Oestrogen metabolites

Oestrogen is broken down along three competing routes: the 2-hydroxylation route, whose products are only weakly oestrogenic; the 4-hydroxylation route, whose products can oxidise into reactive quinones that formed DNA adducts in laboratory and animal studies; and the 16α-hydroxylation route, whose products remain clearly oestrogenic. The 2OHE1/16αOHE1 ratio is looked at when assessing the breakdown routes. COMT methylates the 2- and 4-OH metabolites and thereby makes them less reactive; in addition, their quinones are bound to glutathione. The metabolites themselves are measured in urine; they are not currently part of the ORY analyses. The women's hormone profile measures the parent hormones oestradiol and progesterone in saliva, and the ß-glucuronidase test measures the return route of oestrogen in the gut.

How oestrogen metabolites are formed

Before oestrone and oestradiol are excreted, cytochrome P450 enzymes attach a hydroxyl group. Where they do so determines the properties of the product: CYP1A1 and CYP1A2, mainly in the liver, form 2-hydroxyoestrogens; CYP1B1, which is found especially in breast tissue, the uterus and the ovary, forms 4-hydroxyoestrogens; CYP3A4 and other enzymes form 16α-hydroxyoestrone, from which oestriol can arise. The 2- and 4-hydroxy forms are known as catechol oestrogens. The enzyme COMT attaches a methyl group to them, donated by SAMe, and thereby makes them stable; the products are then linked to glucuronic acid or sulphate and excreted via urine and bile. Urine shows how breakdown is distributed across the pathways.

A lot of 2-hydroxyoestrone – what does it mean for oestrogen breakdown?

2-hydroxyoestrone binds only weakly to the oestrogen receptors and triggers hardly any oestrogenic effects of its own; methylation by COMT produces 2-methoxyoestradiol, which tended to slow cell growth in laboratory studies. When this pathway predominates, oestrogen is therefore broken down mainly into products with little hormonal effect. The CYP1A enzymes are produced in greater amounts in response to substances from cruciferous vegetables, such as indole-3-carbinol, to smoking and to some environmental substances, whereas in studies they worked less with reduced thyroid function. Large studies have not consistently confirmed whether a high share of this pathway in itself protects against disease.

A lot of 16α- or 4-hydroxyoestrone – what happens in the body?

16α-hydroxyoestrone binds to the oestrogen receptor and keeps it occupied longer than oestradiol itself; it therefore continues to stimulate cells in the uterus and breast tissue to grow. A predominance of this pathway means that a larger share of the oestrogen still has a hormonal effect even after breakdown. 4-hydroxyoestrogens are also oestrogenic but can additionally oxidise into reactive quinones. In laboratory and animal studies these formed compounds with DNA, known as adducts, and released reactive oxygen species. If the 4-hydroxy forms are not quickly methylated by COMT, or their quinones are not bound to glutathione and neutralised by the enzyme NQO1, they stay reactive for longer.

What does slow methylation of oestrogen metabolites mean?

How quickly COMT works depends, among other things, on a common gene variant: in Val158Met, position 158 has methionine instead of valine, the enzyme is less stable at body temperature, and its activity with two copies of the variant is markedly lower in studies. In addition, COMT needs SAMe as a methyl group donor, whose production depends on folate, vitamin B12 and vitamin B6; the by-product S-adenosylhomocysteine slows COMT. When methylation works more slowly, 2- and 4-hydroxyoestrogens stay unmethylated for longer, and a larger share of the 4-hydroxy forms can oxidise into quinones. Since COMT also breaks down dopamine, noradrenaline and adrenaline, these messengers compete with the oestrogen metabolites for the same enzyme.

The interpretation is given in your report.