Current clinical understanding and management is built on the medical education of the last 25-30 years. Sadly, this understanding was driven by Pharma investments. As residents, we were not taught to understand hormone physiology but instead were taught disease and what drugs to prescribe. Pharma marketing dominated the narrative. Other than the hormone-disease implication, the narrative of hormones was that men are merely testosterone-fueled erections and women are estrogen-fueled hot flashes. This oversimplified narrative on hormones has driven obesity, disease, and profits.
The Health and Human Services Secretary, on November 10, 2025, announced that the black box label of hormone replacement therapy (HRT) for treatment of menopause symptoms was set to be removed by the FDA. This is a step forward for women and science. Moreover, it is correcting a wrong of twenty years.
The Study
The study in question was the Women’s Health Initiative, initially published in 2002, followed by a follow-up publication in 2004 . I was an obstetrics and gynecology resident in Tennessee at the time, so you can imagine this was front and center in our daily clinical and education discussion.
I must first break down these two publications. The Women’s Health Initiative was designed to assess the risks and benefits of estrogen and progestin in “healthy” menopausal women. There were two primary arms to the randomized controlled study: the estrogen +
Progestin (E + P) in women with a uterus trial and the estrogen only in women without a uterus (E-alone). It is important to note that neither study arm included hormones that were naturally present in a woman’s body. The E + P arm included conjugated equine estrogen (Premarin), estrogen derived from pregnant mares, and medroxyprogesterone acetate (MPA), a synthetic progesterone—progestin. The E-alone arm included only conjugated equine estrogen. The fear started when the E + P arm of the study was for 8.5 years but was stopped after 5.2 years, in 2002, due to increased risk of breast cancer, coronary heart disease, stroke, and pulmonary embolism. The result was a dramatic 66% drop in E + P HRT prescriptions and a 33% drop in E-only HRT by early 2003 per the 2004 publication. The follow-up publication in 2004 was stopped after 6.8 years due to increased stroke risk. Of note, there was no increase in heart disease, and there was a decrease in breast cancer risk in those women taking Premarin only.
These studies negatively impacted several generations of women and doctors. As a result, the movement of bioidentical hormone therapy (BHRT) accelerated. BHRT versus HRT may be called the first war of words in the modern-day medical era. I first wrote of the confusion back in 2012 in a blog post:
“I had a young lady who was a breast cancer survivor in my office the other day to discuss hormones. Her concern, and rightly so, was hormones and her risk of breast cancer recurrence. Of course she lived in the South and had the women’s rite of passage of menopause: “the hysterectomy ceremony.” If you haven’t heard of this ceremony, it is a native rite of passage for about all women in the South.
The question was, can she take hormones? Her cancer doctor had placed her on Premarin many years ago, telling her that it was safe. She also was told that because she had a hysterectomy, progesterone was not necessary. Her gynecologist, in contrast, told her she couldn’t take Premarin. Different doctors, different opinions.
Physicians should want to stay away from opinion and stay focused on the evidence. That is what evidence-based medicine is supposed to be doing. I am sad to say that market forces are clouding evidence-based medicine today and shifting medicine to an opinion-based paradigm.
We have previously talked about progesterone and synthetic progestins and their polar opposite effects on the breast. I want to get a little more specific today. This information comes from an outstanding review of the evidence in Dr. Kent Holtorf’s article, the Bioidentical hormone debate:… This exhaustive review is of 196 research articles.
Synthetic progestins increase breast cell growth, increase the conversion of weaker estrogens into more potent estrogens, promote the formation of toxic estrogen metabolites (16-hydroxyestrone), stimulate the conversion of inactive estrogen to active estrogen (estrone sulfate to estrone), and have antiapoptotic effects (apoptosis is programmed cell death, which is a way to control cancer growth).
Let’s contrast this with natural progesterone. Natural progesterone reduces breast cell growth by 400%, downregulates estrogen receptors in the breast, induces cancer cell apoptosis (programmed cell death), reduces breast cell division and growth, and actually arrests human breast cancer cells.
Studies have shown that synthetic progestins increase the risk of breast cancer: (1) by approximately 25% for each 5 years of use, (2) triple the risk (67%) of breast cancer when added to estrogen therapy, and (3) double the risk to 4% per year when compared to estrogen therapy alone. This is in stark contrast to bioidentical progesterone, which reduces the risk of breast cancer by 10%.
