There is evidence that methoxylated estrogens, especially the 2-pathway methoxylated estrogens (E1 and E2), are associated with decreased breast cancer risk; 2-MeOE2, produced from 2-OHE2, has been described to have anti-proliferative, antingiogenic, and pro-apoptotic activity in multiple types of cancer.

There is evidence that methoxylated estrogens, especially the 2-pathway methoxylated estrogens (E1 and E2), are associated with decreased breast cancer risk; 2-MeOE2, produced from 2-OHE2, has been described to have anti-proliferative, antingiogenic, and pro-apoptotic activity in multiple types of cancer.

2-OH-3ME-Valeric (aka 3-Methyl-2-oxovaleric acid) is an abnormal metabolite that arises from the incomplete breakdown of branched-chain amino acids. 

Moderate increase may result from lactic acidosis, episodic ketosis, or thiamine/lipoic acid deficiency. Significant elevations are associated with genetic issues, MSUD, and pyruvate dehydrogenase deficiency.

- Slight elevations may be due to deficiencies of the vitamins thiamine or lipoic acid.

- Elevated values are also associated with the genetic diseases maple syrup urine disease or pyruvate dehydrogenase deficiency.

Most consider 2-OH-E1 favorable

Estrogen is metabolized (primarily by the liver) down three phase I pathways. The 2-OH pathway is considered the safest because of the anti-cancer properties of 2-OH metabolites. Conversely, the 4-OH pathway is considered the most genotoxic as its metabolites can create reactive products that damage DNA. The third pathway, 16-OH creates the most estrogenic of the metabolites (although still considerably less estrogenic than estradiol) - 16-OH-E1.

Percentages of 2-OH-E1, 4-OH-E1, and 16-OH-E1

When evaluating phase I metabolism, it can be helpful to compare the percentages of 2, 4, and 16 OH-E1 metabolites. Most individuals metabolize the majority of their estrogens down the 2-OH-E1 pathway which is generally considered the “safer pathway”. This is followed by 16-OH-E1 and 4-OH-E1 respectively, both of which are deemed more reactive and potentially genotoxic.

2-OH-E1 % (Pre-menopausal) shows what share of estrone is routed down the 2-hydroxylation pathway to 2-hydroxyestrone—a distribution metric, not a disease diagnosis. A lower percentage suggests a relative shift toward 4-/16-hydroxylation, while a higher percentage indicates more 2-OH routing, which is generally fine if 2-methoxy metabolites are adequate (reflecting healthy COMT/methylation). Your result can be influenced by diet (crucifers, I3C/DIM), alcohol, medications/smoking, cycle timing, and collection quality. Interpret against your lab’s reference range, aim for balanced pathways (not “max 2-OH”), and consider food-first methylation support, fiber, sleep, stress management, and clinician guidance if patterns are off.

2-Hydroxyestrone is an endogenous biomarker and major urinary metabolite of estrone and estradiol. Along with 16α-Hydroxyestrone, 2-Hydroxyestrone is used as an indicator for increased risk of cancer.

Most consider 2-OH-E1 favorable

Estrogen is metabolized (primarily by the liver) down three phase I pathways. The 2-OH pathway is considered the safest because of the anti-cancer properties of 2-OH metabolites. Conversely, the 4-OH pathway is considered the most genotoxic as its metabolites can create reactive products that damage DNA. The third pathway, 16-OH creates the most estrogenic of the metabolites (although still considerably less estrogenic than estradiol) - 16-OH-E1.

In a Hormone Metabolite Assessment Panel (HUMAP) for pre-menopausal women, the ratio of 2-Hydroxyestrone (2-OH-E1) to 16-Hydroxyestrone (16-OH-E1) is a critical metric for assessing estrogen metabolism and its implications for health. This ratio reflects the balance between two major pathways of estrogen metabolism: the 2-hydroxylation pathway, leading to 2-OH-E1, and the 16α-hydroxylation pathway, resulting in 16-OH-E1.

2-OH-E1 is generally considered a safer estrogen metabolite due to its weaker estrogenic activity, and it has been associated with a reduced risk of estrogen-related conditions, such as certain breast cancers.

On the other hand, 16-OH-E1 is known for its potent estrogenic effects and has been linked to an increased risk of estrogen-sensitive conditions.

Research and clinical studies show that the 2-hydroxylated estrogens (2-OH E2 and 2-OH E1) are a safer pathway of hydroxylation than the 4-hydroxyestrogens (4-OH E2 and 4-OH E1), which bind to and damage DNA, leading to mutations that are associated with increased breast cancer risk.

Research and clinical studies show that the 2-hydroxylated estrogens (2-OH E2 and 2-OH E1) are a safer pathway of hydroxylation than the 4-hydroxyestrogens (4-OH E2 and 4-OH E1), which bind to and damage DNA, leading to mutations that are associated with increased breast cancer risk.

3-Methyl-2-oxovaleric acid is an abnormal metabolite that arises from the incomplete breakdown of branched-chain amino acids. 

Moderate increase may result from lactic acidosis, episodic ketosis, or thiamine/lipoic acid deficiency. Significant elevations are associated with genetic issues, MSUD, and pyruvate dehydrogenase deficiency.

- Slight elevations may be due to deficiencies of the vitamins thiamine or lipoic acid.

- Elevated values are also associated with the genetic diseases maple syrup urine disease or pyruvate dehydrogenase deficiency.

2-Oxo-4-methylthiobutanoic acid, also known as 4-(methylsulfanyl)-2-oxobutanoate or 2-keto-4-methylthiobutyrate, belongs to the class of organic compounds known as thia fatty acids. Thia substituted fatty acids are saturated fatty acids which are modified by insertion of a sulfur atom at specific positions in the carbon backbone.

2-Oxo-4-methylthiobutanoic acid, also known as 4-(methylsulfanyl)-2-oxobutanoate or 2-keto-4-methylthiobutyrate, belongs to the class of organic compounds known as thia fatty acids. Thia substituted fatty acids are saturated fatty acids which are modified by insertion of a sulfur atom at specific positions in the carbon backbone.

2-Oxo-4-methylthiobutanoic acid, also known as 4-(methylsulfanyl)-2-oxobutanoate or 2-keto-4-methylthiobutyrate, belongs to the class of organic compounds known as thia fatty acids. Thia substituted fatty acids are saturated fatty acids which are modified by insertion of a sulfur atom at specific positions in the carbon backbone.

Elevated in an inborn error of methionine metabolism. Confirmation of the genetic disorder requires testing of plasma amino acids.

2-OXO-Butyric Acid is also known as Alpha-ketobutyric acid.

- Alpha-ketobutyric acid results from the breakdown of threonine or methionine during glutathione production.

- Specifically, cystathionine is metabolized to alpha-ketobutyric acid and cysteine.

- a- ketobutyric acid enters the mitochondrial matrix and get converted to propionyl-CoA by the branched chain keto-acid dehydrogenase complex (BCKDHC) and enters the Krebs cycle at succinyl-CoA.

- Evaluate lactate and the branched chain keto acids

- Evaluate alpha-hydroxybutyric acid

- Associated Nutrients: Vitamin B3

- a -Ketobutyric acid is produced from cystine, along with hydrogen sulfide (H2S) as a by-product.

- a- Ketobutyric acid is reversibly converted to a- hydroxybutyric acid.