Meet the chemical toxicologist

probing how botanical supplements

treat menopause symptoms
Judy Bolton helps demystify the complex bioactivity of
hops to benefit women’s health
by Carmen Drahl

AUGUST 19, 2018

MOST POPULAR IN BIOLOGICAL CHEMISTRY

Menopause is no walk in the park. Though every person’s experience is different,

the often-distressing effects from depleted hormones—including hot flashes, night
sweats, and anxiety—lead many to seek treatment. Hormone replacement leads to
an increased cancer risk, however, just as continued exposure to natural estrogen
increases a woman’s risk of breast cancer as she ages. So many women turn to
natural remedies such as the botanicals black cohosh and hops. Botanicals have
been used as traditional medicines for centuries, but scientific evidence of the extent
to which these substances can relieve symptoms without increasing cancer risk
varies widely.

Credit: Courtesy of University of Illinois, Chicago

Judy Bolton, who heads the medicinal chemistry and pharmacognosy department at
the University of Illinois at Chicago, aims to understand the mechanisms behind
these hormone alternatives, with an eye toward developing improved ones. Bolton
delivered the Founder’s Award Address at the American Chemical Society national
meeting in Boston today, in the Division of Chemical Toxicology. Carmen Drahl
spoke with her about the challenges of disentangling botanicals’ complex chemistry.
This interview has been edited for length and clarity.
What drew you to studying estrogen and women’s health?

I started working on catechol estrogens when I began my independent career at

Queen’s University in 1992. I had been working on catechols and quinones—
compounds which can form damaging DNA adducts and initiate cancer-causing
mutations—formed from natural products. And I discovered that estrogens formed
catechols and quinones naturally in the body. From there it made sense to write
grant proposals on estrogen carcinogenesis because it was much more significant
than looking at cool molecules with little biological relevance for interest’s sake.

I moved to the University of Illinois at Chicago (UIC) in 1994. The UIC/NIH Botanical
Dietary Supplements Center on women’s health, established in 1999
with myself among the project leaders, was a natural progression. We were
interested in botanicals that women were taking as natural alternatives to
menopause hormone therapies and how these botanicals interfered with the
chemical carcinogenic pathway that involves estrogen in a beneficial way.

VITALS

▸ Hometown: London, Ontario

▸ Studies: B.S., 1984, and Ph.D., 1988, University of Toronto; postdoctoral fellow,
University of Colorado, 1992

▸ Favorite molecule: Estradiol

▸ Proudest career moment: I was recently named Distinguished Professor at UIC. It

really made me think of all the wonderful students and postdocs that have worked
with me over the years to get to that point in my life.

▸ Hobbies: Playing the flute, taking bike trips

Why are women turning to botanical dietary supplements like hops instead of
hormone therapy for treating hot flashes and other menopause symptoms?

The major reason that women and their doctors are less likely to recommend
traditional hormone therapy is because of the Women’s Health Initiative. This was a
large clinical trial comparing Prempro, a medication made from a mixture of modified
estrogens, with placebo. The purpose was to see if the Prempro arm protected
women from cardiovascular disease, in an attempt to corroborate limited clinical
evidence that estrogen was protecting women from cardiovascular disease.
Unfortunately, in 2002 investigators halted the trial early because of increased toxicity
in the Prempro group, including increased breast cancer risk. These data have led
women to search for natural alternatives to hormone therapy such as black cohosh,
red clover, licorice, and hops. The efficacy of these botanicals is questionable and
is mainly based on anecdotal ethnomedicine reports.
Yet work your team conducted in cells suggests that hops not only relieves
symptoms, it also has the potential to prevent breast cancer. What’s the basis
for the cancer-preventive activity?

Work we and others have done suggests that hops has multiple bioactive
compounds that have numerous biological targets. For example, xanthohumol in
hops can induce the synthesis of detoxification enzymes, which could protect from
cancers that can form as a result of long-term exposure to estrogens. And 8-
prenylnaringenin (8-PN) is a potent inhibitor of the enzyme aromatase, a target of
several U.S. Food & Drug Administration-approved drugs for breast cancer.

You’ve demonstrated that hops extracts could in theory be targeted to either

pre-menopausal or post-menopausal women by enriching different
compounds. How does that work?

We have shown that we can make designer extracts that contain the cancer
preventive compound xanthohumol, which is good for both pre- and postmenopausal
women (J. Nat. Prod. 2017, DOI: 10.1021/acs.jnatprod.7b00284). Postmenopausal
women also need 8-PN, which has estrogenic effects in addition to its aromatase-
inhibiting activity, to relieve menopausal symptoms. Premenopausal women have
enough natural estrogens, and it is best not to expose them to a compound which
could induce malignant cell proliferation in excess. As a result, we created two
extracts: one for premenopausal women, which is high in xanthohumol and only has
a trace of 8-PN; and one for postmenopausal women, which has higher levels of 8-
PN relative to the premenopausal extract.

You’ve spoken about a lack of standardization in the supplement industry.

What do you mean by that, and what does your research tell us about why
standardization is important?

One of the main objectives of our center is to standardize botanicals both chemically
and biologically. The idea is to isolate the botanical, make the extracts, and then
“standardize to the bioactive compounds,” meaning that one measures the amounts
of bioactive compounds in the extract and notes a defined amount, or percentage,
of the compounds on the bottle. This will vary from batch to batch. Using hops as an
example, we standardize the extracts to xanthohumol, 8-PN, and 6-
prenylnaringenin, because these are the bioactive compounds we have found in
hops so far. If we find more, they will be added to the list. Standardization is crucial
because it tells the consumer that the correct plant species is in the formulation and
that the formulation contains defined amounts of bioactive compounds. The problem
is we don’t know the physiological ideal dose. Consumers are already consuming
these extracts, and we are trying to extrapolate our findings in animal studies to
people. It’s a bit of the Wild West here. The good news is all of the botanicals we
have looked at are safe, and our findings seem to indicate they contain compounds
that will improve human health.

When does a treatment stop being an herbal supplement and start being a
drug?

As long as a botanical extract is still an extract it will be classified as an herbal

supplement. In the U.S., dietary supplements including botanical extracts are
defined by the Dietary Supplement Health & Education Act (DSHEA) of 1994. Once
the bioactives are isolated from the extract, which goes beyond what we do, then
you start heading towards drug classification. We have argued that one of the
advantages of botanical extracts is they are polypharmacological, having multiple
compounds hitting a variety of biological pathways. Preferably they do so in a good
way, which increases resilience in women’s health.

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