“As far as the east is from the west,” that is how different the effects of progesterone and synthetic progestins are on the breast. Next week we will look at Premarin versus bioidentical estrogen.“
Hormones and Health
Women and Men are not the Same
Seems like an obvious statement. Yet, there seems to be confusion on multiple levels. I want to focus on hormones. It is not that men and women produce different hormones outright, but they produce different balance of hormones and express different tissue receptors, which elicit different effects.
When it comes to hormone replacement therapy, men and women are treated the same. I previously wrote about this uni-sex treatment approach to hormones back in 2010.
Tale of Two Cities
“I am always amazed at the level of knowledge that most physicians practice at. It has been shown in studies that it takes 17 years for scientific knowledge to make its way into clinical practice. Stated another way, the average physician practices 17 years behind the current science. And that is the “average.”
No place is this better seen than hormones. As it relates to hormones, it is not science that drives medical practice. It is marketing that drives medical practice. The medical establishment shouts the mantra “evidence-based medicine,” yet what they really push is “marketing-based medicine.” They push a narrative that propagates profits.
Just look at the marketing on libido. Historically, it is all about testosterone. The typical woman with low libido believes (thanks to marketing) that her libido is the result of low T. Why would she think anything else—the marketing narrative says so. That is what we are bombarded with day after day. Her physician fares no better.
Women have been trained to believe that their low libido is linked to testosterone, because if her husband’s low libido is due to low T, then hers sure must be as well. That is, of course, what the marketing narrative says because the manufacturers of testosterone market directly to the public to generate the narrative that supports the market demand. But that is not what physiology is. The body doesn’t care what marketing says, only what physiology is.
Rarely is low testosterone the cause of a woman’s sexual dysfunction. The clinical situation that does present with libido affected by low T in women is following a total hysterectomy. The pure shock of sex hormone withdrawal in these women can precipitate sexual dysfunction requiring physiological testosterone support.
For most women, testosterone promotes inflammation, weight gain, and disease.
This may make you think twice about those testosterone pellets in your backside. But of course, we don’t make hormones in our backsides either.
The clear example of this is found in women suffering with Polycystic Ovarian Syndrome (PCOS). These women struggle with a hormonal syndrome, in part, driven by elevated androgens (male hormones) from ovarian and adrenal origin. The elevated androgens, DHEA and testosterone, in most cases, drive systemic inflammation through excess weight gain in these women. This inflammation leads to insulin resistance, which results in fat deposition. Vicious cycle! I have yet to have a lady present to my office seeking these effects.
Yet, we see so many lady clients pumped full of DHEA and testosterone dosages worthy of a 20-year-old college man on a Friday night. All this to provide a kick in their libido.
The result? Women filling the shower with hair, women shopping the razor aisle—not for smoother legs, mind you, but for less hairy chin lines. Women encountering acne breakouts that rival their high school days. Singers that notice a lowering of their voice (true case). And of course the confusion of the cause of unwanted weight gain.
Why?
Back to the title—Tale of Two Cities.
These women are being treated through the lens of a male-marketing-based medical philosophy. The obvious warning signal that this is a woman (not a man) sitting in front of the medical provider goes ignored. Not intentional. They are just thinking of that tub sitting on the beach watching the sunset (reference back to low libido marketing in the early 2000s). I mean, who wouldn’t want that?!
In women, low libido is complex. Energy is critical. The ability of a woman to look and thus feel sexy is crucial. And the need for a woman to connect emotionally is paramount. Compared to men, we can be fat, bald, tired, and on our deathbed, and we are good and ready to go.
In contrast, low testosterone is a critical factor in sexual dysfunction in men. Erectile dysfunction has been shown to precede cardiovascular disease by 3-5 years in men. The cause? Low T in many cases. These men will often present to my office having been told that their arteries have the appearance of a 20-year-old (just that statement alone is ridiculous). YET, they can’t get it up. One cannot exist without the other.
So, how does testosterone differ in men? Testosterone is anti-inflammatory in men. Testosterone increases Nitrogen Oxide synthesis. The result is vasorelaxation, vasodilation, improved blood flow, improved erections, which will lower blood pressure and lower cardiovascular disease.
The environment influences the response of the signal. In women, testosterone is generally pro-inflammatory. Yet, the same testosterone in men is generally anti-inflammatory.
Testosterone is the tale of two cities. This post was not to discuss libido but to discuss the context of the environment and its influence on the results of the signal. In this case, testosterone. In reality, it is the tale of an infinite number of cities, as we are all uniquely and wonderfully made. But, there is no famous literary work entitled “The Tale of Infinite Cities.”
What Has Changed?
It is apparent that marketing has not changed. Thinking has not changed. Yet, the human body has changed.
