Hormone Therapy and Breast Cancer Risk: Estrogens, Progestins, and Environmental Factors

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• Estrogens as Cancer Promoters
• Environmental Estrogens Risk Assessment
• Progestins and Breast Cancer Risk
• Women's Health Initiative Findings
• Hormone Therapy Recommendations
• Full Transcript

Estrogens as Cancer Promoters

Dr. Marc Lippman, MD, explains that estrogens function primarily as promoters of breast cancer rather than direct carcinogens. He uses a historical analogy of carcinogens and promoters from mouse ear skin experiments. A low, non-cancer-causing dose of a carcinogen combined with physical irritation (the promoter) resulted in cancer. Similarly, estrogens promote the growth of breast cells that have already sustained genetic damage.

Dr. Lippman provides a powerful clinical example with BRCA mutation carriers. These women have a 90% lifetime risk of developing breast cancer. However, if they undergo oophorectomy (castration), which removes the primary source of endogenous estrogen, their breast cancer risk becomes minimal. This demonstrates how estrogen promotion is required for the manifestation of the underlying genetic predisposition.

Environmental Estrogens Risk Assessment

The discussion with Dr. Anton Titov, MD, turns to environmental hazards that mimic estrogen, such as those found in thermal paper receipts and plastic bottles. Dr. Marc Lippman, MD, acknowledges these compounds are real but remains skeptical about their quantitative contribution to breast cancer risk in a Western lifestyle. He points to studies on Asian women, where high soy consumption (a source of phytoestrogens) shows no significant difference in breast cancer risk compared to those with low intake.

Dr. Lippman suggests that the potent effect of a woman's own endogenous estrogens likely overwhelms the impact of these smaller environmental exposures. He notes an important exception: some estrogens, like the notorious Diethylstilbestrol (DES), can form DNA adducts and act as true carcinogens, not just promoters. This highlights the nuanced complexity of different estrogenic compounds.

Progestins and Breast Cancer Risk

Dr. Marc Lippman, MD, identifies progestins as a major culprit in increasing breast cancer risk. He explains the historical context: estrogen-only therapy relieved menopausal symptoms but caused a dramatic rise in endometrial cancer. Adding progestins was intended to protect the uterine lining, which it did successfully.

However, unlike in the uterus, progestins stimulate growth in the breast tissue. Dr. Lippman cites evidence showing that cell division rates in the breast are highest during the luteal phase of the menstrual cycle when progesterone levels are elevated. Furthermore, hormone replacement therapy containing estrogens plus progestins was shown to increase breast density on mammograms, a marker of proliferation.

Women's Health Initiative Findings

Dr. Marc Lippman, MD, discusses the pivotal Women's Health Initiative (WHI) trials, which provided definitive evidence on hormone therapy risks. The first trial randomized postmenopausal women to either placebo or combined estrogen plus progestin therapy. The results were striking: after five years of use, the incidence of breast cancer had doubled in the hormone therapy group.

A second WHI trial focused on women who had undergone hysterectomies. These women were randomized to receive estrogen-only therapy (Premarin) or placebo. In this study, there was no increase in breast cancer risk associated with estrogen alone. This critical difference confirmed that the progestin component was the primary driver of the increased breast cancer risk observed in the first trial.

Hormone Therapy Recommendations

Based on the evidence, Dr. Marc Lippman, MD, offers a strong clinical opinion on hormone therapy. He states that progestins are "horrible drugs for breast cancer promotion" and should not be given to most people. He emphasizes that they are also detrimental to vascular health and heart disease risk.

The conversation with Dr. Anton Titov, MD, underscores the importance of understanding the mechanisms of cancer promotion. For women concerned about breast cancer risk, especially those with a family history or genetic predisposition, avoiding combined estrogen-progestin therapy is crucial. The findings reinforce why aromatase inhibitors and tamoxifen, which block estrogen's effects, are effective in preventing cancer recurrence by removing the promotional signal.

Full Transcript

Dr. Marc Lippman, MD: But there are also estrogen mimetics and environmental hazards in the environment that people are talking about. There are estrogen mimetics even, I read, in thermal paper. So you take your boarding pass, and that's a thermal paper; you take a receipt from the grocery store, it has a thermal paper.

Dr. Anton Titov, MD: What about the environmental hazards that mimic estrogen hormones?

Dr. Marc Lippman, MD: Yeah, this is a very important question. But I tend to be relatively skeptical. I agree that the environmental estrogens are true. They're the things that get into plastic bottles. They're all kinds of stuff. Some very, very fine investigators have shown these things. That's not the question.

The question is, how quantitatively do they contribute to breast cancer risk? One way to get at that is to look at environments where people are exposed to these things. So one of the main environmental estrogens was soy-like products from soybeans and stuff like that.

But if you look at, for example, Asian women who do or Asian women who don't use soy products, it's no difference in breast cancer risk. And probably, in my opinion, at least in a western lifestyle, these relatively small environmental estrogens are overwhelmed by endogenous estrogens. It's sort of like a mole on your neck. I just don't think it adds too much.

But that could remain to be proven. And I would say that is a potentially still open question. There's one other thing that we need to discuss to answer your question, honestly. And that is, you need to understand that estrogens are fundamentally considered to be promoters of cancer.

To understand what I'm talking about, you have to go back to literature that is between a carcinogen and a promoter. By definition, a carcinogen is something that causes cancer. And usually, it's something that causes DNA damage. A classic example, you may recall from epidemiology, was from chimney sweeps.

