Sex Hormones in Lymphedema

Abstract

Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return resulting in swelling of the extremities and accumulation of undrained interstitial fluid/lymph that results in fibrosis and adipose tissue deposition in the limb. Whereas it is clearly established that primary lymphedema is sex-linked with an average ratio of one male for three females, the role of female hormones, in particular estrogens, has been poorly explored. In addition, secondary lymphedema in Western countries affects mainly women who developed the pathology after breast cancer and undergo through hormone therapy up to five years after cancer surgery. Although lymphadenectomy is identified as a trigger factor, the effect of co-morbidities associated to lymphedema remains elusive, in particular, estrogen receptor antagonists or aromatase inhibitors. In addition, the role of sex hormones and gender has been poorly investigated in the etiology of the pathology. Therefore, this review aims to recapitulate the effect of sex hormones on the physiology of the lymphatic system and to investigate whetherhormone therapy could promote a lymphatic dysfunction leading to lymphedema.

Keywords: hormone therapy; lymphatic system; lymphedema; sex hormones.

Figure 1

Diagram of sex hormones biosynthesis. Schematic representation of main sex hormones (in bold) biosynthesis starting from cholesterol. Enzymes responsible for each transformation step appear in italic. HSD: HydroxySteroid Dehydrogenase.

Figure 2

Estrogen-protective effect on lymphatic endothelium is mediated by the estrogen receptor (ER) α. Schematic representation of the molecular mechanisms implicated in the pro-lymphangiogenic effects of E2. The binding of E2 to ERα stimulates the transcription of lymphangiogenic genes through the genomic pathway. Additionally, E2 treatment activates Erk pathway and increases LEC migration and tubulogenesis.

Figure 3

Hormone therapies in estrogen receptor-positive breast cancer. Schematic representation of the two main hormone therapy drugs used in breast cancer depending on the menopausal status of cancer patients. Tamoxifen abolishes E2-induced protective effect on lymphatic endothelium and thus participates to lymphedema development. At the contrary no effect on lymphatics has been reported for aromatase inhibitors.