According to CDC data, 40.3% of U.S. adults are obese, and 19.7% of children and adolescents are obese. New research reveals that age-adjusted mortality rates from obesity-associated cancers have nearly tripled in just two decades, soaring from 3.73 to 13.52 per million between 1999 and 2020.
The perception has long been that westernization and high-income countries directly correlate with obesity. Yet, the relationship is more between the individual incomes of the households than the country itself. A 2016 study found that higher obesity rates were associated with low-income individuals and households in high-income countries. In middle-income countries, urbanization correlated to obesity rates, yet in low-income countries, higher-income individuals and households correlated with obesity. The study identified key factors driving obesity:
- Processed and ultra-processed foods
- Urbanization
- Decreased physical activity levels
- Education and health literacy.
I recently gave a lecture at a conference that brought physicians, farmers, policymakers, and advocates together. The goal was to focus on regenerative farming. I presented the four horsemen driving the PHARMING of disease as:
- Glyphosate and other pesticides
- Processed and ultra-processed foods
- Antibiotic overuse
- Obesity
Here, just as in the NCD-RisC study, I must add urbanization to the four horsemen. The United States has undergone a significant demographic transformation over the last two centuries, and the impact has transformed our waistlines, health, and disease. Currently, 82% of Americans live in urban areas (cities and suburbs), and 18% live in rural areas. In 1900, the United States population was roughly 40% urban and 60% rural. Specifically, the urban population was just over 30 million, while the rural population was just shy of 46 million. In 1800, the United States was overwhelmingly rural. Around 6% of the population lived in urban areas, while 94% resided in rural areas. In the political circles, it is called flyover country; we have ignored the impact and contribution of flyover country to the detriment of our soil, our gut microbiome, our health, and our soul.
The doorway to disease, in many ways, is obesity. Obesity drives chronic inflammation, immune suppression, and hormone signaling dysregulation. Sadly, these impacts are not confined to one generation but accelerate transgenerationally through epigenetics to propagate disease. Obesity is linked to 13 distinct types of cancer, accounting for 40% of all cancer diagnoses annually.
- Adenocarcinoma of the esophagus
- Breast (post-menopausal women)
- Colon and rectum
- Uterus
- Gallbladder
- Upper stomach
- Kidneys
- Liver
- Ovaries
- Pancreas
- Thyroid
- Meningioma (brain cancer)
- Multiple myeloma
Endometrial (uterine) cancer, post-menopausal breast cancer, and ovarian cancer have strong links to sex hormone imbalances. Though not directly linked to sex hormones, colorectal, renal cell, liver, pancreatic, thyroid, gallbladder, esophagus, meningioma, and multiple myeloma are linked to other hormonal (insulin, IGF1, leptin, adiponectin) affecting metabolism and promoting inflammation.
Each generation inherits a more compromised foundation, leading to earlier and more aggressive disease manifestation. We are exposed to more impacts from the 4 horsemen than our parents were, and they more than their grandparents.
The Impact of a Generation
The WHI (Women’s Health Initiative) first dropped in 2002 and 2004—one generation ago. The impact of HRT on the women of 2002, 2004, and today is quite different. Though the studies were stopped early and stats dropped in 2002 and 2004, enrollment for the WHI was between 1993 to 1998 and the intervention phase was 1993-2005. Statistics published by the National Health and Nutrition Examination Survey point to the reason why. Hint: it is related to the obesity doorway. To best understand the differences in the internal human metabolic environment today versus the WHI, we have to carry the analysis back to 1993.
Our waists are not the same, our metabolism is not the same, our inflammation level is not the same, our environmental toxicant exposure is not the same, and our gut microbiome is not the same; as a result, our hormones are not the same. The implication is that the removal of the black box label for HRT in menopausal women must be taken in light of this information. I believe that the Secretary of Health and Human Services, RFK, recognizes this connection as he moves forward on tackling obesity.
Does medicine get? Do physicians get the connections? Sadly, that is left to be determined. What is needed is better hormone metabolism teaching at the medical school level and better understanding of hormones, hormone metabolites, and crosstalk between hormones and with the gut microbiome and immune system. Testing is available to aid this assessment of hormones and hormone metabolites. Physicians must embrace these and other evaluation tools to assist assessment and therapies in the changed environment of women today compared to the women in the 2002 and 2004 WHI study. One-size-fits-all no longer applies. Precision medicine is the medicine of today: the right treatment for the right patient, in the right combination, at the right time. Currently, this precision medicine and precision oncology can only be found in integrative medicine and integrative oncology.
Connect with Dr. Nathan Goodyear here.
Resources
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