Bathing in Estrogen
Chemicals in many foods and consumer products disrupt estrogen signaling. The structure of the estrogen receptor explains why there are so many.
Not medical advice.
Your five-year-old daughter is experiencing breast development. The age of first menarche has been getting earlier, but five is very early. You go to the doctor. He asks about her diet. Nothing unusual. Maybe she got into a bottle of birth control pills? Toxicology screen: negative.
The screen comes back positive for something else—something that mom was putting on her skin deliberately.
This real-life story was shared with me by endocrinologist Dr. Robert Lustig, who figured out that the girl was being regularly exposed to a plant estrogen at home:
RL: So I asked [the mother], ‘What do you bathe her in?’ And she actually looked at it [the product]—she was on the phone at home. She said, ‘Well, I use this Victoria’s Secret bath gel.’ And I said, ‘What are the ingredients?’ and then she looked at it. She said he says, ‘Not for use in children.’ And the reason is because Victoria's Secret bath gels are loaded with plant estrogens to make your skin silky smooth. So this kid was absorbing the estrogen through her skin from her bath.
NJ: Her mom was inadvertently giving her sex hormone therapy?
RL: Yeah, without knowing it. So, environmental estrogens can also be environmental obesogens because, after all, estrogen lays down subcutaneous fat. As an example, parabens are things that are in cosmetics like lipstick, and haircare products.
See M&M #140
The girl was being exposed to genistein, a naturally occurring plant estrogen (phytoestrogen). It’s an isoflavone, a class of chemicals found in many plants. Genistein is abundant in soybeans, tofu, and other plant-based foods. It has a planar ring structure—a “flat,” two-dimensional molecule parallel to the plane of your screen, with none of its components extending backward (away from you) or forward (toward you). Notice the two hydroxyls (OH) on each end.
Adults don’t have to worry about premature sexual maturation, but phytoestrogens will penetrate mom’s skin, too, posing a risk of endocrine disruption. Estrogen-like chemicals in consumer products have been linked to a variety of issues. For example, microplastics like BPA disrupt insulin signaling. Do a little digging about xenoestrogens and you’ll find no shortage of reading material—everything from phthalates (used in plastics) to parabens found in cosmetics, herbicides like atrazine, and much more.
Something I’ve noticed: you hear a lot about estrogens in the environment but almost never anything about environmental androgens. Why is that? Perhaps it’s just noise in the cultural chatter. People may say stuff, but that doesn’t mean there’s a biological reason why the modern environment would be estrogenic rather than androgenic or hormonally neutral.
Or is there?
Dr. Lustig shared something interesting about the estrogen receptor:
RL: The estrogen receptor just needs two hydroxyl groups [roughly] 22 angstroms apart, and you’re an estrogen. So you know, there are a lot of estrogens in our environment.
NJ: It just happens to be that the estrogen receptor has a structure that is sensitive to things that many components of modernity are made out of?
RL: Yes, exactly.
Two hydroxyl groups on a planar molecule, a certain distance apart, is the shape of the chemical “key” needed to activate the estrogen receptor “lock.” As it turns out, this geometry is common in nature, especially in the plant world (look again at the genistein structure above).
Why would this be? Why would plants need to produce molecules with a structure similar to estrogen hormones found in animals? There are several plausible ecological reasons:
Chemical defense: Phytoestrogens can act as a defense mechanism against herbivores. By mimicking animal hormones, they might disrupt the reproductive or developmental processes of insects or other plant-eating animals, thereby aiding plant survival.
Antioxidant properties: Many phytoestrogens, including genistein, act as antioxidants, helping protect the plant from oxidative stress (e.g. from UV light).
Symbiotic relationships: Phytoestrogens in legumes can play a role in the symbiotic relationship with nitrogen-fixing bacteria.
Growth regulation: Phytoestrogens might also influence plant growth and development.
If you’re interested in the “why” question as it relates to plant biology, try reading this or this. The fact is that phytoestrogens are common and humans are exposed to them often. Many consumer products contain high levels of phytoestrogens by design (they often have effects desired by consumers). For example, their antioxidant properties sometimes make them ingredients in beauty and skincare products. That’s probably why Victoria’s Secret put genistein in the bath gel that triggered breast growth in the little girl mentioned above.
Let’s review some basic information about hormone biology and sexual development, as well as terminology, before digging into the biochemistry of estrogen signaling.
If you want to skip the background stuff, jump to the section: “Estradiol, Exogenous Estrogens & Estrogen Receptor Biochemistry”
To learn more about environmental endocrine disruptors, try these podcast episodes:
M&M #184: Endocrine Disruptors & Metabolism: Microplastics, BPA, Estrogen, Insulin, Pancreas Biology & Metabolic Dysfunction | Angel Nadal
M&M #145: Epigenetics, Hormones, Endocrine Disruptors, Microplastics, Xenoestrogens, Obesogens & Obesity, Inheritance of Acquired Characteristics | Bruce Blumberg
Hormone Biology Basics
Hormones are powerful substances. They are released from endocrine glands, which secrete them into the bloodstream for distribution. In general, hormones affect transcription (which genes are ‘on’ and ‘off’) across multiple cell types and tissue systems, enabling them to coordinate changes throughout the body. Just think about all of the biological rearrangements needed for puberty or pregnancy to unfold: metabolism needs to shift, specific tissues need to grow, and neural re-wiring needs to take place to support behavior change.
