Introduction:
Indeed, pre-menopausal women exhibit a lower incidence of cardiovascular diseases than men. This protective effect is often attributed to estrogens, which offer benefits against arterial issues such as vasodilation, improved healing after arterial injury, collateral arterial growth, and atheroprotection. Recently, the impact of estrogens on lymphedema and lymphatic diseases has been explored with the discovery of lymphatic vessels. These estrogenic effects are mediated through nuclear or genomic actions via estrogen receptors (ER) alpha and beta and rapid extra-nuclear membrane-initiated steroid signaling (MISS). These receptors are present in endothelial, lymphatic, and smooth muscle cells across various types of vessels.
What Is the Lymphatic System?
The lymphatic system comprises blind-ended, thin-walled capillaries and collecting vessels responsible for draining fluids to maintain tissue equilibrium. The lymphatic vasculature primarily transfers fat, fluids, macromolecules, and cells, including extravasated leukocytes, to the bloodstream via the subclavian vein. Collected lymph passes through lymph nodes, which serve as sites for antigen-presenting cells to process antigens and initiate immune responses.
Lymphatic capillaries exist in all vascularized tissues except the central nervous system, bone marrow, and retina. Lymphangiogenesis, the growth of new lymphatic vessels, is crucial in conditions like heart ischemia, tumor metastasis, and chronic inflammatory diseases. Dysfunction in lymphatic function can lead to lymphedema, a severe condition. Recent findings indicate that inhibiting ER-alpha in lymphatic endothelium significantly raises the risk of secondary lymphedema.
What Is Estrogen and Its Source?
Estrogen is derived from androgen precursors are steroid hormones primarily released by the ovaries, placenta, and testes. They stimulate the development of female secondary sexual characteristics. Among these estrogens, E2 is the most potent and affects nearly all cells and tissues in the body. Estrogen production occurs mainly in the adrenal glands and ovaries. While the adrenal gland’s lymphatic system primarily transports hormones, estrogen plays a role in regulating lymphatic function in the ovaries. They facilitate the opening of initial lymphatics in the ovarian bursa, enhancing fluid drainage necessary for maintaining a conducive environment for ovulation.
What Is the Role of Estrogen in the Lymphatics?
Estrogen receptors are activated by estrogen, a female hormone that regulates reproductive function and maintains tissue balance, especially within blood vessels. There are two primary types of estrogen receptors: ER-alpha and ER-beta. A third receptor, known as the G protein-coupled estrogen receptor 1 (GPER), has recently been suggested. GPER is believed to play a role in some positive cardiovascular effects of estrogen, like safeguarding against atherosclerosis and hypertension. Despite this, ER-alpha, not ER-beta, plays a primary role in mediating the majority of estrogen’s effects on the vascular and lymphatic systems, particularly within the endothelial cells of these vessels.
Another mechanism by which ERs can influence is through a tethered process. In this scenario, the receptors do not directly bind to DNA but instead engage with other transcription factors like AP-1 or SP1. Apart from these nuclear activities, estrogens also prompt rapid signaling by activating a subset of ER-alpha at the cell membrane. This membrane-initiated steroid signaling is notably observed in endothelial cells. This specific membrane-associated ER-alpha group resides within endothelial cells caveolae and forms a functional signaling unit with endothelial nitric oxide synthase (eNOS). In response, estrogen quickly stimulates eNOS in cells like human umbilical vein endothelial cells or ovine endothelial cells, leading to rapid nitric oxide (NO) production.
What Is the Impact of Estrogen on the Lymphatic System?
When the normal functioning of the lymphatic system is compromised, it results in a condition referred to as lymphedema. This condition involves impaired lymphatic drainage, leading to swelling in the extremities due to fat accumulation and fibrosis in the arms or legs. It is a long-lasting condition resulting in infections, reduced functionality, persistent skin changes, and emotional distress. Lymphedema can arise from genetic factors (primary lymphedema) or may occur following procedures like cancer surgery, lymphadenectomy, or due to filarial infection (secondary lymphedema). Hereditary lymphedema is divided into two categories based on when it appears: congenital (present at birth), such as Milroy disease, and lymphedema praecox (develops around puberty), such as Meige disease or distichiasis syndrome.
While estrogen’s role is considered significant in primary lymphedema that arises during puberty, the involvement of estrogen receptors in causing lymphatic dysfunction is not well understood. The link between primary lymphedema and sex is well-established, with an average ratio of one male to three females affected. However, the precise role of hormones, particularly estrogens, in this context remains unclear. Many primary lymphedema cases, such as those related to Turner syndrome, are directly tied to issues in female hormone production, which affects ovarian development. The consensus is to provide estrogen supplementation as part of healthcare efforts to improve the condition in these patients.
Estrogen is linked to other rare lymphatic diseases as well. Pulmonary lymphangiomyomatosis, observed in women of childbearing age, involves excessive smooth muscle growth around lung, mediastinal, and retroperitoneal lymphatic vessels. It leads to issues like spontaneous pneumothorax and chylous effusion. Considering the hormone’s role, inhibiting estrogen receptors could halt disease progression and manage chylothorax.
For many years, it has been recognized that estrogen receptors contribute to a higher likelihood of lymphatic invasion in ovarian and breast cancers. This was thought to be caused by tumor cells producing growth factors that encourage the growth of lymphatic vessels around the tumor. Around eight percent of breast cancers are ER-positive and necessitate hormone therapy.
Considering the alluring possibilities, it is worth pondering the potential impact of hormone therapy on lymphatic tissue. Tamoxifen, an ER partial agonist, has long been the primary hormone therapy for premenopausal breast cancer patients. Post-menopause, patients shift to aromatase inhibitors that hinder the conversion of testosterone to estrogen.
Given new findings highlighting ER-alpha’s presence in lymphatic endothelial cells, it is reasonable to hypothesize that selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors could influence breast cancer-related lymphatic issues like lymphedema. Despite its initial focus on targeting epithelial cells, tamoxifen’s effect on the endothelium has been studied in the context of coronary artery disease. Recent evidence also points to the potential role of hormone therapy in impacting the lymphatic endothelium.
Moreover, it is essential to exercise caution when considering lymphangiogenic therapy, as it has been shown to promote tumor metastasis. Each pathological condition should undergo careful safety testing before such treatments are adopted. Given the positive impact of estrogens on lymphatic vessels, exploring estrogen-based treatments could hold promise for lymphedema resulting from ER-negative conditions or cancers.
Conclusion:
The relationship between estrogen and the lymphatic system is complex and influential. Estrogens play a crucial role in shaping female secondary sex characteristics. Estrogen is pivotal in influencing lymphatic systems, potentially influencing lymphatic ailments like lymphedema. A recent study found that ER-alpha regulates lymphatic-related genes like VEGFR3 and Lyve-1. Comparing lymphatic pressure, females have lower pressure than males. Lymphangiogenesis occurs in diseases like tumor metastasis, while lymphedema results from lymphatic dysfunction.
