The “Daughter” Metabolites: E2, E4, E16 in Hormone Harmony

The “Daughter” Metabolites: E2, E4, E16 in Hormone Harmony

Over the last three decades, with evolving interest and tools, researchers have been
paying fresh attention to an additional family of estrogen complexes. We might call
them “daughter” metabolites because they are the estrogen by-products that emerge
after estradiol, estrone, and estriol are processed, or detoxified, by the liver. The
technical terms for these by-products are 2-hydroxyestrone (2-OHE), 4-hydroxyestrone
(4-OHE), and 16α-hydroxyestrone (16α-OHE), and together they give us a very clear
picture of whether the amounts and types of estrogen in your body are apt to cause
trouble.

Once the body uses estrogen, like everything else, the estrogen heads to the liver for
detoxification. Properly metabolizing and excreting estrogens, the essence of
detoxification, is a critical but tricky task. If the estrogens are metabolized into 2-
hydroxyestrone, they lose most of their aggressive activity; thus they are known as
“good” estrogen metabolites. Research indicates that when levels of 2-hydroxyestrone
are higher, the body resists cancer, and when these levels are low, cancer risk increases
(Gaikwad et al. 2008). On the other hand, women who metabolize a larger proportion
of their estrogens into 16α-hydroxyestrone and 4-hydroxyestrone show an elevated risk
of breast cancer (ibid.).

Why would the liver use a pathway that could lead to adversity? Recall from
chapter 9 that gut and liver health are intimately tied to estrogen metabolism. A liver
that is compromised by toxicity, alcohol, or estrogen overload from environmental
sources (see chapter 4), for example, will not do as good of a job at clearing out excess
estrogen as a liver that’s at the peak of health. Likewise, a healthy population of gut
bacteria actually helps to detoxify excess estrogen (via the containment of an enzyme
called beta-glucuronidase). In effect, these desirable microbes provide the “bugpower” to
help carry excess estrogen out of the body.

Where’s the proof ? Examining this premise in context, among 10,786
premenopausal women studied in the 1990s, researchers observed that women who
developed breast cancer had notably less 2-hydroxyestrone—a full 40 percent less—
and more 16α-hydroxyestrone metabolites than women who did not develop breast
cancer (Muti et al. 2000). Another study, this one on postmenopausal women, found
that those with the highest ratio of estradiol to 16α-hydroxyestrone had a 30 percent
lower risk of developing breast cancer than women with lower ratios (Meilahn et al.
1998). If we could only find a way to make sure the liver is turning out healthy
estrogen metabolites, as opposed to unhealthy ones, we could lower our breast cancer
risk. It turns out that we can, and we’ll get back to that part of the estrogen story
shortly.