Steroid hormone receptors like estrogen receptors are often found inside cells rather than in the outer cell membrane. When activated by chemical ligands like estradiol, estrogen receptor proteins bind DNA in the nucleus directly, acting as transcription factors to direct gene expression. When a body needs to undergo coordinated transformations, as with puberty or pregnancy, major changes in gene expression are required.
Endogenous hormones are those native to the body—cortisol, insulin, progesterone, and so forth. We like to categorize them into neat buckets like “stress hormone,” “metabolism hormone,” or “sex hormone.” The truth is that all hormones have multifaceted effects (“pleiotropy”). Biology rarely respects the linguistic boundaries we impose on the world. For example, we call cortisol a “stress hormone” and estrogen a “sex hormone,” but both influence aspects of “stress stuff,” “sex stuff,” and more.
Exogenous hormones and endocrine disruptors are substances originating outside the body that mimic the action of endogenous hormones or disrupt endocrine function in some way. Sometimes, people take exogenous hormones on purpose. Hormonal birth control and hormone replacement therapy are examples. Other times, we are inadvertently exposed to exogenous hormones and endocrine disruptors in the environment. They are everywhere—in our food, water, and consumer packaged goods. Chronic exposure to endocrine disruptors is likely a major driver of metabolic dysfunction.
To learn more about environmental endocrine disruptors, try these podcast episodes:
M&M #184: Endocrine Disruptors & Metabolism: Microplastics, BPA, Estrogen, Insulin, Pancreas Biology & Metabolic Dysfunction | Angel Nadal
M&M #145: Epigenetics, Hormones, Endocrine Disruptors, Microplastics, Xenoestrogens, Obesogens & Obesity, Inheritance of Acquired Characteristics | Bruce Blumberg
One thing you hear a lot about these days is xenoestrogens—exogenous estrogens found in our environment, such as plant-based foods and household products. The phytoestrogen from the opening story, genistein, is abundant in soybeans and related plant-based foods. Here are some estimates of the estrogen content of various foods compared to the average estrogen levels seen in men, women, and children:
Although some plant foods contain high levels of phytoestrogens, these chemicals are not identical to endogenous mammalian estrogens like estradiol. Whether the effects of a given food have a net estrogenic effect depends on the specific estrogen-like chemicals they contain, their concentration, and exactly how they affect estrogen signaling networks. For example, genistein is abundant in soy products. Does that mean that consuming soybeans is equivalent to “more estrogen”? Not necessarily. However, the story we opened with, involving a little girl exposed to genistein through shower gel, shows that it’s possible for such products to have a clear estrogenic effect.
Estrogen signaling pathways are complex. There isn’t a simple, linear “estrogen dial” that gets turned up or down based on a singular “estrogen” signal. Xenoestrogens can mess with estrogen signaling at any number of levels. It’s easy to get lost in the complexity. Here’s a graphic to give some appreciation (chemicals have the potential to affect any point in biological pathways like this):
Hormone biology is complex, and the modern environment is filled with xenoestrogens. Is there any reason to think that the environment has a net estrogenic effect, leading to feminization?
The short answer is yes.
Changes in sex hormone levels and fertility suggest the modern environment is more estrogenic than androgenic. As mentioned above, this may be rooted (at least in part) in the structure of the estrogen receptor itself. Before diving into those details, let’s cover some basic concepts and terminology issues to help ensure we’re speaking the same language.
Biology of Sex: Terminology & Basic Concepts
The study of the biological basis of sex differences is fascinating and complex. It’s also a cultural minefield. A major reason is that people use (and abuse) words differently, causing confusion. For our purposes here, I’m going to use words—male, female, feminine, masculine, etc.—the way that a zoologist would for any other sexually dimorphic animal species.
(Fun fact: I was a zoology major in college. Most of my lab research was in evolutionary developmental biology, but I also did a brief stint in reproductive neuroendocrinology—a major reason why I think in these terms.)
There are two basic morphs seen in humans and other sexually dimorphic species: one with small gametes (sperm), which we call males; one with large gametes (eggs), which we call females. Each morph is produced through a complex developmental process. In rare cases, there are developmental abnormalities. For example, chromosome anomalies can result in morphological abnormalities like ambiguous genitalia. Even in those cases, only one of two possible gametes is present—sperm or egg—never a third or intermediate type.
