women with lipedema. Study Design: Narrative literature review. Methods: A narrative literature review was conducted using the PubMed electronic database. Complementary studies were identified manually using Google Scholar and through citations of relevant authors. Results: Evidence highlights a strong influence of estradiol in the pathophysiology of lipedema, with the imbalance of estradiol receptors (ERα > ERβ), known as the common pathway, as the underlying mechanism. A higher proportion of ERα in adipose tissue triggers a pathological response leading to inflammation, hypertrophy, microangiopathy, immune dysfunction, and fibrosis. Physiological fluctuations in estradiol levels, along with hormonal responses to behavioral and dietary changes, are the most common factors driving lipedema progression. As a result, dietary modifications, specific nutritional strategies, and lifestyle changes remain the primary therapeutic approach. However, in some cases, lipedema shares common pathophysiological mechanisms with estrogen-dependent gynecological conditions. In these cases, progestins, particularly gestrinone and drospirenone, may represent potential therapeutic options for lipedema due to their ability to modulate specific hormonal pathways. Both drugs exhibit anti-inflammatory properties and counteract progesterone resistance by increasing PRβ expression and the production of 17β-hydroxysteroid dehydrogenase 2 (17β-HSD2). This enzyme facilitates the metabolism of estradiol into less potent estrogens, such as estrone, thereby reducing the pathological effects of estradiol on adipose tissue. Additionally, gestrinone reduces ovarian aromatase activity and 17β-HSD1 expression. Conclusion: The study emphasizes the hormonal nature of lipedema and its connection to gynecological conditions, underlining the therapeutic potential of progestins such as gestrinone and drospirenone. By modulating hormonal imbalances, these medications represent promising strategies for managing lipedema and improving patient outcomes. However, the study relies on a narrative review, which limits the strength of the conclusions due to the lack of systematic analysis or meta-analytical approaches. Further research, including well-designed clinical trials and experimental studies, is needed to validate these findings and expand treatment options.