For a long time in England in the 17th and sweeps all got scrotum skin cancers. And why do they get cancer? Because they're climbing up and down chimneys, they're getting these coal tars, which contain nasty things. And they didn't shower as well as they might. They accumulated in certain parts of their body surfaces, their body, and they all got cancers. That makes perfect sense, okay.

And so people started to study that. This is data from the 50s and 60s, but it's wonderful literature. It's fascinating. And one of the models they used was the mouse ear skin. Mice have little ears, and they would paint these ears with all these carcinogens. And sure enough, the mice would all get skin cancers on their ears.

And they did lots of structure, activity, relationships, different amounts, different doses. And eventually, you could find a dose for most of these carcinogens if you painted less and less. Eventually in the animals, hardly surprisingly, it didn't give your cancer. So you had a dose-response, right?

Then they did interesting things. They painted a dose of this carcinogen on the ear at a low dose that would not cause cancer. And then they started doing this. You're rotating the ear or scratching it. All animals got ear cancer. But if they didn't give the low dose of the carcinogen, and they just scratched and irritated the ear, they didn't get cancer.

So the scratching and irritating was a promoter of a carcinogen's effect. In that same sense estrogens promote genetic events that already occur in women. For example, formal proof of this is that for women carrying BRCA mutations, women who have the breast cancer gene, have a 90% chance of getting breast cancer in their lifetime.

If those women are castrated—I'm not recommending it—but if they happen to be castrated, their risk of breast cancer is minimal because the estrogens aren't there to promote the genetic event [BRCA mutation]. Okay.

Why did I give you this long story? One, it's interesting, but number two, I told you this story because now it comes back into environmental estrogens. Some environmental estrogens are not just promoters that make the mammary gland grow. But some of them form estrogen-DNA adducts.

Some estrogens form adducts onto DNA and are steered to the wrong places. Because these estrogens bind to the estrogen receptor, they translocate to the nucleus. These estrogens go to transcriptionally active sites. And because some of them are catechol estrogens, they can cause DNA mutations. They bind to DNA, which explains why a different estrogen was notorious, Diethylstilbestrol (DES).

Diethylstilbestrol (DES) caused cancers in women, not because it promoted tumors. Diethylstilbestrol (DES) caused DNA adducts. It was a true carcinogen. Very interesting.

Dr. Anton Titov, MD: What about the progesterone?

Dr. Marc Lippman, MD: It is interesting. Yeah, it's a fascinating story. And it certainly tells you about the complexity on the one hand, but the simplicity on the other hand. Right, and it certainly explains exactly why it explains why estrogens are promoters, in the same sense that a low dose carcinogen will cause skin cancer in the mouse ear.

If you have exposure to certain carcinogens, you can take away the estrogen promotion with an aromatase inhibitor or Tamoxifen-like drug. You don't get cancer because you are not promoting cancer. You're raising an extremely important point. An interesting point.

A long time ago, people were trying to relieve menopausal symptoms in women, and they would give them estrogens when woman's estrogens went away naturally. And they found that when they gave women estrogens, like Premarin—wonderful news, women felt great. They felt great. They didn't have menopausal symptoms. Their hot flashes went away. They were happy and all was well with the world, except they all got endometrial cancer.

They were indeed low-grade and easily treatable cancers. But the risk of getting endometrial cancer went through the roof when you started giving women estrogens because they promoted the growth of the endometrium in the uterus. So, some wise person said, why don't we give them estrogens plus progestins?

Because we all know that in the normal menstrual cycle, the proliferative endometrium that you have during the first half of the menstrual cycle is converted to a non-proliferative, secretory phase endometrium when you get progestins during the luteal phase of your menstrual cycle. And then when it stops, you shed your endometrium, and a woman has her menstrual period. All as well with the world.

So everybody said, no problem here. Let's just give women estrogen, so they feel good. And let's give them progestins on top of that, so they won't get endometrial cancer. Makes perfect sense. Except it's not true. They don't get endometrial cancer, but they get even more breast cancer.

Because, unlike the uterus, progestins stimulate the growth of the normal breast. So if you do little needle biopsies of the breast and measure cell division, mitotic rates in the breast in a pre-menopause woman, it's highest during the luteal phase of her menstrual cycle. It goes up. So it was already known decades ago that progestins would likely stimulate the breast.

Additionally, in randomized trials that were done many years ago, it was shown that breast density, a sign of proliferation on mammography, went up when you put women on estrogens plus progestins, compared to estrogens alone. So it was entirely predictable.

That was when someone finally got around to the Women's Health Initiative trial. It randomized 8000 postmenopausal women to placebo or 8000 postmenopausal women to estrogens plus progestins. The sad result of that study was that after five years of estrogen plus progestin, so-called hormone replacement therapy, breast cancer incidence doubled.

So estrogens plus progestins are horrible drugs for breast cancer risk. Amusingly women who had already had a hysterectomy and for whom there was no reason to give progestins because there was no uterus to stimulate. A second Women's Health Initiative trial was done, in which women who had had a hysterectomy were randomized to Premarin and estrogen versus nothing.

And amusingly and wonderfully, in that study, there was no increase in breast cancer risk with Premarin alone. So that the real risk factor is progestins. Progestins are horrible drugs for breast cancer promotion. Plus, they're terrible for vasculature and heart disease. They just shouldn't be given to anybody, mostly, is what I think.