We won’t get into the intricate biological details here. For now, the key thing is that the balance of various hormones—how they wax and wane throughout development—influences how the structure and function of tissues throughout the body develop and mature (this includes the brain and behavior). The female and male morphs arise from systematic differences in hormone-directed tissue development.
On average, each morph (male or female) will display patterns of behavior that are more characteristic of that morph than the other. Biologists refer to these as sex-typical behaviors. There are many examples of sex-typical behavior, from toy preferences in male vs. female primates to the frequency of “rough-and-tumble” play in mammals.
M&M content related to this content:
Article: THC, Hormones & Brain Development: Reward Sensitivity & Sex-Typical Behavior
Podcast: Neuroscience of Aggression, Sex, Behavior, Hormones, Emotion & Consciousness | David Anderson
In experimental animals, the frequency of sex-typical behaviors can be shifted in one direction or another through various manipulations. For example, scientists can apply exogenous sex hormones or perform other manipulations that affect the development of sexually dimorphic tissues in the body. This includes sexually dimorphic brain circuits governing behavior. When such manipulations result in more male-typical behavior, whether in males or females, we say the animals have been masculinized. When the result is more female-typical behavior, they are feminized. As a general rule, boosting androgen hormones like testosterone results in the masculinization of behavior—boosting estrogens, in feminization.
If you’re interested in digging into the developmental biology of sex differences and sex-biased behaviors, I recommend the work of Dr. Margaret McCarthy:
If you want to learn more about the details of sexual differentiation during development or the neurobiology of sexually dimorphic behavior, I recommend the podcast episodes below. For the purposes of this article, we simply want to examine the biochemical basis for why so many chemicals in modern society act as estrogens. We will then look at how sex hormone levels and fertility patterns have changed over time.
M&M podcast episodes related to this content:
M&M #68: Sex Determination, Sex Hormones & Chromosomes, Development & the Evolution of Sexual Reproduction | Blanche Capel
M&M #81: Sex Differences in the Brain, Endocannabinoid Biology, Purpose of Juvenile Play Behavior, Cannabis & Pregnancy | Margaret McCarthy
Estradiol, Exogenous Estrogens & Estrogen Receptor Biochemistry
Recall the chemical structure of genistein that we saw above and how it compares to estradiol. Here it is again, with two other estrogens: daidzein (found in soybeans) and equol (produced by gut microbes from daidzein):
Also, recall what Dr. Lustig mentioned about what it takes for a chemical to activate the estrogen receptor: two hydroxyl groups (-OH) the right distance apart. Here are estradiol and equol placed nearly on top of one another:
Each of these molecules varies somewhat in chemical structure but are approximately the same size and shape. They have a flat ring structure with two hydroxyls on each end, a similar distance apart. When you look at the crystal structure of the estrogen receptor, it becomes clear why this basic chemical template enables something to act as an estrogen:
That’s estradiol within the binding pocket of the estrogen receptor. The two hydroxyl groups (red balls) help “lock” estradiol in place. Because genistein, equol, and many other phytochemicals share this basic structue, they can fit into the estrogen receptor binding pocket.
There are lots of natural plant estrogens. In fact, there are so many that scientists have a nomenclature for talking about different types:
As usual, biology is complex. Context always matters. Many factors determine which specific xenoestrogens your body absorbs and metabolizes or whether your body responds to them simply as “more estrogen.”
Xenoestrogens: A brief note about biological context and complexity.
Just because these chemicals can bind to the estrogen receptor doesn’t necessarily mean that exposure to higher levels equates to, “more estrogen.” These compounds should be thought of as endocrine disruptors that interfere with estrogenic pathways in complex ways, not as estradiol equivalents. There are many factors that go into determining exactly how a given exogenous estrogen will affect estrogen pathways in the body, including:
Dose: How much of the estrogen are you exposed to?
Potency: Different xenoestrogens have different potency levels compared to each other and endogenous estrogens.
Specificity: Each chemical may interact with a variety of other receptors or signaling pathways.
Bioavailability & Metabolism: There is lots of variation in how similar chemicals get metabolized and absorbed.
Consider two of the phytoestrogens we examined above, daidzein and equol. Daidzein is found in soybeans and can be metabolized by gut microbes into equol, which is a much more potent estrogen. However, the extent to which equol is produced from daidzein depends strongly on diet: high-carb diets result in more equol production. In other words, overall diet and microbiome composition strongly influence exposure to specific phytoestrogens. In this example, someone who consumes higher levels of soy products in the context of a high-carb diet would likely be exposed to more equol (the more potent estrogen) than someone consuming soy with a low-carb diet, even if they ingested the exact same amount of daidzein.
What are some of the more common xenoestrogens in the modern environment, and just how common are they?
Xenoestrogens in Modern Consumer Products
I’m certainly not the first person to point these things out, and there’s no shortage of online literature. Below is a concise summary of some of the more common xenoestrogens we’re exposed to today, together with good references for those who want more detail.
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