Allison Sayre, MSN, WHNP-BC
Estrogens are critical regulators of growth, reproduction, and metabolism across multiple physiological systems, and their imbalance can challenge health and longevity. The process of estrogen metabolism is not a simple mechanism of deactivation and elimination. It is a complex biochemical cascade, with each step being important to hormonal balance in nuanced and clinically significant ways.
What is Estrogen?
Estrogen is a steroid hormone synthesized in both male and female bodies. There are, as of recently, four recognized types of endogenous estrogen: Estrone (E1), 17β-Estradiol (estradiol; E2), Estriol (E3), and Estetrol (E4). [1] Estrone is the most abundant circulating estrogen in men and postmenopausal women, produced by the adrenal glands, adipose tissue, testes, and ovaries. Estradiol is the most abundant and potent estrogen in reproductive-aged women, and is the preferred ligand for estrogen receptors (ER). [2] It is produced primarily by ovarian follicles, but is also made through the oxidation of estrone. [3] Estriol and estetrol are typically only synthesized during pregnancy, with estriol being primarily produced by the placenta and estetrol being synthesized in the fetal liver.
The biological activity of estrogens is not dictated solely by synthesis and serum levels. Equally important is the way in which estrogens are metabolized, which plays a pivotal role in their effects within the body.
Phases of Estrogen Metabolism
Phase I: Hydroxylation Pathways
The liver is the primary site of phases I and II of estrogen metabolism, but unlike other steroid hormones, the first step of estrogen metabolism is purely oxidative. Phase I metabolism involves hydroxylation of estrogens via cytochrome P450 (CYP) enzymes. Estradiol (E2) and estrone (E1), the predominant circulating estrogens, are hydroxylated differently, and the resulting metabolites often depend on the form of the CYP enzyme the estrogen has interacted with:
- 2-hydroxylation, primarily catalyzed by CYP1A1 and CYP1A2, yields 2-hydroxyestrone (2-OH-E1) and 2-methoxyestrone (2-MeOHE1)
- 4-hydroxylation, primarily mediated by CYP1B1, yields 4-hydroxyestrone (4-OH-E1)
- 16α-hydroxylation, primarily involving CYP3A4, yields 16α-hydroxyestrone (16α-OH-E1) and Estriol (E3) [4]
While the liver generally produces more CYP1A2 and CYP34A than CYC1B1 enzyme, some target tissue for estrogens, such as the breasts, uterus, and ovaries express high levels of CYC1B. This is clinically relevant as CYC1B promotes 4-hydroxylation of estrogens, producing metabolites that are more reactive and potentially damaging to DNA. [5]
Biological Implications of Hydroxylated Estrogen Metabolites
Each of the resulting metabolites possess unique biological activities and effects throughout the body.
2-Hydroxy estrogens are considered “good” or protective metabolites. They are nearly devoid of estrogenic activity, and are typically methylated quickly and cleared from circulation. [3]
As alluded to above, 4-Hydroxy estrogens are less desirable, as they are considered highly estrogenic metabolites. They form reactive quinones that can bind and damage DNA, potentially contributing to mutagenesis if not detoxified quickly. [6]
16α-Hydroxy estrogens also retain potent estrogenic activity and bond with estrogen receptors, resulting in prolonged activation. These metabolites are also associated with cellular mutagenesis and specific health risks. [3]
The 2:16 Estrogen Metabolite Ratio
One frequently studied marker of estrogen metabolism is the urinary 2-hydroxyestrone to 16α-hydroxyestrone ratio, abbreviated as the 2:16 ratio. This ratio summarizes the relative activity of two major pathways of estrogen metabolism:
- The 2-hydroxylation pathway, associated with cessation of estrogen signaling.
- The 16α-hydroxylation pathway, associated with continued estrogen signaling.
A higher 2:16 estrogen ratio means a greater proportion of estrogens being metabolized and excreted through the 2-hydroxylation route. It has been associated in observational studies with cellular integrity in hormone sensitive tissues such as the breast. In contrast, a lower 2:16 ratio may reflect a dominance of 16α-hydroxy metabolites, which maintain higher levels of estrogenic activity and may promote cellular proliferation or mutagenesis. [7]
Additionally, the 2:16 ratio is widely used in research and clinical testing as a biomarker of estrogen metabolism balance, particularly in studies exploring mutagenesis, reproductive health, and estrogen-dominant conditions. The ratio may also reflect genetic and epigenetic differences in enzyme activity, as well as the influence of environmental and metabolic factors.
Phase II: Conjugation and Clearance
Following hydroxylation, estrogens undergo Phase II metabolism, which increases solubility to facilitate elimination. The process of neutralization (called conjugation) is supported by B-vitamins and sulfur rich foods. The key conjugation reactions include:
- Methylation: Catalyzed by catechol-O-methyltransferase (COMT), especially on catechol estrogens like 2-OH-E1 and 4-OH-E1. Methylation reduces oxidative potential and facilitates the elimination of estrogen metabolites. [2]
- Glucuronidation and sulfation: These reactions, mediated by UGT and SULT enzymes, yield water-soluble conjugates that are eliminated in bile or urine. [2]
Conjugation pathways of estrogens vary significantly between individuals, which is often a result of common genetic polymorphisms. Efficiency in these estrogen detoxification pathways influences both the continued activity of estrogens and the potential for formation of harmful intermediates, such as estrogen quinones and semiquinones. [2]
Phase III: Excretion or Recirculation
Once conjugated estrogens reach the gut, the liver has already marked them for excretion. Without further interference, estrogen metabolites are passed in the bile or stool. However, if liver function is impaired, excretion may be reduced leading to the accumulation or recirculation of active estrogens.
Additionally, metabolites can be deconjugated by microbial enzymes such as β-glucuronidase and then reabsorbed as free estrogens into the bloodstream. This microbial involvement in estrogen metabolism underscores the importance of the estrobolome, the subset of microbes in the intestinal microbiome involved in estrogen processing. Imbalanced microbiota populations (dysbiosis) and elevated β-glucuronidase activity can shift estrogen metabolite profiles and influence systemic estrogen levels through this process of reabsorption. [8]
Conclusion
Estrogen metabolism is a tightly regulated, multifactorial process with outcomes that influence a broad range of physiological systems. The 2:16 estrogen metabolite ratio serves as one useful index of this metabolic balance, reflecting how individual differences in enzyme activity, genetic expression, and microbial interaction shape the hormonal balance within the body.
Understanding the full scope of estrogen metabolism, including the roles of hydroxylation, conjugation, and the estrobolome, gives us insight into how estrogens can contribute both to the protection and hindrance of human health. The more we learn about our abilities to steer the metabolic pathways of estrogens, the more control we can gain over maintaining a healthy hormonal balance.
Disclaimer:
The information provided is for educational purposes only. Consult your physician or healthcare practitioner if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.
Allison Sayre, MSN, WHNP specializes in women's health and functional medicine, blending both traditional and integrative approaches. With over 18 years of experience, she has empowered women to reclaim their health through personalized nutrition and supplementation, hormone balancing, and lifestyle modifications. She received her Bachelor of Science from Mount Carmel College of Nursing and her Master of Science from the University of Cincinnati. She has been a certified women’s health nurse practitioner since 2014 and has continued her education and training in functional medicine from both the Institute for Functional Medicine as well as the American Academy of Anti-Aging Medicine.