The way the body handles oestrogens is an important factor affecting both male and female health. Several compounds, including DIM, I3C, sulforaphane and calcium-d-glucarate have the potential to impact this in a beneficial way. Unfortunately, confusion reigns supreme over the mechanism of action and potential clinical application of each. In a bid to increase confidence and understanding in this area, here’s a bit of background and a simple overview of each compound, including information on when you might consider recommending in a clinical setting.

How the body handles oestrogens…
First a bit of background. The term ‘oestrogen’ is used to collectively describe a group of hormones (oestrone (E1), oestradiol (E2) & oestriol (E3)) which have widespread actions throughout the body. Both males and females produce and need oestrogens, in differing amounts.

Once produced, oestrogens need to be processed or ‘activated’ before they can exert their biological effects. And once used, they must then be metabolised before they can be eliminated in urine or faeces. Oestrogen production, processing, metabolism and elimination is complex and involves lots of different steps. To further complicate the picture, there are multiple possible routes through these steps too. Some routes are considered more beneficial, and others more harmful to health.

Many diet and lifestyle factors influence the way the body handles oestrogens. And this is where compounds such as sulforaphane, indole-3-carbinol (I3C), di-indolylmethane (DIM) and calcium-d-glucarate can be very useful. In very simple terms, this is because they have significant potential to promote the more beneficial routes.

Before we get into the nitty gritty of what each compound does, here’s some context on the aspects of oestrogen processing and metabolism that are relevant to these compounds:

• Aromatase
In addition to oestrogen production in ovaries (females) and testes (males) oestrogens are also produced by the aromatisation of androgens in fat cells, skin, bone, brain and other tissues. The aromatase enzyme is also found in tissues of endometriosis, fibroids, endometrial and breast cancer, with aromatase expression found highest in or near breast tumour sites. After menopause, some oestrogen continues to be manufactured by aromatase in body fat.

• Hydroxylation
Once produced, oestrogens are hydroxylated or ‘activated’ via phase I cytochrome P450 enzymes. This involves the addition of an ‘OH’ group. Once hydroxylated they can bind to oestrogen receptors and exert their biological activity. Hydroxylation takes place at different positions on the oestrogen molecule and yields 2-hydroxyoestrone (2-OH), 16µ-hydroxyoestrone (16µ-OH) or 4-hydroxyoestrone (4-OH). The 2-OH metabolite confers very weak oestrogenic activity and is generally termed the ‘good’ oestrogen. In contrast, the 4-OH and 16µ-OH metabolites show persistent oestrogenic activity and promote tissue proliferation. It has been suggested that those who metabolise a larger proportion of their oestrogen via the 16µ-OH pathway may be at significantly elevated risk of breast cancer compared with those who metabolise proportionally more oestrogen via the 2-OH pathway. Evidence is accumulating that some oestrogen metabolites may be directly responsible for the initial genetic damage leading to tumours. 16α-OH and 4-OH are the primary oestrogen metabolites that have been associated with direct genotoxic effects and carcinogenicity. Functional urine testing can provide valuable information on this.

• Glucuronidation
This is a key phase II pathway for detoxification of 16α-OH, 2-OH and 4-OH oestrogens. Glucuronic acid can be conjugated with oestrogens, making them water soluble and ready to be excreted from the body, through bile via the small intestine. Some intestinal bacteria (mainly pathogenic types) are capable of producing an enzyme called β -glucuronidase which can uncouple the glucuronic acid molecule from the oestrogen in the large intestine. Instead of being eliminated, it then re-enters the circulation, thus adding to the overall oestrogen load. Not surprisingly, excess β-glucuronidase activity is associated with an increased cancer risk, including breast cancer. Functional stool testing can provide valuable information on this.

• Glutathione conjugation
The 2-OH and 4-OH metabolites may be readily metabolised to harmful 3, 4 semi-quinones. Fortunately, glutathione transferase enzymes are able to neutralise the 3,4 semi-quinones before they cause damage.

• Nrf2 activation
Another pathway called Nrf2 promotes many different phase II enzymes with important detoxification and antioxidant functions, including many involved in protection against potentially harmful 3, 4 semi quinones including glutathione transferases.

Similarities & differences
As you can see, I3C & DIM are very closely connected. Sulforaphane, I3C & DIM are all derived from cruciferous vegetables and have some similarities in their mechanisms of action, the main difference being that DIM & I3C have the potential to decrease total oestrogens in circulation, whereas sulforaphane doesn’t do this. This isn’t necessarily good or bad, it all depends on the context. Calcium-d-glucarate has a very different mechanism of action altogether and very clear clinical potential for reducing total oestrogens in circulation due to elevated beta-glucuronidase or significant gut dysbiosis.

More broccoli anyone?
There’s no getting away from the fact that oestrogen production, processing and metabolism is complicated but hopefully this overview has made it a bit clearer and will help your clinical decision making. One thing’s for certain though…most people will benefit from adding cruciferous vegetables into their diet! For further reading on the subject take a look at our Functional Medicine Guide to oestrogen balance here

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