Estrogen molecules interacting with immune cells

Estrogen Unveiled: How Synthetic Hormones Impact Your Immune System

Reese Marlowe in Health & Wellness November 2025 • 4 min read.

"A deep dive into the surprising differences between natural and synthetic estrogens like those in birth control, and how they affect immunity, especially for women under 40."

Estrogen, a hormone often associated with female health, plays a crucial role in regulating the immune system. Natural estrogen, known as 17β-estradiol (E2), fluctuates throughout a woman's life, influencing everything from monthly cycles to pregnancy and menopause. These hormonal shifts can alter how the immune system functions, affecting both innate and adaptive immune responses.

However, it’s not just natural estrogen we need to consider. Synthetic analogs, like 17α-ethinyl estradiol (EE), are widely used in hormonal contraceptives and hormone replacement therapy. Surprisingly, the effects of EE on the immune system are not as well-understood as those of natural estrogen, despite its prevalence and the rising concern about its presence as an environmental pollutant.

Recent research comparing the impact of E2 and EE on the immune systems of female mice has revealed surprising differences. The study, focusing on autoimmune-prone mice, sheds light on how these hormones can uniquely influence immune responses and epigenetic regulation, offering important insights for women's health.

EE vs. E2: Understanding the Key Differences in Immune Response

Estrogen molecules interacting with immune cells

The research directly compared the effects of EE and E2 on the immune systems of female NZB/WF1 mice, which are predisposed to autoimmunity. This allowed scientists to observe subtle yet significant differences in how each hormone affected immune cells and their functions.

Both EE and E2 had common effects, such as increasing splenic neutrophils and enhancing the expression of certain enzymes. However, the synthetic EE showed more profound effects, especially concerning cytokine production and epigenetic changes.

Neutrophil Increase: Both hormones increased the number of neutrophils in the spleen, which are essential for fighting infection but can contribute to inflammation if overproduced.
Enhanced Enzyme Expression: Both E2 and EE boosted the expression of neutrophil serine proteases and myeloperoxidase, enzymes involved in immune responses.
Nitric Oxide Production: Both promoted the production of nitric oxide, a molecule involved in immune signaling and defense.
Adaptive Immune Alterations: Both altered adaptive immune T cell subsets, indicating an impact on the long-term immune response.

Where the hormones differed significantly was in their impact on cytokine production. Cytokines are signaling molecules that dictate the immune system's response. In EE-exposed mice, stimulation via the T cell receptor or Toll-like receptor 4 (TLR4) resulted in different cytokine alterations compared to E2. Furthermore, EE exposure suppressed interferon-alpha (IFNα) production upon TLR9 stimulation, whereas E2 increased it. These differences suggest that EE and E2 can trigger distinct immune pathways.

What Does This Mean for You?

These findings underscore the complexity of hormone-immune system interactions. While both natural and synthetic estrogens can influence immunity, they do so through different mechanisms. This has important implications for understanding women’s health issues, particularly autoimmune diseases, and the potential long-term effects of hormonal contraceptives. Further research is needed to fully elucidate these differences and inform clinical practice.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1210/en.2018-00824, Alternate LINK

Title: 17Β-Estradiol And 17Α-Ethinyl Estradiol Exhibit Immunologic And Epigenetic Regulatory Effects In Nzb/Wf1 Female Mice

Subject: Endocrinology

Journal: Endocrinology

Publisher: The Endocrine Society

Authors: Rujuan Dai, Michael R Edwards, Bettina Heid, S Ansar Ahmed

Published: 2018-11-09

Everything You Need To Know

How does natural estrogen affect the immune system?

Estrogen, specifically 17β-estradiol (E2), significantly affects the immune system by influencing both innate and adaptive immune responses throughout a woman's life. These fluctuations are linked to menstrual cycles, pregnancy, and menopause, highlighting the dynamic interplay between hormonal shifts and immune function. This interplay, however, is complex and not fully understood.

How do synthetic estrogens like those in birth control compare to natural estrogen in terms of their effects on the immune system?

Synthetic estrogens, such as 17α-ethinyl estradiol (EE) found in hormonal contraceptives, have different impacts on the immune system compared to natural estrogen (E2). Research indicates that EE can lead to distinct alterations in cytokine production and epigenetic changes, suggesting it triggers different immune pathways than E2. While both affect the immune system, the mechanisms through which they operate differ significantly, and more research is required to fully understand these differences and implications.

What specific effects did synthetic (EE) and natural estrogen (E2) have on mice predisposed to autoimmunity?

In studies involving female NZB/WF1 mice predisposed to autoimmunity, both 17α-ethinyl estradiol (EE) and 17β-estradiol (E2) increased splenic neutrophils and enhanced the expression of enzymes like neutrophil serine proteases and myeloperoxidase. They also both promoted nitric oxide production and altered adaptive immune T cell subsets. However, EE exposure uniquely suppressed interferon-alpha (IFNα) production upon TLR9 stimulation, while E2 increased it, demonstrating distinct impacts on cytokine production.

What role do cytokines play in the differing immune responses to synthetic (EE) versus natural estrogen (E2)?

Cytokines are signaling molecules that orchestrate the immune system's responses. 17α-ethinyl estradiol (EE) and 17β-estradiol (E2) affect cytokine production differently. For example, EE exposure in mice suppressed interferon-alpha (IFNα) production upon TLR9 stimulation, whereas E2 increased it. These variations signify that EE and E2 can trigger different immune pathways, potentially leading to varying immune responses. Further research is needed to understand the comprehensive implications of these differences.

What are the broader implications of the different immune responses triggered by synthetic (EE) and natural estrogen (E2)?

The differing impacts of 17α-ethinyl estradiol (EE) and 17β-estradiol (E2) on the immune system highlight the complexity of hormone-immune interactions. Understanding these differences is crucial for addressing women's health issues, particularly autoimmune diseases, and for evaluating the potential long-term effects of hormonal contraceptives. Further research is essential to fully elucidate these differences and translate findings into improved clinical practices and healthcare strategies for women.